CONSULTATION BY APPOINTMENT W. S. THAYE R, M.D. 406 Cathedral Street BALTIMORE, MD. March 21, 1V12. Dr. Walter B. LcCaw, Surgeon's General Library, V.'ashington, D. C. My dear Dr. McCaw I'am sending you three volumes of my collected reprints of which I spoke to you. As you will see sore or* the earlier articles have had to be typewritten. I hope that they may be of some value to somebody. Very truly yours, COLLECTED REPRINTS - OF - Medical Communications - BY - WILLIAM SYDNEY THAYER, M. D. Series I. 1889-1899. BALTIMORE, MD. 1899- CONTENTS. I. A Case of Haemorrhagic Pancreatitis. Boston Medical and Surgical Journal, 1889, cxxi, 506. II. Remarks on the Blood in Leukaemia. J. U. H. Bulletin, 1891, ii, 86. Ill. Cancer of the Pylorus. J. H. II. Bulletin, 1891, ii, 162. IV. On the Value of Methylene Blue in Malarial Fever. J. II. II. Bulletin, 1892, Hi, 49. V. Super-Secretion of the Gastric Juice; Splenic Myelogenous Leukaemia. J. II. H. Bulletin, 1892, Hi, 141, 142. VI. Remarks on the Clinical Value of Ehrlich's Methods of Examination of the Blood. Boston Medical and Surgical Journal, 1893, cxxviii, 156, 182. VIL Malarial Fever. American Text Book of Diseases of Children, 1893. VIII. Note on the Increase in the Number of Leucocytes in the Blood after Cold Baths. J. II. H. Bulletin, 1893, iv, 3j. IX. Note on a case of Cicatricial Stenosis of the Pylorus, following a Peptic Ulcer. Demonstration of Specimen of Amoebic Abcess of Liver. W. S. Thayer and Simon Flexner. J. IT. II. Bulletin, 1893, iv, 45. X. Note on the value of Guiacol applied externally as an Antipyretic. J 'edieal Mews, 1894, Ixiv, 343. XI. Two Cases of Post-Typhoid Anaemia, with Remarks on the Value of Examination of the Blood in Typhoid Fever. J. H. H. Reports, 1894, iv, 83. Xil. The Malarial Fevers of Baltimore. W. S. Thayer and John Hewetson. J. H. H. Reports, 1895, v, 1. XI11. Types of Malarial Fever observed in Baltimore and their Relations to the Season of the Year. / Maryland Medical Journal, 1895, xxxiii, 161. XIV. Acute Pancreatitis-Parapancreatic Absess-Disseminated Fat Necrosis. American Journal of the Medical Sciences, 1895, ex, 396. XV. Endocardite ulcereuse blennorrhagique. Septicemie d'origine blen- norrhagique. W. S. I'hayer and Geo. Blumer. Arch. de. medecine experimental^, 1895, vii, 701. XVL Hypertrophic Pulmonary Osteo-arthropathy and Acromegaly. New York Medical Journal, 1896, Ixiii, 33. XVII. Remarks on Dr. Barker's Paper on Malaria. J. H. II. Bulletin, 1896, viii, 78. XVI11. Ulcerative Endocarditis, due to the Gonococcus ; Gonorrhoeal Sep- ticaemia. W. S. Thayer and George Blumer. J. H. H. Bulletin, 1896, vii, 57. XIX. Exhibition of a Case of Hemiplegia with motor Aphasia, oc- curring in a Patient Convalescing from Typhoid Fever. George Blumer and w. S. Thayer. J. H. H. Bulletin, 1896, vii, 73. XX. Remarks on Dr. Norton's Paper: "Is Malaria a Water-Borne Disease?" J. H. II. Bulletin, 1897, viii, 43. XXL Remarks on the Papers of Drs. Opie and MacCallum on the Parasites of the Blood of Birds. J. II. H. Bulletin, 1897, viii, 53. XXII. Post-Diphtheritic Paralysis. Maryland Medical Journal, 1897, xxxvi, 221. XXIII. Malaria. Welch and Thayer. Except from a System of Practical Medicine by American Authors, 1897. XXIV. Remarks on Dr. Brown's Paper on Trichinosis. J. II. II. Bulletin, 1897, viii, 80. XXV. An Address on Malarial Fever. Cleveland Medical Journal, 1897, ii, 21^9. XXVI. On the Increase of the Eosinophilic Cells in the circulating Blood in Trichinosis. Lancet, 1897, ii, 787. XXVIL On the Parasites of Malarial Fever. Yale Medical Journal, 1898, iv, 153. v XXVIII. A Third Case of Trichinosis with remarkable Increase in the Eosinophilic Cells. Philadelphia Medical Journal, 1898, i, 654. XXIX. On Nephtitis of Malarial Origin. Trans, of the Association of American Physicians, 1898, xiii, 339. XXX. Hypertrophic Pulmonary Osteo-Arthropathy and Akromegaly. Philadelphia Medical Journal, 1898, xxxvi, 221. A CASE OF HAEMORRHAGIC PANCREATITIS. Reported by William Sydney Thayer, M. D., (Formerly House-Officer at the Massachusetts General Hospital.) Since the appearance last winter, of Dr. R. H. Fitz's paper on Acute Pancreatitis, no further cases of this nature have, I believe, been reported. The real and practical importance of this subject, so strongly set forth by that most valuable work, has seemed to me to make this case well worth recording. The patient was a man of sixty years of age, by trade, a designer of rubber boots. His family history was excellent. He had suffered from no serious illness but had always been unusually strong and healthy. Though not very tall, he was of large frame and rather fat, weighing, three months before his death, two hundred pounds. His habits in early life had been good, but in his later years he had indulged moderate- ly in liquor, occasionally - "once every month or two", according to his friends - to excess. He had never teen subject to digestive troubles. Thirteen months before his death he was seized suddenly one day, with a very severe pain in the epigastrium darting through to the back. The pain was very sharp and continuous, lasting about sixteen hours, and ceasing gradually. Pour months later he had another similar attack, and this time his wife noticed that toward the end of the seizure and on the following day, he was jaundiced. For six or seven months after this there was no recurrence of the pain, and the patient considered himself in the best of health. About three months before his death, however, he began to have similar attacks of pain recurring at intervals of one to two weeks. These attacks were all of a like character; very sudden in onset - "He just knew when they were coming":- lasting usually twelve to eighteen hours, sometimes a shorter time; the pain disappearing rather gradually. Most of the attacks were attended toward the latter part, and followed on the next day, by jaundice. The pain was always in the epigastrium darting through to the back, in the left hypochondrium, and "at the extremity of the ribs on the left side"-The friends are sure that the attacks bore no relation in time or otherwise to the taking of food. The patient, however, thinking that it might relieve him, used, at first, to force himself to vomit, but in the later attacks vomited involuntarily. The vomitus consisted chiefly of food-no haematemesis. During the last month of his life, the patient complained constantly of a "choking feeling" in his throat, "as if something were sticking there and would neither go up nor down. At times, also, he had a similar feeling behind the lower part of the sternum, as if food had "stopped just about entering the stomach." Dur- ing the last month the attacks of pain recurred every two or three days, and the patient, believing that they were in some way connected with his food, lived for nearly three weeks on a liquid diet. He was unable to attend to his work properly, and lost much strength, and twenty-five to thirty pounds in weight. On June 13, 1889, he came to the out-patient depart- ment of the Massachusetts General Hospital for advice. He went back to work but the attacks continued, and on June 23rd, he came to Boston. On this date, for the first time in three weeks, he ate a hearty dinner of beefsteak and potatoes. On the morning of June 24th, at 9 A. M., he had a severe attack of pain, apparently similar to those from which he had previously suffered, and at about 3P.M., he was admitted to the Massachusetts General Hospital, service of Dr. W. L. Richardson. At this time he was in great distress, groaning, and tossing about with pain. He placed his hand, in describing the seat of the pain, in the left hypochondrium and epigastrium, just to the left of the middle line. Physical examination showed a man of large frame and well-nourished; marked pallor; tongue dry; pulse regular and of good strength, 320; temperature 98.80; respiration 28; heart and lungs negative; abdomen rather full but not distended* The patient did not complain much of tenderness* though deep pressure in the left hypochondrium caused him to flinch. Pressure on the left lower ribs did not seem to increase pain. The patient suffered considerably during the afternoon and in the evening was given morph, sulph. gr. 1/6 hypo- dermically* and an hour later a suppository of morphia gr. 1/6* after which he fell asleep, sleeping most of the night. The urine obtained shortly after entrance was rather high-colored, acid; specific gravity 1024; no albumen or sugar; indoxyl increased; sediment slight, microscopical examination showing an occasional leucocyte and bladder cell* no oasts. The Rosenbach color test gave a positive result. The patient was given a liquid diet. On the morning of June 25th, the patient did not complain of pain, but seemed rather dull and stupid, and said he felt sick. He vomited his milk once. Temperature, 98.40; pulse, 100; respiration* 26. A slight yellowish tinge was noticed in the skin and con- junctivae, and soap-suds enemata were given without result. Shortly after 3 P. M., he suddenly sat up and threw himself across the bed. When seen, about ten min- utes later, he was tossing about the bed in great dis- tress, though he seemed unable to say why. His speech was thick and indistinct; when asked if in pain, his answer could not be understood* There was marked cyanosis; skin hot, moist; pulse not to be counted at the wrist, very feeble; by auscultation, heart's action weak but regular, 160; respiration very shallow and rapid, 60-70; temperature, taken by rectum about an hour later, 1050; no orthopnoea; tendency to lie on the left side. Fine * moist rales were heard in the left axilla, and a general fulness of the abdomen was noted. Stimulants were ad- ministered by the mouth, and when in a short time the patient became unable to swallow, hypodermically and by enemata, In an hour the patient became unconscious, and at 7.10 P. M,, died.' An autopsy was made by Dr. R. H, Fitz, thirteen hours after death. The following extracts are taken from the record: "Heart: right side distended with liquid and clotted blood, the latter differentiated; left side comparatively empty.... The duodenum contained a faceted gall stone about the size of a hazel nut. "Pancreas: in length, 8 in.; longitudinal diameter of head, 1-1/2 in.; longitudinal diameter of tail, 1-1/4 in.; transverse diameter of head 1-1/3 in.; transverse diameter of tail, 1 in. Consistency soft. Surrounding fat tissue moderately infiltrated with blood, which toward the tip and along the posterior surface was in spots and patches dried, of a reddish-brown color. Posterior surface of the pancreas adherent by easily separated adhesion to the posterior wall of the lesser omental cavity. Fat tissue in front of pancreas and at root of mesentery showed nu- merous opaque, white superficial spots, sharply defined. The pancreatic duct readily admitted a director. On longitudinal section of the gland the color of the head was an opaque reddish gray; of the tail a greyish pink. Spots and streaks of an opaque white and others of a' reddish-brown color were seen, especially at the tip. The tubules in general were indistinctly defined, but in the head, and more rarely in the tail, were apparent patches of thickened interstitial tissue. The splenic and portal veins were free from thrombi... "Gall Madder, thickened, firmly contracted, con- taining more than a hundred calculi, for the most part faceted and varying in size from that of a hazel nut to that of a split pea. One large, white calculus was oval, rounded and as large as the end of the middle finger. The gall bladder also contained a small quantity of viscid, opaque yellow fluid* Mucous membrane thickened and rough. "Common duct dilated to nearly the size of the little finger. Cystic and hepatic ducts also moderately dilated." With regard to symptomatology few conclusions can be drawn from this case, owing to the close association of the pancreatitis, with the frequent attacks of probably biliary colic. But whatever the nature of these attacks, it is of interest that the pain was always in the region of the pancreas. The possibility that the patient may have had previous attacks of pancreatic inflammation, is certainly suggested by the patches of apparently thickened interstitial tissue found on autopsy. The occurrence of disseminated fat necrosis is interest- ing. This condition was found in more than one-third of the cases of haemorrhagic pancreatitis tabulated by Dr. Fitz. The case seems to me to be of peculiar interest in view of the possible etiological relation between the cholelithia- sis and the pancreatitis. The probably frequent passage of gall stones and the resulting dilatation of the ducts would surely seem to afford an excellent opportunity for the en- trance of any infectious agent from the intestinal canal. While the evidence obtained during the life of the patient was not sufficient to justify a positive diagnosis, acute pancreatitis was throughout considered to be the probable condition. From the Johns Hopkins Hospital Bulletin,- May,- June,- 1891. Dr. Thayer said:- Dr. Toulmin has kindly given me this chance to say a few words with regard to the condition of the blood in this patient which he has offered me every opportu- nity of examining. Since I first saw the patient on November 2d, I have on various occasions made careful counts of the blood corpuscles, estimated the percentage of haemoglobin, and studied the formed elements on cover glass specimens prepared and s ained a cording to the methods of Ehrlich. The estimates of the number of the corpuscles were carefully made. In each case one whole field of the Thoma-Zeiss blood counter was first counted, and then at least three more fields were counted for the white alone. In this way, I believe, a fair estimate may be obtained of the number of white corpuscles. One is also able to control the original count of the red, for if, on examina- tion of the second slide, any material difference in the number of red corpuscles is noted, a second or even a third count can be made. Where the proportion rises as high as 1:3, as on January 29th, two, three or four whole fields were counted for both white and red. The accompanying chart shows the variations in the number of the red and white corpuscles and in the percentage of haemoglobin since the first visit of the patient to the dispensary. The first two estimates are not mine. The first estimate, that of September 17th, showed: R. 2,008,000. Proportion of white to red 1:4. Haemoglobin 30 per cent. On October 2nd, after taking arsenic, the estim- ate was: R. 2,700,000. Proportion of white to red 1:4.48. November 2d (my first examination), R. 3,430,000. Proportion of white to red 1:19.8. Haemoglobin 51%. From this time to January 29th, 1391, the patient was not seen, and, as Dr. Toulmin has stated, had discontinued treatment. On this date the estimate was: P., 2,171,000, W. 714,000. Proportion of white to red 1:3. Haemoglobin 41^. (The great number of white corpuscles gave the diluted blood so cloudy a color, that the reliability of this estimate, though carefully made, is I think doubtful.) February 14th,- Patient has been taking Arsenic in increasing doses,R. 2,779,333, W. 33,000. 1:84.2. Haemoglobin 35 per cent. February 21st. R. 2,647,333, W. 7,500. 1:352.9. Haemoglobin 41 per cent. Thus in 19 days the number of leucocytes in a cubic millimeter fell from 714.00 to 7,500, an hundred fold diminution. February 25th. R. 2,779,333, W. 7,000. 1:397. Haemoglobin 39 per cent. (On March 5th, the estimate was R. 3,250,000, W. 9,500. 1:342.1. Haemoglobin 44 per cent. Thus, in less than three wekks after return to treatment, the excess in leucocytes entirely disappeared. And this condition has persisted, so that today the mere numerical estimate of the blood would give us no hint that a leukaemic condition had ever existed. I have also studied the elements of the blood with some care according to Ehrlich's methods of differential staining. Before describing the results, let me say a few words with regard to the methods and the elements which one sees in normal blood. In 1879-80, Ehrlich first announced the result of careful researches he had made in the "color analysis" as he called it, of the elements of the blood. He made use of dried cover-glass specimens according to the methods of Koch, which were care- fully prepared so as to have as thin a filme of blood as possible, and were "fixed" by heating for from one to two hours on a copper bar at a point between 100° and 120°C. By studying the effect of various coloring matters, he discovered that the protoplasm of certain of the leucocytes contained granules which had affinities for certain distinct classes of coloring matters cells which might otherwise be indistinguishable from one another could be differentiated. In view o' these properties, brought out by the "color-analysis", and of the fact that he never found but one variety of granulation in a single cell, he proposed the term "specific granulations of the blood." The coloring matters Ehrlich divides into two great groups, (1) the acid, and (2) the basic. An acid coloring matter is one in which the staining principle is the acid part of the salt. The reaction of the solution of the salt, or the fact that the salt is or is not chemically acid has nothing to do with the case. An example is picrate of ammonium; Polynuclear neutrophiles are present in nor- mal, increased, or, more often, in diminished relative proportion. The most characteristic feature of the blood is, however, the appearance of a form of cell which does not appear in the normal blood of adults. This is a cell as large, or larger then the large monunuclear variety in normal blood and similar to this morphologically, except that the protoplasm is filled with fine neutrophilic granules. These forms would seem, possibly, to represent an arrest or perversion of development. The nucleus of the ordinary mononuclear leucocyte does not be- come polymorphous, and the neutrophilic granules, which usually appear coincidently with this change, are developed, while the cell may acquire a larger size than any other element which occurs in the blood. These elements seem never to acquire the power of amoeboid movement which the polynuclear cells possess. They appear to rise in the marrow and have been called by Ehrlich ''myelocytes". Varying numbers of "mastzellen* also appear in this form of leukaemia; also a certain number of polynuclear cells which, with mixtures stain- ing the neutrophilic and eosinophilic granules, (the Ehrlich-Biondi triple stain) show no granula- tion. The red corpuscles may show a greater or less poikilocytosis, and nucleated red corpuscles are present, often, in considerable numbers. The characteristic features then, in the blood of this form of leukaemia, are (1) The enormous increase in colorless elements. (2) The increased number of e©sinophiles. (S) The presence of myelocytes. (4) The presence of nucleated red cor- puscles. This picture is characteristic, and a marked contrast to that in all other considerable leuco- cytoses, where the increase takes place solely in the polynuclear neutrophiles; with a relative diminu- tion in all other forms. Acute lymphatic leukaemia is the only exception; here the increase occurs solely in the lymphocytes. The blood in this case has been typical of splenic-myelogenous leukaemia. Specimens have been examined with various different staining solutions- i. e., methylene blue; methyl green; dahlia; eosin and methylene blue; eosin, migros- in and aurantin; and Ehrlich's triple stain of methyl green, ac. fuchsin, and orange G. In the first specimens recorded, those of . Nov. 9, 1890, there was a slight poikilocytosis, and a moderate number of nucleated red corpuscles, chiefly of small size, with intensely staining, round, somewhat refractive nuclei ("normoblasts", Ehrlich). Lymphocytes were present in greatly reduced relative proportion, while eosinophiles were numerous, and there was a considerable number of myelocytes. Mastzellen were also present in certain proportion, as were also polynuclear cells which, with the triple stain, showed no granulation. The so-called "degenerative forms" of red corpuscles, i. e., those taking up basic coloring matters to a certain extent, were present. This characteristic was also noticed in the bodies of most of the nucleated red cor- puscles. The accompanying chart shows the percentage of the different varieties of leucocytes on different dates. These estimates are based on differential counts of at least 1,000 leucocytes in each case. Normal Nov.9 Jan.29 Feb. 7 Blood 1890 1891 1891 Lymphocytes, 20-30/ 2.1/ 0.96/ 1.5/ Polynuclear. Mononuclearj 60-75% 73.8/ 70./ 83.9/ and . 6.0/ 4.6/ 3./ 1.5/ Transition , Eosinophiles i, 2-4/ 4.8/ 2.3/ 4.2/ Myelocytes, 0/ 14.7/ 23.5/ 8.6/ Feb.14 Feb.21 Feb. 25 Lymphocytes, 2.7/ 6.9/ 10/ Polynuclear Mononuclearj 84.7/ 83.2/ 78.1< and j 1 2.1/ 2.5/ 2.3/ Transition J 3./ Eosinophiles ( 1.6/ 4.0 Myelocytes, 3.5/ 14./ 4.7% Thus it will be seen that on his return to Baltimore, after giving up treatment, the percent- age of lymphocytes was under 1 per cent, while this is an acid coloring matter because the picric acid is the staining principle. A basic coloring matter, on the other hand, is one where the staining principle is the base. Now Ehrlich has discovered in all, seven different varieties of granulations in the blood of various dif- ferent animals, but of these, only three come into consideration in the study of human blood, and only two, indeed, have as yet been shown to be of practical diagnostic value. (1) In the first place, there are found in human blood, cells with relatively large, ovoid or round, yellow ish, highly refractive, fat-like granules, which have an affinity for acid coloring matters, and are stained by these alone and by all of this group. The chemical nature of these granules is doubtful; they have been proven to be neither fat nor haemoglobin as has often been thought, and Ehrlich considers them to be of an albuminoid nature and a specific product of the cell protoplasm. These granules have been called Eosinophi- lic because of their affinity for eosin. (2) Under certain conditions one finds in human blood a granulation which stains only in basic color- ing matters. This basophilic granulation has not as yet any great importance from a diagnostic point of view. It seems to be identical with the granulation of the "mastzellen" which appear in the tissues, and the name has been applied to these basophilic cells in the blood. (S) The most common granulation in the blood iB one which is stained by neither acid nor basic color- ing matters alone, but which takes on a stain when a fluid is used containing examples of both, as a result of a combination of the two. This is the so- called ''Neutrophilic" granulation; it occurs in the majority of leucocytes. In normal blood one finds the following varieties of the colorless elements: (a) Lymphocytes. Small cells about the size of red corpuscles, somewhat larger or smaller, with a large, round, deeply stain- ing nucleus, surrounded by a narrow rim of non-granular protoplasm. These cells seem to be derived in main part from the lymphatic apparatus - hence the name. (b) Large mononuclear leucocytes. Large cells, several times as large as the red corpuscles, with a large oval or elliptical nucleus, and relatively considerably more protoplasm, which is also ungranulated. (c) Transition forms. Cells which resemble the last mentioned variety except that there are indentations or irregularities in the nuclei indicating that these are beginning to be polymorphous. These seem to be simply transition forms between the large mononuclear leucocytes and (dj Polynuclear leucocytes ("neutrophiles*). These are of about the same size or somewhat smaller than the last variety. The n cleus consists of a long intensely staining body, which is bent and twisted on itself into most bizarre and irregular shapes. Often the nucleus seems to be broken and the cell seems to have two or three nuclei; it is however probable, as Ehrlich himself says, that the nucleus is, during life, only polymorphous, and that the polynuclear appearance is due to the preparation. The protoplasm of these cells is thickly filled with a very fine neutrophilic granulation. *e) Eosinophiles. Cells of about the same size as the last variety with a single round, ovoid, or polymorphous nucleus and containing large round or ovoid eosinophilic granules. In normal blood these varieties occur in a quite constant and definite proportion one to another, as follows: lymphocytes, 20-30 per cent.; poly- nuclear, 60-75 per cent.; mononuclear and transition forms, 6 per cent.; eosinophiles, 2-4 per cent. The lymphocytes, as has been said, seem to come from the lymphatic apparatus while the large mononu- clear and polynuclear forms seem to come from the spleen and bone marrow. The eosinophiles seem to arise solely in the bone marrow. Under certain pathological conditions these proportions vary, and the changes which occur in the common form of leukaemia, the splenic or more properly the splenic-myelogenous leukaemia, are characteristic. In this form of leukaemia, we see the greatest increase in white corpuscles which occurs under any conditions; the proportion of white to red may be as 1:1. And, as we might expect, the cells which take part in this increase, are mainly those which seem to be derived from the spleen and bone marrow. The lymphocytes take little or no part in this increase, and are, therefore, present in a greatly reduced relative proportion. Eosinophiles are present in a normal, or commonly increased rela- tive proportion, and thus, of course, in a greatly increased total number. Their presence in nearly every field under the microscope, often in large numbers, is a striking picture, and characteristic of this disease. The proportion of the large mononu- clear and transition forms presents about the normal variations. that of the myelocytes had increased at the expense of the polynuclear.forms. In this specimen the nucleated red were numerous. Many were much larger than the ordinary red corpus- cles, and certain of these contained large round weak- ly staining nuclei ("megaloblasts",Ehrlich). Many of the nucleated red corpuscles showed dividing nuclei, and in one instance the whole corpuscle was found to have assumed an hour-glass shape with a half of the divided nucleus at each pole. Poikilocytosis was more marked. With the sudden drop in the total number of white elements, the immediate diminution in the proportion of i yelocytes and the increase in the percentage of the lymphocytes and polynuclear varieties will be noticed. In the latter specimens examined the poikil- ocytosis was very'marked and striking. "Degenerative forms" were very numerous as were nucleated red corpus- cles. A considerable number of these latter were me- galoblasts. A large number of the nucleated red cor- puscles showed signs of nuclear division, and several bodies were found showing an hour glass constriction as above described; one, where the division had already taken place save for a fine filament which still con- nected the two daughter cells. The specimens under the microscopes are stained with the triple stain of methyl green, acid fuchsin, and orange G. The nuclei are stained green, those of the nucleated red corpuscles nearly black; the red corpuscles orange; the eosinophilia granules red; the neuthrophilio granules a violet or lilac color. This case is remarkable in many respects from a haematological point of view. I am not aware that any other case of undoubted leukaemia has been re- ported where the excess in white corpuscles has fallen in so striking and critical a manner. Just such a case as this demonstrates the value of these methods of study which we owe to Ehrlich. Though the physical examination of the patient at the present time might suggest more strongly, a leukaemia, the mere numerical estimate or, indeed, the examination of the fresh blood might give us no hint that such a process had ever existed. The presence, however, Of an appreciable per- centage of typical myelocytes, as revealed by these methods of contrast staining, might put us upon the proper clue, and lead us to anticipate or recognize the possibility of a future return of the leukaemia. The examination of cover-glass specimens from case II shows the blood to be typical of splenic-myelo- genous leukaemia. Ehrlich, Verhandl. der Berliner Physiolog. Gessel., May 15th, 1397, January 17th, 1379; Zeitschrift fur Klin. Med., 1, 1880; Berlin. Klin. Wooh., 1880, No. 28; Berlin. Klin. Wooh., 1881, No. 3; Deutsoh Med. Wooh., 1883, No. 46; Charite Annalen, Xll jahrg. Westphal. Diss., Berlin, 1380. Schwarze, Diss., Berlin, 1884. Uthemann, Diss., Berlin, 1887. Gollasch, in Friedlander-Eberth's "Mikroscopische Teohnik". Gabritchewsky, Arohiv. fur Experiment. Path. u. Pharm., 1390, 28, 1 and 2. SPECIMEN OF CANCER OF PYLORUS. Dr. Thayer exhibited a specimen of cancer of the pylorus and said: The specimen which I have this evening comes from a patient who entered the Hospital on the 19th of September. He was a colored man, 40 years of age, a coachman. The family history had no particular bearing upon his complaint at that time. He said that he had had occasional "bilious attacks". In these attacks he would vomit considerably, but he never vomited blood. A clear history was not easi- ly obtained, but the trouble of which he then com- plained dated two or three weeks back, since when he had been troubled by continual vomiting. The vomit- ing was not due to any particular pain, though he complained at times of a "rolling, grumbling pain" in the epigastric region. The appetite had been poor, and the bowels constipated. On entrance to the Hospital the patient was found to be fairly well nourished, the mucoous membranes of a fairly good color. Nothing abnormal was discovered on examination of the thorax. The abdomen was some- what retracted. Hepatic flatness began at the lower border of the sixth rib, border not palpable. The spleen was not palpable. In the right hypochondrium just to the right of the median line a body about the size of an English walnut was felt to descend on inspiration, returning on expiration to a point under the end of the eighth cartilage. The mass was freely movable. The note reads: "This body gives one the impression of being at the pylorus." There were no glandular enlargements. The urine on entrance was of a normal color, acid, specific gravity 1017, no albumen, no sugar, no diazo reaction. The sediment contained cylin- droids, amorphous urates, occasional leucocytes and epithelial cells. The patient remained in the Hos- pital until the 29th of September. For the first several days all food was rejected, the patient vomiting continuously a green bile-stained fluid. Attempts were made to give a test breakfast, in order to examine the contents of the stomach, tut the patient was refractory and refused to eat the bread. On the 22nd he was ordered four nutrient enemata, each to contain two eggs and four ounces of milk, four times a day, and all food by the mouth was withheld. He was allowed, however, to suck ice and drink a little water, but the vomiting, though somewhat diminished, still continued. Later on he was allowed small quantities of liquids by the mouth, but vomiting several times a day persisted. The patient became weaker and more emaciated under observation. On the 28th the examination of the blood showed: Red corpuscles, 3,605,000; colorless corpuscles, 16,000; haemoglobin, 103 per cent. The dried specimens showed nothing remarkable. The corpuscles were of normal shape and appearance. The moderate leucocytes consisted of an increase in the poly-nuclear neutrophiles. No nucleated red blood corpuscles were to be seen. On the 29th the patient was discharged at his own request* A diagnosis of cancer of the pylorus was made notwithstanding the remarkable condition of the blood. No attempts were made to inflate the stomach, owing to the extremely nervous condition of the patient. After being taken home he rapidly failed and died two days ago. The autopsy, which I made yesterday at his home, showed a fairly well developed man, consid- erably emaciated* The pericardium and heart showed nothing abnormal. The pleurae and lungs, beyond some old fibrous adhesions, more marked on the right side, were not remarkable. The spleen was small, not more than one half the size of the normal organ. On section the consistency was normal, follicles and trabecula! distinct. The liver, kidneys and bladder, and intestinal tract showed nothing remarkable. The stomach was somewhat dilated. At the pylorus a firm diffused thickening was to be felt the size of an English walnut. On introducing the finger from within there appeared to be a distinct sten- osis, but the tip of the little finger could be introduced on pressure. On section the tissues at the pylorus offered considerable resistance to the knife and* cut with a distinct crackling sound. The muscular coat appeared to be greatly hypertrophied, the mucous and sub-mucous coats were infiltrated with a firm whitish substance which appeared to send arms down into the muscular coat. The mucous membrane was not ulcerated, and over the rest of the stomach appeared normal. Fresh microscopical sections showed the condition to be a scirrhous carcinoma. No lymphatic glands showed any evidence macroscopically of infection. The glands about the portal fissure were small, of normal size and appearance. The case, I think, is of remarkable interest, owing to the rapidity of the course after the first onset of the symptoms. Cases of this nature, where almost the only symptom is sudden and constant vomiting, are mentioned in literature, but are certainly not frequent. The absence of any evidences whatever of metastasis is also a point of interest in the case. The condition of the blood is partic- ularly striking. The blood in cancer of the stomach almost always shows a distinct oligocythaemia associated with a slight leucooytosis and a decided oligochromaemia, the amount of haemoglobin being relatively much more diminished than the number of the corpuscles. The presence of nucleated red corpuscles may also be very commonly, if not usually, demonstrated, a point which is often of considerable value in discrininating between obscure cancerous and tuberculous affections, for in the latter anaemia is usually very much less marked, and nucleat ed red corpuscles are rarely present, while in the former they are usuallv to be found. The marked increase in both corpuscles and haemoglobin above the normal standard in this case one may perhaps ascribe to an actual condensation of the blood as a whole, owing to the extremely small quantity of fluid which the patient had been able to take, but from the examination of the dried specimens and from the general appearance of the blood it is scarcely to be supposed that any ap- preciable diminution in the number of the corpuscles as a whole can have been present, a fact which may have been due to the rapidly fatal course of the disease. ON THE VALUE OF METHYLENE-BLUE IN MALARIAL FEVER BY W. S. THAYER Resident Physician to the Johns Hopkins Hospital. Several months ago a report was made to $he Medical Society of the Johns Hopkins Hospital' concerning some cases of malarial fever which were under treatment with methylene-blue, and the conclusion was reached, from what experence we had at that time, that methylene-blue had a distinct anti-malarial action and was possibly of some real value as an anti-malarial agent. It was then stated that a definite report would be made at a later date when increased experience might justify us in arriv- ing at definite conclusions. These conclusions we now feel justified in expressing. The first suggestion of the anti-malarial value of methylene-blue was made by Guttmann and Ehrlich. These observers were led to undertake their experi- ments in consideration of the fact that methylene- blue stains the plasmodia not only in dried specimens but also in fresh blood, Celli and Guarnieri having stained the living plasmodia by mixing a drop of fresh blood with some slightly colored human blood serum; and also from the fact that certain elements in the red blood corpuscles and particularly the nuclei of the nucleated red blood corpuscles, in warm and cold-blooded animals, were also stained after the injection of methylene-blue into the cir- culation. They observed two cases. The first case was one of tertian ague, the chills occuring on the 21st, 23d, 25th and 27th of June. On the 28th of June methylene-blue 0.5 was given at 8 P. M. At 10.30 P. M. the patient complained of slight strangury. On the following day the temperature arose to 38.3°C., but there was no chill. After this the temperature remained normal. No malarial organisms were seen in the blood after July 1st, the third day, the patient having taken methylene- blue daily 0.1 five times in the 24 hours. The second case was one of quotidian ague* daily chills occurring for three weeks. On the loth of July at 3 P. M. methylene-blue 0.1 was given, to be repeated five times in the day. At 4 A. M. of the following day there was a chill lasting two hours, the temperature rising to 39°C. No chills or fever after this. On the 24th, six days later, the plas- modia had disappeared from the blood. They concluded that methylene-blue had a decided anti-malarial ac- tion, and they laid particular stress upon the im- portance of the discovery in view of the fact that none of the synthetical products, such as chinoline, kairin, antipyrin, antifebrin, ptyalin, phenacetine, etc., have ever had a^y effect on this disease. More recently Grawitz has tried this drug in one case of chronic malarial intoxication without any marked effect. In Professor Osler's wards in the Johns Hopkins Hospital seven cases of malarial fever have been systematically treated with methylene-blue. CASE 1• Tertian ague; no fever 24 hours after administration o^ methylene-blue^disappear- ance of the organisms on the third day.(Temperature chari accompanying.") ,J. k., aged 68, a German by birth, was admitted to the Hospital on October 7th, 1891. Family history negative; previous history has no bearing on the present trouble. Has been living in a malarious district. Patient does not give a very clear history, but states that some time within the last two weeks he had three chills, after which he was given ''medicine'* which relieved him tempora- rily. Complains now of general weakness. STATUS PRESENS, Oct. 8th. Large, well-formed man; lips and mucous membranes rather pale; respir- ations 16; pulse 48; temperature normal. Examina- tion of thorax negative, barring a soft systolic souffle at the base of the heart; abdomen negative. Splenic dullness obliterated by abdominal tympany, borderof the spleen not palpable. Legs were somewhat oedematous on entrance, but are now free from pitting. Large varicose veins on either leg. URINE free from albumen or sugar. BLOOD. Examination of one slide of blood showed no malarial organisms. The patient was given a nourishing diet and a bitter toniQ» and after a day or two he was dressed and about the ward. On October 18th the patient had a slight chill, tem- perature rising to 102,2° at 4 P. M. By 8 o'clock at night the temperature was 98.4°. The fall in temperature was accompanied by sweating. On the 20th the patient had another chill, the temperature reaching 105° at 12 noon, the fall being accompanied again by profuse sweating. On the 21st examination of the blood showed numerous malarial organisms of the amoeboid, intra-cellular variety, with fine, active pigment granules. At 8 P. M. methylene-blue 0.1 in capsules was given, to be repeated every three hours during the night, and to be continued five times in the twenty-four hours afterwards. On the following morning the temperature rose to 105° at 8 A. M., but there was no chill. On the 23d there was a marked diminution in the number of organisms present. On the 24th the temperature was normal and remained so afterwards. On this date the patient complained of burning with micturition and vesical tenesmus, which was relieved by a small amount of powdered nutmeg, about a quarter of a teaspoonfull three times a day, as suggested by Guttman and Ehrlich. On the 24th, the third day after the be- ginning of treatment, no organisms were found in the blood and the patient was discharged well on the second of November, repeated examinations having revealed no more organisms. This patient reported again at the Dispensary on the second of February, 1892. Had been perfectly well till a week or two before that date, when after being in a malarious district he had had a chill. He had taken quinine and at that time no organisms could be found. CASE 2. Chronic remittent fever y^ith hyaline bodies and pigmenied crescent blood, ^all of temperature to nearly normal point in 5 days, with marked diminution inthe number of organisms. Irregu- lar slight febrile attacks during the next month, with eventual Increase in ihe number of organisms in the blood. Entire disappearance of the fever in twenty- four hours under quinine, though occasional organisms were to be found in the blood twelve days later, (temperature chart accompanying.) A. P., single, 20 years of age, admitted to the Hospital on the 24th of October. Family history good; personal history bears no relation to his present trouble. Present illness began 20 days ago with headache and general malaise and "creeping chills. These were relieved for a time by "medicine", but for the past few days he has been worse again. STATUS PRESENS. Well-formed and nourished; lips and mucous membranes slightly pale; tongue thickly coated; skin warm and moist; pulse 84, di- crotic; general appearance typhoidal. Lungs and heart negative, excepting a soft systolic souffle in the pulmonary area. Abdomen not distended, splenic dullness (relative) begins at the eighth rib, border of the spleeneasily palpable. No rose spots. URINE free from albumen or sugar. BLOOD. Numerous small, actively amoeboid intra-corpuscular hyaline bodies. On the afternoon of the 25th of October methylene-blue 0.1 five times a day was ordered. The temperature fell during the next three days and on the 29th was perfectly normal. On the 30th the temperature touched 101.7°, and from the first to the 7th of November remained somewhat elevated, rising or the 3d as high as 103.5°. On the 2d of November the blood still contained a moder- ate number of hyaline bodies, also crescentic and ovoid bodies'with coarse collections of pigment in the middle. Nov. 3d methylene-blue 0.2 four times a day ordered. From the 7th to the 16th of November the temperature remained practically normal and the patient was out of bed and feeling much stronger. Occasional hyaline bodies, pigmented crescents and ovoid bodies were still, however, to be found. From the 16th to the 25th the tempera- ture remained somewhat elevated, touching several times points about 101°, and the patient complained of headache and general malaise. On the 21st, as the patient was rather anaemic Fowler's solution, three minims three times a day, was ordered, to be increased one minim every third day, in addition to the methylene-blue. On the 25th, 26th and 27th the temperature remained near- ly normal, but on the 28th it rose again to a point about 99.5°. November 30th Fowler's solution omitted on ac- count of slight conjunctivitis. On December 3d, as the patient had shown no improvement and the temperature had been rising for several days while the number of organisms in the blood was increasing, all medication was omitted and quinine gr. iv. three times a day was ordered. The temperature fell to normal on the 5th and remained so until his discharge on the 14th, eleven days after the beginning of treatment with quinine. In this time the patient had improved rapidly. physical examination otherwise negative. On Novem- ber 9th methylene-blue 0.2 four times a day was ordered. The temperature remained practically normal through- out his stay in the Hospital. On November 13th, six days after his entrance, hyaline hodies were still to be found in the blood. On the 18th, nine days after the beginning of treatment, no organisms were seen. Dizziness disappeared within a few days after begin- ning of treatment. On November 27th the patient was discharged apparently well. CASE 5. Continued fever with irregular chills* Hyaline bodies and pigmented crescentspresent in £he blood* Rapid fall of temperature to normal in four days with great diminution in the number of the organisms. "No total disappearance of the organisms, irregular febrile attack after a month's treabmenx, the number of organisms increas- ing. Marked improvement in general condition under quinine with disappearance or fever. Occasional organisms found in the blood at the date of discharge, two weeks after the beginning of treatment with quinine. (Temperature chart accompanying.) Man, single, 26 years of age, admitted to the Hospital on November 11th. Family history negative. Previous history has no bearing on present trouble. Has been working at Sparrow's Point (a very malarious district) for one year. A month ago had an attack of tertian ague, took quinine and was benefited, but the chills never entirely ceased, though they became irregular. On the 10th of November had a severe chill. On the 11th was admitted with a chill, temperature reaching 104.3° at 3.30 P. M. STATUS PRESENS. Well-formed and nourished, skin somewhat yellow in color, lips and mucous membranes rather pale; tongue thickly coated. Thorax negative. Spleen easily palpable. Abdomen otherwise negative. Urine negative. BLOOD shows fairly numerous hyaline, actively amoeboid organisms. Methylene-blue p.l every four hours was ordered at 8 P. M. Nov. 12th, temperature touched 102.9° at 8 P. M. Nov. 13th, temperature touched 103.4° at 4 P. M. Methylene increased to 0.2 four times a day. Nov. 14th, temperature touched 100.6° at 6 P. M. Nov. 17th: since the fifteenth the tem- perature has been normal. Blood today showed an occasional crescent. November 24th: the temperature rose today to 101.4° at 6 P. M. and at midnight was 101.5°, patient oomplaining of headache. November 26th; the temperature has remained more or less elevated. The blood, which has shown for ten days previously only an occasional orescent, now shows numerous byaline, actively amoeboid bodies. Fowler's solution, Miij three times a day, ordered, to be increased Mi every third day. The temperature remained somewhat elevated until December 1st; from December 1st it was normal until the 7th, when it rose again to about 99.5° and the patient complained much of headache. Organisms were still present in the blood. Methylene-blue discontinued. Fowler's so- lution also discontinued on account of diarrhoea. December 11th. The temperature rose at 4.P. M. to 100.7°. Quinine, four grains three times a day, ordered. On the 21st of December the temperature rose to 102.5° at 4 P. M., owing probably to a slight tonsillitis. On the 22d, an occasional ovoid body was found in the blood and an occasional organism was still found when the patient was discharged on the first Of January. The improvement in the general condition of the patient after quinine was begun was very marked. In the week from the 17th to the 26th the patient gained nine pounds and a half. CASE 6. quartan ague with pigmented, intra- cellular organisms; pigment rather large and not actively motile; organisms apparently not so large as those in ordinary tertian fever. Ko fever after the beginning of treatment. Ko or- ganisms seen after the $th day. Death from influ- enza and brohclio-pneumonia one week after the omission of treatment by methylene-blue. Ko irages of blue found in the organs. (/temperature chart accompanying.) R. R., single, 52 years of age, admitted to the Hospital on the 10th of December. Family history negative. Previous history good. The present illness began on the 8th of December, when he had a severe chill, lasting for about an hour, followed by fever and sweating. Had none yesterday nor today. STATUS PRESENS. Well-formed, rather sparely nourished, moderate muscular development. The blood, however, still showed an occasional hyaline body and pigmented orescent. The patient was heard from by letter two weeks later. He stated that he felt perfectly well; he had been taking quinine. In this case, after the first day or two of treatment there was slight burning with micturition which was relieved by a small amount of nutmeg with each dose of methylene-blue. CASE 3. Quotidian ague with pigmented intra- cellular organisms, possibly of the tertian types, associated later with ovoid and crescentic bodies. One chill after the beginning of treatmeht' ho rise above 100° after the fourth day. fro organisms seen after the twelfth day. Patient discharged on the 15th day." feelapse a week after discharge. temperature chart accompanying. Man, single, aged IT, admitted to the Hospital on the 27th of October. Family history good. Has had no previous ilnesses.- Present illness began 14 days ago with a chill followed by fever and this has been repeated every day, chills occurring at about ten in the morning. STATUS PRESENS. Well built, well nourished man; mucous membranes somewhat pale. Thorax negative; abdomen negative; spleen not palpable, though the splenic dullness begins at the upper I order of the 8th rib and appears to pass the costo-articularline. URINE, negative. BLOOD shows numerous large amoeboid intra- cellular bodies with rather large pigment granules. The patient on admission was just recovering from a chill. On October 29th patient had a chill, the temperature rising to 104° at 12 noon. At 2 P, M, methylene-blue 0,1 five times a day was ordered. On October 30th patient had a chill, temperature reaching 103,2° at 12 noon. October 31st, temperature rose to 103,4° at 12 noon, but there was no shaking. November 1st, temperature 100.1° at 2 P, M; no chill. November 2nd, temperature 100.0° at 2 P. M, November 3d, temperature 99.6° at 12 noon. From that time on the temperature remained near- ly normal, though it rose every day above 99°. On November 3d, five days after entrance, an occas- ional pigmented, crescentic body was seen, but none of the pigmented, intra-cellular bodies be- fore observed. On the 7th of November, nine days after entrance, pigmented ovoid bodies and cres- cents and an occasional active hyaline body were found. On the 10th, twelve days after the begin- ning of treatment, no organisms were to be found, and from that time none were to be seen. On the 13th the patient was discharged with directions to continue treatment. In this case also there was slight stranguary, which was relieved by nut- reg. This patient reported at the Dispensary on November 24th, stating that he had felt well up to three days before that time, eight days after discharge, when he began to lose his appetite and have headaches. Complained of thirst. Blood showed "intra-cellular pigmented organisms". No careful search made. The patient was given quinine and has not reported since then. The examinations of the blood in this case were not as thorough as they might have been, and it is quite possible that a more careful search might have revealed organisms even at the time of his discharge, as the early relapse would suggest. It is perfectly possible, however, that there was a new infection, as the district in which the patient lives is most malarious. The case is of particular interest because of the presence of organisms apparently of the tertian type, together with the hyaline bodies and crescents which are usually associated with the more remittent and irregular forms of fever. CASE 4. Chronic malarial intoxication; no fever on entrance; vertigo and dizziness, hyaline bodies and pigmented crescents In ihe blood. Rapid" disappearance of the symptoms under methylene-blue; no organisms seen after the ninth day^ J. S., married, aged 3'7, enterea the Hospital on November 7th. Family history negative. Previous history has no bearing on present trouble. Has been working on fishing boats on the bay since August. Complains now of weakness and a stagger- ing gait. His present illness began six weeks ago with headache, malaise and fever, for which he took quinine pills. STATUS PRESENS. Well-formed and nourished, lips and mucous membranes of good color, temper- ature normal, pulse slow and regular; thorax negative; abdomen negative except that the border of the spleen is easily palpable. URINE, negative. BLOOD shows ovoid and crecentic bodies with coarse, granular pigment in the middle, also an occasional small, actively amoeboid intra-oorpus- cular hyaline body. On attempting to stand and walk the patient finds great difficulty in keep- ing his balance. After swaying to and fro for several moments he steadies himself and stands fair- ly well, but on any change of nosition loses his balance. The knee Jerks are slightly exaggerated; The autopsy, made by Councilman on January 9th, showed a considerable dgree of chronic intersitial pneumonia with old gummata in both lungs, particularly the right. In the right lower lobe numerous patches of broncho-pneumonia. Chronic interstitial orchitis; splenic tumor. No traces of methylene-blue could be found in any of the organs, though death occurred only six days after its omission. CASE 7. Quotidian ague with organisms of the tertian type, probably a double tertian Infection. Entire disappearance of fever after the third day with a greax diminution in the numbers of organisms. Recurrence of the chills twenty-two days after the last appearance of the fever, with increase in the' number of organisms. Immediate disappearance of the fever with total disappearance of the organisms under quinine. (Temperature chart accompanying.) C. m., single, o3 years of age. Patient is a Pole and speaks no English or German, so that little history can be obtained. He has been working recently in a very malarious dis- trict. For the past seven months has had repeated attacks of chills and fever, which had been temporarily controlled by quinine. The chills were at first definitely tertian in type, but later became more irregular, and of late, according to the patient have been quotidian. The patient was ad- mitted just as he was recovering from a chill on January 8th. Temperature 102.2°, pulse 124, res- piPatidns 22. At four P. M. the temperature reached 104.8°. STATUS PRESENS, Large frame, well-nouiished; lips and mucous membranes slightly pale, tongue somewhat coated. Thorax negative; spleen easily palpable; abdomen otherwise negative. At 4 P. M. on the 9th the patient began to have another chill, the temperature reaching 101.8° at 6 P. M. At 2.30 P. M. on that day the blood showed numerous actively amoeboid, intra-cellular bodies, filling up about half of a cell body and containing small active pigment granules. There was also a number of fully grown organisms with active pigment granules, some of which were beginning to show signs of segmentation. At the height of the chill numerous segmenting bodies with 15 to 20 seg- ments were found, and towards the end of the chill small hyaline, intra-cellular bodies began to appear. At 6 P. M. methylene-blue 0.2 every four hours was ordered. On the following day this was reduced to five doses in the 24 hours. Lips and mucous membranes of good color; tongue slight- ly coated. Chest is somewhat barrel-shaped and rather hyper-resonant. Respiration clear through- out. Heart negative; spleen easily palpable; ab- domen otherwise negative. URINE, negative. BLOOD showed fairly numerous round and ovoid, coarsly pigmented, intra-cellular bodies not quite filling the corpuscle. In some no motion at all could be made out. The pigment granules appeared coarser than those in the ordinary ter- tian form of the organism and of a slightly dif- ferent color. No hyaline bodies, no crescents. On the 11th, the patient had a chill, the tem- perature reaching 103.8° at 8 P. M. No segment- ing bodies were seen, though a very careful search was not made. The fully developed organisms seen on this date did not seem to be as large as those seen in the ordinary tertian fever. The pigment granules seemed possibly larger and were not as motile. On the 14th the patient had another chill, the temperature rising to 104.3° at 6 P. M. On the 15th methylene-blue 0.1 four times a day was ordered, and from this date until the 30th of December there was no rise of temperature. On the 15th and 16th several plasmodia were found. On the 18th after a long search one pigmented organism was found* On the 22d, seven days after the beginning of treatment, careful exam- ination of five slides showed no organisms. On the 1st of January the temperature, which had been slightly elevated on the two previous days, rose to 101.4°, and at 4 P. M. on the 2d touched 104.4°. The patient complained chiefly of head- ache. He had a cough with a muco-purulent ex- pectoration. He was dull and listless. Repeat- ed examinations of the blood on the 3d of January and on previous days had shown no organisms. Methylene-hlue omitted. Dullness was made out at the right base, with somewhat enfeebled res- piration and occasional fine rales. From this time until the patient's death on the 9th of Janu- ary the temperature remained between 99.6° and 104°• The signs of bronchitis with areas of consolidation developed more markedly at the right base. On the 11th there was a chill, beginning shortly after 2 P. M., temperature after the chill reaching 106° at 3 P. M. On this date very numerous segment- ing bodies and fully grown organisms were seen, but a relatively small number of half-developed organisms were present. On the 12th the temperature rose to 101° at 6 P. M., but there was no chill. From this time on until the 4th of February, the temperature remained perfectly normal. The general condition of the patient was im- proved, but at no time was the blood entirely free from organisms. On the 4th of February, the blood not having been examined for fully a week, the patient had a slight chill, the temperature rising to 103.2®, the fall in temperature being accompanied by sweating. On the 5th the temperature remained normal but the blood showed quite numerous, actively amoeboid, pigmented, intra-cellular bodies abrut half filling the corpuscle, and on the 6th of February the patient bad a chill, the temperature reaching 104.60® at 5.30 P. M. On the following day, the 7th, methylene-blue was discontinued, and quinine, gr. v. four times a day was ordered. From this time on the temperature was normal and the patient felt perfectly well. During the first three or four days after the beginning of the quinine occasional organisms were seen. Unfortunately no careful examination of the blood was made during the next ten or twelve days. On the 22nd careful search re- vealed no plasmodia. Slides examined on the g4th and 25th were also negative. On the 25th patient was discharged well. The patient went back immediately to a very malarious district and went to work in the fields. He returned on March 17th with a fresh attack of quotidian chills, with organisms exactly similar in character to those on his first entrance. These have at the date of writing disappeared under quinine; no organisms were found after the fourth day. In all these cases the urine while under treat- ment was of a deep-blue color* No albumen was pre- sent in any of the cases, excepting in Case 7, where on February 9th, two days after the omission of methylene-blue, there was a faint trace present. This was also seen two days later. No tube casts were found. No marked increase in the quantity of urine passed was noted. The faeces when first passed were natural in color, but on exposure to air turned rapidly blue. The saliva and sweat ware not colored. In the last four cases powdered nutmeg was. given with each dose of the drug, about 1/5 of a teas- poonful at a time, and in none of the oases was there any strangury. The preparation of the drug was from the labor- atories of Merck in Darmstadt; it was administered in capsules* The examinations of the blood were all made with fresh unstained specimens and the Zeiss 1/12 oil immersion lens, eye-pieces 2 and 4. SU1.1MARY:- Thus out of seven cases, in two, Cases 1 and ^1, one of tertian and one of quartan fever, a definite cure seems to have been effected* In two more, Cases III and iV, one a chronic case without fever but with symptoms of vertigo, and one a quotidian fever, a definite cure may have been obtained. In the former, how- ever, it is highly probable that a more thorough examination would have revealed an occasional crescent, as the disappearance of this variety of organism is not usually so rapidly effected even with quinine; and in the second the examinations of the blood, as already noted, were not so thorough but that the rapid relapse might give rise to suspicion that organisms were still present in the blood on discharge* Of the three other cases, in two, Nos. 11 and V, which were chronic cases with hyaline bodies and crescents in the blood, an immediate temporary benefit was noted, followed later by an increase in the organisms and a return of the fever, which in the end yielded rapidly to quinine. In the other. Case Vil, a quotidian, the chills dis- appeared rapidly and the temperature remained abso- lutely normal for twenty-two days, but the organisms never entirely disappeared and at the end of this time the typical tertian ague appeared again. All of these cases were of such a nature that one might have safely expected no secondary rise of temperature after the administration of quinine, and though in the two cases in which the hyaline bodies and crescents were present the organisms might have been relatively certain of a speedy and entire cure in Case 7• From these onservations I think the following conclusions are justified: 1. Methylene-blue has a definite action against malarial fever. Accomplishing its end by destroying the specific organism; but it is materially less efficacious than quinine, failing to accomplish its purpose in many cases where quinine acts satisfacto- rily. 2. The action appears to be rapid, the chills disappearing, or the temperature, in the remittent cases, falling to normal during the first four or five days; but later, however, if a sufficient number of organisms has resisted the drug, they appear to develop* again directly under its influence, causing a return of the symptoms. 3.Methylene-blue seems to have no advantages over quinine which would warrant its further use. Note:- Since the writing of this article.my attention has been called to the work of Mya4, whose conclusions seem to agree essentially with those above expressed. IJohn Hopkins Hospital Bulletin, 1892, No. 19. p Berliner Klinische Wochenschrift, 1891, No. 39. '^Berliner /{linische Wochenschrift, 1392, No. 9. ^Ref. British Med. Journ., March 19th, 1892. A Case of Super-Secretion of the Gastric Juice.-Dr. Thayer. The patient is a man forty years of age, who was admitted to the Hospital about two weeks ago. His trouble has lasted about two years. During all that time his complaint has been of severe periodical attacks of pain in the epigastrium, extending through into his back and radiating around on both sides. These attacks came on mainly during the night and when the stomach was empty. At times this pain was associated with the vomiting of large quan- tities of extremely acid and burning fluid. He complained also of sour, burning eructations and of considerable steady epigastric pain and soreness. His appetite was perfectly good, but he found that eating a general diet did not seem to "agree" with him, that his pains were worse afterwards, and consequently he restricted his diet very much. He lost much in weight; he weighed about 190 pounds when well, and on entrance his weight was but 125 or 130 pounds. Phvsical examination on entrance showed a man rather emaciated, complexion sallow, mucous membranes of fairly good color. Thoracic organs entirely negative. Abdomen flat; no abnormal masses to be felt on palpation ; on inflating the stomach, however, we found that it was markedly dilated, extending some three or four finger-breadths below the umbilicus. The pylorus was not palpable. On the following morning the patient was given a test breakfast, consisting of one slice of bread (about 20 grammes) and one glass of water or a cup of tea without milk or sugur. Normally, after taking such a breakfast, if the tube is introduced an hour later one obtains about 20-40 cc. of slightly straw-colored cloudy fluid which gives a distinctly acid reaction to litmus paper, and deposits but a slight sediment. On testing further with Congo paper, which turns blue in the presence of a free acid, we should get evidence of a free acid, and that free acid should be found to consist largely of free hydrochloric acid (Gunzburg's test). The starches in the ordinary process of digestion are so far changed in their way towards sugar that they should, under normal circumstances, give no reac- tion with Lugols' solution of iodine. The patient was given this test breakfast. He had nothing to eat during the night. On introducing the tube, nearly a quart of slightly cloudy fluid was obtained. There was a slight sediment. The fluid was intensely acid in reaction, and the- test for free hydrochloric acid showed a markedly positive result. In the normal gastric juice the free acid present is almost entirely hydrochloric acid. The simplest clinical test is that for the total acidity, which is practically, under normal circumstances, the test for the quantity of hydrochloric acid. This is done by titra- tion. One uses a decinormal solution of sodium hydrate in a burette, allowing it to fall drop by drop into 10 cc. of gastric juice (filtered). The acid of the normal gastric juice is such that it takes from 4-6-6.5 cc. of this solution to make alkaline 10 cc. of gastric juice, and one speaks shortly of a total acidity of one, three, four, six, etc. Above 6.5 one speaks of the gastric juice as being super-acid. The total acidity in this case was 11.3, that is, nearly twice the pro- portion of hydrochloric acid present under normal circumstances. Last Sunday the patient's stomach was washed out with an alka- line solution and emptied. He was given nothing whatever during the night. Towards three or four o'clock in the morning he vomited quite a large quantity of fluid, and at about 8.30 or 9 o'clock in the morning the tube was introduced and 420 cc. of clear fluid secured, which had been secreted by the stomach during the night without any stimulation by the presence of food. This had an acidity of 11.7, even greater than we found at first. This is one of those cases of super-secretion of the gastric juice associated, as it usually is, with super-acidity. One sees cases of the super-acidity of the gastric juice unassociated with super- secretion, that is, a condition where the normal call for acid which is given by an ordinary breakfast is answered by a secretion of gastric juice containing a greater amount of hydrochloric acid than is normally present, which appears sooner than it normally does and which produces distinct symptoms of pain, heartburn, etc. Then one sees cases of super-secretion, the great majority of which are associated with super-acidity. In Riegel's clinic, 19 out of 20 cases of super-secretion were associated with super-acidity. Two years ago Dr. Osler had a patient in his practice whose gas- tric juice I had the opportunity to examine six or seven times. In that case, just as in this, quantities varying from half a pint to nearly a quart were obtained, the total acidity ranging from ?yXto Kit^even higher than it has been in this case. If a continuous super-secretion of this kind is going on when the stomach is empty, the result after a certain length of time is a marked dilatation, and, in addition to the symptoms produced by super-acidity, one sees the symptoms of dilatation of the stomach. It has been observed that it is in this class of cases one occasion- ally sees the so-called idiopathic muscular hypertrophies of the pylorus. Ewald thinks this is due to the spasmodic contraction of the pylorus as the result of irritation by the quantities of gastric juice in the stomach. The treatment of these cases of super-secretion with super-acidity which is quite satisfactory. Of course one sees immediately that a stomach which is secreting the gastric juice so rich in its most important constit- uent can very easily digest albumen. In such cases the patient should be allowed albuminoids in quantity and albuminoids of almost any sort. It has been advised to give albuminoids of the grosser kinds. Evald says that pork is better than the more delicate albuminoids. The patient may be given con- siderable quantities of meat and egg-albumen. Fats are found to be fairly well borne, but it is better "0 give the simpler and more easily digested fats. Good butter is very well borne. The carbohydrates should be cut off as much as possible. Boas, in a very interesting article some years ago in the Berliner Med.' Woch, laid great stress on the inadvis- ability of shutting off any one particular class of foods absolutely from the diet in ordinary diseases of the stomach, and I think this is a point which is often forgotten. If the patient is put on too strict a diet of one variety of food he becomes tired of it and rebels. We aim in this case to give the patient such « diet as his stomach will easily digest, which will at the same time use up as much of this super- acid gastric juice as is possible, and then again to give him a diet which will call for as little work as possible from the dilated stomach,. We have tried to give him relatively small quantities of more solid food frequently during the day and to make that as albuminous as possible. He has four main meals in the day- at 8 A .LI., 12 M., 4 and 8 P .M . At each meal he has meat, fish or eggs in moderate quantities. He is allowed & slice of to st or a cracker and good butter, and at two or three of these meals he is allowed a small cup of black coffee. Every two hours between meals he is given either a hard-boiled egg or a glass of mils, beef tea, beef juice, egg albumen or something of that sort, so that he gets something every two hours. He drinks only soda water, not more than 30 cc. at a time. He has borne his diet extremely veil and has complained of no distress after eating since he has been in the Hospital. His stomach is washed out every morning with an alkaline solution of bicarbonate of soda and water. He has oeen given also small quantities of bicarbon- ate of soda every two hours while awake. He has two hard-boiled eggs placed by his bedside at night, and if he vaxes up in the middle of the night with any pain he takes these eggs often with relief. The patient has gained four or five pounds during the last ten days. Rosenheim recommends in these cases the admin- istration of nitrate of silver. It seems to relieve the pain somewhat and he things that it also tends to correct the super-acidity to some extent. He gives a grain of nitrate of silver in water three times a day on an empty stc .ach. These conditions do not as a general thing yield very quickly to treatment; they last for years. The condition of the patient is, however, very greatly ameliorated. Dr. Osler's patient gained about thirty pounds under treatment, and the patient which \e now nave will go out in a day or two and be able to lead p comparatively comfortable life. In about a month he has gained 20 pounds. This condition comes under tne head of the gas- tric neuroses. It is more commonly found in hysterica] and nervous individuals. It is interesting that the condition sometimes occurs periodically in hysterical individuals and at times in cases of tabes. Dr.' Hurd- I remember seeing, a number of years ago, a patient who suffered in a similar manner, and his symptoms were largely relieved by eating the most indigestible sort of cheese. He formed the h bit of eating cheese almost as frequently as Dr. Thayer's patient has formed the habit of eating other things. The Doctor's description of the number and variety of meals is very attractive, and I am sure that this disease cannot be wholly an evil . Dr,. Osler.- I would lixe to mention that I have seen the patient to whom Dr. Thayer refers within the past six or seven months, and he re- mains perfectly well. He came to me almost a skeleton. He was supposed to have malignant disease of the stomach, and had lost, I think, 50 or 60 pounds. Under Dr Toulmin's management he he recovered completely, and he has had no return of symptoms toms for fully two years, and has regained his weight and takes an ordinary diet. Dr. Welch.-I would like to ask Dr. Thayer the condition of the urine. Dr. Thayer.-Since entrance to the Hospital, no marked changes in the urine have been noted. In some cases of this nature a markedly diminished acidity has been described. I should have said that cheese is also allowed at his four main meals. Splenic Myelogenous Leukaemia-Exhibition of Patient.-Dr. Thayer. I wish to speak briefly to-night of this case because the patient is soon to leave the Hospital. The patient is a man 48 years of age, who first came to the Hos- pital on the 15th of October. He is a watchman, doing light work by day. He complained on entrance of fulness and distress after eating, with some nausea, and of a tumor on the left side of the abdomen. His family history is good and his personal history has no particular bearing on the present trouble. He had malaria three years ago ; no chills since then. Habits good. Fifteen months ago he had an attack of what he calls influenza, and since that time he has not been wholly ■well. He has complained of vague dys- peptic symptoms and increasing weakness, and for two months dyspnoea on exertion. He noticed the tumor in his side two or three months ago. No hemorrhages; no priapism ; eyesight per- fectly good. On entrance his appearance w'as much the same as now, though somewhat paler. Examination of thoracic organs entirely negative. No oedema of any part. Abdomen found to be slightly prominent on left side. This was found to be due to a greatly enlarged spleen, reaching below and to the right of the umbilicus, and at the level of the umbilicus 7 cm. to the right of the median line. In the right margin, which was sharp, there were two or three distinct notches, a large one just above the umbilicus. The margin of the liver was not palpable, but apparently extended two or three finger-breadths below the costal margin. Examination of blood at that date showed no evidence of malarial organisms. Blood count gave 2,916,000 red corpuscles and 360,000 white corpuscles in the cubic millimeter. He had 47 per cent of haemoglobin. Examination of dried and stained specimens of blood showed the characteristics of splenic myelogenous leukaemia. The patient was started immediately with Fowler's solution, three drops three times a day, and was told to increase the dose by one drop every fourth day. One week later there were 3,050,000 red corpuscles and 427,000 wThite corpuscles. Haemoglobin slightly in- creased, 52 per cent. The next examination was made on November 2d, when he wras taking 7 minims of Fowler's. Red corpuscles 3,547,000, white corpuscles 239,000, haemoglobin 53 per cent. The count this afternoon shows red corpuscles 3,848,000, white cor- puscles 256,000 to the cubic millimeter. Haemoglobin 56 nor rent EXHIBITION AND EXPLANATION OF CHART. I have under the microscopes several stained specimens of the patient's blood* They show very clearly the main characteristics of the blood in this form of leukaemia: (1) The great increase in the number of colorless corpuscles. (2) The number of the snail mononuclear elements (lymphocytes) is greatly diminished* (3) In a blood showing extensive increase in the number of the leucocytes, the eosino- philic cells, that is, the leucocytes with coarse granules which stain only with acid coloring matters, are present in about normal relative proportions, whereas in most leucocytoses the eosinophilic cells take no part in the increase and are present in greatly reduced proportion. (4) A distinct number of very large leucocytes, larger than any we ordin- arily see, containing a single nucleus and having in their protoplasm granules stained by neutral coloring matters. (5) We also find a considerable number of nucleated red corpuscles. (6) Another striking point is the great difference in size between different polynuclear cells as well as with the eosin- ophils. REMARKS ON The Clinical Value of Ehrlich's Methods of Examination of the Blood. BY WILLIAM SYDNEY THAYER, M. D., Resident Physician to the Johns Hopkins Hospital, Baltimore. Reprinted from the Boston Medical and Surgical Journal of February 16 and 23, 1893. BOSTON: DAMRELL & UPHAM, Publishers, 283 Washington Street. 1893. S. J. PARKHILL 4 CO., PRINTERS BOSTON REMARKS ON THE CLINICAL VALUE OF EHRLICH'S METHODS OF EXAMINATION OF THE BLOOD. BY WILLIAM SYDNEY THAYER, M.D., Resident Physician to the Johns Hopkins Hospital, Baltimore. Von Jacksch, in an excellent address delivered at Franzensbad in May, 189 0,1 speaks particularly of practical methods of examination of the blood. He lays stress on the value of the microscopical examination of the fresh blood, a point of considerable importance, which is very often overlooked. He says later: "The microscope, the counting of the cells, the estimation of the haemoglobin are the methods which are feasible to the modern practising physician. Other methods of examination of the blood, which have given valuable results, cannot be used in all cases by the practitioner on account of their inconvenience. Thus the methods of blood-staining practised by Ehrlich2 possess cer- tainly great value, but their employment is too com- plicated." I mean to speak to-night mainly of just these methods of preparing and examining dried specimens of blood, for which we are chiefly indebted to Ehrlich; for I feel, in opposition to Von Jacksch, that they are in many ways the most valuable and easily applied methods open to the practising physician. Upon other more familiar, and perhaps not less useful, methods, such as the counting of the individual elements and the 1 Prager. Med. Woch., 1890, Nos. 31 -33. 2 Ehrlich: Verhand, der Berlin. Physiolog. Gesell., 1878-9, Nos. 8 and 20 ; Zeitschrift f. Klin. Med., i, 1880; Berlin. Klin. Woch., 1880, No. 28; Ibid., 1881, No. 3; Deutsch. Med. Woch., 1883, No. 46; Charite Annalen, xii, jahrg.; Ibid., xiii, jahrg.; Farbenanalytische Untersuchungen z. Histologie u. Klinik des Blutes ; Verhand, des xit Congres. f. Innere Medicin, 1892; Westphal, Diss., Berlin, 1880; Schwartze, Diss., Berlin, 1880 ; Spilling, Diss., Berlin, 1880 ; Einhorn, Diss., Berlin, 1884 ; Uthemann, Diss., Berlin, 1887. 2 estimation of the haemoglobin, I shall speak only in- cidentally. The enormous multiplication in late years of methods of examining and studying the vari- ous morphological elements of the blood can be seen by a glance at the article of Mueller in the Centralblatt fur Allgemeine Pathologic und Pathologische Anatomic for the 31st of October and the 18th of November, 1892, where there are nearly five pages of references alone. Many of these methods, valuable as they may be, are not practicable to the ordinary practitioner; and I wish particularly to show in what ways the ex- amination of dried specimens may be of real value in every-day work. The methods of examining cover-glass specimens of blood were introduced by Ehrlich in 1878 and 1879. Following the methods which Koch and others used in staining preparations of bacteria, he found that when an extremely thin layer of blood was spread out upon the cover-glass and allowed to dry immediately, the shape and general characteristics of the blood corpus- cles were preserved as well, if not better, than by any known methods. In preparing such a specimen, how- ever, one must exercise considerable care. The slight- est moisture from the fingers may be alone sufficient to spoil the specimen of blood. Any impurity on the cover-glass will bring about the same result; therefore the greatest care should be taken in the preparation of the glass; it should be washed in alcohol immediately before use. If this precaution is literally carried out much of the difficulty in making a preparation of blood is already overcome. The cover-glasses should not be handled by the fingers; it is best to use two pairs of forceps, which have the blades filed down to almost a knife edge; one may be a clamp forceps, and the other may be an ordinary dressing forceps, the blades of which have been filed down in order that they may not break the thin cover-glasses. After the cover- glasses have been carefully wiped, so that no visible 3 particle of dust lies upon them, one of them is touched to the drop of blood flowing from the finger-tip or the lobe of the ear,8 and allowed to fall immediately upon the other. If the glasses are clean, the drop of blood spreads out instantly, and the upper glass is drawn off the lower one, care being taken not to change its plane. The thin layer of blood on each glass will then dry almost immediately, particularly if it is held for a moment above a flame, so as to be very slightly heated. Particular stress is laid upon this instantane- ous drying by Uskow,4 who is able by this method to preserve the most minute chromatin network in the nuclei. Well-prepared specimens of this sort show'the red corpuscles lying side by side in the field of vision with their natural shape, free from any crenation or other changes which one may observe so soon in the fresh specimen. The presence of crenated corpuscles is a sure sign that the preparation has not been properly made, and that it is unreliable. The specimens thus dried may be kept for almost any length of time. They are, of course, more satisfactory if examined im- mediately ; but I have stained perfectly clear specimens which were three or four years old. It is well to wash the finger or the ear in alcohol and ether before taking blood, but it may be just as satisfactory to wipe away the first several drops of blood, thus washing the part, as it were, in the blood itself. Before examining the specimens, however, further steps must be taken to "fix" the various elements, particularly the red corpuscles, that the haemoglobin, which is easily soluble in water, may not be dissolved 3 It is best to use a sharp lancet; its application is much less pain- ful than that of a needle, while much more blood flows from a small stab. I prefer to take the blood from the lobe of the ear ; the part is much less sensitive than the flnger-tip. If a sharp knife or lancet is used, the small cut necessary may be scarcely felt by the patient. The situation of the ear, moreover, is such that the instrument may often be concealed from the patient, a point of considerable impor- tance in nervous individuals and young children, ' The Blood as a Tissue. St. Petersburg, 1890 (Russian). 4 and washed away on applying the stain. This result may be accomplished in several ways. To go into a thorough analysis of the different methods would more than occupy my whole time, and I will merely mention one or two of the most simple and reliable methods. A very satisfactory method is to drop the cover- glass into a solution of absolute alcohol and ether of equal parts (Nikiforoff's method). In a half-hour the specimen will be ready to stain. For quick work a shorter time may suffice. Absolute alcohol alone for ten to thirty minutes will give fairly good results. Ehrlich first recommended the use of heat in fixing a specimen of blood, a method which is probably, upon the whole, the most satisfactory of all. He advises the use of a copper plate (mine is about 40xl0x £ centimetres), which is placed over a flame, burning at a fixed height. By finding the boiling point (by adding drops of water), 100° C. may be easily deter- mined. The specimens are placed with the face up upon the plate, about three centimetres inside the boiling point, a temperature of between 100° to 120°, and may be left there for a varying time, according to the solu- tion with which the specimen is to be stained. For watery neutral solutions a short time suffices; very acid solutions and those containing glycerine call for a longer heating of the specimen. Ordinary specimens may be heated from one to two hours, though for quick clinical work a much shorter time often suffices. The specimen is now prepared for staining. Before speaking more exactly of the methods of staining, I want to speak first of the theory on which Ehrlich proceeded in his work. He was first led into applying his method of contrast staining or " color analysis," as he calls it, in the study of the leucocytes. Max Schultze 5 was the first to direct attention to the B Archiv. fiir Mikroskopische Anatomie, Bd. 1, p. 9. 5 fact that the leucocyte is not a morphological unity ; and Ehrlich in studying these elements discovered that the granules which they contained, which many had noticed, and Max Schultze in particular, had described, might be divided into classes having affinities for cer- tain distinct chemical classes of coloring matters. He found that between these various granulations there existed constant differences: (1) in their relation to dissolving substances - water, acids, alcohol, glycer- ine, etc.; (2) in their size, form and degree of refrac- tion ; (3) in the way they are influenced by high tem- peratures; (4) in their distribution in the cell body. He believes that these granules originate in the cell, and are products of a specific secretory property of the protoplasm. He has called them the " specific granu- lations of the blood." These granules he has classified mainly according to their affinity for the aniline color- ing matters. He divides the aniline colors into two groups: (1) the acid coloring matters, and (2) the basic coloring matters. The acid coloring matters are those in which the staining principle is an acid ; for instance, picrate of ammonium, where the staining principle is the picric acid. Some of the more important acid colors are eosin, martius yellow, the salts of picric acid, aurantia, indulin, nigrosin, tropseolin 0. O., Bordeaux, ponceau, and acid fuchsin. The basic coloring matters are those in which the staining principle is a base, where the acid is an indif- ferent substance as regards the staining; for instance, fuchsin, Bismarck brown, safranin, methylene blue, methyl violet, methyl green, etc.6 Ehrlich, as was said above, has differentiated various distinct classes of granules - seven in all. Of these, however, three only are of practical importance in human blood, and only two, indeed, have any great 6 For a more minute classification see Hueppe, "Die Methoden der Bakterien Forschung." 6 value. In the first place Ehrlich found, in certain leucocytes in human blood, large granules of a round or ovoid shape, having in the fresh state a peculiar yellowish-green refractive appearance, suggesting fat (the coarsely granular leucocytes of Schultze). These granules had a particular affinity for the acid coloring matters; they were stained by all members of this group, and by this group alone. Owing to their marked affinity for eosin, Ehrlich named these eosino- philic granules. Again he found a class of granulation which was stained by basic coloring matters alone. This baso- philic granulation occurs in a very small proportion of the leucocytes in normal blood, and is as yet of little practical value in blood examination. The cells con- taining these granules were first called in German " Mastzellen," a name which they have retained in other languages. This granulation is more common in cer- tain connective-tissue cells in the fixed tissues than in the blood. Here the granules have been not infre- quently mistaken for micro-organisms. The basophilic granules of the blood are of an equal size. They are less refractive than the eosinophilic granules, and in the dried specimens they are usually seen surrounding the central clear nucleus in the shape of a ring. They rarely have the morula appearance that the eosino- philic cells often show. The third granulation, which is by far the common- est one in the human blood, is one which is stained neither by acid nor by basic coloring matters alone, but only by a fluid which contains a mixture of an acid and a basic coloring matter together, the acid color being in excess. This granulation Ehrlich calls neutrophilic. The neutrophilic granules are smaller and more irregularly shaped than either the eosino- philic or basophilic granules. They occur in about three-fourths of the leucocytes in normal blood. 7 METHODS OF STAINING. It will be worth while here to mention only a few of the staining methods which have seemed to me most practical; of other methods a full summary may be found in Mueller's article before referred to. The basic colors generally stain the nuclei. The best examples of these are perhaps methylene blue and ordinary basic fuchsin. Either employed alone stains the nuclei beautifully, and also any bacteria or pro- tozoa which may be present in the blood. For in- stance, in staining malarial organisms I have found a simple aqueous solution of methylene blue as satis- factory a stain as any. The basophilic granules (mastzellen) are also stained by this class of coloring matters. The acid colors stain the red corpuscles and the eosinophilic granules. A very convenient stain for practical use is as fol- lows : Eosin 0.5 Alcohol (70%) 100.0 The prepared cover-glass should be stained for a few minutes in this solution (which has been diluted one- half with water), washed with water, dried in the air or between filter paper, and stained for three-quarters of a minute in a saturated aqueous solution of methy- lene blue, which should be diluted one-half with water before using. By this method the red corpuscles are stained red, the nuclei blue, the eosinophilic granules a brilliant red. and any bacteria or protozoa blue. An- other solution which gives satisfactory results is that of Czinzinski: Methylene blue, concentrated aqueous solution . 40 One-half per cent, solution of eosin in 70% alcohol 20 Distilled water 40 The covers may be fixed in absolute alcohol from five minutes to half an hour, and stained from three to 8 six hours in the thermostat at 37° C. This method is particularly recommended by Canon 7 for showing the eosinophilic cells and the mastzellen; it has also been used by the same author to demonstrate the bacilli of influenza in the blood. To bring out the neutrophilic granules the best solu- tion is that recommended by Ehrlich, the mixture of acid fuchsin, methyl green and orange G.; it brings out most of the more important points in the blood. This stain is perhaps the most convenient for every- day use, while it has formed the basis for the most valuable classifications of the leucocytes which have been made. The methods of preparation are very numerous (see Mueller's article). Ehrlich advises the following mixture:8 Saturated aqueous solution orange G 125 Saturated solution (in 20 % alcohol) of acid fuchsin 125 Alcohol, abs. 75 Saturated aqueous solution methyl green . . 125 The methyl green must be added drop by drop while stirring or shaking the solution. The solution must stand some weeks, and the fluid to be used should be taken with a pipette from the middle of the solution. Later Ehrlich advises a different procedure: Saturated aqueous solution orange G . . 120-135 " " " acid fuchsin . . 80-165 " " " methylene green . 125 Water 300 Absolute alcohol ....... 200 Glycerine 100 A satisfactory solution may be prepared as follows : Saturated aqueous solution of acid fuchsin . . 2 Water 3 7 Deutsche Med. Woch., 1892, No. 10. 8 There is, unfortunately, a considerable difference between dif- ferent preparations of these aniline colors and it is always well to determine the source of the materials one uses. I use generally the colors from the Berliner Gesellschaft fur Anilin Fabrikation, which can be obtained from G. Kbnig, Dorotheen Str. 28, Berlin, N. W. Griibler's colors are also reliable. 9 Saturated aqueous solution of orange G . 6.25 Saturated aqueous solution of methyl green . . 6 To be added drop by drop, while shaking the solu ion. Water 15 Alcohol 10 Glycerine 5 The cover-glass which has been heated for from five minutes to two hours at a temperature of 100°-120° C., or has been hardened in alcohol and ether, is stained in this solution for from two to five minutes, washed in water, and dried in the air, or, if the speci- men has been heated for an hour or more, between filter paper and mounted in oil or balsam. Specimens heated one to two hours9 stain better than those which have been heated a short time, but perfectly satisfac- tory results for ordinary work may be obtained with specimens heated from five to ten minutes. With this stain the red corpuscles are stained an orange or buff color, the nuclei of the colorless cor- puscles green, the neutrophilic granules a violet or lilac color, the eosinophilic granules a deep red. The nuclei of nucleated red corpuscles, when present, are stained an intensely deep green, almost black. With a little practice the differentiation of the eosinophilic and neutrophilic granules is generally easy. Ry the employment of various staining reagents - I say reagents because the staining of these granules is a distinct micro-chemical reaction - Ehrlich differenti- ated the following varieties of leucocytes in normal human blood: 19 (1) Lymphocytes, small cells about the size of a red corpuscle, the body of which is filled with a large, round, intensely staining nucleus, while the proto- plasm is reduced to a small border surrounding the nucleus. 9 In some cases of pernicious anaemia the specimen should be placed at boiling point or even outside of it and must not be heated longer than one hour. 10 For careful study of the blood, lenses of high power must be used. The Zeiss 1-12 oil immersion lens, the Leitz 1-12 or the Winkel 1-14, are all satisfactory. 10 (2) Voluminous cells, which have a relatively large oval, or ovoid, faintly staining nucleus, and a rela- tively extensively developed protoplasm. (3) Structures of a similar character, which are distinguished from the former only in that the nucleus has certain indentations which often give it the shape of a wallet. (4) Very numerous, somewhat smaller bodies, which are characterized particularly by the polymorphous shape of the nucleus. This nucleus, Ehrlich says, may, under the influence of reagents, break into sev- eral separate fragments ; hence the perhaps not entirely fitting name " polynuclear." The protoplasm of these cells is filled with fine neutrophilic granules. (5) Eosinophilic leucocytes; cells of about the same size as the latter variety, with a single, round, ovoid or polymorphous nucleus, while the protoplasm is filled with eosinophilic granules. The origin of the lymphocytes, Ehrlich traces to the lymphatic tissues of the body. The large mononuclear elements come apparently from both the bone marrow and the spleen, changing in the blood-current into the polynuclear neutrophilic elements. The eosinophilic leucocytes arise in all probability in the bone marrow. Uskow 11 has recently studied the colorless corpuscles by the method of contrast-staining with great care, and has made a more minute classification. He di- vides the corpuscles into : A. Lymphocytes: the smallest form of corpuscle, consisting of a round nucleus (sometimes having an in- dentation) surrounded by a thin rim of protoplasm. The protoplasm in the preparation is often separated from the nucleus by a bright, sharp ring. Both proto- plasm and nucleus are stained intensely. These he divides into: (1) Small lymphocytes, which are the size of red corpuscles, or smaller. ii The Blood as a Tissue. St. Petersburg, 1890, (Russian). 11 (2) Large lymphocytes, which are somewhat larger, in which the protoplasmic ring about the nucleus is slightly larger and more irregular, sometimes show- ing rounded projections. B. Transparent corpuscles : these are distinguished by their richness in protoplasm, which takes no stain whatever, and looks like a vacuum in the faintly stained field of the preparation. The nucleus is homogeneous, round, oval or bean shaped, and lies usually excentrically ; it stains more feebly than the nucleus of the lymphocytes. He divides them into: (3) Small transparent corpuscles, which are about the size of large lymphocytes; these have often a somewhat squarish shape, with sharply-rounded cor- ners. (4) Large transparent corpuscles, which are three to five times the size of the red corpuscles. The nucleus in the preparation is almost always excentric. (5) Giant transparent corpuscles. These are the largest white corpuscles seen in the blood. They have often one or two deep indentations in the nucleus. C. Transitional forms: corpuscles with proto- plasm which stands about midway between that of the lymphocytesand that of the transparent corpuscles in its affinity for coloring matters. The smallest are slightly larger than lymphocytes, and the largest are almost as large as large transparent forms. The nucleus stains more intensely than the protoplasm, and has almost no light rim about its periphery. These he divides into : (6) Small transitional forms (giant lymphocytes) which are like small transparent forms with a slight staining of the protoplasm. (7) Large transitional forms. (8) Giant transitional forms. These last two forms correspond in every respect to the transparent leu- cocytes, excepting in their slight ability to take stain. D. (9) " Multinuclear " neutrophilic leucocytes. 12 These are two or three times as large as red blood corpuscles and are easily distinguished by the deeply- staining irregularly-shaped nucleus. The protoplasm is relatively of considerable extent, as compared with the size of the nucleus. It takes little stain itself, but is filled with small neutrophilic granules. These he divides into : (a) Those with a thick, rod-like nucleus, which takes a comparatively light stain, while the neutro- philic granules also are less intensely stained than in those with the more irregular nuclei. These, Uskow thinks, are transitional forms between the mononuclear leucocytes and the forms with more markedly poly- morphous nuclei. (b) The leucocytes with a single rod-like nucleus which is bent and twisted upon itself, being rounded at both ends. (c) The apparently multinuclear leucocytes. Here the nucleus is not really divided, but all the pieces are united by small filaments. They are larger than the other kinds of neutrophilic cells. These neutrophilic cells are of various sizes, from but little above the size of a red corpuscle, to nearly that of the larger transitional forms. The fact that one at times finds very small neutrophilic elements, Uskow suggests may be due to the fact that the change to multinuclear may occur from transition forms before these have reached the giant size, though this, he believes, is not the rule. He describes also multinuclear leucocytes with vac- uoles. (10) Eosinophilic leucocytes. Uskow believes that the lymphocytes arise from the lymphatic tissues of the body, the large lymphocytes arising mainly from the follicles of the spleen, the smaller from the lymphatic glands. In the bone-mar- row, one finds on cover-glass specimens, or on sec- tion, scarcely any lymphocytes, but mainly trans- parent and transitional forms, which are also found in 13 the spleen. In the bone-marrow the transparent forms are in excess, in the spleen the transitional forms. The small transparent forms are found particularly in the marrow. The multinuclear leucocytes may be found in cover-glass specimens from the spleen, marrow and glands, more markedly in the spleen and marrow than in the glands. But on section, Uskow finds multi- nuclear forms only in the blood-vessels. In the living rabbit, pieces of marrow, spleen, mediastinal glands, and also a piece of the portal vein, which was included between two ligatures, were placed in Fleming's solu- tion, cut and stained; and nowhere, excepting in the blood, were found multinuclear leucocytes. Hence Uskow concludes that either in the blood or in the tissues, the multinuclear forms arise from the mono- nuclear. They arise probably, he thinks, from the large transitional corpuscles. The smaller size of the multinuclear elements may, he believes, be due to the condensation of the nucleus. In other words, Uskow believes that the small and large lymphocytes and the small transparent leucocytes are the youngest elements in the blood. They, by their growth in protoplasmic richness, their diminution in affinity for coloring mat- ters on the one hand, and their increase in affinity for coloring matters on the other hand, merge into a com- mon, indistinguishable variety, the transitional forms, changing in their further progress into the multi- nuclear neutrophilic cells. This, he considers the last stage of development, and the multinuclear neutro- philic leucocyte he traces through various degenera- tive processes to its final dissolution. Uskow thus classifies the leucocytes: (a) Young elements. (1) Small transparent leucocytes. (2) Small lymphocytes. (3) Large lymphocytes. (6) Ripe elements. (4) Small transitional leucocytes. 14 (5) Large transitional leucocytes. (6) Giant transitional leucocytes. (7) Large transparent leucocytes. (8) Giant transparent leucocytes. (c) Over-ripe elements. (9) Multinuclear leucocytes. (10) Eosinophilic leucocytes. This classification seems rational. A careful study of the blood with the triple stain cannot fail to im- press one with its objective accuracy. Tschistowitsch 12 divides the leucocytes into the fol- lowing classes : (a) Young elements, after Uskow. (1) Small lymphocytes. (2) Large lymphocytes. (3) Small mononuclear leucocytes. Here he in- cludes leucocytes of the size of a large lymphocyte or somewhat larger, with around or ovoid nucleus, which stains more feebly than in the lymphocytes, and with a more developed protoplasm, which stains either very feebly (the small transitional forms of Uskow) or not at all (the small transparent forms of Uskow). (b) Ripe elements which differ from the small mononuclear leucocytes only by their greater dimen- sions. (4) Large mononuclear leucocytes. (5) Mononuclear leucocytes with an indentation in the nucleus. They are distinguished from large mononuclear leucocytes only by the indented form of the nucleus. In this group he includes also those rather unusual multinuclear leucocytes without a trace of granulation, with an uncolored or a very slightly staining protoplasm. These latter, he thinks, are probably a transitional form between those with a single indented nucleus and the multinuclear neutrophiles (?). (c) Over-ripe leucocytes, after Uskow. (6) Multinuclear neutrophilic leucocytes. 12 Berlin. Klin. Woch., 1891, No. 34. 15 (7) Eosinophilic leucocytes. This division differs from the last which was advised by Uskow only in that he places the small transparent leucocytes and the small mononuclear leucocytes with but slightly stained protoplasm in the same group, because he could distinguish no essential difference between these two. These various elements exist in normal blood in certain fairly definite proportions one to another. If we make a differential count according to Ehrlich's classification, we find : lymphocytes, 15 to 25 per cent.; mononuclear and transparent forms, about 6 per cent.; polynuclear, 70 to 75 per cent. ; eosinophiles, 1 to 5 per cent. Taking Uskow's estimates that in a healthy man there should be about 18 per cent, of the young, 6 per cent, of the ripe, and 75 per cent, of the over-ripe elements, we see that in Uskow's more minute clas- sification the class of young elements corresponds fairly accurately to the lymphocytes in the classifica- tion of Ehrlich and his students; the class of ripe elements to the large mononuclear and transitional forms; and the class of the over-ripe elements to the neutrophiles and eosinophiles. For minute, accurate work the classification of Uskow seems to be unquestionably the best that has yet been made. The modification of Tschistowitsch, in which he includes under the small mononuclear the small transparent forms and the small transitional forms, and classes the other elements as large mononuclear, with- out distinction, is perhaps more simple and nearly as satisfactory. In ordinary clinical work, however, one can expect to do little more than to count the divi- sions into: (1) Small mononuclear leucocytes, including the small and large lymphocytes, the small transparent forms, and possibly some of the small transitional forms of Uskow. 16 (2) Large mononuclear and transitional (indented) forms. (3) The multinuclear neutrophiles. (4) The eosinophiles. Most of the counts which I have made in my own work, before I was familiar with Uskow's classification, have been on this basis, and have included under lymphocytes or small mononuclear elements almost exactly those elements which Uskow and Tschistowitsch have included under their young elements ; and under the large mononuclear and transitional leucocytes just those forms which they have included under his ripe elements. There is one point in these classifications with regard to which there will always be some differences, depending on the individual who makes the estimations ; that is, the point where the small mononuclear elements end and the large begin. Now what practical information can we gain from the study of dried specimens 2 (I) The red corpuscles. The skilled observer can readily detect a diminution in number by the behavior of the drop of blood, and the thickness of the corpuscles on the slide (if he prepare the specimen himself). A marked deficiency in color may be detected by the in- creased pallor of the middle of the corpuscles ; that is, the point of greatest biconcavity is much more marked than in normal blood. Different stains, of course, give different appearances, but one who is familiar with the stain he is using can readily detect these points. Any difference in size or shape (poikilocytosis) of the corpuscles is readily observed. Nucleated red corpuscles are particularly well seen ; there is no method by which they are so readily brought out. Two varieties of these elements are seen in the human blood: (a) In all acute anaemias of any intensity, and in 17 almost all of the more chronic secondary anaemias, as well as in the so-called essential blood diseases, one finds bodies about as large as an ordinary corpuscle, containing a small, round, intensely staining nucleus, which has a peculiar refraction. This nucleus may be seen in the middle of the corpuscle, towards its edge, protruding from the corpuscle, or again free in the blood current, suggesting very strongly that this is probably the normal manner in which the red corpuscle parts with the nucleus which belongs to it in its youngest stages. (J) In some grave anaemias, particularly in pro- gressive pernicious anaemia, and the leukaemias, one finds elements much larger than these, containing large, much more palely staining nuclei, the body of the cell taking a stain similar to that of the ordinary red corpuscle. With the proper technique a well-marked nuclear network may be made out in these cells while the nuclei of the smaller variety show only a dif- fuse stain. Karyokinetic figures may often be found in the nuclei of these large elements, particularly in some forms of leukaemia. At times one finds these large nucleated red corpuscles where the nucleus has the same intense stain that it takes in the younger forms, but where it is apparently breaking up or is represented only by several small fragments. The process of extrusion of the nucleus in these large forms is more rarely observed. This has led Ehrlich to believe that what he considers the normal process of parting with the nucleus (extrusion) does not take place in some of the more grave anaemias, but that the nucleus becomes fragmented, and absorbed, as it were by the cell itself. Ehrlich, with Rindfleisch, is of the opinion that in the normal process of blood regeneration the extruded nucleus develops about itself a second corpuscle, and, being extruded again, the same process may go on for a considerable time. If one accepts this idea, which is certainly rather hard to believe, it 18 s easy to conceive that the process of absorption of the nucleus would represent a much less satisfactory and active method of blood regeneration. The smaller variety, that is to say, the normal variety of nucleated red corpuscles EhrlMi calls normoblasts the larger, megaloblasts or gigantoblasts. The fact that one observes in some of these large nucleated red corpuscles, particularly in some leukaemias, unques- tioned signs of karyokinesis is, it seems to me, reason- ably good evidence that they are not all, to say the least, degenerate forms, but perhaps in some instances earlier forms of red corpuscles than one ordinarily sees in the blood. In an anaemia of any particular degree one may also observe red corpuscles which take up, in addition to the acid coloring matters, a certain amount of basic stains, that is, which show, with the eosin-methy- lene blue stain, a bluish-purple color, while others show throughout their substance small spots and indica- tions of a network of bluish stain. These forms Ehrlich considers degenerative. He believes that the process taking place within them is akin to co- agulative necrosis. Gabritschewski18 is inclined to believe that these elements are rather young than de- generate forms, from the fact that he has found certain nucleated red corpuscles which show this same charac- teristic stain. Ehrlich, however, remarks that this is only true of the nucleated red corpuscles of the second class, the gigantoblasts, particularly those in which the nucleus is fragmented. He asserts, moreover, that corpuscles with affinity for basic stains may be found in the blood of acute anaemias before regenerative forms appear, while they are found in considerable numbers in the blood of starving animals where there is no sign of regeneration. They are clinically, of course, found in association with what we consider regenera- 13 Archiv. f. Experimeutelle Pathologic u. Pharmak, 28 B ; 1, 2, H ; p.83. 19 five forms (nucleated red corpuscles). Ehrlich well speaks of " Der haupt Charaktere des aummischen Blutes, das Ineinandergreifen von degenerations und regenerations Formen." (II) The colorless corpuscles. With stained speci- mens information can readily be gained with regard to the number and the varieties of the colorless ele- ments. There is no method by which so careful a differential analysis can be made. The occurrence of a leucocytosis can be made out almost as satisfactorily by the practised eye as by counting the corpuscles. Under the term leucocytosis I shall understand, in the sense of Ehrlich, an increase in the total number of leucocytes where the differential count shows only a marked increase in the percentage of the multinuclear neutrophiles at the expense of the small mononuclear leucocytes. In considering now briefly the main diagnostic points which may be obtained from a morphological examin- ation of the elements of the blood, let us first take up the so-called diseases of the blood itself. Ehrlich, in his address last April before the Eleventh Congress for Internal Medicine, says : " With diseases of the blood, in contrast to most other affections, we find ourselves in a favorable position in that we are able to obtain during life, and not for the first time post-mortem, satisfactory information concerning the nature of the changes taking place." Here, perhaps, the examination of the blood is of the most positive ad- vantage, but as I shall try to show later, there are many other conditions where it may be of considerable help. First, then, let us consider schematically the charac- teristics of the various types of anaemias, noting how much may be determined from an examination of the dried specimens alone. Before taking up the essential anaemias it may be well to consider the general features common to most secondary anaemias. 20 Secondary Anaemias. Oligocythaemia. Oligochromaemia. (The relative loss in haemoglo- bin being considerably greater than in corpuscles.) Variations in size of the red elements with perhaps slight average diminution in diameter. Poikilocytosis. Pallor of the individual elements, that is, the point of greatest biconcavity more marked than normally. Degenerative forms. Nucleated red corpuscles (normoblasts). Leucocytes. There is a leucocytosis in acute cases. In old chronic seconcyiry anaemias the leucocytes may be about normal or even sub-uormal in number, and in these cases where the course is much less favorable,. nucleated red corpuscles are not nearly as numerous, and an occasional megaloblast may be seen. The fol- lowing case is a good example of a secondary anaemia. D. Grave Secondary Anaemia following repeated Venesections (practised by the patient herself). Red corpuscles 1,775,000 Colorless corpuscles 10,500 Haemoglobin 19% Specimens of blood stained with the triple stain showed: considerable difference in the size of the cor- puscles ; moderate poikilocytosis. Three typical nor- moblasts seen while making a differential count of over one thousand leucocytes. Differential count: Small mononuclear 10-+% Large mononuclear L5% Transitional forms 1.1% Multinuclear neutrophiles . . . . 85.-|-% Eosinophiles 2.1% It is easy to see that many of the most important points are to be obtained here from the examination of a dried specimen ; only the actual count of the ele- ments is lost. 21 Primary Pernicious Ancemia. Oligocythaemia (more marked than in any other known condition). Oligochromaemia, which is absolute but not relative : the relative proportion of haemoglobin being higher than the number of corpuscles (a most characteristic point). Great variation in the size of the elements with probably an average increase in size. Poikilocytosis (marked). Degenerative forms. Nucleated red corpuscles in varying numbers, a most characteristic point being the presence of a distinct pro- portion of megaloblasts which, when present in a con- siderable proportion are almost diagnostic. Megalo- blasts are to be found, as has been said above, in other " essential blood diseases," and sometimes in grave secondary anaemias. As Ehrlich has pointed out, an occasional megaloblast with a considerable number of normoblasts is a point of relatively little significance, while the presence of a small number of nucleated red corpuscles consisting largely of megaloblasts would be a grave sign. Nowhere does one see so large a pro- portion of megaloblasts as in pernicious anaemia, and nowhere are such typical large forms found. Leucocytes: usually diminished in number, showing a relative increase in the small mononuclear elements (lymphocytes, small transparent forms), while the multinuclear elements are relatively diminished, some- times being under 50 per cent. The number of eosinophiles varies. The following case is an example of this : The blood was from a case of pernicious anaemia with between one and two millions of red corpuscles in the cubic millimetre and a small number of leucocytes : Small mononuclear 38.4% Large mononuclear and transition forms . . 3.8% Multinuclear neutrophiles 54.3% Eosinophiles 3.1% 22 Here the difference between the relative proportion of red corpuscles and haemoglobin is an important di- agnostic point, but with the presence of the marked poikilocytosis and megaloblasts, and in severe cases the changes in the relative percentage of the colorless cor- puscles, the diagnosis may be made with more cer- tainty from a dried specimen than by the blood-counter. That there are grave and even fatal anaemias which do not fall under this heading, which show deviations from this type of blood, is undoubted. Some of the anaemias associated with an enlarged spleen (" splenic anaemia,") as well as some of the anaemias with Hodg- kin's disease do not fall into this class. The great majority, however, of the cases which have been classed clinically as progressive pernicious anaemia show this type of blood; and in this brief summary we can only mention those definite types that have been so far made out. Chlorosis. Oligocythaemia (variable, usually moderate). In 64 cases in which I counted the blood and estimated the haemoglobin, the average number of red corpuscles was 4,096,544, while the average per cent, of haemoglobin was only 43.3 per cent. Oligochromaemia (relatively very great). Difference in size of the corpuscles with possibly a slight average diminution in the size in severe cases. Poikilocytosis, considerable in severe cases. Pallor of the individual elements. Degenerative forms. Nucleated red corpuscles in severe cases where there is marked oligocythaemia. Leucocytes. There is little if any increase in leu- cocytes. In my 64 cases the average number of leu- cocytes was 8,467, a very slight increase. Thus it may be seen that while the morphological characteris- tics of the blood in chlorosis are nearly the same as in secondary anaemia, the essential characteristic, that of 23 the great relative diminution in haemoglobin, cannot be entirely denied, as v. Limbeck 14 has attempted to do. The so called "simple anaemias," in my experience, show generally the same characteristics as the second- ary anaemias. This class, as a matter of fact, simply includes those anaemias for which we can find no cause, and which do not fall into the definite class of primary pernicious anaemia. They are probably usually exam- ples of chronic secondary anaemia. Leukaemia is generally met with in two forms: (I) Spleno-Myelogenous Leukaemia. The blood shows quite distinct characteristics. Oligocythaemia, rarely under 2,000,000. Oligochromaemia, relatively considerable. Difference in size of the corpuscles with possibly a slight diminution in the average size. Poikilocytosis, marked in severe cases. Degenerative forms. Nucleated red corpuscles : generally more numerous than in any other condition of the blood. Both nor- moblasts and megaloblasts may be found - numerous large elements in the process of division are not un- common. Leucocytes: generally increased in number more than under any other circumstances, while in their individ- ual characteristics and the relative proportion of the different varieties one to another they show marked deviations from the normal. (1) There is a very small relative proportion of the small mononuclear elements. (2) The polynuclear neutrophilic elements are nu- merous, but in actual proportion often diminished. Great variations in size may be noted. (3) The large mononuclear elements are very nu- merous, and among these are certain elements in which the protoplasm is filled with fine neutrophilic granules. Ehrlich has termed these elements - 14 Prager. Med. Woch., 1891, No. 10. I 24 (4) Myelocytes. These are found (in adults) bar- ring an occasional unimportant exception, only in this form of leukaemia; on examining the blood-forming organs they are to be found alone in the marrow (Ehr- lich), hence the name. There is also a number of large mononuclear elements with protoplasm staining deeply like lymphocytes. (5) The eosinophilic leucocytes are present in about a normal relative proportion, that is, are absolutely greatly increased. They, too, as in the case of the polynuclear neutrophiles, show the greatest variations in size. (Of certain amphophilic and basophilic leucocytes occurring in leukaemic blood it is not worth while to speak in this brief summary. Their practical diagnos- tic importance is not yet great.) The proportion of these elements in an average case of leukaemia may be shown in the following count, from a case in Professor Osler's wards at the Johns Hopkins Hospital, in which the proportion of white to red corpuscles was as one to three. Small mononuclear leucocytes .... .96% Large mononuclear and transition forms . . 3.0% Multinuclear neutrophiles 70.0% Myelocytes 23.5% Eosinophiles 2.3% The diagnosis of this form of leukaemia depends then largely upon the histological examination of the blood. The most characteristic points are: (1) the presence of nucleated red corpuscles; (2) the relative diminution in the small mononuclear elements; (3) the great difference in size in the multinuclear ele- ments ; (4) the presence of myelocytes; and (5) the presence of a normal proportion of eosinophiles in so extensive an increase of leucocytes. The presence of a nearly normal percentage of eosinophiles I still con- sider a point of some value in the diagnosis of this form of leukaemia. Many authors have, I think, 25 entirely misunderstood Ehrlich's original statements with regard to this point. He has, so far as I know, never asserted that the presence of eosinophilic cells in leukaemia was diagnostic ; and he has not, as so many have assumed, asserted that they were neces- sarily present in an increase relative proportion. Neither has he said that they are present in increased numbers in all forms of leukaemia. In twelve cases of typical spleno-myelogenous leukaemia, from which I have specimens of the blood, the presence of at least a normal percentage of eosinophiles has been in all a marked characteristic. (Il) Lymphatic Leukcemia. This form is much rarer. It is often the most acute and rapidly fatal of the so-called blood diseases. Here the oligocythaemia is often more marked than in the other forms, while the proportion of white to red elements is commonly not so great. Nucleated red corpuscles are rare, and when present are often megaloblasts. The colorless corpuscles here show a great increase in the small mononuclear elements. In a case, for the blood of which I am indebted to Dr. F. C. Shattuck, there were found: Small mononuclear elements (almost entirely lymphocytes) 97.9% Large mononuclear elements 0.4% Multinuclear ncutrophiles 1.4% Eosinophiles 0.1% That forms of leukaemia may occur where the blood does not answer to either of these types, is true, but they are probably uncommon. In 16 cases of leukaemia from which I have specimens of the blood, 12 corresponded exactly to the first type, three to the second ; while in one case, which occurred at the Johns Hopkins Hospital, where all the lymphatic glands, the spleen and the marrow were markedly affected, the proportion of white to red corpuscles being as one to twenty-five, the blood contained but six per cent, of multinuclear elements, 5.4 per cent, of myelocytes, one 26 per cent, of eosinophlies, the large mononuclear and small mononuclear leucocytes representing the rest of the elements, 87.6 per cent.; nucleated red corpuscles were scanty. (In this case karyokinetic figures were found in the nuclei of some large mononuclear leuco- cytes in the blood, and in a great number of similar elements in the bone marrow ; they were present, but less numerous, in the spleen, lymphatic glands, and lymphatic tissues generally. The case will be reported later.) Some other conditions in which the examination of the blood may be of value. All conditions associated with any inflammatory process, if it be of any extent, are accompanied by a leucocytosis; and, as has been before said, this leuco- cytosis in man consists generally in an increase in the relative proportion of the multinuclear neutrophiles, the increase being at the expense of the small mono- nuclear elements. Such conditions are abscess, phleg- mon. erysipelatous processes, acute tonsillitis, inflamma- tions of the serous membranes, pleurisy, peritonitis (appendicitis'), meningitis. This leucocytosis varies in extent in various conditions. It varies within certain limits, proportionally to the extent of the process. The following is an example of an excessive leucocy- tosis : K. Pneumonia, Acute Haemorrhagic Nephritis. Red corpuscles 5,094,000) Colorless corpuscles .... 114,7501 Differential count of the leucocytes : Small mononuclear 0.32% Large mononuclear * 1.12% Transitional forms 1.12% Multinuclear neutrophiles .... 97.44% GENERAL DISEASES. Tuberculosis. - In al) forms of tuberculosis there is usually a relatively slight anaemia. The anaemia of 27 tuberculosis is often more apparent than real. In the latest stages of pulmonary tuberculosis there may be a relatively high proportion of corpuscles and haemo- globin, while on superficial examination there would appear to be grave anaemia. Leucocytosis is present to a greater or less extent in almost all forms of tuber- culosis, particularly in chronic pulmonary tuberculosis. In acute general tuberculosis this is probably usually the case; and several counts by Uskow show that in his cases the increase was simply in the multinuclear elements with a relative diminution in small mono- nuclear elements alone. One case, which I have ob- served was, however, a marked exception to this rule, the colorless corpuscles being present in diminished number. Typhoid Fever.- Here the blood shows certain quite important changes. It has been shown by vari- ous authors that typhoid fever may be followed by a grave anaemia. In one case whiqji I observed in Pro- fessor Osler's clinic at the Johns Hopkins Hospital, this amounted to 1,300,000. The colorless corpuscles on the other hand, have been shown not only to be present in a not increased number, but actually during the height of the fever to be somewhat diminished, a fact of considerable importance from a diagnostic standpoint. This point has been verified by Dr. J. S. Billings, Jr. and myself in nearly 200 counts of the blood in typhoid fever. Furthermore, the careful analyses of the blood by Uskow 15 and Chetagurow 16 have shown that in patients suffering from typhoid fever (1) there is a sharp fall- ing off in the relative number of multinuclear elements, it may be under 50 per cent.; (2) this fall begins us- ually in the first week, is more sharply expressed in the second or third or even fourth weeks ; (3) the per- is Prager. Med. Woch., 1891, No. 10. >8 Pathologisch Anatomische Veranderungen des Blutes bei Ty- phus Abdominalis, Diss. St. Petersburg, 1891; cf. Vir. Archiv, Bd. 120, F. xii, B. vii, 187, 28 centage of " over-ripe " elements begins to increase about three to twelve days after the disappearance of the fever. Chetagurow finds that it does not reach the normal until the tenth or eleventh weeks. (4) The percentage of the small mononuclear elements average only one and a half times as much as that of the large mononuclear, instead of being normally three times as great. (5) The decrease in the number of the multi- nuclear elements depends not so much on the parallel increase in the percentage of the small mononuclear leucocytes as on the increase in the percentage of the large mononuclear cells. This point appears to be one of considerable importance, and on various occasions I have been able to make a probable diagnosis of typhoid fever when without the examination of the blood it would have been extremely difficult. In most of my counts in typhoid fever I have found the large mono- nuclear elements even more numerous than these authors. # Case : H. Typhoid Fever, 4th week: Small monunuclear 1S.1% Large mononuclear 22.4% Transitional forms 4 5% Multinuclear neutrophiles 53.1% Eosinophiles 1.9% The differential diagnosis thus between typhoid fever and tuberculosis in its various forms, or the various inflammatory conditions, and particularly pneumonia, of which we shall speak next, is made materially easier. Pneumonia. - That a leucocytosis of considerable extent occurs in pneumonia has long been known. The researches of Uskow,17 Kikodse,18 and others have led to interesting results. Kikodse's conclusions are as follows : (1) The number of white blood corpuscles in the blood of a patient with pneumonia exceeds the normal one, two, or three times. (2) In severe cases 17 Loc. cit. 18 Ceutralblatt f. allgem. Path. u. Path. Anat., Bd. ii, p. 109. 29 which threaten a fatal result, there is no leucocytosis to be observed.19 This is therefore of great prognostic importance. (3) The number of colorless blood cor- puscles increases largely through the increase in the multinuclear elements. (4) These changes in the blood appear at the beginning of the disease, and, indeed, be- fore very important changes have developed in the lungs, remaining without marked variation until the crisis. (5) The most constant change in the number of leucocytes is observed on the day before the crisis when there is an increase in the percentage of the multi- nuclear elements. (6) The development of the leuco- cytes, as also the increase in the number of multinuclear elements in the blood, takes place pari passu with the increase of the temperature. (7) The morphological elements of the blood during the fever of acute pneu- monia seem to be delayed in their progress towards final destruction. (8) At the time of the crisis in the temperature there is a crisis in the number of the white blood corpuscles, which fall sharply to normal and of- ten under normal, the percentage of multinuclear ele- ments becoming at the same time less. (9) On the day of the crisis the colorless corpuscles showa special tendency to degeneration. The most valuable point here shown is the fact that pneumonia is usually associated with an extensive leucocytosis, which is coincident with the fever. That in some fatal cases this leucocytosis has not been ob- served is of great interest, but of how much importance we cannot yet be sure. Among other diseases which are generally associated with a leucocytosis, in which, however, no other im- portant changes have been noticed, are diphtheria, acute rheumatism, endocarditis, and small-pox. In scarlet fever Kotschetkoff 20 found in an analysis of 20 cases, that there was a considerable anagmia com- 1B This though observed in some cases, is probably not always true. 20 CentralbJatt f. alJgemeine. Path, und Path. Anat., 1892, No. 11. 30 ingon gradually, and that there was an extensive leuco- cytosis : in several fatal cases, over 30,000. This leu- cocytosis appeared from two to three days before the eruption, and reached its maximum two or three days after its disappearance, where it remained for several days to fall gradually. The percentage of the polynu- clear elements with the eosinophiles was at all times markedly increased, in some cases as high as 98%. All the cases which he observed, with over 95% of " over-ripe " elements died. A leucocytosis of over 30,- 000 was a grave symptom. The behavior of the eosinophilic cells was particularly typical. In mild cases the number of eosinophilic cells was normal or even sub-normal in the beginning. From the second or third day it gradually increased until it reached its maximum (eight to fifteen per cent.) in the second or thir^ week of the disease. It then gradually sank until it reached its normal point about the sixth week. In severe cases the opposite took place, namely, the number of eosinophiles fell rapidly and disappeared perhaps in two or three days. The percentage of the small mononuclear elements fell in the first part of the disease to two or three per cent., and gradually re- turned to normal. The percentage of the large mono- nuclear elements showed nothing characteristic. These variations in percentage were so typical that the author believes that a prognosis may be based on their course. New Growths.- In some rapidly growing tumors a considerable leucocytosis has been noticed. In almost all neoplasms at an advanced stage there is a considerable degree of anaemia; the blood show- ing the changes typical of a secondary anaemia. In some cases of obscure abdominal trouble the evidences of a grave secondary anaemia may be of considerable value in differential diagnosis, particularly between tuberculosis, where the anaemia is usually slight, and carcinoma, where it is generally severe. Parasites and Bacteria.- It is hardly within the 31 scope of these remarks to enter into particulars con- cerning the various organisms which may be found in the blood. Suffice it to say, that most of the basic stains will demonstrate bacteria or the malarial para- site. For the malarial organism the various combina- tions of eosin and methylene blue give particularly good results, though the examination of fresh, unstained specimens is, I think, more satisfactory. Returning then in conclusion to the original theme, the value of these methods of contrast staining, we may, I think, justly assert that, in the first place, the red corpuscles may be in almost all respects as satis- factorily studied as in the fresh specimen. Degenera- tive (?) and regenerative forms, which are difficult or impossible to demonstrate by other methods, are here easily studied. The leucocytes we have been enabled to analyze and classify in a manner heretofore impossible. Well-prepared specimens can, as Mueller 21 says, be subjected to every method of examination that has been applied to microtome sections. By the practis- ing physician the blood-counter and the hasmometer are not easily carried about and applied at the bed- side ; a fresh specimen often spoils before one reaches the office; it is, however, easy to carry two small for- cipes, a few cover-glasses, and a small vial of alcohol in the pocket, and a dried specimen once made can be examined at leisure. The classification of leucocytes may at first seem complicated, but a little study soon clears it up. That one cannot become familiar with such methods in a day or in a week is true, but few valuable clinical methods are introduced into medicine which do not require study and practice before one can appreciate them and apply them intelligently. I believe that no one who devotes himself for a time to acquiring proficiency in these methods of examina- 21 Loc. cit. 32 tion of the blood will fail to find them of considerable assistance in his daily work. These particular methods have given us valuable hints as to the nature of some of the so-called diseases of the blood ; they have given us the most reliable means of diagnosis in some of these processes which we now have ; they have opened a large and hopeful field for observation in many other pathological processes. Here some may be disappointed to find few, if indeed any, changes in the blood pathognomic of any particular disease ; but from the few examples I have cited in this short review of the subject, we may, I think, justly hope to add to our present knowledge more of those small points which, though they may not of themselves be diagnostic, form by their accumulation the symptomen-complex, as the Germans call it, of a specific disease. THE BOSTON MedicalandSurgical Journal. A FIRST-CLASS WEEKLY MEDICaCnEW|pAPER. PUBLISHED EVERY THURSDAY. Two Volumes yearly, beginning with the first Nos. in January and July. But Subscriptions may begin at any time. This Journal has been published for more than sixty years as a weekly journal under its present title. Still it is incumbent upon this Journal, no less than upon others to assure its patrons from time to time, as the occasion arises, of its desire, ability, and determination to meet all the requirements of the most active medical journalism of the day, without sacrificing any of that enviable reputation which is an inheri- tance from the past. It is under the editorial Management of Dr. George B. Shattuck, assisted by a large staff of competent coadjutors. Communications from all quarters of the country are acceptable. Liberal arrangements are made for reprints of original articles, and for such illustrations as serve to increase their value or interest. All editorial communications, and books for review, should be addressed to the Editor. Subscriptions and advertisements received by the undersigned, to whom remittances should be sent by money-order, draft, or registered letter. Terms of Subscription : In the United States, and to Canada and Mexico, $5.00 a year in advance. To Foreign Countries embraced in the Universal Postal Union, $1.56 a year additional. Single numbers, 15c. Ten consecutive numbers free by mail on receipt of $1.00. Sample copies sent free on application. Published by DAMRELL & UPHAM, 383 Washington St., Boston. MALARIAL FEVER by W. S. Thayer, M. D., Baltimore. SYNONYMS.- Intermittent fever; Swamp or Marsh fever; Paludism or Paludal fever; Fever and ague; Chills and fever. The term "malaria", which has been applied in a general way to a variety of febrile and non- febrile processes, must now be limited to a certain definite class of febrile affections which we know to have a specific infectious origin. The specific micro-organisms which are the cause of these pro- cesses belong to the class of protozoa and inhabit the blood of the infected individual. ETIOLOGY AND PATHOLOGY:- The geographical distribution of the malarial fevers is a point of considerable interest, particularly inasmuch as it is not entirely constant. In Europe, France, Germany, and England are comparatively free from malarial fever, while in Southern Russia and Italy the disease is very frequent. In many parts of Africa and India some of the severest forms of malaria are seen. In this country there are various localities in which malaria is endemic, particularly in certain regions in the Southern States, in Louisiana, Mississippi, Arkansas, and lexas. In the low, marshy lands along the coast throughout the Southern and Central States there are many places in which malarial fevers are common. In parts of New England malaria also occurs, particularly in the. Connecticut Valley, while of late a considerable number of cases has been seen along the course of the Charles River in Massachusetts. In New York City the disease is rare, though certain low-lying districts in the neighborhood give rise to a number of cases. In Philadelphia the disease is perhaps more fre- quently seen, but most of the cases in that city come from outlying districts. In parts of Baltimore also malarial fever occurs, though a great majority of the cases come from the dis- tricts bordering on Chesapeake Bay. In the West- ern States malaria is less common, but in certain parts about the Great Lakes it is more or less prevalent* A very interesting point in connection with the geographical distribution of malarial fever is the manner in which the disease wanders from one region to another, diminishing greatly in intensity or almost dying out in a district where it has for- merly been endemic, and developing perhaps in a region where it has been for many years an unknown disease. An instance of this is the appearance during the last five or six years of malarial fever along the basin of the Charles River in Massachusetts, where it had been for many years unknown. Again, in districts in which malarial fever has for years been endemic there seem to be cycles in which the intensity of the process increases and diminishes* S alarial fever is particularly prevalent in low, swampy, and badly-drained diotriots, and es- pecia'ly in areas which are rich in vegetable matter and have been allowed to fall out of cul- tivation* It is much more prevalent in tropical or semitropical regions, and is more severe in climates where the moisture is considerable. It has been thought that winds have possibly some connection with the carrying of the contagion; for instance, in some malarial districts the residents on one side of a stream may be relatively free from the disease, while those upon the other side toward which the prevailing winds blow, may suffer considerably. The danger of contracting malarial fever is apparently greater among those living in the lower stories of a house than in the upper. In temperate climates the frequency of the malerial fevers varies greatly with the seasons. The majority of cases occurs in the late summer and fall though a certain number develops in the spring and early summer, while in the winter it is very rare, in tropical climates, where the disease occurs all the year sound, the greater number of cases is seen in the fall and spring months. THE SPECIFIC NICRO-ORGANISM.- All our accurate knowledge of the causal element of malarial fever dates from the discoveries of Lavernn in 1380. While studying malarial fever in Algiers, Laveran discovered certain pigmented bodic s in the blood of affected individuals. These bodies had long been observed by others, and by some accurate- ly described, and even pictured, but, while the older observers considered them to be altered blood corpuscles, Laveran recognized them as parasites, and asserted that they were the defi- nite exciting agent of malarial fever. These discoveries have been confirmed by numerous other observers in Italy, the United States, Russia, Germany, and India. In this country Councilman Abbott, Osler, James, andDock have made valuable observations. Laveran and his school have pub- lished careful and accurate descriptions of the different forms of the parasites, which may be seen in the blood, but they assert that they are unable to associate any definite types of organism with distinct types of fever. From the observations which have been made, however, by the numerous Italian Observers, led by Golgi, there can be today little doubt that certain definite types of the organism are associated with certain definite types of fever. In this country, as in Italy, there are several main types of fever: (1; The milder forms of intermittent fever, which form the great majority of the cases in the spring and early summer, but which occur at all malarial seasons: (a) Tertian and double tertian (quotidian) fever; (b) quartan fever, with its combinations. (2) The more severe, often more or less irregular, fevers which occur here, as in Italy, more commonly in the later summer and fall- the aestivo-autumnal fevers of the Italians, the tropical malaria of the Germans. This type of fever includes the so-called remittent malarial fevers as well as most of the cases of perni- cious malaria and of the malarial cachexiae. Some of the Italian observers have attempted to divide these fevers, again, into (c) quotidian fever, and (d) malignant tertian fever. In this country, however, we see probably only the quo- tidian type. With each of these types of fever is associated a distinct type of the specific micro-organism. (a) The Parasite of Tertian Fever.- Golgi was the first observer who accurately described and differentiated the organisms of the tertian and of the quartan forms of malarial fever, and his admirable observations have remained prac- tically unassailed. If we examine the blood from a case of tertian fever just after the paroxysm, we find in certain of the red blood-corpuscles small round, colorless bodies which appear to have a slight depression in the centre, and when stained in dried specimens show a paler central area with a darker periphery. These bodies, exam- ined in the fresh specimen, show active amoeboid movements. A few hours later the organism will be found to have increased somewhat in size, and to contain a few fine brownish pigment-granules which dance actively under the eye, the motion probably being due to undulatory movements in the protoplasm. On the day between the paroxysms the bodies will be found to have about half filled the red corpuscle. They are still actively amoeboid, and the number of pigment-granules has considerably increased. The red corpuscle at this stage will be seen to be a trifle larger than its unaffected neighbors, and to be considerably decolorized. On the day of the paroxysm the organism has entirely filled and almost destroyed the red blood-corpuscle which is represented only by a faint pale rim about the full-grown parasite, if indeed it has not en- tirely disappeared. The pigment-granules may show at this stage a very active motion, but the amoeboid movements of the organism as a whole are but little marked. At the time of the paroxysm an interest- ing change takes place; the pigment gathers to- gether in a more or less solid clump, usually in the centre of the organism, while the rest of the protoplasm looks somewhat granular and shows a suggestion of lines radiating outward from the centre. This appearance gradually changes, the lines becoming more distinct, until finally we see the central clump of pigment surrounded by from fifteen to twenty small ovoid or round glistening segments, each one having a central more refrac- tive spot, and resembling strongly the hyaline bodies which we see immediately following the chill. This segmentation of the organism is always coinci- dent with the paroxysm, and the presence in the blood of a segmenting body is a sure indication that the paroxysm is present, or is about to occur. Immediately following the paroxysm fresh hyaline bodies appear in the red corpuscles. Though the invasion of the corpuscles by these fresh segments has nover been actually observed, the evidence that this occurs is so strong that we can safely accept it as a fact. Besides these forms we see not infrequently small or large extracellular pigmented bodies; that is, organisms resembling exactly those within the red blood-corpuscles, excepting that they are free in the blood current. These may be seen at times to break up into several smaller bo- dies, whtle at other times they may show a long- tail-like, non-motile process, containing sometimes a few pigment-granules. They are probably organisms which have escaped from + he red corpuscles, or full- grown bodies which have broken up; they are consid- ered to be degenerative forms. At times also we find the so-called flagellate bodies. Their development from the pigmented organism may indeed be observed, the pigment of the full-grown body becoming very actively motile, then collecting in the centre of the organism, while several long, thread-like flagella burst out of the body and move actively about among the surrounding corpuscles. Sometimes we may see one of these flagella which has broken away from the organism and is moving rapidly through the field. This is also thought by all Italians to be a degen- erative process. The characteristics of this form of organism, which is observed in tertian fever alone, are so marked that with a little study of the parasite one can make a definite diagnosis of the type of fever from an examination of the blood alone. (b) The Parasite of Quartan Fever,- Quartan fever is not at all common in this country, but in the few cases which the writer has observed the organisms differ distinctly from the tertian parasite, and show accurately the characteristics described by Golgi. Here the first stage of the organism is similar to that observed in Tertian fever, excepting that the amoeboid movements are not so active. As the body develops the rods and clumps of pigments are larger and darker than those in tertian fever, while the amoeboid movements of the organism is relatively slight. The full-grown forms are materially smaller than in tertian fever, while the red blood-corpuscle, instead of being expended and decolorized, appears at times shrunken about the body, and of a somewhat deeper old-brass color (Messihgfarbe). In segmentation the organism divides into from six to ten different parts in- stead of twenty or thirty, as in the tertian form. (c) The Organisms of the Aestivo-autumnal Fevers.- The organisms associated with the aestivo-autumnal fevers have been carefully studied, but much remains to be done, particularly in this country. There is some difference of opinion as to whether there are not two types of organism associated with these fevers. Some Italian observers divide them into the quotidian and the malignant tertian organisms. The differences made out by the Italians are, however, very slight, and have not been observed in this country. In the first place, we see just after the paroxysm small hyaline bodies which may or may not be actively amoeboid; these can sometimes be distinguished in that they are generally somewhat smaller and have oftentimes a characteristic ring-like appearance. In the early stages - during the first week, for instance- of an attack of this form of fever we may see only the hyaline, unpigmented forms, but commonly, if we ob- serve carefully, we may see, sometime after the exac- erbation of temperature, shortly before the begin- ning of another, bodies which are a trifle larger than these smallest hyaline forms, and which contain one or two very minute pigment-granules lying near the periphery. Just before or during the paroxysm we may see bodies with a sms 11 central clump of motile or non-motile pigment granules lying usually in cells which are more or less shrunken and crumpled, and of a deeper color than the normal corpuscles (Messingfarbe) These bodies are generally not half as large as the red corpuscle. After the first week or ten days of the disease, or after treatment has begun, we see, however, certain very characteristic and easily recognizable forms which are only seen with this type on fever. These are, first, round, or ovoid bodies about the size of a red blood-corpuscle, a little smaller or a little larger, with clear, rather highly refractive, waxy-looking protoplasm, and coarse dark pigment-granules, which are usually collected in a ring or a mass in the centre of the organism. The granules are usually very slightly motile. At one side of the body we often see a small bib-like attachment which may show a slightly yellowish color. On examination this proves to be the remains of the red blood-corpuscle in which the organism has developed. In association with these are seen cres- centic bodies, the protoplasm of which shows the same characteristics as that in the forms above de- scribed, while the pigment is collected in the middle in a similar ring or bunch, and is but slightly motile. On the concave of these crescents one may also often see a bib-like attachment, just as in the ovoid forms. At times during the examination of the fresh specimen we may see the change from an ovoid body into a crescent take place. The development of these forms from the hyaline bodies can be followed out on careful observation. They are thought by some to be a resting stage of the organism. Seg- menting bodies are almost never seen in the circu- lating blood of this form of malarial fever, though the presence of the round intracellular bodies with central pigment is a sure sign that segmentation is going on elsewhere. It has been found by the Itali- ans that after the accumulation of a few pigment- granules the organisms seek the internal organs where segmentation takes place. The bodies are still small and contained within the red corpuscle. The pigment gathers in the centre, as in the other types of segmentation, while the segments are very small and rarely more than twelve in number. Dur- ing the paroxysm we may see large numbers of leu- cocytes containing pigment granules and clumps which are probably the remains of segmenting organisms. Flagellate bodies may be observed here as in the tertian and quartan fevers, but only when ovoid and crescentic pigmented bodies are present. They may be seen to develop from the round bodies with central pigment. Careful studies concerning the morphological characteristics of the malarial parasite have shown that it belongs to the class of Protozoa, and is possessed of a nucleus containing one or more nu- cleoli. At the time of sporullation this nucleus divides - according to some directly according to others by karyokinesis. PATHOLOGICAL ANATOMY.- In the acutely fatal cases of malarial fever (pernicious ma- laria) certain characteristic changes are found in the various organs. The brain may show few changes. At times, however, there may be a slight subpial oedema, with hyperaemia of the cerebral substance and perhaps punctuate haemorrhages. Melanosis may be entirely absent. Microscopically, however, the changes are most characteristic. The cere- bral capillaries are crowded with malarial par- asites * which may be in all stages of development, marked. At times the organisms may not be so numerous, but free clumps of pigment may be found, and large endothelial cells and leucocytes containing pigment-clumps and red corpuscles. There is usually a marked granular and fatty de- generation of the endothalium of the vessels, a change upon which the punctuate haemorrhages may depend. These lesions are particularly marked in co- matose forms of pernicious malaria. Tn other forms the cerebral lesions may be much less marked. The spleen is always enlarged; the capsule is tense; the parenchyma is cyanotic, of a slaty-gray color, and almost diffluent. In some cases of acute malaria death may occur from rupture of a greatly enlarged spleen. The pulp contains enormous numbers of red blood-corpuscles, many of which contain parasites. It also contains numerous large white elements rich in protoplasm, containing usually a single bladder-like nucleus, and at times coarse granulations. These elements are usually laden with pigment, which at times has the same arrangement as it does in the body of the par- asite itself. Sometimes these cells may contain the entire red corpuscle with the organism. There may be free pigment in the intercellular spaces of the pulp. The small mononuclear elements and the lymphocytes of the follicles never contain pigment* The capillaries are usually filled with the plasmodia, while the splenic veins show relatively few, though they always contain large cells enclosing pigment or the remains of red blood corpuscles. The liver has usually a slqty-gray color. There is always cloudy swelling, while micorscopically small areas of necrosis have been described by Guarnieri. The capillaries are filled with leu- cocytes which contain numerous pigmented bodies. Re- latively few plasmodia are found in the blood-cor- puscles in the vessels. Numerous liver-cells are found containing clumps of haematin and altered red corpuscles - a condition similar to that which has been found in pernicious anaemia, which, as Bignami suggests, may explain the polycholia which is common- ly found in subjects who have died of pernicious mal- aria. On this probably depends the icteroid hue in severe malaria. The Lungs show in their capillaries numerous cells containing pigment-clumps and well-preserved parasites, though it is unusual to find pigment in the endothelial cells, in the capillaries, and smaller veins. In the areas of broncho-pneumonia which may occur, polynuclear leucocytes are chiefly found, while the large pigmented cells take no part apparently in the active inflammatory process. The vessels of the kidneys contain relatively few organisms. The glomeruli may be considerably pigmented. There may be marked degeneration of the epithelium of the capsules, and at times changes in the parenchyma, especially areas of necrosis of the epithelium of the convoluted tubules. The other viscera show no especially characteristic changes excepting at times the melanosis. In the more chronic forms of malaria and in malarial cachexia the aneamia is usuallyparti- cularly marked. The spleen is always enlarged and very firm. There is a marked thickening of the capsule, which is often adherent to the neigh- boring tissue. On section the spleen is generallv of a dark brownish gray color, the bibrous tissuothrourh- out the organ being greatly thickened. The liver is considerably enlarged, and usually has a grayish brown or slaty color. Microscopically, Kupfer's cells and the perivascular tissue may contain much pigment. At times there is a considerable in- crease in the connective tissue. The Kidneys show no particular characteristic changes, though there may be considerable pigmentation; the pig- ment is most marked about the blood vessels and the Malpighian bodies, and sometimes in the region of the convoluted tubules. There are no character- istic changes in the other organs, excepting the slaty-grayish pigmentation. SYMPTOMS:- As may be gleaned from what has already been said concerning the specific organ- isms, malarial fever occurs in several main types: (1) The milder intermittent fevers, which form the majority of all cases in the more temperate climates, and occur in the warmer climates more commonly in the spring and early summer: (a) Tertian intermittent fever and its combinations; (b) Quartan intermittent fever and its combinations. (2) The more irregular, aestivo-autumnal fevers, which usually show quotidian paroxysms. TERTIAN INTERMITTENT FEVER.- This is by far the commonest form of malarial fever in this coun- try, and with the quartan fever forms the mildest type of the disease. It is the type of the inter- mittent fever of the spring and early summer, though it may be seen at any time of the '/ear. It shows often no pa' ticular tendency to increase in severity, while in many instances, under proper care and change of climate, spontaneous recovery may occur. It depends, as we have seen, upon the invasion of the blood bv an organism which passes through its cycle of existence in forty-eight hours. The febrile paroxvsms occur when these parasites have reached their full development and begin segmentation. These periods occur with con- siderable regularity at intervals of forty-eight hours one from another. In older children the paroxysms may usually be divided into three stages; first, the chill; secondly, the fever; and thirdly the sweatingZ The child, who may have been feeling fairly well beforehand,becomes suddenly uneasy, may begin to yawn, or may have an attack of vomiting or diarrhoea, which is followed or accompanied by a well-marked rigor, associated with cyanosis and coldness of the extremities. The temperature rises to a considerable height, possibly to 108° F. This stage lasts for a varying time, from ten minutes to an hour. As the chill ceases the pa- tient passes into a stage in which there is marked flushing of the skin, with great heat and dryness. The child complains bitterly of thirst and headache, and. is usuaj.lv very fretful. There may be, as in the first stage, renewed attacks of vomiting or diarrhoea. This stage, after lasting for a variable length of time, from half an hour to three or four hours, is followed by profuse sweating, the temper- ature falling within an hour or two to a normal or even a subnormal point. With the sweating the child may seem exhausted and weak, but shortly afterward appears again perfectly well. Such an attack as this differs but little from the intermittent fever of adults, end indeed above the age of six the differences are very slight. Under this age, however, there are mark ed differences in the paroxysm. Very commonly in young children both the first and the third stages those of the chill and sweating are abeent. The first stage is then generally represented by a slight restlessness, the face looks pinched, the eyes sunken, the finger-tips and toes may become cyanotic and cold, while the child may yawn or stretch itself. Oftentimes there is nausea or vomiting, and possibly diarrhoea* This may be the only manifestation of the first stage, though it nay be followed by slight or severe nervous symptoms. These usually begin with a slight spasmodic twitching of the eyelids or of the extremeties, and may go on to general convulsions. T e chill in the adult is very often represented in the young child by the convulsion,- a fact which is as true in all other acute febrile processes as in malarial fever. This stage lasts usually for a short time, not more than an hour or so. The temperature rises rapidly, possibly to 108°F.; then comes the period of fever, during which the child is much flushed, is restless, thirsty and fretful, while, as has been already said, various gastro-intes- tinal disturbances may occur. The fever remains at its height for an hour or two; afterward there is a gradual fall of temperature, unaccompanied by sweating* In many instances, besides the slight coldness of the hands and blueness of the finger- tips, and a somewhat pinched expression of the face in the first stage, the first and the third stares of the attack may be entirely lacking. Pure tertian fever is rare in children, as the process is almost always a double infection; that is, the blood contains two sets of organisms, which attain maturity on alternate days, and give rise to quotidian paroxysms* If, as is unusual, the case is one of pure tertian fever, the child may seem perfectly well on the day between the attacks. Physical examination during the very first attack may reveal little or nothing, but usually by that time, and always after one or two paroxysms, an enlarged spleen may be made out. If a child had had more than two supposed male rial paroxysms and the spleen is not distinctly enlarged, we have al- most sufficient evidence to put aside the diagnosis of malarial fever. Herpes labialis is a very common accompaniment. Anaemia is usually noticeable if the process has lasted for any length of time. The discovery of the specific organism in the blood is the one diagnostic point* The paroxysm in tertian malarial fever may last altogether from twelve to fifteen hours, though commonly it is much shorter, the first stage lasting from ten minutes to an hour, the second stage from an hour to three or four hours, and the third stage a varying length of time. As the length of time which the tertian organism requires to attain its full growth is almost exactly forty-eight hours, the attacks dependent upon one group of parasites occur almost regularly forty-eisht hours apart, though in some instances we may find a tendency to anticipation or to retardation in the attacks. This point can only be determined by observation, so that one cannot definitely prophesy the hour at which at attack will occur until he has seen several paroxysms. It is easy to see that in the quotidian cases, which depend upon the presence of a double infection, the chills on the alternate days may occur at different hours, one group of organisms segmenting perhaps,at ten o'clock, and the other at two. Usually, however, these differences are slight. Not infrequently we find the history of tertian a'tacks at first, and later on daily attacks of fever. The commonest time for the paroxysm in tertian fever is in the early part of the day, between eight in the morning and two in the afternoon, though they may occur at all hours either of the day or right. Irregularities in the course of the fever, no matter what the type may be, are much commoner in children than in adults. QUARTAN FEVER.- This form of fever is rarely observed in this country. Out of about 500 cases of malaria treated a the Johns Hopkins Hospital in four years, it only occurred twice. Here the length of time required for the development of the organism is reventy-two hours, and the paroxysms occur every fourth day. The nature of the paroxysm does not differ from that observed in tertian fever* As one may easily see, complex attacks of fever may arise from a double or triple infection with quartan organ- isms. Thus, we may have a daily paroxysm due to a quartan infection, or, on the other hand, paroxysms on two days in succession, with one day intermission, a triple or a double infection. The diagnosis of quartan fever may be made by a skilled observer from one examination of the blood by the discovery of the characteristic quartan organism. THE AESTIVO-AUTUMNAL FEVERS. "TROPICAL MALARIA". "FEBRIS IRREGULARIS".- The malaria occurring in the late summer and fall is often of a much more severe type than that occurring in the spring, and, as has been shown by the Italian observers, most of these cases are due to a different type of the specific or- garism. It is in the later summer and fall that we see most of the cases of apparently irregular fever, and the so-called remittent malarial fever* The typical malarial cachexia, while it may follow any form of intermittent fever, usually results from this type of malaria. Most of the pernicious forms also come under this heading. THE SO-CALLED IRREGULAR REMITTENT FEVERS.- The recent Italians observers, asserting that there is in reality no actual irregularity, divides these fevers into the quotidian, in w^ich a daily par- oxysm occurs, and the tertian, in wl ich the paroxysm occur on every other day; but in both instances there is a greater tendency to irregularity in the time required for the development of each brood of organisms. On the one hand, there is often a very marked tendency for the paroxysms to anticipate one another, or there may be a retardation, while again the attacks do not pre- sent themselves in so clean-cut and regular a form as in the spring fevers. They may be much lengthened out, so that one attack may follow another without the temperature ever actually reaching a normal point. Most of the cases of this type of fever seen in this country shows a distinct daily paroxysm; it is doubtful whether we see in American the "ma- lignant tertian fever" of the Italians^ The attacks may differ little from those in the ordinary tertian for , excepting that they are often more severe and of a somewhat longer duration, so that the afe- brill periods are shorter or even absent. On the other hand, the onset may be very gradual, with daily ex- acerbations of temperature, accompanied by restless- ness, flushing, often vomiting or diarrhoea, and headache, but without chills or perhaps even sweating. The attacks may be prolonged and run into one another, so that a remittent temperature results. There is often delirium or drowsiness and somnolence; the spleen is always enlarged. In this condition the diagnosis from typhoid fever or meningitis may be impossible without an examination of the blood. Such cases as this, however, do not generally go on to re- covery without treatment, but tend to become perni- cious, the paroxysms in severity till death. MALARIAL CACHEXIA.- The fever in some instances may never rise as high as it does in the paroxysms of tertian fever, nor may the immediate symptoms of the paroxysm $e as striking, and the attention of the prysician is often called to the patient for the first time when the stage of malarial cachexia has be n reached. The child may then show a pitiful ap- pearance. It is pale of a sallow parchment-like color, and often much emaciated. The skin is dry, the face has a drawn, pinched look, the eyes are sunken, there may be marked symptoms on the part of the digestive tract, frequent attacks of vomit- ing and diarrhoea. The fever may stand in the back- ground. Indeed, in some of these cases there may be for weeks relatively little fever. The spleen is always enlarged. Malarial cachexia does not exist in children without an enlarged spleen. In all instances, no matter whether our attention is called to the child on account of the fever or of the gastro-intestinal derangement, an examination of the blood will show the organisms, usually those characteristics of the aestivo-autumnal or tropical malarial fever, the small hyaline bodies, and the pigmented crescents and ovoid forms. Malarial cachexia may follow all forms of the disease, and not •infrequently is seen in improp- erly treated cases of tertian fever or in those who have been subject to repeated attacks, but it is much more commonly seen in this type of fever. PERNICIOUS MALARIAL FEVER.- It is in the eastivo-autumnal fevers that we see more common- ly the pernicious forms of malaria, though these are rare in temperate climates. In these cases a previously healthy child may begin to show a slight restlessness, with a pinched expression of the face and some blueness of the extremeties. An attack of vomiting or diarrhoea may occur, which may be follwwed suddenly by severe convul- sions and a very rapid rise in temperature, which may be as high as 108°. The convulsions may continue or thechild may pass into a dull, comotose condition, the pupils being fixed and possibly with little or no rise in temperature. These severe attacks are rare in this country» and it is not at aJl improbable that in regions in which severe mal- srial fever prevails many non-malarial attacks are ascribed to this disease. The definite diagnosis can only be made by the discovery of the parasite in the blood. Some of the most severe of these attacks are probably due to the infection with several groups of the organisms at once, so that segmentation is going on continuously. AFFECTIONS OF OTHER VISCERA SOMETIMES ASSO- CIATED WITH MALARIAL FEVER.- Respiratory Appara- tus. In all forms of malarial fever bronchitis is a common complication, as it is, indeed, with any acute febrile affection. This is particularly true in children. The appearance of a profuse coryza in the absence of the sweating stage has been noted. Alimentary Tract.- In almost all cases of malarial fever in children symptoms are present on the part of the stomach and intestines. Vomiting in the first and second stages of the paroxysm is extremely common, while diarrhoeas are also very frequently seen in all forms of malaria, particularly in the more remittent forms and in the chronic cachexia, where it is probably generaly due to a secondary infection to which the debilitated child is more readily subject. Little is to be noticed on the part of the circulation. Kidneys.- Slight albuminuria may often be observed, and in rare instances haematuria occurs. Malarial haematuria is generally considered a grave symptom. It is probably, however, a rare condition, except in districts where the severest forms of the disease are common, Many of the so- called malarial haematurias are due to other causes. The literature of malarial fever contains numerous references to "malarial pneumonia" "malarial bronchitis", "malarial neuralgia", "malarial diarrhoeas", and the like, most of which, in the light of our present knowledge, have probably little or no connection with mal- arial fever. It is easy to understand that the child debilitated by a severe malarial fever, may more readily fall a victim to a variety of other diseases. In this way probably the gastro- intestinal and bronchial disturbances so coirmonly observed are to be explained. That there is any such thing for instance, as a specific malarial pneumonia is wholly out of the question. The chills which may occur sometimes with some reg- ularity in the course of many of the specific fevers are commonly attributed to a malarious influence. These inferences are for the most part unjustifiable. In rare instances a patient who is subject to an acute or chronic malaria may develop typhoid fever at the same time, or the converse may occur, but these instances are few and far between, and the great majority of instances of chills occurring in typhoid fever have no connection whatever with malaria. Pneu- monia may develop during the course of a malarial attack, but it is due in these cases to its specific cause. The examination of the blood is our one safe clue to the explanation of such complications. DIAON0 SIS. - The Milder Tertian and Quotidian (double tertian) Fevers.- The diagnosis of malarial fever in children may be made, in the first place, from the character and periodicity of the attacks; secondly, from the enlargement of the spleen, which is always present after the first or second attacks; and thirdly, by the presence of the malarial organism in the blood. In some instances there may be relative- ly few parasites, but the careful examination of several fresh specimens of the blood will always re- veal the organism if present. Even in the absence of definite data with regard to the attacks, the diagnosis may be made by the type of organism found. The commonest type, as has been said, is the double tertian, quotidian fever. The commonest condition with which malarial fever is confounded is tuberculosis in its various forms; the hectic evening temperature is often ascribed to malaria. Most pediatrists may, I fancy, remem- ber more than one instance where after a diagnosis of malarial fever evidences of pulmonary, abdominal, or even glandular tuberculosis have developed. The absence of definite signs of tuberculosis, the splenic enlargement, and the aneamia, which may be marked, speak in favor of the malarial nature of the affection, while the absence of malarial or- ganisms in several specimens of fresh blood even in the presence of marked febrile paroxysms, is a sur° sign of the absence of the malarial fever. The same rules of diagnosis apply to quartan fever. The characteristic organism of that type will be found on examining the blood. Aestivo-autumnal Fevers.- It is the more irregular and remittent fevers and the malarial cachexiae which give the most trouble to the di- agnostician. The regularly intermittent fever may not here give us our clue to the diagnosis. On the other hand, the pres nee of a considerable aneamia in association with a markedly enlarged spleen, which is always present in this form of fever, will lead us to suspect the r.roper diag- nosis, which will be confirmed by the discovery of the small ring-like hyaline intracellular, orgenisms, and, if the case has lasted a week or more, the ovoid and crescentic pigmented bodies in the blood* This form of fever may often be confounded with tuberculosis. It may also sim- ulate very closely, from the physical examination alone, leukaemia or the anaemia infantilis peudo- leukaemica of Von Jacirsh. In some instances where the paroxysms tend to run into one another and produce a more or less remittent fever, the differ- entiation of the process from f ev'r may be impossible from the physical examination alone. The frequent herpes, the large size and prominence of the spleen as well as the rapidly developing anaemia, may be suggestive, but here, as elsewhere, the examination the blood alone gives us our certain diagnosis. In the absence of an examination of the blood, the chronic cachexiae may be considered to be the result of the concomitant gastro-intestinal derangements or of the bronchitis, while in many instances the atrophy, the dyspepsia, and the diarrhoea may be found to depend upon the presence of the malarial organisms in the blood. In the cases of severe pernicious malarial fever the examination of the blood is also our only safe clue to a diagnosis. METHODS OF EXAMINATION OF THE BLOOD,- The examination is best made with fresh spe- cimens. The lobe o** the ear is punctured with a sharp, spear-pointed lancet; a very small cut is all that is necessary. This may be done behind the back without the child seeing the instrument, so that it may not be alarmed, while if the instru- ment is sharp the process is almost painless. In some instances it may be done while the child is asleep, without even awakening it. After wiping away the first drop or two of blood, a perfectly clean cover-glass is brought into contact with the tip of a small drop of blood, and allowed to fall immediately upon a freshly-cleaned slide. If the slide and cover-glass have been washed in alco- hol just before using and are perfectly clean, the drop of blood will spread out regularly under the glass, and the corpuscles may be seen lying side by side free from crenation or any other artificial changes. Pressure on the cover-glass may spoil the specimen. It is best to hold the cover-glass in, a forceps in order to avoid any injury to the corpuscles from the moisture of the hand. The specimen is then examined at best with a 1/12 oil-emersion lens, and a 2, 3, or 4 eye- piece. A 4 eye-piece with an 8 objective, or a Zeiss E or F, will answer the purpose well, though an oil-emersion lens is clearer and better. In this manner all forms of th? organism may be seen while yet alive. When it is impossibld to examine the fresh specimen, dried and stained specimens may be used. A small drop of blood is taken upon one cover-glass, which is then allowed to fall upon the second glass. The drop immediately spreads out, and the two glasses are separated by being gently drawn apart. These specimens are allowed to dry in the air. They may be kept for almost any length of time before examin- ing. There are numerous different methods for pre- paring and staining the specimen. As satisfactory a method as any is to place the glass in a solution of absolute alcohol and ether, equal quantities, for a half to one hour, or the specimens may be heated for from one to two hours at 100-120° C. The specimen may then be stained in a concentrated aqueous solution of "methylene blue for about a minute, washed in water, dried between filter-paper, mounted in balsam or oil, and examined. The red corpuscles remain unstained. Only the nuclei of the leuco- cytes, the malarial organisms, and occasional blood-platelets take up the blue coloring. In case a double stain is desired, one may make use of two solutions: Solution 1. Eosin 1 part; 70 per cent, alcohol 100 parts; Solution 2. Saturated aqueous solution of methylene blue. After preparing the spe- cimen in absolute alcohol and ether as before, place it in Solution 1 for from fifteen seconds to half a minute, wash in water, dry between filter-paper; place it then in Solution 2, which has been diluted one-half in water, letting it stain for from one- half to one minute; wash in water, and dry. By this method the red corpuscles and the eosinophilic granules in the leucocytes are stained red by the eosin, while the nuclei of the leucocytes and the malarial parasites are stained blue. Good results may be obtained by Romanowsky's method: saturated aqueous solution of methylene blue 1 part, 1 per cent, aqueous solution of eosin 2 parts. Do not shake or filter the mixture. Place the specimen (heated as above) in this mixture fortwo or three hours, and then in water for one to two hours, and dry. The parasites are stained blue. In this manner any practitioner who possesses a microscope may, without much labor, make the diagnosis of malari- al fever. The examination of the fresh specimens will probably be found to be more satisfactory, and the observer who studies only stained specimens must beware of certain mistakes which one who is not familiar with the examination of the blood may readily make, such as the confusion of the blood-plates, the haemato- blasts of Hayem, with the malarial parasites- a mis- take which certain good observers have recently made. COURSE AND PROGNOSIS. Excepting in the acute pernicious cases the prognosis in malarial fever is good, provided the case is recognized and properly treated. If untreated the fever may take one of three courses: (1) Mild cases may go on to spontaneous recov- ery; (2) The paroxysms may gradually diminish in intensity, the fever becoming less marked, while grave amaemia develops, and the patient passes into the condition of chronic cachexia. (3) The paroxysms may increase in severity assuming finally a pernicious type. TREATMENT.- Prophylaxis.- In a malarial district certain prophylactic measures should be taken with children as well as with adults. The child should be kept in the house after sundown and should be carefully kept away from those regions in which experience has shown that malaria is present. Sleeping on th" ground floor of houses in malarious districts should be avoided. , Medicinally, we possess in quinine one of the few specific drugs which are at the command of the physi- cian. In almost all cases of malarial fever we may expect with confidence a complete recovery after the • * use of quinine. There is only one form of malarial fever, and that rarely seen in this country, the acute pernicious malaria, in which we cannot entirely rely upon this drug. In the milder forms of the disease the tertian and quartan fevers and their combinations, small doses of quinine are rapidly efficacious. One or two grains of quinine (.065-.13), three times a day in children under six years of age, will be followed by the rapid disappearance of all symptoms. The best time to administer a single larger dose of quinine is immediately after a paroxysm. In the more chronic and irregular ^orms, which are so apt to occur in the later summer or fall, the forms in which the smaller organisms are found, much longer treatment and larger doses of quinine may be required. Ordinarily, however, doses larger than two or three grains (0.13-0.2) three times a day are not required under five or six years of are. Relativelt large doses of quinine may, however, be well borne, and in cases of pernicious malaria must be administered. Ferreiera states that he has given doses as large as 15 grains in infants under one year of age without noticing ill effects: In pernicious cases the quinine must generally be administered hypodermatica'ly. A good preparation is the muriate of quinine and urea. In ordinary cases it is probably better to give smaller doses several times a. day than it is to give one large dose with the idea of breaking up the fever. In some children it is very difficult to administer quinine by the mouth, on account of the difficulty in disguising the taste, and because in some cases it is constantly vomited. In some cases in infants the drug is with difficulty retained. Here small doses should be given and often repeated. In these instances it may be administered by the rectum: the dose under these circumstances should be double that by the mouth. The administration of quinine through the skin by means of ointments is probably of little value. In cases of the more chronic aestivo-autum- nal forms of malaria, associated with crescent organ- isms in the blood, the treatment by quinine may have to be continued for a considerable length of time. The crescents may be found in the blood for months. The fever, however, if the case is truly one of malaria, will surely yield to the treatment after a few days. Much has been written about those forms of malaria both in children and adults which do not yield to quinine. These cases are probably not true malarial fever, as examination of the blood will show. Few cases of fever in this country do not yield within a few days to treatment by quinine. By this it is not said that relapses may not occur; they are frequent in cases where the treatment has been continued too short a »time. In some of the acute forms of fever, and more particularly in the more chronic forms and in the malarial cachexia, the anaemia and various gastro-intestinal disturbances may also demand our attention. In most instances with proper attention to the diet, the gastro- intestinal symptoms will disappear after the dis- appearance of the fever. The anaemia, however, may require extended treatment with various prep- arations of iron, and even in the severe cases with arsenic, which is particularly well borne by children. The administration of arsenic, which is common in chronic malaria, has its chief value in its effect on the anaemia. Various other drugs have been tried in malarial fever, some of which have some influence on the attacks. The ost important of these are preparations of eucalp- tus and of late, methylene blue. None, however, approach quinine in efficacy. One attack of malarial fever does not, un- fortunately, render the patient immune* On the other hand, he seems, if anything, to be more readily subject to fresh attacks, and in some instances these attacks may be so frequent and prolonged that a removal of the child to a proper climate is necessary. NOTE ON THE INCREASE IN THE NUMBER OF THE LEUCO- CYTES IN THE BLOOD AFTER COLD BATHS. By William Sydney Thayer, M. D., Resident Physician to the Johns Hopkins Hospital. (From the Medical Clinic of Prof . Osler.) [From The Johns Hopkins Hospital Bulletin, No. 30, April, 1898.] [From The Johns Hopkins Hospital Bulletin, No. 30, April, 1893.J NOTE ON THE INCREASE IN THE NUMBER OF THE LEUCO- CYTES IN THE BLOOD AFTER COLD BATHS. By William Sydney Thayer, M. D., Resident Physician to the Johns Hopkins Hospital. (From the Medical Clinic of Prof . Osler.) In the Centralblatt fur Klinische Medicin for March 4, 1893, Prof. Winternitz of Vienna makes a communication concerning " Leucocytosis following Application of Cold." He finds that in normal individuals as well as in cases of fever an appreciable leucocytosis is found as early as half an hour after the exposure to cold. In some cases he found that this lasted as long as two hours. He calls attention to the recognized fact that the mere reduction of the temperature cannot of itself account for the many good effects of the treatment of fevers by cold baths, and he refers to the interesting experiments of Roque and Weill,1 who showed that in typhoid fever treated with cold bathing the " urotoxic coefficient " was increased to from six to eight times its amount when the cases were treated by internal antipyretics or by other methods. He suggests that the application of cold calls forth in some way an increased number of leucocytes from the blood-forming organs into the blood current, where they probably exert a destructive influence on any pathogenic organisms which may obtain entry into the circulation. Some such process as this, he thinks, accounts possibly for the favorable influence of cold in the treatment of various infec- tious diseases. The appearance of this note may justifiy a preliminary com- munication concerning some unfinished observations which have been made during the last six months in Prof. Osler's wards at the Johns Hopkins Hospital. 1 Revue de Medecine, Sept. 1891. Last November Dr. J. S. Billings, Jr., called attention to the fact that in several cases of typhoid fever in which he had been counting the blood, he had found a distinct increase in the number of the leucocytes following the cold baths. These counts Dr. Billings followed with others, and since then further observations have been made. The leucocytes have been counted before and after baths in twenty cases of typhoid fever, in one case of acute pneumonia, and on two occasions in the healthy individual. The baths were all given at 70° F. and were of twenty minutes duration. The temperature of the water was kept constant by means of ice. The blood was taken from the lobe of the ear from cuts made by a small spear-pointed lancet. Care was taken in making the second count to avoid the region of the first cut, and in the later observations the blood was taken from different ears. The Thoma-Zeiss blood counter was used and the blood was diluted with Toison's solution. In the first eight counts the blood was diluted two hundred times, and four whole fields of the blood counter were counted; the mean was then taken. In the later counts six whole fields with a one to two hundred dilution were counted, or four with a one to one hundred dilution. With several blood counters-in some instances six were used-such a method is quite rapid and gives a fair estimate of the number of the corpuscles. The results may be seen in the accompanying tables. In Table I it will be seen that in twenty observations in cases of typhoid fever there was an increase in the number of the leucocytes after bath in eighteen instances, while in two there was a slight diminution. In the twenty cases the average number of leucocytes before the bath was 7724-|-; after the bath, 13,170-f-. In the first eight cases where the exact time at which the blood w'as taken was not noted the average increase in leucocytes was, it may be seen, much smaller than in the latter twelve. In the first eight cases the average number of leucocytes before and after the bath averaged respectively 8000 and 10,437; in the second twelve cases 7541 and 14,492. It may be possible that a some- what longer time elapsed between the bath and the second examination in the first cases than in those which followed. In one instance a bath was given to a patient with acute pneumonia; here the blood showed little change. Following these two observations were made with the healthy individual. The writer himself took a bath of exactly the same character as those given to the patients with typhoid fever, i. e. at 70° F., lasting twenty minutes. The results may be seen on the chart. In the second observation the bath was a trifle colder and the cyanosis and shivering were much more marked than in the first instance. It will be seen that while on the first occasion the number of leucocytes was but little influenced, in the second instance it was nearly quadrupled. Thus it may be seen that in typhoid fever, at all events, cold baths are followed in most instances by a considerable increase in the number of the leucocytes; in some instances the num- ber is increased nearly fourfold. And these, with the two counts in the healthy individual, would tend to fully confirm the observations of Winternitz. The first suggestion which this discovery brought to mind -before any knowledge of the work of Winternitz-was that this marked increase in leucocytes might be in some way or other connected with the beneficial effects of the baths. But the extreme rapidity of the increase in the number of the leu- cocytes suggested also that the condition might be a local instead of a general one. Might it not be possible that the action of the cold in slowing the peripheral circulation should result in the accumulation of the leucocytes in the small peripheral vessels and capillaries ? This question suggested a series of further observations which we hope to carry out, some of which are now in progress. 1. Assuming that we have in the leucocytes of the blood, elements in different stages of development, we might justly expect that if this increase in their number occurring in so short a time were actual, we should find some changes in the relative proportion of the diff erent varieties of leucocytes one to another. Careful differential counts of the leucocytes were therefore made in dried and stained specimens made at the time of counting before and after the bath. It will be seen from the accompanying Table II that such have been made five times in cases of typhoid fever and twice in normal blood. These counts were made in specimens stained with Ehrlich's triple stain of acid fuchsin, methyl green and orange Gr. The particular mixture used in staining these specimens was made as follows: Acid fuchsin (saturated aqueous solution), 9 Water (distilled), 6 Orange G. (saturated aqueous solution), 18 Methyl green " " " 20 Alcohol, 15 Water, 30 Glycerine, 5 To this several cc. of the saturated aqueous solution of methyl green were added, as the stain was not quite deep enough. The specimens were heated on the copper plate at 100°-120° C. for from one to two hours and were stained from two to five minutes. The classification adopted is essen- tially that of Tchistowitch,1 excepting that the large and small lymphocytes are classed together, and that the large mononuclear forms with indented nuclei are classed as tran- sitional forms. Several specimens were used, and at least one thousand leucocytes were counted in each instance. The increased relative proportion of the large mononuclear and transitional (indented nuclei) forms in the blood of the typhoid fever cases will be noted, points to which Uskow4 and Chetagurow3 have called attention. It will be seen from the tables that the differences in the counts before and after baths have been very slight. In the five counts in the cases of typhoid fever there has, however, been one constant change, namely, a slight diminution in the multinuclear neutrophiles with a slight increase in the mono- nuclear forms. In cases 1, 3, 4, and 5 the increase appeared mainly in the lymphocytes and small mononuclear forms. In case 2 there was a diminution in the lymphocytes and small mononuclear forms, with an increase in the large mononuclear and transitional forms. In one case in which a count was made, but was not recorded in the list because of imperfections in the specimens from which the estimations were made, the opposite occurred, i. e. there was an increase in the multinuclear neutrophiles after the bath. In the two instances in which estimates were made in the blood of a healthy individual the similarity between the counts before and after the baths is remarkable; there is practically 'Berliner klin. Woch. 1891, No. 34. 2"The Blood as a Tissue," St. Petersburg, 1890. 3Virch. Archiv, Bd. 120, F. XII, B. VII, 187. no change whatever. This is all the more striking in the second instance where the increase in the number of the leu- cocytes was nearly fourfold. So far then as we have gone the differences in the relative proportion of the different varieties of leucocytes one to another before and after the baths would appear to be only slight, if indeed they are appreciable. 2. Do those cases in which the bath is followed by an imme- diate reaction give the same results as those where there is cyanosis and coldness ? This question cannot yet be satisfactorily answered, but it will be observed that in case 17 of the typhoid fever cases, one of the two instances in which there was no increase in the number of leucocytes after the bath, the absence of cyanosis and chilliness was noted, while in the case of the writer the blood after his first bath, where there was an immediate reac- tion, showed but little change. On the second occasion, how- ever, when there wras shivering and cyanosis and the ear was blue and cold, the leucocytes were increased nearly fourfold. In case 9 of the typhoid fever cases where the greatest number of leucocytes was found after the bath, it was also noted that the patient was blue, cold and shivering. This was also noted in case 12 where there was a marked increase in the number of leucocytes. Cyanosis or coldness was also noticed in cases 19 and 20, where there was a considerable increase in the number of colorless corpuscles. 3. In any given case does blood from parts which are cold and blue show the same conditions as that taken from parts which are warm and red ? This point has not yet been properly studied. 4. Does blood from a superficial cut with a lancet show the same condition as that from a deep needle prick or possibly from a larger vein ? This point also has not been determined. 5. Do local applications of cold bring about the same result in the part as the more general baths ? This important point we are not yet prepared to answer. It may be said that on two occasions the arm of a healthy individual was im- mersed in ice-water for a half an hour and the blood from a finger-tip counted before and after. In the first instance there were before the bath 7333 leucocytes in the cubic millimetre: immediately after a bath of 35 minutes, 9666. On a second occasion there were 12,000 leucocytes before the bath, 10,666 immediately after, and 14,666 eighteen minutes later. 6. How soon does the increase in the number of leucocytes appear and what is its course ? One can only yet say that a marked increase has been noticed inside of a half an hour after the beginning of a bath and also a half an hour or more after the bath. 8. Is there any change in the number of the red corpuscles in the cubic millimetre ? In two of the cases of typhoid fever the red corpuscles were also counted. In one-case 17-there was an increase, while in case 19 there was a slight diminution noted. In the case of pneumonia there was a slight increase in the number of the red corpuscles. From this it would appear that there is no great constant change. In conclusion, then, it is clear that in most cases prolonged cold baths are followed by a marked and rapidly appearing increase in the inumber of leucocytes in the blood obtained according to th^ .ordinary methods of clinical examination. The question, however, as to whether this increase is general throughout the circulating blood or whether it is only local, due to the accumulation of leucocytes in the smaller peripheral vessels, is not so easily determined and requires further inves- tigation. From the results of the differential counts which have been made, and from the few observations concerning the condition of the peripheral circulation in the cases in which examinations of the blood have been made, one would perhaps be rather inclined to expect that further observations would tend to show that the increase in leucocytes following cold baths is more a local than a general condition. TABLE I. A.-Blood in Cases of Typhoid Fever. NUMBER. DATE. NAME. LEUCOCYTES BEFORE BATH. LEUCOCYTES AFTER BATH REMARKS. 1 6-11-92 M. 5,500 11,000 2 29-11-92 do. 6,500 10,000 3 6-11-92 M. 9,500 10,500 * 4 15-11-92 H. 8,000 12,000 5 16-11-92 AV. 9,500 10,000 6 20-11-92 do. 7,500 9,500 1 7 16-11-92 N. 9,000 12,500 8 20-11-92 Me. 8,500 8,000 9 31-12-92 B. 6,666 24,000 First count made at 10.45 a. m. Bath given at about 11. Second count at 11.40. 5-1-93 do. Patient blue and cold-shivering. 10 4,500 9,715 17,000 First count at 9.50 a. m. Second at 11.05 a. m. Bath 9.55-10.15 a. m. 11 27-1-93 H. 6,857 First count at 3.05 p. m. Bath 3.40-4.00 p. m. Second count at 4.10 p. m. Patient 29-1-93 do. was cold and shivering. 12 6,000 9,000 First count just before the bath at 12.20 p. m., second count at 1.15 p. m. 13 29-1-93 K. 8,000 18,000 First count 11 a. m. Second count 11.45 a. m., 10 minutes after bath. 14 29-1-93 do. 8,500 17,000 First count at 3 p. m. Bath 3-3.20 p. m. Second count 3.30 p. m., 10 minutes after Date not recorded. bath. 15 do. 10,284 16,000 First count at 3.45 p. m. Second at 4.15 p. m., just after the bath. 16 Date not recorded. H. 5,500 13,000 10,857 First count at 5.10 p. m. Second count at 5.45 p. m. 17 4-2-92 A. 12,587 First count at 3.30 p. m. Second count at 4.30. Bath 3.40-4 p m. Patient was warm Date not recorded. and red. Red corpuscles ?lfore' I mean of 3 counts of 200 squares r ( After, 5,736,000 f each with dilution. 18 B. 10,600 19,000 First count at 11.25 a. m. Bath 11.40-12.01 p. m. Second count at 12.25 p. m. 19 23-3-93 do. 6,333 16,000 First count at 4.45 p. m. Bath 4.50-5.10. Second count at 5.40 p. m. Blood taken from different ears. Hands cold, ears bluish but warm. 20 5-4-93 W. 4,666 Red corouscles / Before> 5,138,000 ) mean of 3 counts of 200 squares each with p (After, 5,104,000/ ^dilution. 10,333 First count at 9.10 a. m. Bath 9.17-9.37. Second count 9.47 a. m. Patient was not shivering, but ear was cold. Mean 7,724 + 13,170 + B.-Acute Pneumonia. 1 16-2-93 R. 30,666 34,333 Blood taken at 3.45 p. m. Bath 4.15 p. m. Second count at 4.35 p. m., when patient was shivering but not blue. Red-^ 5'755'333 mean of 3 counts of 200 squares each with dilution. C.-Blood of Normal Individuals. 1 T. 10,333 12,333 First count made immediately before bath, which lasted 20 minutes. Second count 15 minutes after bath. Patient warm and red ; no shivering. 2 16-4-93 T. 3,250 12,500 First count at 12 m. Bath 12.01-12.23. Second count at 12.25. Ear cold and slightly blue. Patient blue and shivering. At 12.40, when patient was still cold and shivering and ear cool, the count showed 10,250 leucocytes. TABLE II.-DIFFERENTIAL COUNTS. A.-Typhoid Fever. to H-* B.-Normal Blooj Q< 4^ CO t>0 »-* NUMBER. 16-4-93 CO to to to O1 WON 4^ CO H-* 4-* tO CD CD CD CD CD co co c o co to DA.TE. 4 NAME. 10,333 3,250 4^ C5 C5 C5 C5 ® wbooa OWOC'C os co o -t ci Number of Leucocytes. BEFORE BATH. 25.2 15.2 6.6 8.7 Lymphocytes. w. 4* Cl -Jw t-> 05 JcJOO GO CH Small Mononuclear. 1.8 1.7 27.9 17.7 11.5 7.0 7.2 Large Mononuclear. 4* to Jo w 4- 05 4- ci to © H- O Transitional (Indented Nuclei). 59.0 74.7 58.6 64,2 76.9 74.8 76.8 Multinuclear Neutrophlles. 8.8 .8 co Eoslnophlles. REMARKS. 12,333 12,500 o 24,000 17,000 9,000" 16,000 10,333 Number of Leucocytes. H- IO o< cn QI O AFT 9.1 5.8 10.5 -I o ] Lymphocytes. •1 3.3 8.8 4.7 Small Mononuclear. 2.3 1.5 ER BATH. 28.5 14.0 13.6 7.1 7.9 Large Mononuclear. d o'? J S't 05 to 05 to Cn ^ 4'1 ii Transitional (Indented Nuclei). 4- 9° do bo 55.3 62.1 73.4 73.7 73.7 Multinuclear Neutrophlles. 9.5 1.9 to t-* tO Eoslnophlles. - REMARKS. NOTE ON A CASE OF CICATRICIAL STENOSIS OF THE PYLORUS FOLLOWING A PEPTIC ULCER. By William Sydney Thayer, M. D. Resident Physician to the Johns Hopkins Hospital. DEMONSTRATION OF SPECIMEN OF AM(EBIC ABSCESS OF LIVER. By W. S. Thayer, M. D., and Simon Flexner, M. D. [From The -Johns Hopkins Hospital Bulletin, No. 51, May, 1893.] [From The Johns Hopkins Hospital Bulletin, No. 31, May, 1893.J NOTE ON A CASE OF CICATRICIAL STENOSIS OF THE PYLORUS FOLLOWING A PEPTIC ULCER. By William Sydney Thayer, M. D. Resident Physician to the Johns Hopkins Hospital. Mary G., unmarried, 22 years of age, a colored domestic, was admitted to the Johns Hopkins Hospital on July 29,1892, com- plaining of a " knot in the stomach " and " vomiting spells." Her family history was good; there was no history of tuber- culosis or carcinoma in any branch of the family. She had had measles and whooping cough, and thought that she had pneumonia eight years before entrance. The year after this she had malarial fever. With these exceptions she had always been strong and well. The catamenia began when she was 11 years old and had always been regular and pain- less. The illness of which the patient then complained began, she said, about three and a half months before entrance to the hospital, with loss of appetite and emaciation. About two weeks later she noticed a small lump in the epigastrium, and at about the same time she began to suffer from frequent attacks of vomiting. These attacks were not associated with much nausea, and the vomitus was often greenish and contained much fluid; no blood. The vomiting resulted, she thought, from the taking of food. There was no abdominal tenderness, though she said there had been some. The appetite from the beginning was very poor. The bowels were constipated and there were frequent frontal headaches. There was marked emaciation. She was somewhat short of breath, and there had been some cedema of the feet three weeks before entrance. The note on July 30th was as follows : S. P. In bed, on back; lips and mucous membranes pale; tongue shows a slight white coat. Pulse 82, regular in force and rhythm, tension not increased. Thorax long, costal angle rather narrow; resonance and respiration clear throughout. Heart.-The point of maximum impulse is palpable in 4th interspace a little inside of the mammary line. Relative dull- ness begins at the third rib and does not pass the left sternal border. The sounds are clear, rather soft, and accompanied everywhere, when the patient is in the recumbent posture, by a soft systolic souffle, which almost disappears at the apex when the patient is in the erect posture. The second sounds at the base are of relatively normal intensity. The hepatic flatness begins at the 6th rib in the mammary line and does not quite reach the costal margin. The border of liver is not palpable. The splenic flatness reaches from the 9th to the 11th rib, does not pass the costal articular line; border not palpable. Abdomen.-Symmetrical; not distended. In the right epi- gastric region just below the right costal margin opposite the cartilage of the 8th rib is a small nodule, apparently about the size of a horse-chestnut. It descends slightly with inspir- ation and gives one the impression that it is situated at the pylorus. Its firmness seems to vary. On inflating the stomach with bicarbonate of soda and tartaric acid the area of gastric tympany is found to be markedly increased, extending from the 5th rib above to three fingers' breadth below the umbili- cus. Owing to the tenseness of the abdominal muscles the position of the small nodule above mentioned could not be accurately determined. It does not appear to be in its former position. There is no enlargement of the lymphatic glands. The urine was negative. On the second of August a test breakfast was given (a glass of water and 30 grams of bread) and an hour later 300 ccm. of a cloudy fluid was removed by the stomach tube. This con- tained fragments of undigested bread and curds of milk which had been taken on the previous day. It had a strong rancid smell suggesting butyric acid. The reaction was acid. Tests with congo red paper and tropaeolin o. o. were negative. Gunz- burg's test for free hydrochloric acid negative. Uffelmann's test for lactic acid gave a sharply positive result. Nourishment was ordered to be given at short intervals in as concentrated a form as possible; stomach to be washed out daily. 3 Infusion of condurango 20 cc. t. i. d. before meals. On the 5th of August the condurango was omitted and tincture of nux vomica (0.5 to be increased to 1.3) t. i. d. before meals was ordered. The patient did not improve under treatment, and notwith- standing the fact that nutrient enemata were given in addition to her other diet she lost 9^ pounds between the 8th and 15th of August. The tumor remained of the same size and showed the same characteristics. On August 22d an examination of the blood by Dr. Billings showed red corpuscles 4,630,000, colorless corpuscles 12,500, haemoglobin (mean of two estimations) 69 per cent. On August 23d another test breakfast was given with a result similar to that following the former; that is, there was no free hydrochloric acid, and lactic acid was present. The patient had been steadily losing ground, the vomiting had continued, and the emaciation had progressed rapidly, the patient having lost 11 pounds since entrance. An exploratory operation was advised and the patient was transferred to the surgical side; Dr. Finney on duty. At the operation the condition was found to be a cicatricial stenosis of the pylorus following a gastric ulcer, the nodule measuring about four to five cm. in diameter. Gastro-enterostomy was successfully performed by Dr. Finney, but the patient died 14 days later of an acute dysen- tery. She had at that time been taking food by the mouth for a week. The autopsy showed a markedly thickened and indurated pylorus. Just at the pylorus there was an irregular ulcer about 6x2.5 cm. in size, with several small ulcers near by. The induration was partly due to fibrous thickening extending from the base of the ulcer, and in part to a great muscular hypertrophy, the muscular coat at the pylorus measuring 12 cm. in depth, the hypertrophy extending far back into the stomach wall. This case is of interest from several points of view. The clinical symptoms, if we pass by the youth of the patient, simu- lated remarkably those of a carcinomatous stricture of the pylorus. The absence of previous dyspepsia, together with the rather sharp onset of the symptoms, a point to which Ewald calls attention, which has certainly been borne out in the writer's experience, the rapid emaciation, the vomiting, the localized tumor, and the absenceof free hydrochloric acid, with the presence of organic acids in the gastric juice, make rather a striking picture. The anaemia was perhaps not of that degree which one might have expected in cancer, but grave anaemia is not a constant symptom in this affection. In two cases of cancer of the pylorus in which the writer has had occasion to examine the blood, a distinct increase in the number of red blood corpuscles above the normal, with a large percentage of haemoglobin, was noted in each case within a week of the patient's death : Case P., 28-10-91, red corpuscles, 6,605,000; colorless cor- puscles, 16,000; haemoglobin, 103 per cent. Case A., 25-12-91, red corpuscles, 6,472,000; colorless cor- puscles, 30,000; haemoglobin, 87.5 per cent. In both of these instances there was stricture of the pylorus, with obstinate vomiting and great emaciation, and it may be an actual con- centration of the blood as a whole. The presence of a gastric ulcer in this case seemed during life scarcely probable, owing to the absence of pain and the absence of free hydrochloric acid in the gastric juice. In a muscular hypertrophy one might also have expected to find at least some evidences of free hydrochloric acid in the gastric juice. A point of considerable interest is the rapid diminution in the secretory power of the stomach, in a condition where we usually expect to find a normal or increased secretion of hydro- chloric acid. It is unfortunate that more thorough estima- tions of the gastric juice (estimations of the pepsin and curd- ling ferment and of the hydrochloric acid in combination) were not made. The undigested condition of the food in the test breakfast and in the vomitus tends, however, to show that the diminution in the secretory power of the stomach was really considerable. It is also interesting to note how clearly a pylorus of this size may be palpable. It is not impos- sible, however, that the pylorus is really palpable in many instances when it is in a normal condition. In several instances of late in individuals with thin abdominal walls and enteroptosis or dilated stomachs, a small movable nodule has been felt in the pyloric region in the epigastrium which showed the characteristic rhythmic contraction and relax- ation so often to be noted in pyloric tumors. In most instances the pylorus is behind the liver, but when one considers its firmness and distinctness as we see it post-mortem it is but reasonable to expect that should it by any reason descend below its usual position it might in many instances be a pal- pable organ. [From The Johns Hopkins Hospital Bulletin, No. 31, May, 1898.] DEMONSTRATION OF SPECIMEN OF AMCEBIC ABSCESS OF LIVER. W. S. Thayer, M. D., and Simon Flexner, M. D. Dr. Thayer first spoke of the clinical side of the case, as follows: The patient from whom the specimen came was admitted to the Hospital on the 9th of February of this year. He was a single man, 51 years of age, a native of this country. When admitted he complained of chills, fever and sweating. His family history was negative. He had always been a perfectly healthy man excepting for an attack of ague at the age of ten. He had been a barkeeper for 15 years and a hard drinker. He had had gonorrhoea, and had syphilis fifteen years before entrance. The illness of which he then complained began about two months before entrance with an attack of nausea and vomiting. Six weeks before entrance he complained of chilly sensations and severe sweating every morn- ing at about 3 o'clock. The night before entrance he had a very severe chill. His appetite was failing. He had lost 20 or 30 pounds in two months. On examination we found a large well-formed man, with slightly sallowr complexion, but not of a cachectic appear- ance. The pulse was 84 and soft; vessel wrall slightly thickened. The tongue was dry and brown. There was nothing remarkable about the thoracic organs. The rest of the note was as follows : "Abdomen a little full, sym- metrical ; veins quite distinct; soft and painless on pressure. The edge of the liver is indistinctly felt about at the level of the um- bilicus on the right side and in the middle line about 5 cm. above the umbilicus ; it does not feel prominent and the edge is not at all distinct. The upper 1 imit of absolute dullness in the mid-sternal line is at the base of the ensiform cartilage ; in the para-sternal line, at the lower border of the 5th rib ; in the mammillary line, on the 5th rib ; in the mid-axilla, on the 6th rib ; in the nipple line there is 19 cm. of liver flatness. Behind there is flatness at the upper margin of the eighth rib. There is distinct tenderness on deep pressure in the liver region and along the costal margin. There are no enlarged glands." The rectal examination was negative. Urine clear, pale, acid, 1012 ; faint trace of albumen ; microscopically a few hyaline and granular casts were seen ; no diazo reaction. The stools negative upon examination. Amoebae were looked for but none were found. A rectal tube was also introduced, but no amoebae were obtained. The blood was examined on the 11th, two days after entrance, with the following result: Red corpuscles, 3,088,000 ; col- orless corpuscles, 22,500. On the 10th and 11th the patient had shaking chills followed by sweating, the temperature reaching 104.6° on the 10th and 103° on the 11th. Thus we had a man who gave the history of chills and fever. He was pale, had a distinctly sallow look, and appeared like a man with some septic trouble. His only distinct physical sign was a very much enlarged, tender and soft liver. Two days after entrance he had two very severe chills in the afternoon, followed by sweat- ing at night. The diagnosis lay between abscess of the liver and a possible neoplasm. Dr. Osler was inclined to think the case one of abscess of the liver and advised an exploratory incision, an opinion in which Dr. Halsted, who had also seen the case, concurred. In order not to interfere with the surgeons, no puncture was made with aspirating needles. The patient gave absolutely no history of having had diarrhoea or anything like an appendicitis, and it was only after the operation, on further inquiry, that he said he did remember having had during the previous summer a diarrhoea which lasted about four weeks off and on. The patient was transferred to the surgical side on the 12th, and on the 13th Dr. Halsted operated, making an incision about 14 cm. long parallel to and about 3 cm. below the costal mar- gin. The liver was found to be free from adhesions excepting a few far up under the diaphragm. The surface was smooth and the liver appeared to be symmetically enlarged. Aspirating needles were introduced in various directions with a negative result. The abdominal wound was then closed and the needle was introduced in several of the lower intercostal spaces. Finally on introducing the needle in the 6th space, in about the anterior axillary line, after passing through the diaphragm and about 5 cm. of liver substance, the needle passed into a cavity from which about 30 cc. of a brown- ish puriform fluid of an anchovy sauce appearance were removed by the aspirator. A second incision was then made parallel to the first and about 8 cm. above it, and portions of the 6th and 7th ribs were resected. From this opening the pleural cavity was shut off by packing with strips of sterilized gauze. The diaphragm was then incised and the peritoneal cavity shut off in the same way, leaving the surface of the liver exposed for an area of about 6 X 3.5 cm. The patient was then sent back to the ward to wait until adhesions had formed about the opening. The thick puriform fluid I examined microscopically, and found in the fresh specimens no well-preserved cells of any sort-merely a granular debris. In three or four stained specimens not a single well-preserved cell was found ; occasionally a more or less broken off liver cell was seen, but no leucocytes. No bacteria and no amoebae were seen in these specimens. On the 14th Dr. Halsted made an incision into the liver through the opening, and at a depth of about 5 cm. a large cavity was opened, from which 1000-1500 cc. of a fluid escaped similar to that which was obtained by the aspirating needle. A large drainage tube was introduced and the wound packed with iodoform gauze. The patient did well until the 25th, eleven days after the opera- tion, when he had a severe hemorrhage into the wound, from which he never recovered. He died on the 27th, thirteen days after operation. The temperature after the operation ranged between 98.4° and 102°. The contents of the abscess were similar to the fluid obtained on aspiration. No well-preserved cells were found, only an occasional degenerated liver cell. No bacteria were found in the cover-glasses, and cultures were negative, but after some search I found a certain number of quite actively motile amoebae showing every character- istic of the amoeba coli. I think that the presence of a puriform fluid without actual pus cells or bacteria, such as was obtained on the first aspiration, might have justified us in strongly suspecting the presence of the amoeba coli even though the amoebae were not to be found themselves. It is certainly very interesting that from a relatively slight diar- rhoea, of which the patient made no particular note, an amoebic abscess of this sort should have arisen. No other point of origin suggests itself. Dr. Flexner.-This case came to autopsy thirteen days after the operation. There was an incision obliquely along the edge of the ribs on the right side which communicated with the interior. There was a funnel-shaped opening in the outermost part of it which contained gauze. This opening led directly into a cavity in the liver. On account of the fact that an incomplete autopsy was made, the same care which could have been exercised had a com- plete autopsy been permitted was not possible, so that the relations were worked out after the viscera were removed from the body. This cavity in the liver which communicated with the outside was discovered, after removal of the liver, to be in the right lobe and but a short distance beneath the diaphragm. There were very firm adhesions between this cavity in the liver and the abdominal wall. The cavity reached through the entire breadth of the liver, pene- trated through the liver, and on the posterior surface was an abscess cavity having for its boundaries the diaphragm above, the right kidney and suprarenal capsule below, and the abdominal walls to one side and behind. This cavity contained a considerable amount of pus and some necrotic material. The whole of this abscess was almost as large as an orange. The smallest portion of it was the external portion which was in communication with the outside of the body. The contents of the abscess consisted of pus, necrotic material and blood. There was a history of a severe haemorrhage two or three days before the death of the patient. This haemorrhage was traced to a perforation in the inferior vena cava. I have here a portion of the vena cava which was removed with the liver. In the cava are two openings wrhich can readily be seen by holding it up to the light. A portion of the wall of the abscess is made up of the adventitial coat of the vena cava. The contents of the abscess were examined and amoebae, alive and moving, were found in them. In addition to this abscess there were twelve or more abscesses limited to the right lobe of the liver. In addition there were small areas of simple necrosis of tissue. None of these small abscesses contained amoebae, but streptococci in pure cultures were found. In the larger abscess there was found a mixture of bacteria. There were metastatic abscesses in the lung in connection with the pulmonary artery, which were clearly due to infectious emboli which had entered the vena cava and then passed through the right side of the heart to the lungs. There was a considerable clot of blood, as large as a pigeon's egg, in the gall-bladder. Just how it got there we do not know. Although no ulcerations w'ere discovered in the intestine, yet there were evidences of ulceration that had entirely healed. There were several cicatrices in the large intestine and one distinct cicatrix above the valve. I think that this variety of fluid from an hepatic abscess is very suggestive of its amoebic origin. I think that one of the points that Dr. Councilman made out in refer- ence to pure amoebic abscesses was that there was more necrosis than actual pus formation. NOTE ON THE VALUE OF GUAIACOL APPLIED EXTERNALLY AS AN ANTIPYRETIC. BY WILLIAM SYDNEY THAYER, M.D., RESIDENT PHYSICIAN TO THE JOHNS HOPKINS HOSPITAL, BALTIMORE, MD. FROM THE MEDICAL NEWS, March 31, 1894. [Reprinted from The Medical News, March 31, 1894.] NOTE ON THE VALUE OF GUAIACOL APPLIED EXTERNALLY AS AN ANTIPYRETIC. by WILLIAM SYDNEY THAYER, M.D., RESIDENT PHYSICIAN TO THE JOHNS HOPKINS HOSPITAL, BALTIMORE, MD. In The Medical News for January 27, 1894, Dr. Da Costa publishes some interesting clinical remarks on the use of guaiacol externally in reducing high temperatures in typhoid fever and other febrile dis- eases. Following the observations of Sciolla, Bard, Lannois and others, concerning the powerful anti- pyretic action of guaiacol applied in this manner, Dr. Da Costa states that he was induced to try its effect in the "systemic fevers." The guaiacol was applied with a camel's-hair brush, and then rubbed in for fifteen minutes with the hand, or covered imme- diately with an impermeable bandage. Thirty to sixty drops at a time were applied, thirty being about the average dose. A very marked effect on the temperature was noticed, a fall of several degrees occurring through two to three to four hours. The effect was so marked in cases where large quantities were used that Da Costa advises small doses in the beginning-not more than twenty minims, for in- stance, is advised as an initial dose in a temperature of 1030. During the fall in temperature no ill 1 Liebeault: Therapeutique Suggestive, p. 109. Paris, 1891. 2 effects were noted on the pulse or the respiration. In one case, after the temperature had reached its lowest point, there were chills on three occasions, but in the other cases no particular reference was made to excessive sweating or to chills. Dr. Da Costa suggests the possible value of this method of treatment in cases of typhoid fever, in which, for one reason or another, baths are inadvisable. On the appearance of Dr. Da Costa's note we proceeded to test the action of guaiacol in various cases in Professor Osler's wards at the Johns Hopkins Hospital, with results which are perhaps of sufficient interest to note. Guaiacol has been used in all in eight cases. The skin, geneially of the abdomen, was washed carefully with soap and water, and dried. The guaiacol was then painted on with a camel's-hair brush and immediately covered with an impermeable dressing, or else rubbed in for fifteen minutes with the hand, the area being afterward covered with a similar dressing. The results, in brief, are as follows : Case I.-Acute pneumonia ; fall of in tem- perature, with profuse sweating in two hours and a half after the application ofguaiacol,gtt. xx ; chilliness between three and four hours after the application, with rapid return of fever. The patient was a male, eighteen years of age, at the fourth day of the disease (January 30, 1894). The temperature, at 8 a.m., was 102.8° ; at 10 a.m., 103°; at 12 M., 104.2°; at 2 p.m., 103.6°; at 4 p.m., 102.8° ;'at 6 p.m, 99.8°; at 8 p.m., 103.4°; at 10 p.m., 103.6°; at 12 midnight, 104°. At 3.30 p.m., guaiacol, gtt. xx, was rubbed into the abdomen. Between 4 and 6 o'clock there was profuse sweating; 3 between 6 and 8 o'clock chilliness. The pulse fell from 92 to 72 at 6 p.m. ; at 8 p.m. it was 112. The crisis occurred on the following day. Case II.-Typhoidfever ; applications of guaiacol, gtt. xxx (z c.cf, followed by falls in temperature vary- ing from to 4.5° ; profuse sweating ; chills or chilly sensations with the reaction. The patient was a woman, twenty-four years old. On the ninth day of a mild attack of typhoid fever, the temperature being at about 1030, twenty drops of guaiacol were applied to the outer side of the thigh, without previously washing the skin ; no effect was noted. On the two ensuing days six applications of guaiacol, each of thirty drops (1 c.c), were made; the skin was washed and the guaiacol rubbed in with the hand. The falls of temperature varied between 30 and 4%°, the lowest point being reached in from two to four hours. In all instances, shortly after the lowest point was reached there were either chilly sensations or a distinct chill, with a rapid rise of temperature. An example of one of these falls after the application is as follows : On February 1st, the temperature at 4 a.m. was 1020; at 6 a.m., 103.20; at 8 a.m., 99.8°; at 10 a.m., 100.40; at 11 a.m., 103.40. Thirty drops of guaiacol were applied at 6 a.m. ; profuse sweating followed between 6 and 8 o'clock; at 10 a.m. there was a chill. The patient was much relieved by the applications, and expressed a desire that they should be continued. The profuse sweating and the chills or chilliness following the applications had had, however, a visibly weakening effect, and the appli- cations were discontinued. Tub-baths and cold sponge-baths were renewed, and there was an unin- terrupted recovery. Case III.-Pneumonia ; application of guaiacol, ^ss (2 c.c.f followed by a fall of only, o.8° ; further application of gtt xx followed by a fall of 0.2°. 4 A male, aged fifty-four, had acute pneumonia. On February 3d, the third day, the temperature at 8 p.m. was 1020; at 10 p.m., 101°; at 12, midnight, 100.20; at 2 a.m., 101°; at 4 a.m., 101.2°; at 6 a.m., 102.40. Guaiacol, gss, was applied at 10 p.m. At 1.30 p.m., on the following day, guaiacol, gtt. xx, was applied, when the temperature was 103°, with no visible effect. Several counts of the leukocytes, before and after the application of the guaiacol, showed no particular change. Case IV.-Typhoid fever ; application of guaiacol, ^3-75 C-tT), followed by a fall of temperature of about five degrees in three and a half hours; profuse sweating ; chill, with rapid rise of temperature, in about four hours. The patient was a woman, nineteen years of age. On February 6th, in the third week of the disease, the temperature at 4 p.m. was 103.8°; at 6 p.m , IO3-5°; at 8 p.m., 1034°; at 9 p.m., 102.3°; at 10 p.m., 99.8°; at 12 midnight, 97.6°; at 2 a.m., 104.2°; at 4 a.m., 103.2°. Guaiacol, 3j (3.75 c.c ), was applied at 8.30 p.m. ; this was followed by pro- fuse sweating between 9 and 12 o'clock, and a chill between 12 and 2. The dose in this case was (accidentally) larger than those used previously, and the effect was correspondingly more marked. The chill was quite severe. Case V.-Pulmonary tuberculosis; five applica- tions of guaiacol, v^xxx ; falls in temperature vary- ing from 1.2° to 5.8°, occurring in from one to two and a half hours, with profuse sweating and chilliness. The patient was a man, thirty-three years of age, with bilateral pulmonary tuberculosis, with excava- tions. The fever was remittent, with evening exacerbations. The applications in this case were on each occasion thirty minims (2 c.c.) The sweating was so profuse, and the patient complained so bitterly of weakness and exhaustion after the 5 applications, that they were omitted. An example of a moderate fall is the following: On February 15th the temperature at 2 p.m. was 1010; at 2 45 p.m , 102.2° ; at 3.45 p.m, 100.80 ; at 445 p.m., 99.8°; at 6 p.m., ioi°; at 8p.m., 1020. Guaiacol, n^xxx, was applied at 2.30 p.m. ; there was profuse sweating during the fall in tem- perature, and chilliness later on. Case VI.-Pulmonary tuberculosis ; applications of guaiacol, gtt. xx and 7s s respectively ineffectual; fall of 48* in three hours after {3.75 c.c.); chill in about four hours, with rapid return offerer. The patient was a colored woman, thirty years of age, with evidences of infiltration at both apices. She had had a steady, continuous fever, varying for three days from 100.6° to 103.4°. On February 10th, guaiacol, gtt. xx, was applied at 5.30 p.m. ; this was followed by a slight chill at 10 p.m. ; there was no effect on the temperature. On February 19th, guaiacol, $ss (2 c.c.), was ap- plied at 9.20 a.m., the temperature being about 1010, without any effect. On February 19th, the temperature at 2 p.m. was 102 2° ; at 3.50 p.m., 102.8° ; at 4.50 p.m., 103° ; at 550 p.m, 98.8°; at 6.50 p.m.,98°, at 8 p.m., 98°; at 9.30 p.m., 103.6°; at 10.30 p.m, 103°. Guaiacol, 5j (3.75), was applied at 3.50, followed by sweating and a slight chill between 8 and 9.30 o'clock. This patient was a colored woman, with thick skin, hence, possibly, the inefficacy of smaller doses. Case VII.-Acute rheumatism; application of n^xxx (2 c.c.) of guaiacol followed by a fall of 3.4° in four hours, with profuse sweating. The patient was a woman, thirty-two years of age, with acute rheumatism. On February 19th the temperature at 2 p.m. was 101°; at 3.50 p.m., 101.4° ; at 4.50 p.m., 100.4° ; at 550 p m., 99.6° ; at 6.50 6 p.m., 99-2° > at 8 P.M., 98°; at 10 p.m., 1010. Guaiacol, npxxx, was applied at 3.50 o'clock; there was profuse sweating during the fall in temperature. Case VIII. - Typhoid fever; fall of temperature of six degrees in three and a half hours after the application of 2 c.c. (^ss) of guaiacol; profuse sweat- ing ; chill lasting an hour, with a return of the tem- perature in two hours to a point higher than before the application. The patient was a man, twenty-one years of age. On February 3d, the ninth day of the disease, the temperature at 8 p.m. was 104 50 ; at 10 p m., 103 50 ; at 12 midnight, 103 8° ; at 1 a.m., 1040 ; at 2 a m., 1030; at 3 a.m., roo°; at 4 am., 98°; at 5 a m , 103.20; at 6 a.m., 1050 ; at 7 a.m., 104 6°. Guaiacol, 2 c.c., was applied at 1 a.m ; profuse sweating began at 1.45 a.m. ; a chill, lasting an hour, occurred between three and four hours after the application. In almost all of these eight cases the cutaneous application of guaiacol was followed by a marked fall in temperature. In Case II the first application of only twenty drops had no effect. The dose, however, was very small and was applied to the outer side of the thigh without previous prepara- tion of the part. In Case III the results, with twenty drops and with half a dram, were either negative or very slight. This was a case of pneu- monia in a fat man. In Case VII twenty drops and half a dram were followed by slight effect, while a dram (3.75 c.c.) showed a marked result. This case was that of a colored woman, in whom the skin was possibly thicker than in the other patients. The lowest point of the temperature was reached generally in from two to four hours, the average time being between three and four hours. In almost all of the 7 cases there was very profuse sweating, of which in one instance the patient complained bitterly. In the majority of the cases after the lowest point in the temperature was reached there was a rather rapid rise, associated in almost all instances with chilly sensations, in several instances with severe shaking chills, the temperature within two hours generally reaching a point as high or higher than at the time of the application. In none of the instances was there any marked effect upon the pulse or respiration During the fall of temperature there was generally some slowing of the pulse; in the cases in which there were marked chilly sensations with the reac- tion, the pulse was somewhat quickened. In none of our cases were there symptoms of collapse. The urine showed no marked changes. The breath shortly after the application of guaiacol gave a distinct odor of the drug. Hence, while the antipyretic action of guaiacol was certainly very striking in these cases, the profuse sweating, the marked chills, in some instances even with small doses, and the decidedly weakening effect which was noted in those cases in which it was frequently repeated, have led us to take a somewhat less hopeful view of its possible value than Dr. Da Costa's experience would suggest; and these con- clusions would on the whole seem to agree with those which have been reached by the majority of observers who have recently experimented with this drug. Sciolla (quoted by Stolzenburg, Berliner klin. Woch- enschr., 1894, No. 5) used guaiacol in a variety of different febrile affections. He applied the drug with a camel's hair brush to different parts of the 8 body, covering it immediately with a protective dress- ing. The doses used varied between 2 c.c. and 10 c.c. In all cases there was a fall in temperature last- ing between three and four hours, amounting to several degrees C. This fall was generally associated with profuse sweating. After six or eight hours there generally occurred a rapid rise in temperature asso- ciated with a chill or chilly sensations. Shortly after the application of guaiacol the characteristic taste was noticed. Sciolla determined that the drug was excreted in the urine and in the respiration in from five to six hours without deleterious effects. He concluded that, used in this manner, guaiacol is a prompt and harmless antipyretic. Bard {Lyon Medical, June 4, 1893) used the drug by this method in cases of tuberculosis, erysipelas, and pneumonia. At first he used doses of 3 c.c., but soon diminished the doses to 2 c.c. or 1 c.c., or even 0.5 c.c. He noted the profuse sweating in almost all of the cases, and frequently the following chills. He believes that the drug, applied in this manner, may be of value in some cases of tubercu- losis, though he recommends special care in the dose with weak patients. Lannois {Lyon Medical, August 6, 1893) ob- tained exactly similar results in a number of obser- vations. He notes, however, that in some instances the local effects upon the skin may be unpleasant. In one case, for instance, in which the drug was applied on an area on which tincture of iodin had been recently painted, there was marked exfoliation of the skin, while in another, in which the sweating 9 was profuse, the skin over the seat of application was raised in quite large bullae. Stolzenburg (Berliner klinische Wochenschrift, 1894, No. 5) made an extensive series of obser- vations in Senator's clinic with similar results, ex- cepting that he notes the falls in temperature as last- ing rather longer-between five and eight hours. At the time when the lowest point was reached there was, in a majority of instances, chilliness, or a defi- nite chill, with a rise in temperature to a point even higher than before. There was almost always pro- fuse sweating. In weak patients he has seen symp- toms of collapse. While in most instances no ill effects on the respiration and pulse were noticed, the patients often complained of the weakening effect of the sweating. In a few instances a dark color of the urine was noted, similar to that seen in carbolic- acid poisoning. In his conclusions Stolzenburg states that the initial dose should not be above 2 c.c., and that it should probably never be above 4 c.c. on account of the danger of collapse. On account of the weakening sweats and chills, with the reactive fever, he concludes that the continued use of guai- acol is not to be recommended. It will be noted that all observers agree as to the efficacy of guaiacol applied externally. Its employ- ment has been so far limited to the fever of infec- tious diseases of various sorts, but in all it has been efficacious. There can be no doubt also that it is absorbed directly through the skin. Lannois (loo. cit.') tested in three cases the inhalation of guaiacol in considerable quantities for a considerable time, but without effect. Stolzenburg (loe. cit?) tried similar 10 experiments with Curschmann's mask. More re- cently Linossier and Lannois {Comp. rend. hebd. de la Soc. de Biol., February 9, 1894) have shown that while a small amount was actually absorbed by inhalation, as proved by its appearance later in the urine, this quantity was insufficient to affect the temperature. Its elimination has been shown by Sciolla and Lannois to take place by the urine and the respiration. The early appearance of the taste sug- gests that it appears in the saliva. The elimination, according to Sciolla {loo. cit.'), is accomplished in from five to six hours. Lannois and Linossier have shown that in most instances traces appear in the urine a quarter of an hour after the beginning of the application. The part to which the guaiacol is applied would appear to have some influence upon the rapidity and thoroughness of the action. This would be suggested by the result in Case II of our series, in which the first application on the external part of the thigh showed no result, while afterward doses but slightly larger applied to the abdomen were so efficacious. There is, of course, no difference in the effect of guaiacol absorbed through the skin from that which follows its introduction into the system in other manner. Lannois, for instance, showed that its action in enemata was exactly the same, the effects appearing in almost the same time. In one instance we have made a similar experiment, the patient being the same colored woman who figures in Case VI in the earlier part of this note. On March 4th the temperature at 8 a.m. was 100.70 ; at 12 m., ioo 20; at 4 p m., 99.8° ; at 5 p.m., (?); at 6.30 p.m., 100.8° ; at 7.30 p.m., 98.8° ; 11 at 8.30 p.m., 970; at 9.30 p.m, 95.20 ; at 10.30 p.m., 96 8°; at 11.30, 97.20; at 12.30, 97.3°; at 4 a.m., 104.20; at 5.30 p.m. guaiacol, 2 c.c., was given by enema. At about 12.30 there were well marked chilly sensations; there was, however, no very marked sweating. The urine after the appli- cation showed a well-marked, smoky, greenish-brown color. Interesting as may be these results concerning the antipyretic action of guaiacol, there is really little that is new, excepting in so far as they prove the readiness of its absorption through the skin. Ex- actly similar effects have been shown from the hypo- dermatic and rectal use of creosote, of which drug guaiacol forms the most important part. Lepine, who used creosote hypodermatically (Se- maine Medicale, 1890, No. 20, page 221), noted marked sweating after the injections. Gimbert (Gaz. hebd., Paris, 1891) also noted sim- ilar results from the subcutaneous introduction of creosote-i. e., the sweating, the fall of temperature, the chill with reactive rise in temperature. Revillet (Semaine Medicale, 1891, page 266) used creosote by enemata in doses of from 2 c.c. to 4 c.c. He noted the almost immediate taste of the drug in the mouth, the elimination by the respiration, by the urine, by the saliva, the well-marked antipyretic action, with the profuse sweating, and the subsequent disagreeable chilly sensations. Though the creo- sote was free from carbolic acid, he noted in one instance, two hours after a dose of 3 c.c., a well- marked dark color in the urine. The exact simi- larity of all these results with those formerly obtained by the administration of carbolic acid may be noted. 12 Lannois {Lyon Med., 1882, No. 30), for instance, in speaking of the results of the treatment of typhoid fever by carbolic acid, notes the same train of symp- toms-the fall in temperature with profuse sweating, the reactive chill and rise in temperature, the dis- coloration of the urine. This similarity is, of course, not remarkable when one considers the close chemic relation between guaiacol and carbolic acid. In conclusion, then, from the few experiments which we have made here, and from a consideration of the results obtained by other observers, we are perhaps justified in asserting that guaiacol applied to the skin is readily absorbed into the economy; that its ap- plication is followed in most instances of fever by a gradual reduction in temperature, which reaches its lowest point generally between three and four hours after the application; that this fall of tem- perature is almost always associated with disagree- ably profuse sweating; at a variable period, usually a short time after the lowest point is reached, the temperature rises rapidly, generally in association with marked chilly sensations, if not with an actual chill; that a dose of more than 2 cc. is rarely advis- able ; that exactly similar results are produced by the absorption of guaiacol through any other channel (the rectum, or the subcutaneous tissues) ; that the antipyretic action is exactly similar to that which has been previously observed to follow a corresponding use of creosote and carbolic acid; that owing to the disagreeable effects of the immediate application of guaiacol (sweating and chilliness) and the weakening effects of the continued use, its employment as an antipyretic, as in the case of carbolic acid and creo- sote, will probably have but a limited application. The Medical News. Established in 1843. A WEEKLY MEDICAL NEWSPAPER. Subscription, $4.00 per Annum. The American Journal OF THE Medical Sciences. Established in 1820 A MONTHLY MEDICAL MAGAZINE. Subscription, $4.00 per Annum. COMMUTA TION RA TE, $7.50 PER ANNUM. LEA BROTHERS & CO. PHILADELPHIA. TWO CASES OF POST-TYPHOID ANEMIA, WITH REMARKS ON THE VALUE OF EXAMINATIONS OF THE BLOOD IN TYPHOID FEVER. By W. S. THAYER, M.D., First Assistant in the Medical Clinic of the Johns Hopkins Hospital, Baltimore, Md. From the Johns Hopkins Hospital Reports, Vol. IV, No. 1, Baltimore, Md. TWO CASES OF POST-TYPHOID ANAEMIA, WITH REMARKS ON THE VALUE OF EXAMINATIONS OF THE BLOOD IN TYPHOID FEVER. By W. S. THAYER, IV!. D., First Assistant in the Medical Clinic. While the changes in the blood during the course of typhoid fever have been studied by many observers, but little attention has been paid to the fact that a post-typhoid anaemia may in some instances become so profound as to be of itself a grave complication of the disease. LeCanu(2) (1837) found a diminution in the number of corpuscles in two cases of typhoid fever. Andral and Gavarret(4) (1840) called attention to the unusually large proportion of red corpuscles present at the beginning and throughout the first part of the febrile period, a con- dition which they thought was due to the fact that most of the patients were young and healthy individuals. They state that while a fall in the number of corpuscles takes place during the fever, it is unimportant and due largely to the treatment by bleeding. Simon(5) (1842) noted that while the blood at the beginning of the attack and during the febrile period showed a normal or increased number of corpuscles, there was an anaemia during convalescence. Bequerel and Rodier<7) (1844) denied that the proportion of red blood corpuscles was ever actually increased, and asserted that the effect of typhoid fever on the blood was the same as that of any severe disease, namely, a marked diminution in the number of red corpuscles, a diminution which was probably increased by the frequent venesections. Popp(8) (1845), in ten cases, noted that with a normal or increased number of corpuscles in the beginning there was a gradual diminution during the fever. Jansen(10), in 1847, described a case of fatal anaemia with enlarged spleen coming on after a fever which may have been typhoid. No examinations of the blood were noted. Otto(11) (1848) found also a moderate falling off in the number of corpuscles. Welker(U) (1854) found a slight anaemia in three convalescents; the lowest point reached was 3,200,000. Denis(13) (1859) found in one case, on the fifteenth day, a decided diminution in the proportion of red corpuscles as well as of the other albuminoid constituents of the 84 W. S. Thayer. [84 blood. Jaccoud(16) (1863) held that the red corpuscles suffered in typhoid fever just as they did in any acute disease. Ernesti0^ (1864) reported an interesting case of post-typhoid anaemia which deserves repetition. A man, aged forty-six, previously healthy, passed in the early fall through a severe fever which was associated with consider- able diarrhoea. Though he recovered from the attack and was able to leave his bed, he was never strong enough to return to his occupa- tion, and in February, on account of progressive loss of strength and oedema of the dependent parts, he entered the hospital (Greifswald). The most striking symptoms were the excessive pallor, the soft and rapid pulse and the oedema. The temperature was normal; the spleen was not enlarged. The anaemia increased steadily and the patient died five months later. There was diarrhoea at times, and during the last three weeks of the patient's life there was a moderate daily evening rise in the temperature. Four weeks before death, dulness on percussion with a prolonged expiratory murmur were noted just below the left clavicle. No mention is made of any examination of the blood. On autopsy, beyond undoubted evidence of a previous typhoid fever, freshly cicatrized ulcers, and the extreme emaciation and anaemia, there was found to be a marked atrophy of the mucous membranes of the ileum and jejunum. There were also areas of tuberculous consolidation in both lungs, a cavity as large as a walnut at the left apex, and fresh tuberculous pleurisy. Consid- ering the history of the case, the author believes that the tuberculosis had no influence on the development of the anaemia, but was, on the other hand, itself secondary process. See(18) (1866) admits that the anaemia which develops in typhoid fever may be so severe as to mate- rially retard convalescence. Gautier(28) (1874) notes an anaemia developing, during the course of typhoid fever. Bonne(25) (1875) found a marked anaemia in two cases-2,500,000 and 2,400,000 red corpuscles per cubic millimetre. The lowest point in the latter case was reached on about the twentieth day, after which there was a gradual rise to normal. Sorensen(27) (1876), in eleven cases examined during the febrile period, found eight with more or less anaemia; while in three patients who were cyanotic and moribund, the pro- portion of red blood corpuscles was normal in two instances and somewhat increased in the third. These last three cases of Sorensen were doubtless instances of an actual condensation of the blood. That this condition does occur has been very clearly shown by 85] Post-Typhoid Ancemia. 85 Brouardel<26) in his studies on the blood after purging and in conditions of inanition. The writer(53) has also reported two cases of a similar nature. Arnheim(30) (1879) in one case found but a slight change in the blood during the febrile period. Baxter and Willcocks(31) (1880), after examining the blood in six cases, state that "enteric fever, even where it directly threatens death, does not seem to affect either the number or the quality of the red corpuscles to any marked extent." All of the examinations, however, were made at the height of the fever. Zaeslein(32) (1881), in thirty-seven cases, noted that the number of red corpuscles in the cubic millimetre began to diminish perceptibly only after the fever had lasted for some time. As soon as the fever was over, if there was still a further diminution in the body weight, there was a slight temporary increase in the number of red corpuscles per cubic millimetre. As soon, however, as the body weight began to increase, that is, at the beginning of convales- cence, there was a rapidly developing oligocythsemia, which was most marked at the time of the first appreciable increase in weight. This oligocythsemia is more severe than that occurring during the febrile period, and lasts usually for weeks and possibly for months; relapses and complications cause, of course, vari- ations in these conditions. The post-typhoid polycythsemia, when it occurs, is due, he thinks, to a concentration of the blood from the loss of fluid constituents, while the post-febrile oligocythaemia is due to a more rapid increase in the fluid constituents of the blood than in the formed elements. Halla(33) (1883) in fifteen cases found during the febrile period a diminution in the red blood corpuscles amount- ing on an average to 200,000, while in convalescence he found a marked fall, the blood-count in one case being as low as 2,162,000. Laache(34) (1883) in thirteen cases found a constant diminution in the red corpuscles Averaging 18 per cent. This was independent of hemorrhages or unusual complications. Malassez(86) (1883), as the result of numerous observations, says: (1) In typhoid fever the proportion of red corpuscles is subject to the same variations as in health; for instance, a severe diarrhoea may cause a marked temporary increase in their number; (2) apart from these fluctua- tions, the proportion of red corpuscles changes but little during the height of the fever, but falls markedly with defervescence, to rise again progressively after the beginning of convalescence. Robin,("5) on the other hand, is quoted by Hutinel(S6) as saying that on examina- 86 IF. & Thayer. [86 tion of the urine during typhoid fever, one finds that those pigments which appear to be derived from the destruction of the haemoglobin are found in normal or diminished quantities, while those which come from an increased corpuscular destruction are absent or very rare. If, however, there is an inflammatory process in connection with the typhoid fever, then the red corpuscles diminish in number and the pigments derived from them begin to appear in the urine. Holst(87) (1885) reports a case of typhoid fever complicated with a grave (" pernicious ") anaemia in a young girl of 20 which ended fatally at about the beginning of the third week. The anaemia, however, apparently preceded the fever. Leclerc(38) (1887), in an interesting study of the effects of the cold bath, antipyrin and acetanilide on the blood in ten cases of typhoid fever, concludes that the cold bath alone has little if any effect on the blood corpuscles. While antipyrin has but a slight effect, acetanilide has a deleterious action. In the three cases treated with the cold bath alone, the diminution in the number of red corpuscles was moderate. Tumas(40) (1887) in twenty cases found that while the number of red corpuscles was normal or even increased at the beginning of the process, it diminished gradu- ally during the fever, but showed a more marked and sudden falling off at the beginning of the afebrile period. This anaemia lasted for a considerable time, as the blood was restored very slowly to its normal condition. Hayem(41) lays more stress upon the importance of this post-typhoid anaemia. According to him, the number of corpuscles per cubic millimetre is but slightly modified during the first weeks of the disease. It oscillates between 4,500,000 and 5,000,000, and sometimes more, a fact which he thinks can only be explained by supposing a very slight destruction of corpuscles, or an actual con- densation of the blood as a whole. This condensation, he thinks, cannot be doubted in some cases. He has, in fact, seen as a result of profuse sweating or very profuse diarrhoea, a sudden increase in the number of corpuscles to a point even above normal, in one case as high as 5,700,000, a phenomenon comparable to that which is seen in the algid stage of cholera. During the course or towards the end of the third week there is a rather sudden diminution in the number of red corpuscles, which have so far resisted the process of the disease. The continued fever is, he believes, the principal cause of this destruction of the red corpuscles, as in the milder cases there is but little change in the number of the colored elements. In one 87] Post-Typhoid Anosmia. 87 case in which death occurred on the fifty-third day of the disease, the blood contained at that time only 2,500,000 red corpuscles with a corpuscular value of 1,950,000. Haemoglobin. With regard to the haemoglobin, Welker,(18) Naunyn,(20) Quincke,(21) and Quinquaud(22) found little change in the amount of haemoglobin during the febrile period. Arnheim(30) noted no great change in four examinations during the earlier part of the fever, but a slight diminution in one case in the fourth week. Leichtenstern(28) noted that during the fever in the first, second and third, or even fourth week, there was but little change in the amount of haemoglobin, while with the beginning of convalescence the curve sank rapidly. He found in one case with a relapse a fall, followed by a rise during the relapse, with a second fall afterwards. He suggests that this post-febrile oligochromaemia is due to a more rapid increase in the water, albumin and salts in the blood than in the red corpuscles-i. e., to a relative thinning of the blood, an opinion which agrees with that of Zaeslein. Laache and Tumas both note a considerable diminution in the amount of haemoglobin, the curve running nearly parallel to that of the corpuscles, but being somewhat lower. Laache(34) (twelve cases) disputes the statement of Leichtenstern that the fall in haemoglobin occurs in the beginning of the afebrile period. He found that in all but one case the minimum of haemoglobin occurred towards the end of the fever. He asserts also that the fall is more gradual. Ollivier(39) mentions a case of chlorosis in a young girl apparently following typhoid fever. Hayem notes also that the oligochromaemia is rela- tively greater than the oligocythaemia. Colorless corpuscles. Virchow,(9) in his article on the white corpus- cles and leukaemia and also in the Cellular Pathology,(19) assumes that a certain amount of leucocytosis must follow the hyperplasia of the lymphatic tissues affected in typhoid fever. He quotes Allen Thompson,(6) who says that in about a dozen cases of an epidemic fever occurring in Edinburgh he found a distinct leucocytosis. It is probable, however, that this fever was typhus and not typhoid fever. He also quotes a case of Andral(1) in which the blood of a patient with typhoid fever, dying in the third week, looked like that which escapes from an abscess opened before maturity. This case was, however, complicated with pneumonia of the left lower lobe. Bonne(25) examined the blood of three cases and found in all a [88 88 W. S. Thayer. small number of leucocytes during the height of the fever, but in two an increase at the beginning. In one of these the proportion of color- less to red corpuscles was 1 to 120 on the eighth day, but normul throughout the rest of the time. In the other case, which he saw first on the sixth day, he asserts that he found 47,000 leucocytes to the cubic millimetre, while on the seventh there were 62,000. On the following day there were but few leucocytes, and on the ninth in three counts (Hayem's method) he found none-an interesting and unique observation. It is worth mentioning, perhaps, that some of his other counts of leucocytes are unusually high. Bonne also found a slight temporary leucocytosis in one case at the beginning of con- valescence; this was probably associated with certain suppurative complicating processes. On the other hand it has been generally recognized by almost all recent observers, as well as by some of the older ones who have investigated this special point, that there is not only no increase in the proportion of colorless corpuscles (leucocytosis) during the fever, but that, on the contrary, there is rather a ten- dency toward a diminution in number at the height of the disease. Many of the older authors call attention to the fact that the fibrin in the blood is diminished during typhoid fever, in contradistinction to the increase always observed in acute inflammatory affections. Raci- borski(3) in 1839, as the result of the inspection of the clot obtained from the first blood-letting in a large number of cases of typhoid fever, noted the almost complete absence of the buffy coat, a striking- contrast to the increase which is always observed in acute inflamma- tory processes. He asserts that in a case of typhoid fever in which the buffy coat is well marked we may be sure that a complicating inflammatory process exists. Durozier,(12) Sorensen/27) Halla(83) and Tumas(40) all note the absence of leucocytosis. Tumas thinks that the proportion of colorless corpuscles may be slightly diminished at the height of the disease. Hayem(41) finds that the leucocytes diminish appreciably during the fever, sometimes reaching a point as low as 1000 per cubic millimetre, often falling under 2000. Pee(42) found in two cases a diminution in the number of leucocytes. Ouskow(48) and Khetagurow(46) note also the diminished proportion of colorless corpuscles, the latter in three cases finding that the number of leuco- cytes fell gradually, reaching its lowest point (2500 to 3000) at about the end of the third week, and beginning at the end of lysis to return to the normal, which is reached by the sixth or seventh week. 89] Post-Typhoid Anosmia. 89 In a considerable number of observations in Prof. Osler's clinic we have been able to confirm essentially the views of the majority of these writers. At the beginning of typhoid fever the blood shows generally a normal number of red corpuscles, and often, as the indi- viduals are commonly strong and healthy, the upper limit of normal may be reached. During the height of the fever there is generally a moderate and gradual diminution in the number of corpuscles, which often becomes more accentuated toward the end of the fever,* the most marked anaemia being reached at about the beginning of convalescence. The recovery from this anaemia has been in most instances rather slow.f The haemoglobin falls with the corpuscles, but usually to a somewhat greater extent. The colorless corpuscles, which at the beginning are about normal in number, fall gradually during the fever, reaching a slightly subnormal number and return- ing to the normal point again with convalescence. We have not noticed in our cases the slight leucocytosis at the beginning of con- valescence which Bonne believes to be the rule. It should be remembered that intercurrent inflammatory processes, as well as certain methods of treatment, may have a marked influence on the proportion of leucocytes in the blood. Cold baths, for instance, have been shown by Winternitz(50) and the writer(51) to be followed by a decided temporary increase in the number of colorless corpuscles. It is perhaps more probable that this increase in the leucocytes after cold bathing is the result of local conditions on the surface of the body, whence the blood for examination is obtained, rather than that it is a true leucocytosis. We have never seen any large white elements containing red blood corpuscles as described by Eichorst.(24) In most of the cases which we have observed, the degree of anaemia following typhoid fever has been but slight, an observation agreeing with those of the majority of the above-mentioned authors. Few of these observers have, however, laid stress on the fact that this post- typhoid anaemia may be severe enough to form of itself a grave com- plication of typhoid fever, and for this reason the two following cases may be of interest. * It is not impossible that the suddenness of the fall may depend to some extent on the presence or absence in the earlier stages of diarrhoea or sweating, which might, through the resulting concentration of the blood, mask temporarily the first corpuscular losses. t We do not refer here to the grave anaemia which may be produced by certain drugs such as pyrodin (Lafleur<44>). Our observations have been wholly on cases which have been treated entirely by the cold bath. 90 W. S. Thayer. [90 Case 1. C. C., single, aged 30, a native of Italy, was admitted to the Johns Hopkins Hospital on November 17, 1890. He was a fireman on a steamer and had been but seven days in Baltimore, whither he had come from Port Antonio, Cuba. He spoke but little English and the history was not as full as could be wished. The family history was good so far as could be made out, and the patient asserted that he had always been healthy and strong. The illness of which he then complained began quite sharply seven days before entrance, with headache, general pains and feverish sen- sations. There was no cough, no nose-bleed, no vomiting, no actual abdominal pain, though he complained of a "heavy feeling" in the abdomen and an aching pain in his back and legs. There was anorexia and at times nausea. Present condition. On entrance he was found to be an able-bodied man. The lips and mucous membranes were of good color. The face and upper part of the thorax were flushed; the conjunctivae injected. The tongue showed a thin brownish fur; edges clean and indented. The temperature on admission was 104.5°, and rose later in the afternoon to 106°; pulse 96, dicrotic; respiration 30. The lungs were everywhere resonant; the heart sounds were clear and normal; possibly a very faint systolic murmur at the base ; cardiac impulse normal. The abdomen was not distended, and showed no eruption beyond a rose-red papule in the epigastrium and two rather deep-colored papules on the left side. There was slight tenderness in the right iliac fossa. Hepatic flatness extended from the sixth rib to the costal margin. Edge of the spleen palpable, soft, not sharp; splenic flatness from the ninth to the lower border of the eleventh rib to the costal margin. The pillars of the fauces and pharynx were somewhat swollen and congested. The blood showed no malarial organisms. A liquid diet was ordered, 180 cc. of milk or broth every two hours, and tub-baths at 70° every three hours if the rectal temperature was above 102.5°. From the 18th to the 21st the temperature ranged between 98.2° and 105.4°. The fall of temperature after the baths was in many instances very marked, on one occasion amounting to nearly six degrees. November 22nd.-The temperature during the past 24 hours has risen as high as 105°; the patient has had four baths; is a little nervous, not delirious; pulse 130, not so dicrotic; no fresh typhoid eruption. 91] Post-Typhoid Anaemia. 91 November 23rd.-The patient is quite rational; tongue a little dry; slight lividity of surface; fever tends to reach 104.5° between the baths; pulse 96 to 120, quite compressible, distinctly dicrotic. Car- diac sounds very faint at apex, the first sound being especially weak. Breathing clear at the bases, no rales; has been having 180 cc. of w'hiskey during the twenty-four hours, against which he rebels. Port wine, 350 cc. in the twenty-four hours. November 24th.-The pulse is soft and compressible; it has lost its dicrotic character entirely. Superficial veins dilated ; no definite rash ; heart sounds feeble. Patient has had diarrhoea ever since entrance; has now about five liquid stools a day. November 25th.-Delirious; involuntary micturition and defae- cation. November 28th.-Patient seems a trifle better; pulse 108, dicrotic, occasionally dropping a beat. Heart sounds feeble; no murmur. Urine clear, acid, 1013, trace of albumin, numerous hyaline and finely granular casts; epithelium and mucous cylindroids; diazo reaction present. November 30th.-The temperature has fallen somewhat; patient, however, seems very feeble, though he is quite conscious. The bases of the lungs are clear. December 1st.-The pulse is feeble; there is some subsultus; patient is rational but drowsy; the diarrhoea has entirely disap- peared. The patient is very anaemic. From this time on the fever diminished; the temperature on December 2nd touched a normal point. The anaemia, however, appeared to increase in intensity. The patient was of a waxy pallor, and the throbbing of the carotids was striking. From the 5th to the 20th the temperature was most of the time above 99°, touching a point between 100° and 101° daily, occasion- ally above 101°. The patient was extremely anaemic and very feeble. December 16th.-Splenic dulness extends from the eighth rib to the lower border of the tenth. The patient is profoundly anaemic. December 21st.-Urine free from albumin. The patient slowly improved, without further interruption, excepting for a slight febrile attack between the 6th and 10th of January, for which no cause could be found. The spleen remained enlarged and the anaemia was very marked, and it was not until the 20th of January that the patient was allowed to get out of bed. This was followed by dizzi- 92 W. S. Thayer. [92 ness and marked oedema of the legs, and after about five days the patient was put to bed again. Again on the 13th of February he was allowed to sit up, but even at this time he still developed con- siderable oedema of the legs. From this time on, however, he made a satisfactory improvement. At the time of his discharge, March 13th, the patient considered himself well, though he was still some- what pale. He had gained 28 J pounds. While on entrance the patient presented the appearance of a man with at least a normal condition of his blood, by the time he had been in the hospital for two or three weeks he began to show evi- dences of marked anaemia. The blood, counted for the first time on December 11th, the thirty-first day of his disease, showed red cor- puscles 1,996,000; colorless corpuscles 5,500. The accompanying chart shows the blood-counts and estimation's of haemoglobin that were made during the patient's stay in hospital. The count was unfortunately not made on entrance, but it is safe to say that the number of corpuscles must have been normal, as the patient was a strong, large man with a very full color. The appearance also of the dried specimens was sufficient evidence that the blood was in a normal condition. The following examinations of the blood were made : The Thoma-Zeiss blood-counter and the von Fleischl haemometer were used. In counting the blood, the whole or one-half of one field* of blood in the Thoma-Zeiss instrument was counted for the corpuscles, the cell washed, and the same process repeated from one to three times more, the mean of the counts being taken. At least four whole fields of the blood-counter were always counted for the colorless corpuscles. Where the number of the colorless corpuscles was rela- tively constant, the mean of the four fields was taken; otherwise five or six, or in several instances seven fields were counted. In this way a fair estimate was probably obtained of both varieties of corpuscles. Toison's solution f was used to dilute the blood. The dilution was usually 1 to 200. Dried cover-glass specimens were examined after the method of Ehrlich.(3S) These were first heated for from one to *By this is understood the whole 400 squares. t Sodii chloridi 1. Sodii sulphatis 8. Glycerini pur. (neutral at 30° C.) 30. Aquae 160. Methyl violet 5B 0.025 Methyl violet from Merck's or Grubler's laboratories gives good results. 93] Post-Typhoid Anosmia. 93 two hours on a copper plate, at a temperature between 100° and 120° C. They were for the most part stained with the triple stain of acid fuchsin, methyl green and orange G. In other instances eosin and methylene blue, or a stain of eosin, nigrosin and aurantia in glycerine were used. Differential counts of the leucocytes were made upon a movable stage of Zeiss's construction. The Zeiss oil immersion lens was used, and eyepieces Nos. 2 and 4. On November 19th, approximately the tenth day of the disease, the examination of stained specimens showed an essentially normal blood. The red corpuscles were natural in appearance, showing no undue variation in size, shape, or staining propensities. The differential count of 1000 leucocytes showed : Lymphocytes* 8.7 per cent. Large mononuclear leucocytes 22.5 " " Transitional forms 1. " " " Multinuclear " neutrophilic leucocytes ....66. " " Eosinophiles 1.8 " " In these differential counts the leucocytes were divided according to Ehrlich's classification, which he gives in the Charite Annalen, 12 Jahrgang. (1) Lymphocytes, small cells approaching the red corpuscles in size, the body of which is filled with a large, round, deeply staining nucleus, while the protoplasm is represented by a small ring about the nucleus. (2) Mononuclear leucocytes, larger cells which have a relatively large oval or ovoid, less deeply staining nucleus, and a relatively large amount of protoplasm. (3) Transitional forms, cells of a similar appearance to the fore- going, which differ from them only in that the nucleus shows certain indentations which may give it the appearance of an hour-glass. (4) The so-called " multinuclear "f elements, which are perhaps a * It would be more correct to call this first class "small mononuclear leuco- cytes<49>," as it includes some small transparent forms. I have decided, however, to publish the counts and remarks just as they appear in my notes. f The terms " multinuclear " and " polynuclear '' are incorrect, as the nucleus is really single, though polymorphous. In Germany the term " polymorphkernige leucocyten '' is common and much better, and we should be more correct if we used in English some such term as poikilonuclear, in the absence of a better transla- tion. It is a question, however, whether it is advisable to add any more terms to those now existing in the classification of the various formed elements of the blood, and it seems, on the whole, best to continue at present using the terms " multi " and " polynuclear," protesting at the same time against their inaccuracy. 94 W. S. Thayer. [94 trifle smaller than the large mononuclear, and show the characteristic polymorphous nucleus. These cells contain a thick, neutrophilic granulation. (5) Eosinophilic leucocytes, similar cells, usually "multinuclear," containing the larger and more refractive eosinophilic granules. As a general thing, the protoplasm of the lymphocytes takes with the triple stain a red violet color, while that of the large mononuclear elements has but a slight affinity for coloring matters. There exist, however, in all bloods, a number of mononuclear and some " multi- nuclear " elements, which have a protoplasm which remains entirely unstained, looking like a white spot or small vacuole in the middle of the stained specimen. By far the greater part of these elements were included under the large mononuclear leucocytes in these counts, though it must be said that a certain distinct though small proportion were considered in the class of lymphocytes. In this first count a very considerable number of the large mononuclear leuco- cytes and a few of those classed under the head of lymphocytes showed a perfectly hyaline, transparent protoplasm. From this time until the 11th of December, no examination of the blood was made. It had been noticed for some little time that the patient had been developing a marked anaemia. December 11th, thirty-second day of the disease.-Red corpuscles, 1,996,000; colorless corpuscles, 5,500; no estimation of the haemo- globin. December 15th, thirty-sixth day.-Specimens of blood stained with the triple stain showed some difference in the size of the red corpus- cles; no marked poikilocytosis. The leucocytes appeared to be present in a slightly subnormal, or at all events not an increased number. Differential count: Lymphocytes 20.6 per cent. Large mononuclear leucocytes 15.4 " 11 Transitional forms 2.0 " " " Multinuclear " neutrophiles 52.2 11 " Eosinophiles 9.8 " " A considerable number of mononuclear leucocytes with transpar- ent protoplasm were seen. As before, however, the majority were classed under the head of large mononuclear leucocytes, some in the column of lymphocytes. Occasional small leucocytes with transpar- ent protoplasm and polymorphous nuclei were seen. 95] Post-Typhoid Anaemia. 95 December 18th, thirty-ninth day.-Red corpuscles, 2,140,000; colorless corpuscles, 4,000 ; haemoglobin not estimated. The stained specimens showed the same condition as on the last examination ; the specimens were not so good. There were numerous distorted and broken leucocytes on the cover-glasses, which appeared to be mainly large mononuclear elements. The differential count, which was therefore not so reliable, showed : Lymphocytes 19.4 per cent. Large mononuclear leucocytes 10.3 " a Transitional forms 2.7 " " " Multinuclear " neutrophiles 54.5 " " Eosinophiles 12.8 " " Two nucleated red corpuscles of the normoblastic (Ehrlich) type were noted. From this time on no further differential counts were made until the day of discharge. During the next several weeks numer- ous stained specimens were made, and for a short time after this the nucleated red corpuscles were found to be more numerous. They were always of the normoblastic type. December 29th.-Red corpuscles, 2,464,000; colorless corpuscles, 5,000. January 8th.-Red corpuscles, 2,424,000; colorless corpuscles, 4,000; haemoglobin, 32 per cent. January 15th.-Red corpuscles, 3,551,000; colorless corpuscles, 7,000; haemoglobin, 56 per cent. January 26th.-The patient has been sitting up and walking about for several days. There has been oedema of the feet. Red corpus- cles, 3,152,000; colorless corpuscles, 10,000; haemoglobin, 47 per cent. February 9th.-The patient has been kept in bed since last entry. Red corpuscles, 3,897,000; colorless corpuscles, 8,000 ; haemoglobin, 56 per cent. February 25th.-The patient has been up and about for a week or ten days. Red corpuscles, 3,325,000; colorless corpuscles, 4,500; haemoglobin, 59 per cent. March 13th.-The patient was discharged to-day, 123 days after the beginning of his illness. Red corpuscles, 4,604,000; color- less corpuscles, 9,000; haemoglobin, 70 per cent. The stained 96 W. S. Thayer. [96 specimens showed essentially a normal blood. The differential count showed: Lymphocytes 13.2 per cent. Large mononuclear leucocytes 2.7 " " Transitional forms 1.0 " " " Multinuclear " neutrophiles 70.4 " u Eosinophiles 12.7 " " Case 2. E. H., aged 25, fireman, was admitted to the Johns Hopkins Hospital on the 17th of December, 1890, complaining of fever, headache and general pains. Family history. Father and mother living and well; the patient knows of no hereditary disease in his family. Personal history. He has always been in good health excepting for an attack of pneumonia and "acute gastritis" about eight years ago. About a week ago he suddenly began to complain of feverish- ness and chilly sensations, severe headache, pains in the limbs and back, and some abdominal pain. The bowels have been constipated; no bleeding from the nose; slight cough at times. Has not worked for a week. On admission to the hospital he was quite rational and answered questions promptly, but at times during the rest of the day he was somewhat delirious. December 18th.-Present condition: Sunburned, flushed, eyes bright, pupils normal; tongue dry and brown in the middle. Tem- perature on admission 100°; pulse 108, dicrotic; respiration 48. Lungs clear on percussion, now and then a sibilant rale is heard on auscultation. Heart sounds clear at apex and base. Abdomen full, tympanitic, no rash. Spleen not distinctly palpable. Some tender- ness in the upper part of the right iliac region. The blood showed no malarial organisms. Urine high-colored, acid, trace of albumin ; diazo reaction well marked. A liquid diet was ordered, milk and broths, 180 cc., every two hours; tub-baths at 70° every three hours when the rectal temperature was above 102.5°. December 20th.-The temperature has ranged between 100° and 105.4.° The falls in temperature after the baths have been moder- ate. Has had nine baths. The abdomen is soft, no rose spots; spleen not palpable; urine acid, specific gravity 1010, trace of albu- min ; diazo reaction not so marked. 97] Post-Typhoid Anosmia. 97 The temperature after the 20th gradually fell, on the 26th between 8 a. m. and 8 p. m. touching no point higher than 100.8°, and on the 28th being under 100°. The general condition of the patient improved on the whole, excepting for a very marked and rapidly developing anaemia. From the 31st of December throughout Janu- ary the temperature touched nearly every day a point above 101°, and at times above 102°, while occasionally it would reach a point as low as 97° or 98°. On the 10th of January the patient was profoundly anaemic; skin of a waxy pallor; pulse very soft, carotids throbbing. Fowler's solution was ordered, Ill iib three times a day. This was increased to F[iv on the 14th. On the 22nd of January the edge of the spleen was to be made out 4 cm. below the costal margin. The patient has been improving in many ways and the diet has been materially increased, but the grave anaemia still remains and the patient is very feeble. From the 5th of February to the 20th the temperature ranged between 97.4° and 100.6°, rarely reaching a point as high as 100.5°. On the 13th the patient, though still very anaemic, was allowed to sit up out of bed. February 21st.-Patient had yesterday a slight chill, at noon the temperature rising to 103.2° and remaining elevated throughout the day. The spleen is still enlarged. The blood shows no malarial organisms, no leucocytosis. The temperature to-day is normal. February 23rd.-Temperature was normal on the 21st from 8 a. m. to 12 m., when it began to rise, and at 6 p. m. was 102°. This was followed by sweating; no actual chill. Temperature fell to 97.2° at 8 a. m. No pain, no cough or expectoration; no rose spots visible. Abdomen full, not tense. From this time on the tem- perature was practically normal. After a few days' rest in bed the patient was allowed to sit up again and made an uninterrupted recovery, leaving the hospital well on the 14th of March, the 95th day after the beginning of his disease. Though the condition of the blood was greatly improved, the anaemia was still somewhat marked on his discharge. Examination of the Blood. December 17th.-On the day of entrance, apparently about the seventh day of the disease, dried and stained specimens of the blood 98 W. S. Thayer. [98 were examined. The red corpuscles showed nothing abnormal in size or shape; no poikilocytosis. The leucocytes appeared to be about normal in number. The differential count of 1000 leucocytes showed: Lymphocytes 11.3 per cent. Large mononuclear leucocytes 11. " " Transitional forms 3 " " " Multinuclear" neutrophiles 73.2 " " Eosinophiles 4.2 " " December 19th, ninth day of the disease.-Red corpuscles, 4,092,- 000; colorless corpuscles, 5,500. December 26th, sixteenth day of the disease.-Red corpuscles, 2,226,000; colorless corpuscles, 6,800. January 6th, twenty-seventh day.-Red corpuscles, 1,426,000; colorless corpuscles, 8,000; haemoglobin, 24 per cent. Dried and stained specimens showed a marked pallor of the red corpuscles and considerable difference in size, though there was no great poikilocy- tosis. A few nucleated red corpuscles (normoblasts) were found. While making a differential count of 1000 leucocytes two normo- blasts were seen. The differential count of 1000 leucocytes showed : Lymphocytes 18.1 per cent. Large mononuclear leucocytes 22.4 " " Transitional forms 4.5 " " "Multinuclear" neutrophiles 53.1 " " Eosinophiles 1.9 " " A large number of mononuclear leucocytes with almost transpa- rent protoplasm were noticed here as in the specimens of blood in Case I. Specimens stained with eosin and methylene blue showed considerable numbers of red corpuscles taking a diffuse stain, "degen- erate forms" (Ehrlich), "polychromatophilic corpuscles" (Gabrit- chewsky(45)). January 14th, thirty-fifth day.-Red corpuscles, 1,352,666; color- less corpuscles, 6,500; haemoglobin, 27.5 per cent. January 24th, forty-fifth day.-Red corpuscles, 1,648,666; color- less corpuscles, 7,000; haemoglobin, 28 per cent. Stained specimens showed, as in the last specimen, a considerable difference in the size of individual red corpuscles; no great poikilocytosis. Numerous 99] Post-Typhoid Anaemia. 99 polychromatophilic corpuscles. A considerable number of large transparent mononuclear leucocytes, and also a good many which were small and were classed with the lymphocytes. Nucleated red corpuscles (normoblasts) were numerous; six were seen while count- ing 1000 leucocytes. The differential count showed: Lymphocytes 23.7 per cent. Large mononuclear leucocytes 29.8 " " Transitional forms 4.6 " " "Multinuclear" neutrophiles .37.3 " " Eosinophiles 4.6 " " January 31st, fifty-second day.-Red corpuscles, 2,234,000 ; color- less corpuscles, 8,000; haemoglobin, 37.5 per cent. February 9th, sixtieth day.-Red corpuscles, 2,314,000 ; colorless corpuscles, 2,000; haemoglobin, 37.5 per cent. February 20th, seventy-first day.-Red corpuscles, 2,109,333; colorless corpuscles, 2,000; haemoglobin not estimated. February 26th, seventy-seventh day.-Dried specimens examined showed no leucocytosis, considerable difference in the size of the corpuscles, but scarcely as much as on the last examination. A considerable number of nucleated red corpuscles were seen. The differential count of the leucocytes showed: Lymphocytes 23.9 per cent. Large mononuclear leucocytes 11.2 " " Transitional forms 4.2 " 11 " Multinuclear " neutrophiles 58.8 " " Eosinophiles 1.7 " " Myelocytes 0.2 " " The most marked change in this specimen was the appreciably smaller number of transparent leucocytes. Two mononuclear leuco- cytes with neutrophilic granules were seen. The nucleus, however, was not very large. March 10th, ninetieth day.-Red corpuscles, 3,757,000; colorless corpuscles, 9,333; haemoglobin, 52.5 per cent. March 14th, ninety-fourth day.-Red corpuscles, 4,096,000; color- less corpuscles, 8,000; haemoglobin, 66 per cent. Dried specimens were made on this day, but were unfortunately lost. 100 IT. R Thayer. [100 A glance at the appended charts * shows that in Case I a man who must have had a normal blood on entrance, showed a fall of over 3,000,000 on the 31st day of the disease. Whether this represented really the lowest point, or whether during the week before it had been yet lower, one cannot say. The patient was at this time practi- cally afebrile; the fever he had after this was in all probability the fever of anaemia. Three months afterwards, at the time of the dis- charge, the blood had not yet reached its normal condition. In Case II the fall in the number of red corpuscles had already begun on the tenth day of the disease, the number of red corpuscles being 4,092,000, a loss of at least 1,000,000. In the next seven days, during the second and third weeks, before the temperature had reached the normal point, there was a loss of 1,866,000 corpuscles. This fall continued during the next nineteen days, during which time the patient lost 94,400 corpuscles to the cubic millimetre. The lowest point occurred when the patient was probably free from his disease, the fever present at that time being probably the fever of anaemia. In this case, then, we see a gradual fall in the number of red corpuscles from the beginning, which was accentuated toward the latter part of the febrile period; the fall extended into the period of the beginning of convalescence. The curve is thus similar to that described by the majority of observers who have been mentioned above, while it corresponds entirely with our observations in cases where the loss of corpuscles was slight and unimportant. On the ninety-fourth day after the beginning of the disease the blood had not yet reached the normal point. The haemoglobin in both cases was diminished in greater propor- tion than the number of the corpuscles. * Before commenting on the charts it may be well to state what we consider to be the normal number of red and colorless corpuscles to the cubic millimetre of blood. There are marked variances between the results of different observers, depending probably on slight differences in instruments and technique, and oftentimes a con- sideration of the individual standard of each observer will assist considerably in elucidating the results. From the counts made in Prof. Osler's clinic by Dr. J. S. Billings, Jr., and the writer, we are inclined to place the normal number of red corpuscles between 5 and 6,000,000, with the mean nearer 5,500,000 than it is to 5,000,000, while the mean normal number of leucocytes we have found to be not far from 7,000 to the cmm. A discussion of this whole question, with an interesting table showing the changes in the number of red and colorless corpuscles in a healthy individual at different times of the day, will be found in the work of Reinert.<46> 101] Post-Typhoid Anaemia. 101 The colorless corpuscles were found in Case I to have been somewhat subnormal during the first part of convalescence, and to have been a trifle higher, though still close to the normal point dur- ing the latter part. The dried specimens examined at the beginning of the process left little doubt that the number was normal or sub- normal at that time. In Case II during the febrile period two counts showed about a normal or slightly subnormal number. During the greater part of convalescence the number was close to the normal point, tending toward the end, in the last two counts, to be a trifle higher. The picture, then, which one obtains from the charts is that of an ordinary secondary anaemia, barring the rather unusually small number of the colorless corpuscles, a fact which was probably due to the typhoid fever itself, and may be found to be somewhat charac- teristic of these anaemiae, as most acute secondary anaemiae are asso- ciated with a slight leucocytosis. On referring, however, to the differential counts of the colorless corpuscles which were made in the dried and stained specimens, we find another condition which is somewhat at variance with that which is commonly observed in a secondary anaemia. Here we usually expect to find a relative increase in the multinuclear neutrophiles at the expense of the small mononuclear elements (lymphocytes, small transparent forms). Under normal circumstances counts show from 15 to 25 per cent, of small mononuclear elements, about 6 per cent., more or less, of large mononuclear and transitional forms, about 70 to 75 per cent, of " multinuclear " neutrophiles, and 2 to 5 per cent, of eosinophiles. We note, however, in these counts, that while the small mono- nuclear elements remain in most instances about normal in number, the large mononuclear leucocytes are very markedly increased, while the "multinuclear" neutrophiles show invariably a diminu- tion. In only one of these counts does the condition of the blood approach the normal: the final count in Case I. Here, however, we see a slight relative diminution of the lymphocytes with an increase in the number of "multinuclear" elements (neutrophiles and eosinophiles), a fact which is accounted for by the slight leuco- cytosis, 9,000. This condition of the blood, a diminution in the "multinuclear" neutrophiles with a relative increase in the large mononuclear and transitional elements, has been shown by Ouskow(43) and Khetagurow(46) in a number of careful observations to be a 102 W. S. Thayer. [102 characteristic point during the course of typhoid fever. Ouskow has made a much more minute classification of the leucocytes than that originally proposed by Ehrlich, and this very minute classification he resolves again into three classes, which he calls (1) the young elements, (2) the ripe elements, and (3) the over-ripe elements. In the young elements he includes the typical lymphocytes of Ehrlich, the small bodies a little smaller or a little larger than red corpuscles with deeply staining protoplasm, and a nucleus which likewise has a strong affinity for coloring matters, and almost entirely fills the cor- puscles. He also includes in the young elements bodies which are somewhat larger than these lymphocytes, which have a round nucleus resembling in size those of the lymphocytes, but taking a somewhat paler stain, and showing a greater quantity of protoplasm which is usually but very faintly colored or entirely transparent. Under the class of ripe elements he includes the large mononuclear leuco- cytes with transparent or with slightly colored protoplasm, and the so-called transitional* forms (Uebergangformen) of Ehrlich; while under the over-ripe elements he includes the multinuclear neutro- philes and the eosinophiles. He believes that the multinuclear neutrophiles develop in common from both the varieties of young elements, the typical lymphocytes, and the small transparent corpus- cles, the lymphocytes coming from the lymphatic apparatus, the lymph glands, the Malpighian bodies of the spleen, the small trans- parent corpuscles coming in great part from the bone-marrow.f He *By the term " transitional forms " Ouskow and his pupils designate an entirely different variety of leucocytes from that to which Ehrlich originally gave the name. Considering all the varieties of leucocytes with which we meet in the blood to be simply different stages in the development of one cell, Ouskow has given the name "transitional forms'' to that variety of large mononuclear leucocytes, the proto- plasm of which shows some affinity for coloring matters, in contradistinction to the "transparent forms"; it is a transitional stage between the other mononuclear leucocytes and the " multinuclear " neutrophiles. Ehrlich's transitional form is simply one step further ; it is the large mononuclear element which already shows indentations in its nucleus, evidences of its transition to a more polymorphous condition. Ehrlich has not apparently considered it a proven fact that the lym- phocytes do actually develop into " multinuclear " neutrophiles. The term " tran- sitional form" when used in this paper should always be understood in the sense of Ehrlich. f The explanation of the fact that from smear preparations from the spleen we always find so large a number of large mononuclear leucocytes may be, as Emeli- anow<52) suggests, namely, that the meshes of the spleen form, as it were, a hotbed in which the growth from the small to the large mononuclear forms takes place. 103] Post-Typhoid Ancemia. 103 finds under normal circumstances about 18 per cent, of young elements, 6 per cent, of ripe elements, and 75 per cent, of over-ripe elements present in the blood. In a careful series of observations started by Ouskow and continued by Khetagurow, it has been shown that during typhoid fever (1) there is a sharp falling off in the relative number of " multinuclear " elements which may represent less than 50 per cent, of the total number of leucocytes; (2) this fall begins usually in the first week, but is more sharply expressed in the second or third, or even fourth week; (3) the percentage of over-ripe elements begins to increase about three to twelve days after the disappearance of the fever; Khetagurow finds that it does not reach the normal point until the tenth or eleventh week; (4) the propor- tion of the small mononuclear elements to the large mononuclear and transitional forms is usually about as If : 1, instead of being as is normal about as 3:1; (5) the decrease in the number of multi- nuclear elements depends not so much on a parallel increase in the percentage of the small mononuclear elements, as on the increase in the percentage of the large mononuclear cells. The varieties of leucocytes, however, which these authors found to be particularly increased-observations which the writer has been able to verify-are the transparent and faintly staining mono- nuclear leucocytes, which closely border upon the line separating the small mononuclear (young) from the large mononuclear (ripe) elements; they are included for the most part among the large mononuclear (ripe) elements. It is this point which will make, and has made in some of our cases, considerable variations in indi- vidual records, between the proportion of young and ripe elements. In some instances, as in the first count in Case I, a number of corpuscles which probably should have gone into the class of small mono- nuclear elements, were classed as large mononuclear,* the class *As these different forms are probably simply different stages of development-a gradual growth-it is hard to draw an exact line in such necessarily artificial divi- sions as these. The writer generally observes the following rule: where the nucleus of a mononuclear element is similar in size and shape to those of the lymph- ocytes, even though the affinity for coloring matters be less, the cell is classified under the small mononuclear elements, until the size of the cell as a whole passes that of the ordinary " multinuclear " neutrophile. Thus to a certain extent more attention is paid to the nucleus than to the cell body as a whole. Some cells, no larger than the largest of those which are classed under small mononuclear leucocytes, may be at times classed under large mononuclear elements, because of their larger, more ovoid, paler nucleus. At the time when these counts were made the writer had no such fixed rule. 104 IL. S. Thayer. [104 of " lymphocytes" being mainly restricted to the true lymphocytes. All these differential counts were made before the author was familiar with the work of Ouskow or Khetagurow, and it is interesting to note how thoroughly confirmatory they are of the work of these two observers ; the increase in mononuclear leucocytes and the decrease in multinuclear were noted in each case and com- mented upon. We have been able further, in a considerable number of cases, to entirely corroborate these observations, and while these changes in the proportion of the different varieties of leucocytes may not be pathognomonic of typhoid fever, they form quite a character- istic point, distinguishing the blood of typhoid fever from that of most of the other febrile processes with which it is likely to be confounded. A majority of these conditions are inflammatory in nature, and all show at least a normal, and usually a considerably increased number of "multinuclear" neutrophilic elements, with a relative diminution in the small mononuclear. These points alone, the small number of leucocytes and the changed relative proportion of the different varieties, are the distinguishing features of these two cases of post-typhoid ansemia from a haematological standpoint. Another interesting point in the blood of each of these patients, particularly in Case I, is the relatively large proportion of eosino- philes. In all other cases of typhoid fever in which the writer has had occasion to examine the blood, eosinophiles have been present in a very small percentage, if indeed they were found at all. The causes of so grave an anaemia as occurred in these two cases are not easy to appreciate. Leichtenstern and Zaeslein, as has been mentioned above, are inclined to ascribe the anaemia largely to a dilution of the blood, while Hayem on the other hand is more inclined to assume that it is the result of a definite destruction of the corpuscles; the corpuscles which have resisted the high fever during several weeks, finally give way in considerable numbers. It is not impossible, considering the observations of Leichtenstern and Zaes- lein, that an actual dilution of the blood may occur, but there can be no doubt, after the examination of the blood in such cases as these two, in either fresh or dried and stained specimens, that a very severe actual antemia exists (changes in the size and shape of the red discs -nucleated red corpuscles). In both of these instances, after the dis- appearance of the toxic symptoms, the condition was such as to cause grave apprehension, the patients showing all the physical symptoms 105] Post-Typhoid Ancemia. 105 of an extremely severe anaemia, while the examinations of the blood, as has been said, can leave no doubt that an actual amemia existed. The length of the fever alone is probably insuffi- cient to account for such anaemia as this. In neither case was the fever of remarkably long duration. The first case was one of more than usual severity and was associated with considerable diarrhoea. In Case II, however, where the anaemia was graver, the case was regarded as rather mild. The symptoms during the fever were at no time alarming, and the temperature reached practically a normal point on the nineteenth or twentieth day; the fever on the days fol- lowing was probably the fever of anaemia. Most of the very severe cases, no matter whether they resulted fatally or not, in which the blood was examined, showed a relatively slight anaemia. The patient, for instance, in the next bed to that occupied by Case II passed through an extremely severe attack of typhoid fever, which lasted 93 days; at one time the patient was almost pulseless, and yet the lowest point to which the red corpuscles sank was 4,434,000. This patient entered the hospital two days after Case II, and left perfectly well fourteen days before. It is not improbable that an actual ansemia in these cases is due to the direct destruction of the red cor- puscles by the toxine which produces the symptoms, but it is hard to understand why, in the case of a robust man with an apparently mild infection and no untoward symptoms, the red corpuscles should fall to 1,352,000 per cubic millimetre, while in that of his neighbor, a much less vigorous-looking man, with a most severe attack, the red corpuscles should never have fallen below 4,434,000. It is not impossible that there may be in some cases a dilution of the blood as a whole, which may affect the blood-count, but it is hard to believe that this is the important element in most cases. The importance of such cases as these cannot be overlooked. A patient with this degree of ansemia would be assuredly much more liable to complications and secondary infections, of which, possibly, the case reported by Ernesti(17) is an example, while the danger of sudden death from syncope would certainly suggest itself. Out of 2000 fatal cases of typhoid fever occurring at the General Hospital in Munich, Holscher(48) found 54 cases, or 2.7 per cent., which show'ed a marked general ansemia. With regard to the treatment of such cases as these there is little to say. There is apparently no reason for deviation from the meas- 106 IK S. Thayer. [106 ures usually adopted in any grave secondary anaemia. In both instances the patients were given iron in the form of Bland's pills, and in the more severe case arsenic (liq. kali arsenitis) was added. In relation to one point, however, these cases are instructive. The importance of rest in bed in the treatment of grave anaemia is emphasized in an interesting manner by the blood charts of both patients, particularly by that of Case I. Here we see that on Jan- uary 15, 1891, the blood-count showed 3,551,000 red corpuscles to the cmm.; while on the 26th, after having been out of bed for several days, the patient had developed oedema of the dependent parts, and the blood-count showed a loss of nearly 400,000 red corpuscles per cmm. After two weeks' rest in bed there was a rise of 745,000, while again, a week after leaving bed the second time, there was a loss of over 500,000 red corpuscles. In Case II the chart shows on February 9, 1891, 2,314,000 red corpuscles, but eleven days later, after the patient had been out of bed a week, the count showed a loss of over 200,000. The writer has observed a similar curve in a case of pernicious anaemia which was improving under treatment. There is surely no reason to ascribe such changes to a mere dilution of the blood; in both in- stances the patient had been on a full diet a long time before leaving his bed. This point-the importance of rest in bed in the treatment of grave anaemia-has been, perhaps, hardly emphasized enough by most writers. In many of the more severe cases of chlorosis, for instance, cases where there is an actual corpuscular anaemia, an initi- ation of the treatment by a week or ten days' confinement to bed would probably materially hasten convalescence. Remarks on the Value of the Examination of the Blood in Typhoid Fever. From the results of the examinations of the blood made by the observers who have already been quoted, and from a considerable number of observations which we have been able to make ourselves, the following may be said in summary to be the more important changes occurring in the blood in typhoid fever. Red corpuscles. At the beginning of the fever the number of red corpuscles is usually normal, and often at the upper limit of normal, for the reason that the patients are usually young and strong indi- viduals, while in some instances an initial diarrhoea may cause some 107] Post-Typhoid Anaemia. 107 concentration of the blood. During the first weeks the number of corpuscles, with some fluctuation, falls gradually, but usually to a relatively slight extent. With defervescence there is, however, a more rapid fall in the number of red corpuscles, continuing often into and reaching its lowest point usually about the first week of convalescence. Recovery from this anaemia is generally rather gradual. From cases in Prof. Osler's clinic, where careful blood- counts* were made during the fever, the following table may be made: First week. Second week. Third week. Fourth week. Fifth week. Sixth week. 2 counts 10 counts 9 counts 6 counts 7 counts 4 counts 5,636,000 4,960,599 4,951,535 4,038,333 3,856,786 4,364,250 The counts made after this show a gradual increase, but are too scattering to classify. The averages in these few instances are somewhat low because of the inclusion of the two severe cases above recorded. Ordinarily, the fall in the number of red corpuscles is relatively slight, and as a rule bears a direct relation to the severity of the case, but at times a grave anaemia may follow an apparently mild case of the disease, as shown in Case II. The anaemia may be severe enough to form of itself a dangerous complication of the process. Hemoglobin. The haemoglobin falls always with the red corpus- cles; the loss, however, is relatively greater than the corpuscular loss, and the return of the curve to normal is further delayed. The observations which I have recorded in thirteen cases are not numer- ous enough to make a table of any value. They agree, however, entirely with the preceding statement. Leucocytes. The number of leucocytes in the cubic millimetre at the beginning of the fever is about normal, but tends throughout the course to diminish, reaching its lowest point toward the end of defer- vescence. With the beginning of convalescence begins the return to normal, which may last several weeks. This gradual fall is well shown in the following table taken from over 200 counts made by Dr. J. S. Billings, Jr., and myself :f First week. Second week. Third week. Fourth week. Fifth week. Sixth week. 22 counts 50 counts 41 counts 28 counts 16 counts 5 counts 7,212 6,468 6,351 5,877 6,621 7,000 * I am indebted to Dr. J. S. Billings, Jr., for several of these counts, f All counts made directly after baths were omitted. 108 W. S. Thayer. [108 After this the blood-counts are too scattered to make a reliable table, but they show about a normal mean. It should be said, however, that this table includes one case in which two counts were made, one in the first and one in the third week, both of which were unusually high; and as this is one of the earliest cases, it is not impossible that the counts may have been made shortly after baths, though it was not noted on the record. If we omit this case we have a table which is probably more correct: First week. Second week. Third week. Fourth week. Fifth week. Sixth week 21 counts 50 counts 40 counts 28 counts 16 counts 5 counts 6,984 6,468 6,260 5,877 6,621 7,000 These figures are not so low as those given by some authors (Hayem and Khetagurow), but they show clearly the absence of leucocytosis and the tendency toward a slight progressive diminution in the num- ber of leucocytes during the progress of the disease. They do not show the leucocytosis in the early stages and at the beginning of con- valescence, which some have assumed to exist. One should not, however, overestimate the value of such a table as this for fixing a true mean. It should be remembered that slight and unimportant circumstances-baths, for instance-may cause a tem- porary increase in the number of leucocytes per cmm. to many times the normal number, where a fall of this extent is, of course, impos- sible. The effect of this in any large number of counts would be, of course, to give a mean which is really a trifle above the usual normal number. In stained specimens the red corpuscles show either a normal condition or those changes common to any secondary anaemia. The colorless corpuscles, however, show markedly the interesting changes in the relative proportion of the different varieties which have been pointed out by Ouskow and referred to above, namely, a progressive diminution in the percentage of multinuclear (" over-ripe ") elements, with a relative increase in the large mononuclear leuco- cytes ("ripe elements"). This condition may not be well marked in the first or second weeks, but becomes more so as the fever continues. At its height it forms a striking picture on the examination of the blood. The only difference between our results and those of Ouskow and Khetagurow is that we have been rather inclined to estimate the proportion of large mononuclear leucocytes and transitional forms (" ripe elements ") as compared to the small mononuclear forms (lym- phocytes, small transparent forms)-(" young elements ")-a little 109] Post-Typhoid Anaemia. 109 higher than these two observers. Among the few cases where careful differential counts of over 1000 leucocytes were made, the average number of over-ripe elements was as follows : Second week. 5 counts Third week. 1 count Fourth week. 3 counts Fifth week. 1 count Sixth week. 2 counts 71.7 pei' cent. 66.5 per cent. 65.3 per cent. 58.6 per cent. 53.4 per cent. These results were wholly confirmed by a considerable number of superficial counts of one or two hundred leucocytes. In all of these cases the proportion of the large mononuclear elements was markedly increased. From a diagnostic point of view the condition of the red corpuscles and the haemoglobin in the blood of typhoid fever is of little import- ance. On the other hand, the examination of the leucocytes numer- ically and histologically may give us valuable help. The commonest conditions with which typhoid fever may be confounded are perhaps (1) malarial fever, (2) tuberculosis in various forms, (3) typhus fever, (4) other infectious processes of various kinds-general or local- when the seat of infection is not evident. The examination of a fresh specimen of blood will enable us to distinguish the case from malarial fever by the absence of the haematozoa. In tuberculosis when there is any local inflammatory process such as exists in the great majority of cases, there is always a certain degree of leucocytosis, showing a distinct increase in the number of over-ripe elements. In the cases of general acute miliary tuberculosis this is also probably the rule. In some rare cases of acute miliary tuberculosis, where the primary focus of infec- tion is not the seat of an inflammatory process of any extent, the leu- cocytosis may be absent, but in two cases of this sort reported by Ouskow(12), though it is not stated whether there was a leucocytosis or not, there were respectively 82 and 83 per cent, of multinuclear leucocytes. Typhus fever, according to Ouskow (I. c.) (three cases), shows no appreciable change in the blood from the normal. The majority of the other infectious processes with which typhoid fever may be confounded are usually associated with hidden inflammatory foci. In such cases there is almost always a marked leucocytosis with an increased proportion of multinuclear neutrophiles. In some cases of malignant pneumococcus infection* there is an absence * This may possibly be true in some other malignant general infections (strepto- coccus). 110 W. 8. Thayer. [110 of the leucocytosis, though, so far as I know, a subnormal number of leucocytes has never been noted, nor a diminution in the proportion of" multinuclear " neutrophiles. The examination of the blood should never be neglected in any suspected case of typhoid fever. In the absence of leucocytosis and the change in the relative proportion of the different varieties of colorless corpuscles, one to another, we have two valuable points which, while neither may be pathognomonic, are of considerable diagnostic value. The change in the relative proportion of the leucocytes is particularly striking where the case has existed for some time and has perhaps shown anomalous symptoms. Here the dis- covery of a much reduced percentage of " multinuclear " elements with a corresponding increase in the large mononuclear and transi- tional forms, may be the deciding point in the diagnosis. Literature. 1. Andral: Clinique medicale. 8vo. Paris, 1834, 3me edition, vol. I, p. 95. 2. Le Cann: Etudes chimiques sur le sang humain. 4to. These de Paris, 1837. 3. Raciborski: Gaz. med. de Paris, 1839, p. 82. Andral and Gavarret: Annales de chimie et de physique, vol. LXXV, p. 184, 1840. Andral: Essai d'hematologie pathologique. 8vo. Paris, 1843. 4. < 5. Simon: Physiolog. u. patholog. Anthropochemie. 8vo. Berlin, 1842. 6. Thompson: In Cormack: The natural history of the epidemic fever, etc. 8vo. London, 1843. 7. Bequerel and Rodier: Recherches sur la composition du sang dans 1'etat de sante et dans 1'etat de maladie. 8vo. Paris, 1844 and 1846. 8. Popp: Untersuchungen uber die Beschafienheit des menschlichen Blutes in verschiedenen Krankheiten. 8vo. Leipzig, 1845. 9. Virchow : Med. Zeitung, Berlin, 1847, Nos. 3 and 4, and Gesam- melte Abhandlungen. 8vo. Frankfurt, 1856. 10. Jansen: Nederl. Lancet, Gravenh., 1847-8, 2 S., iii, 522-530. 11. Otto : Beitrag zu den Analysen des gesund. Blut. Inaug. Diss. 8vo. Wurtzburg, 1848. 12. Durozier: Gaz. des Hop. Paris, 1853, pp. 601 and 605. Hl] Post-Typhoid Ancemia. 111 13. Welker: Ueber Blutkorperchenzahlung. (Archiv d. Vereins f. gemeinschaftl. Arbeiten, Bd. I, p. 161, 1853.) Jahresber. 1853, I, 29. 14. Welker: Pragervierteljahrschrift, 1854, Bd. IV, p. 57. 15. Denis (de Commercy): Memoire sur le sang, etc. 8vo. Paris, 1859, pp. 146-51. 16. Jaccoud: De 1'humorisme ancien compare a 1'humorisme mod- erne. These d'aggregation. 4to. Paris, 1863. 17. Ernesti: Anaemiae post typhum abdominalem exortae exem- plum. Inaug. diss. 8vo. Gryphiswaldiae, 1864. 18. See: Du sang et des anemies. 8vo. Paris, 1866. 19. Virchow: Cellularpathologie. 8vo. Berlin, 1871. 20. Naunyn: Corresp. Bl. f. Schweitzer Aerzt., 1872, No. 14, p. 300. 21. Quincke: Virchow's Archiv, Bd. 54, pp. 537-545, 1872. 22. Quinquaud: Compt. rend. d. l'Acad. d. Sciences, Paris, 1873. 23. Gautier: Chimie appliquee a la physiologic. 8vo. Paris, 1874. 24. Eichorst: Deutsch. Archiv f. klin. Med., Vol. 14, p. 223, 1874. 25. Bonne: Variation du nombre des globules blancs, etc. 4to. These de Paris, 1875. 26. Brouardel: Bull, et Mem. Soc. med. d. hop. de Paris, 1876, 2 s., XIII, 177-184. 27. Sorensen : Untersogelser om Antallet af rode og hvide Blodlege- mer under forskjellige physiologiske og pathologiske Til- stande. Kjobenhavn, 1876. Quoted by Reinert: Die Zahlung der Blutkbrperchen, etc. 8vo. Leipzig, 1891. 28. Ehrlich : Farbenanalytische Untersuchungen z. Histologie u. Klinik des Blutes. 8vo. Berlin, 1891. For special refer- ences to his earlier and later works and to those of his pupils vide Muller: Centralblatt fur allgem. Path. u. path. Anat., 1892, 19 and 20, and Thayer: Remarks on the clinical value of Ehrlich's methods, etc., Bost. Med. and Surg. Journ., 1893, Feb. 16th and 23rd. 29. Leichtenstern: Untersuchungen uber den Hsemoglobingehalt des Blutes in gesunden und kranken Zustanden. 8vo. Leipzig, 1878. 30. Arnheim: Jahrbuch der Kinderheilkunde, N. F., XIII, 1879, p. 293. 31. Baxter and Willcocks: Lancet, 1880, Vol. 1. 32. Zaeslein : Blutkorperchenzahlung u.Blutfarbstoffbest.bei Typhus abdominalis. Inaug. Diss. Basel, 1881. 8vo. 112 IE S. Thayer. [112 33. Halla: Zeitschr. f. Heilk., Prag, Bd. IV, 1883, p. 198. 34. Laache: Die Anaemie. 8vo. Christiania, 1883. 35. Robin, quoted by Hutinel: Etude sur la convalescence et les rechutes de la fievre typhoide. 8vo. Paris, 1883. (These d'aggregation.) 36. Malassez : Unpublished notes quoted by Hutinel: Etude sur la convalescence et les rechutes de la fievre typhoide. 8vo. Paris, 1883. 37. Holst: St. Petersburger med. Woch., 1885, N. F., II, 1-4. 38. Leclerc: A propos des traitements de la fievre typhoide, etc. Lyon Med., 1887, LVI, 494-501. 39. Ollivier : Semaine Med., 1887, p. 504. 40. Tumas: Deutsch. Archiv f. klin. Med., 1887, Bd. 4, p. 323. 41. Hayem : Le sang. 8vo. Paris, 1889. 42. Pee: Ueber Leucocytose. Inaug. Diss. 8vo. Berlin, 1890. 43. Ouskow : The blood as a tissue (Russian). 8vo. St. Peters- burg, 1890. 44. Lafleur: On pyrodin. The Johns Hopkins Hospital Reports, Vol. II, 1890. 45. Gabritchewsky: Archiv f. experiment. Pathol, u. Pharmak., Bd. 28, H. 1, 2, p. 183, 1890. 46. Khetagurow: Pathological changes in the blood in typhoid fever. Inaug. diss. St. Petersburg, 1891. Summary in Virchow's Archiv, Bd. 120, F. XII, B. VII, 187. 47. Reinert: Die Zahlung der Blutkorperchen, etc. Leipzig, 1891. 48. Hblscher: Miinchener med. Woch., 1891, XXXVIII, 43, 62. 49. Thayer: Boston Med. and Surg. Journ., Feb. 16th and 23rd, 1893. 50. Winternitz: Centralblatt f. klin. Med., March 4th, 1893. 51. Thayer: The Johns Hopkins Hosp. Bull., No. 30, 1893. 52. Emelianow: Archives des sciences biologiques, St. Petersburg, 1893. 53. Thayer: The Johns Hopkins Hosp. Bull., No. 31, 1893. THE MALARIAL FEVERS OF BALTIMORE. AN ANALYSIS OF 616 CASES OF MALARIAL FEVER, WITH SPECIAL REFERENCE TO THE RELATIONS EXISTING BETWEEN DIFFERENT TYPES OF HAEMATOZOA AND DIFFERENT TYPES OF FEVER. BY WILLIAM SYDNEY THAYER, M. D., and JOHN HEWETSON, M. D„ Assistants in the Medical Clinic of The Johns Hopkins Hospital. Reprinted from The Johns Hopkins Hospital Reports, Vol. V, 1895. BALTIMORE The Johns Hopkins Press 1895 ERRATA. On p. 28, line 1, for "degenerate" read "sterile." " " 165, " 25, " " " " " " 172 " 8 " " " " THE MALARIAL FEVERS OF BALTIMORE. • AN ANALYSIS OF 616 CASES OF MALARIAL FEVER, WITH SPECIAL REFERENCE TO THE RELATIONS EXISTING BETWEEN DIFFERENT TYPES OF HAEMATOZOA AND DIFFERENT TYPES OF FEVER. BY WILLIAM SIDNEY THAYER, M. D., and JOHN HEWETSON, M. D„ Assistants in the Medical Clinic of The Johns Hopkins Hospital. Reprinted from The Johns Hopkins Hospital Reports, Vol. V, 1895, BALTIMORE The Johns Hopkins Press 1895 JOHN MURPHY & CO., PRINTERS, BALTIMORE. THE MALARIAL FEVERS OF BALTIMORE. AN ANALYSIS OF 616 CASES OF MALARIAL FEVER, WITH SPECIAL REFERENCE TO THE RELATIONS EXISTING BETWEEN DIFFERENT TYPES OF HAEMATOZOA AND DIFFERENT TYPES OF FEVER. By WILLIAM SYDNEY THAYER, M. D., and JOHN HEWETSON, M. D., Assistants in the Medical Clinic. DIVISIONS OF THE SUBJECT. PAGE. I.-Preliminary Remarks, ---------5 II.-Literature, 6 Development of our Knowledge concerning the Malarial Organism; its Main Morphological and Biological Characteristics, 6 Culture and Inoculation Experiments, ----- 35 Methods of Examination of the Blood, ------ 40 The Finer Structure of the Malarial Parasite, - - - - 45 Manner of Reproduction, - 49 Classification, ---- - 50 Similar Haematozoa in Other Animals, ------ 51 Form in which the Parasite Exists Outside of the Body ; Manner of Infection, --------- 53 Relation of the Parasites to Some of the Main Symptoms of Malarial Fever, - -- -- -- -- --54 (1). The Intermittent Fever, - -- -- -- 54 (2). The Anaemia, --------- Fl (3). Other Symptoms ; Cerebral, Intestinal, etc., - 61 Melaniferotft Leucocytes; Phagocytosis; Spontaneous Recovery, - 62 Action of Quinine on the Parasites, ------ 66 III.-General Analysis of 616 Cases of Malarial Fever, - - 69 Age, ----------- - 69 Sex, ------------70 Race, 70 Relation of Cases to the Time of Year. - - - - - - 71 (1). With Regard to Admission, ------ 71 (2). With Regard to the Time of Development, - - - - 71 General Summary of Some of the More Prominent Symptoms and Complications, 72 3 4 W. S. Thayer and J. Hewetson. PAGE. IV.-Varieties of the Haematozoa Observed in the Malarial Fevers of Baltimore, - 76 Methods of Examination of the Blood, 76 The Parasite of Tertian Fever, - -- -- --78 The Parasite of Quartan Fever, 85 The Parasite of Aesti vo-autumnal Fever, ----- 90 V.-General Analysis of 544 Cases in which the Type of Organ- ism was Clearly Distinguished, 96 Classification of Cases according to Type, 96 Relation of the Different Types to the Time of Year, - - - 97 The Question of the Permanency of the Types, - 98 Relation of the Different Types of Infection to Race, - - - 100 VI.-Analysis of the Types of Fever Associated with Infection with the Different Types of Organisms, - 101 Tertian Infections, - -- -- -- -- 101 (1). Single, ---------- 101 (2). Double, --• ------- 105 Quartan Infections, - 114 (1). Single, 114 (2). Double, 115 (3). Triple, - - -115 Aestivo-autumnal Infections, ------- 119 Pernicious Malarial Fevers, - - - - - - - - 144 Combined Infections, -------- - 154 General Conclusions with Regard to the Types of Fever, - - 159 VII.-Concerning the Nature and Significance of the Crescentic Bodies of Laveran, 161 VIII.-The Flagellate Bodies, 176 IX.-The Action of Quinine on the Malarial Parasite, - - 185 X.-General Conclusions, 186 XI.-Table of References to the Main Works Treating of Malarial Fever Since the Recognition of its Parasitic Origin, 189 Appendix, ------------ 209 The Malarial Fevers of Baltimore. 5 I.-PRELIMINARY REMARKS. During the five years between June 14th, 1889, and August 1st, 1894, 616 cases of malarial fever were treated in the wards and in the medical out-patient department of the Johns Hopkins Hospital. In a considerable number of cases occurring in the out- patient department, hasty or insufficient examinations of the blood failed to show the specific micro-organisms, while in other instances examination of the blood was omitted on account of lack of time. Most of these cases are classified in the hospital records as " malarial fever ? "; they have not been included in our analysis. Excepting two or three instances where the patients entered the hospital during convalescence, the specific micro-organism was found in every case of malarial fever treated in the wards. The writers of this article have observed practically all the cases here classified after October, 1890. In a number of those observed before this time careful notes or drawings were made, which enabled us to draw definite conclusions with regard to the type of the organism. In other cases, however, the entries upon the records were so vague that, while the charts might justify a more or less decided opinion as to the nature of the infection, we have not included them among those cases where the type was definitely differentiated. As a result of our observations, we believe that we have been able to recognize certain distinct types of parasites which appear to be related in turn to certain almost equally characteristic types of fever. It is the principal object of this paper to determine by a careful analysis of all of our cases in how far our impressions may be justified, and to compare our results with those of the numerous recent observers in this and in other countries. We have prefaced our analysis by an historical summary of the more important literature concerning the malarial parasite. At the end of the article will be found a table of references arranged, as far as possible, in chronological order. This we believe to be a fairly complete list of the publications concerning malarial fever which have appeared since the recognition of its parasitic origin. 6 IF. S. Thayer and J. Hewdson. A great mass of literature from sources where the relation of the haematozoa to the disease is as yet unrecognized has been of neces- sity passed by. The table also contains references to the works which have recently appeared on the haematozoa of birds, as well as to the more important articles on haematozoa in other animals. II.-LITERATURE. Development of our Knowledge concerning the Malarial Organism : Its Main Morphological and Biological Characteristics. Since the discovery by Lewis,(8) in 1879, of living parasites in the blood of rats, the pathogenic importance of haematozoa, both in man and in other warm-blooded animals, has claimed yearly more and more attention; and doubtless the most important discovery which has been made in this field is that of Laveran, who in 1880, was able to announce that he had found, in the blood of individuals suffer- ing with malarial fever, living parasites which were, in his opinion, the probable cause of the disease. The infectious origin of malarial fever has, as is well known, been suspected for many years; it is, however, quite beyond the scope of this article to enter into a discussion of the numerous and interesting theories which have existed in the past. The presence of pigment in the blood was first noted by Meckel(1) in 1847. In an autopsy on the body of an insane woman who had suffered from malarial fever, he not only observed the presence of pigment in the blood, but pointed out in addition that the pigment was contained for the most part in round, ovoid or spindle-shaped protoplasmic masses which were doubtless the malarial parasites. He did not, however, recognize any connection between the pigment and the malarial process. As long ago as 1848 Virchow(2) described and pictured, in the blood of an individual dead of malarial fever, pigmented bodies, many of which were probably phagocytes, while others, from the descrip- tion and from the accurate drawings, were unquestionably examples of what were not to be recognized for thirty-two years as the patho- The Malarial Fevers of Baltimore. 7 genic parasite. Hischl,(3) in 1850, recognized the connection between the presence of pigment and intermittent fever. Planer,(4) in 1854, noted the pigment in the circulating blood, and suggested its origin there as well as in the spleen. He believed that the pigment circu- lating in the blood arose during the fever, and that it was the cause of many of the symptoms. The association of melanaemia and pigmented leucocytes with malarial fever, and the diagnostic importance of this condition was thus recognized in many quarters when Laveran in 1880 discovered the fact that the pigment was primarily contained in the body of a living parasite. Laveran/14,15, &0) a French military surgeon, was at this time stationed at Constantine in Algeria. He had set for himself the task of studying carefully the malarial fevers. In November 1880, while examining the blood of a patient with malarial fever, he noted several of these pigmented bodies which possessed long, actively moving filaments which oscillated about among the surrounding corpuscles in so active a manner as to convince him that he was looking upon a living parasite. On the 24th of December, 1880,(15) in a report to the Societe des HSpitaux, Laveran presented the results of his studies in 44 cases of malarial fever, in 26 of which he had found elements which he believed to be parasitic. He described three forms of the organism : (1). Crescentic or ovoid bodies, 8 to 9/z in length by 3/z in diameter; these were quite transparent and colorless, except for a collection of rounded pigment granules near the centre, or more rarely, collected toward one end of the body. Oftentimes the granules were arranged in the shape of a crown or wreath. At times the extremities of the crescentic bodies were connected by a pale, curved line. Change of shape, if there was any, was very slow and slight. (2). Bodies which in repose were spherical, transparent, about 6/z in diameter, containing a ring of rounded pigment granules of about equal size. In activity, however, these bodies were surrounded by from three to four fine filaments in active, worm-like motion. The length of these was three to four times that of a red corpuscle, possibly longer, while their ends were slightly swollen and clubbed. They arose at times all from one side of the body, while at others they took their origin from different parts of the periphery. The central body was at this time in extremely active motion, the pig- 8 W. S. Thayer and J. Hewetson. ment granules dancing about and changing their position, while the movements of the central body as a whole were like those of an amoeba. At times one of the filaments might be seen to separate from the body and move about free among the corpuscles. (3). Bodies which were generally spherical, 8 to 10/z, in diameter or sometimes more, slightly granular and non-motile, without peri- pheral filaments. The pigment granules were generally arranged without regularity, and varied in number. The bodies might be seen to become gradually irregular in shape, while the pigment was usually non-motile. He believed that these were simply cadaveric forms of the former parasite. Furthermore he found generally in his preparations small, rounded, refractive, motile bodies and granulations of pigment of a fiery red or of a clear blue color. These organisms he found only in malarial fever. They disap- peared on treatment with quinine. He concludes that " there exist in the blood of patients with malarial fever, parasitic elements which have heretofore been confounded with melaniferous leucocytes; the presence of these parasites in the blood is probably the principal cause of the manifestations of paludism." Concerning the nature of these bodies Laveran raised the question as to whether they were amoebae or whether possibly bodies 1 and 2 were produced by an agglomeration in a species of cyst formed, perhaps, at the expense of normal elements of the blood, of parasites which, in their full devel- opment, were represented by the motile filaments which might, at times, become detached and lead an independent life. To this latter view he inclined. This preliminary report, which was received with general scepti- cism, was followed by a number of other notes, in which Laveran defended his former statements, while in 1881 a small monograph (25) appeared, setting forth his observations at greater length. In this monograph the name " Oscillaria malariae" was suggested as a proper one for his newly-discovered parasite. In the same year, before the Academy of Sciences,(23) Laveran added still another form of the parasite to those already described : These bodies were spherical, transparent elements, containing motile or non-motile pigment granules; they were, however, much smaller than the other forms which had been described, the diameter vary- ing from one-sixth that of a red blood corpuscle upwards to nearly The Malarial Fevers of Baltimore. 9 an equal size. The smallest had but one or two fine pigment gran- ules, while again they might be nearly the size of a leucocyte, and con- tain numerous actively motile granulations. " These bodies, some- times isolated, sometimes together, as many as four, sometimes free in the blood, sometimes attached (accoles) to the red corpuscles or leuco- cytes, seem to represent simply one of the phases of development of the parasitic bodies above described." He still adhered to the view that these pigmented bodies were cysts containing the motile filaments, which in the free stage represented the organism at its stage of most perfect development. He also stated bis belief that "it is because it kills these parasites that quinine causes the disappearance of the manifestations of paludism." The first observer to confirm these observations was Richard,(26) who pursued his studies in 1882 at Phillippeville, in Algeria. He describes carefully the development of the body, stating that in the beginning it is represented by a small, perfectly clear spot in the otherwise normal corpuscle ("toute petite tache claire"). This, grow- ing, develops pigment, while the corpuscle containing the organism becomes decolorized, and finally is reduced to a mere shell, the body developing within it like a weevil in a lentil. At times the organism may escape from this shell which may be seen as a pale rim upon one side. He describes vividly the motile filaments, the crescents, and the melaniferous leucocytes, enlarging thus the obser- vations of Laveran by describing a little more definitely the earliest stages of the body (non-pigmented forms), and differing from him in considering the bodies intra-corpuscular instead of being attached merely to the body of the red corpuscle. Later,(33) however, Richard abandoned the idea of the intra-corpuscular condition of the parasites, accepting Laveran's theory that they were attached to the surface of the corpuscles. He believes with Laveran that the motile filaments represent the organism at its most perfect stage of development. He agrees also with Laveran in the statement that the organisms are present in greater numbers on the days of the paroxysms. They develop rapidly, their number increasing till the beginning of the paroxysm; " they produce the fever, the fever kills the parasite, and falls in its turn." During apyrexia the parasites grow again, until finally another paroxysm is produced. The continuous fevers, where quinine fails to act, Richard believes to be non-malarial. 10 W. S. Thayer and J. Hewetson. At the time of these discoveries by Laveran and Richard, the eyes of the world were directed much more toward the work which was then being carried on in Italy by Klebs, Tomassi Crudeli, and other observers,(9,12,13,17,21, 28132,&c ) who believed that they had isolated a bacillus which had a direct etiological relation to malarial fever, and the work of the French observers was received with great scepticism, nowhere more so than in Italy. There, Marchiafava and Celli/34,35136) who, among others, were believers in the bacterial origin of malarial fever, studied, by means of dried and stained specimens, the changes which occurred in the red blood discs in paludism. In many of the red corpuscles they found small round bodies resembling micrococci, which took up methylene blue, as well as slightly larger ring-shaped forms; further they found larger areas containing dark pigment granules, until finally whole corpuscles were sometimes taken up by large, palely staining pigmented bodies. They suspected that the small spots first mentioned might in some instances be parasitic (micrococci) in nature, while the larger pigmented areas they believed to be degen- erative changes in the red discs, changes which had been brought about possibly by the presence of parasites. The plates show that most of these stained bodies were unquestionably malarial parasites.* They noted that the pigment was formed in the circulating blood at the expense of the red blood corpuscles. Later,(36) in a more extensive article, they followed carefully the development of pigment, and described again these so-called degenerative changes in the corpus- cles. They referred to the changes which occur in the red corpuscles when exposed in tubes to high temperatures, 42° to 48° C. (the develop- ment of motile filaments), and stated without further discussion that these represented the filaments observed by Laveran and Richard. The crescents, they said, were due simply to decolorization of the periphery of the corpuscle while the rest retained its color. It was not until 1885 that Marchiafava and Celli(41,45) recognized the fact that they had been dealing with a parasite and not alone with degenera- tive changes. They had then seen the flagellate bodies of Laveran in four cases out of forty-two; they had also seen bodies similar to these with an extremely active, wave-like movement of the peri- * A number of the smaller dots, those resembling micrococci, were probably similar to those areas found in all anaemias, and described by Ehrlich as degenera- tive changes. The Malarial Fevers of Baltimore. 11 phery. They described also bodies where the pigment had collected in the middle, the substance of the parasite showing evidences of differentiation into a number of smaller bodies, while in others the pig- ment was surrounded by a collection of distinct segments into which the organism had divided. They laid particular stress upon the smaller forms of the parasite, and stated that it was then certain that they did not belong to the class of schizomycetes. They inoculated healthy individuals in five cases with the blood of malarial patients with fairly good results, in as much as in all instances, after several inoculations, symptoms of malarial fever with the presence of parasites in the blood were produced in the individuals upon whom the inoculation was practised. Later(46) in the same year they described with great care and accuracy the characteristics of the small hyaline forms. These they described as showing an outer, thicker, more refractive zone, and an inner, less refractive part, which appears sometimes finely granular. The organisms are actively amoeboid, the pseudopodia extending from the outer zone. This outer zone alone is colored by staining reagents, the central part being so thin that the red corpuscle shines through; at times it has the appearance of a clear or slightly colored nucleus. In some instances no pigmented forms whatever were seen, though in several of these cases pigmented leucocytes were found. Among these cases were some of the most severe and pernicious forms. They believed that these parasites were contained within the red corpuscles in opposition to the views of Laveran and Richard, who, it will be remembered, considered them attached to the surface. They described more extensively the segmenting bodies, and suggested that these might represent a process of reproduction, as they had noticed, in one instance, their occurrence during the paroxysm simultaneously with the appear- ance of new hyaline bodies in other corpuscles. In this early com- munication they described, in the organs of certain pernicious cases, the appearance of these segmenting forms in small parasites which were quite free from pigment. They claimed for themselves the honor of having first described the small non-pigmented forms, which they con- sidered the most important elements, asserting that the bodies described by Laveran and Richard were vacuoles or other changes in the red corpuscles. They proposed for these small bodies the term " Plas- modia." Thus it will be seen that Marchiafava and Celli have the 12 W. 8. Thayer and J. Hewetson. honor of having first called attention to the extreme amoeboid activity of these small forms, and also that they were the first to describe and suggest the importance of the segmenting bodies. It can, however, hardly be doubted that Richard's description of the hyaline forms was based upon observations of these same bodies, and not upon vac- uoles as Marchiafava and Celli assume, and, while the honor of first describing and of hinting at what has later been shown to be the true significance of the segmenting forms, belongs unquestionably to them, there is, at the same time, no doubt that these bodies had been observed by Laveran some years before. Laveran(60) has indeed published a very clear and accurate plate of a segmenting form occurring during-the paroxysm in a case of quartan fever; the sketch was made in 1881. Marchiafava and Celli further vigorously assailed Laveran's ideas concerning the nature of the organisms, denying that they are cystic in character, and denying also the double con- tour which Laveran and Richard describe in the crescents and ovoid bodies. Following these articles of Marchiafava and Celli, the literature of malarial fever shows an almost continuous series of articles confirma- tory of the discoveries of Laveran. No observers, indeed, of impor- tance who have had opportunities for proper study of malarial blood, have failed to confirm his observations. Among the first of these observers were Councilman and Abbott,(40) who in 1885, in the study of the organs from two cases of comatose pernicious malaria, described pigment-containing bodies in and outside of the red corpuscles, par- ticularly in the capillaries of the brain, and also in the liver and spleen, as well as numerous pigmented phagocytes. They had not been able to find these bodies in the fresh blood, but they remarked their similarity to the parasites described by Laveran. They had not been able to find the bacilli of Tomassi Crudeli. In 1885, then, our knowledge of the malarial parasite, based upon the observations of Laveran, Richard, Marchiafava and Celli, Councilman and Abbott, may be summed up as follows. There had been observed small, hyaline, amoeboid, intra-cellular parasites, which grew gradually, developing within themselves fine, actively motile pig- ment granules; these bodies eventually generally filled up the entire corpuscle, decolorizing and perhaps destroying it. Having reached this full-grown stage, the organisms were in some instances seen to show The Malarial Fevers of Baltimore. 13 a concentration of the pigment in the centre of the body with the development of a radial striation and the formation of segments, while in other instances, they appeared to give rise to the motile filaments first described by Laveran. Sometimes the small, intra-cellular bodies appeared to develop into ovoid or crescentic forms with the pigment granules in the middle. The crescents had apparently the power to change again into the ovoid, and then into a round shape, from which, commonly, the flagellate bodies of Laveran were seen to develop. The significance of these different forms was a much disputed point, Laveran believing the most perfect forms of the organism to be the free flagella which develop in the interior of small cysts which were represented by the earlier forms, while Marchiafava and Celli were inclined to believe the parasite to be more like an amoeba, denying entirely its cystic nature. Concerning the significance of the segment- ing bodies, Laveran was, at first, apparently inclined to believe that these were rather degenerative forms, while Marchiafava and Celli sug- gested, distinctly, their reproductive nature. The observations of Lav- eran showed that the crescentic forms were found more particularly in the patients who had been suffering from chronic and severe mala- rial fever or relapses. In the year 1885 a new era in the study of the malarial organisms was introduced with the publication of the researches of Golgi,(49) of Pavia. And from this time, as Barbacci(239) has pointed out in his admirable review of the subject, we must recognize two main schools, with essentially different views concerning the nature of the malarial parasite. The first party is represented by Laveran and his followers who believe that the malarial parasite is a single polymorphous organism; that there is no constant relation between the different forms in which it appears and the various types of fever. The second party, at the head of which stands Golgi, believes that, corresponding to and associated with the main types of malarial fever, one may distinguish different types of the malarial parasite, or, pos- sibly, different parasites. The views of the first party may be summed up in part in Lav- eran's own words : a This parasite is to be seen in a considerable variety of forms, which one can, however, resolve into the four follow- ing types: (1) spherical bodies; (2) flagella; (3) crescentic bodies; (4) segmenting bodies or rosette forms." 14 IF. S. Thayer and J. Hewetson. (1). He describes the different stages of development of these bodies from the small amoeboid hyaline forms onward. The movements of the pigment granules he believes to be communicated by undulations of the protoplasm. The bodies themselves are sometimes free, some- times attached to the red blood corpuscles; sometimes several may be attached at one time to a single corpuscle. The development of the parasite occurs at the expense of the red blood corpuscle which becomes decolorized and sometimes disappears altogether. Sometimes one large body may be seen to break up into a number of smaller ones. At times also small sarcodic buds may be seen to form at the periphery of a larger body. These he apparently considers to be reproductive processes. He describes also the gradual deformation and death of some of the large pigmented forms. (2). The flagella, he asserts, may be seen immediately after the specimen has been prepared, especially if the weather be warm, though ordinarily it is easier to find them in from fifteen to twenty minutes after the beginning of the examination. At the further extremity of the flagellum one may often see a pyri- form swelling, and similar ovoid enlargements may, at times, be made out at different points in the course of the filament. At times a small particle of pigment may be seen to pass into the flagellum as if through a central canal. After the breaking off of the flagella, which doubtless pursue a separate existence, the body of the parasite is left deformed and motionless-a cadaver. (3). After describing the crescents as before, he notes that the fine line, which often connects the two horns, represents, doubtless, the remains of the red blood corpuscle at the expense of which the cres- cent has developed. (4). The segmenting bodies he describes and pictures as has been noted before. The plates illustrating the segmenting bodies, it is interesting to note, were from drawings made in 1881, which had not been published at that time. Concerning the development of the parasite he says : " The small hyaline bodies not yet pigmented, which form the little clear spots on the red corpuscles, represent, probably embryonic forms of the parasite; little by little these bodies increase in size till finally their volume equals or even exceeds by a little that of the red corpuscles ; The Malarial Fevers of Baltimore. 15 at the same time the number of pigment granules increases; these elements, which possess the power of amoeboid movement, live in a free state in the serum of the blood, or adhere to the red corpuscles at the expense of which they derive their nourishment and their pigment; the flagella develop in the interior of the spherical bodies and at a given moment become free." The crescents(280) he believes to be encysted forms which develop from the spherical bodies. These forms show a much greater resist- ance to quinine than the spherical bodies; they may be seen to change into round, ovoid and flagellate forms. He writes as follows in his last work :(277) a I do not believe that there exists a constant relation between the forms under which the haematozoa appear in the blood and the clinical manifestations of paludism ; one can only say that certain forms of the parasite are more often seen in certain cases, the crescents, for example, in relapses and in malarial cachexia, as I have demonstrated long ago "... " The differences which one makes out in the evolution of the haematozoa of paludism are not sufficient to authorize one in admitting the existence of several distinct varieties of parasites." The views of the other school must be entered into at greater length; they date, as has been said, from the researches of Golgi in 1885. With the appearance of the articles of Golgi on the organism of quartan fever begins, as we have already said, a new era in the history of the haematozoa of malaria. In the study of twenty-two cases of quartan fever Golgi(49) followed with singular care and accuracy the development and life history of the parasite, determining for the first time the close relations which exist between the development of the organism and the clinical symptoms. Marchiafava and Celli had already mentioned that they had found segmenting bodies during the paroxysm, but Golgi was the first to point out that each paroxysm is always associated with the segmentation of a group of malarial organisms, in other words, that the beginning of every malarial paroxysm corresponds to the ripening of a generation of parasites. He further determined that, generally speaking, the severity of the attack is dependent upon the number of parasites present in the blood. The parasite of quartan fever, upon the study of which these conclu- sions were based, requires seventy-two hours for its complete develop- 16 W. S. Thayer and J. Hewetson. ment. In their earliest stage the parasites are represented by small, amoeboid, hyaline, intra-corpuscular bodies. Early in the first day of apyrexia one finds, in the red corpuscles, unpigmented forms which are from about one-sixth to one-fifth the diameter of the corpuscle itself; these move slowly, changing their outline. The blood corpuscles in which they lie are of normal size and appearance. These bodies grow gradually larger without changing their general appearance, and develop rather coarse, dark brown pigment granules. Some- times they may be seen free in the plasma, but this occurs rarely. The movement of the granules, as well as the amoeboid move- ment of the organism, whether it be intra- or extra-cellular, is always rather slow. Early in the day of the paroxysm the process of reproduction begins, the organisms having by this time so far increased in size as to entirely fill the red corpuscle, of which there is often only a slight peripheral rim remaining. Often, indeed, there is apparently no trace of the corpuscle left, so that one sees free bodies of a colorless substance with irregularly distributed pigment. Gradually the pigment becomes concentrated toward the middle of the body, until finally it forms a sharply defined clump in the centre. At this time one begins to see the appearance of a slight radial striation in the hyaline substance of the organism, the striae becoming more distinct until finally the central pigment clump is surrounded by eight to ten round or pear-shaped bodies, each with a small refractive central point, as regularly arranged as the leaves of a marguerite, the so-called rosette or marguerite forms of Golgi. Soon these bodies become more distinctly separated from one another and from the central mass, until the central pigment clump may be seen to be surrounded by four, to six, to eight, to twelve ovoid or round, clear, hyaline bodies, each with a small refractive central point. This segmentation begins eight to ten hours before the paroxysm, and continues during its first hours, while at the same time fresh hyaline bodies begin to appear in the red corpuscles. The resemblance between these segments and the fresh hyaline bodies is striking, although the actual entry of the newly formed segment into the corpuscle has never been observed. Based upon these observations Golgi founded the following laws : Each febrile paroxysm is closely connected with the cycle of development of a generation of parasites: the beginning of each paroxysm corre- The Malarial Fevers of Baltimore. 17 sponds to the maturity of a generation of parasites: the severity of the paroxysm is, in general, proportional to the number of the para- sites which are found in the blood. Some cases of quotidian fever which Golgi observed were due to infection with three groups or generations of quartan organisms, the groups maturing on successive days, causing thus a daily paroxysm, while in other instances, where chills were observed on two successive days with an intermission on the third, he was able to trace infection with two groups of parasites. This description of the cycle of existence of the quartan organ- ism was confirmed a few months later by Osler(55) in Philadel- phia, and has since then been accepted by practically all who have had opportunity to study quartan fever. Antolisei,(126) in a systematic study of the parasite of quartan fever, added little to Golgi's observations. He laid more stress upon the beginning of segmentation before the actual onset of the fever. While Golgi believed the paroxysm to be due to the invasion of the red corpuscles by the new generation of parasites, Antolisei held that the chill depended rather upon the act of segmentation than upon the actual invasion of the corpuscles. For, by administering quinine in sufficient quantity shortly before an expected paroxysm, the invasion of the red corpuscles by a fresh generation of parasites may be com- pletely prevented, while it is quite impossible to prevent the impending segmentation or the paroxysm. He believed the segmenting parasite to be surrounded by a membrane consisting of the more resistant outer layer of the red corpuscle in which it has developed; this membrane is broken through with the setting free of the segments. These observations concerning the quartan organism were followed in 1886 (50) and 1889 (94) by further careful studies of the parasite of tertian fever. This parasite begins its cycle, as does that of quartan fever, as a small, hyaline, unpigmented body; this increases in size and develops pigment during forty-eight hours, at the end of which time it reaches its complete development; it then undergoes segmen- tation just before and in association with the paroxysm, at which time the appearance of a new generation of organisms in the red corpuscles is to be observed. Golgi noted, however, distinct differences between the tertian and the quartan organisms. In the first place, the amoe- boid movements of the young tertian parasite are much more active; the granules are smaller and of a somewhat different color (a lighter, 18 IK. S. Thayer and J. Hewetsan. more reddish brown); the outlines of the body in general, which are quite clear and sharply defined in the quartan parasite, are, in the tertian, very indistinct. The dancing of the granules is also much more active in the tertian organism. With the growth of the quartan parasite the red corpuscle remains about its normal size, or, indeed, tends to shrink about the body, while the decolorization does not occur until later on, so that the organism may have reached almost its complete development without any particular change in the color of the red disc. In tertian infections, however, the corpuscle begins to be decolorized early in the development of the parasite, and instead of tending to shrink about the body, it becomes considerably expanded and swollen, so that at the time of complete development of the parasite it may be very much larger than its normal neighbor. The full grown tertian organism is then somewhat larger than the quartan parasite. In segmentation also there are material differences between the organism of tertian and that of quartan fever. Golgi describes two distinct varieties: (1). The pigment gathers in the centre of the body, while a certain differentiation may be made out between the peripheral clear proto- plasm and the central part with the pigment; indications of a radial striation begin to appear in the peripheral clear protoplasm, which eventually becomes divided into from fifteen to twenty small hyaline segments. The differences between this mode of segmentation and that of the parasite of quartan fever are, according to Golgi: («). The greater number of segments, from fifteen to twenty. (6). The difference in the size of the individual segments which are smaller in the tertian parasite. (c). The absence of the central refractive spot in the tertian par- asite. (d). The fact that the pigment which gathers in the centre appears here to be contained in a protoplasmic body. These pigmented bodies Golgi believes to be for the most part, taken up by phagocytic leucocytes, though he does not feel sure that some of them may not remain in function and produce other bodies. (2). This variety of segmentation differs from the first in that after the pigment has collected into a small clump, the whole mass of the protoplasm becomes divided into small round bodies, which do not The Malarial Fevers of Baltimore. 19 have the regular daisy-like arrangement of the segments in the first variety, but form simply an irregular clump of small spheres about a central free pigment mass. Golgi suggests a third variety of segmentation, which is probably rather a degenerative process. Here, in the free pigmented body, which has entirely destroyed the red corpuscle, the pigment collects in a point nearer the periphery, leaving a part of the corpuscle entirely clear and transparent. Within this clear area one and sometimes two small spheres develop, which resemble the true spores. With the tertian as with the quartan organisms, Golgi observed that quotidian feVer depended on infection with more than one group of the parasite; he had observed no organism whose cycle of existence lasted but twenty-four hours. This description of Golgi's of the cycle of the parasite of tertian fever has been in the main confirmed by later observers, though it has met with criticism in some respects and with certain additions. Antolisei,(129) in 1890, in a careful study of the parasite of tertian fever, agrees with Golgi in the main points. He has, however, met with Golgi's second form of segmentation only, while he asserts that the third variety of segmentation is a degenera- tive process. He describes this process of vacuolization at length. When the pigmented body has wholly destroyed the red corpuscle, and is free in the blood current, one sees, at a certain time, the develop- ment, toward the periphery of the body, of a spherical area, into which the pigment granules which are in very active motion, never enter. Within this area one may see a white, sharply outlined sphere, about which there is very often a vacuole which has a semi-circular appear- ance because the sphere does not lie in the middle but presses to one side. Later there develop elsewhere in the protoplasm of the organ- ism numerous smaller spherules of varying sizes. Between these lie the pigment granules which become motionless, while in the remain- ing protoplasm the activity of the movements seems to increase. Gradually more spherules appear, of varying size, often becoming steadily smaller, so that finally the whole body is represented by a collection of minute spherules with sharp outlines, between which lies motionless pigment; about them is an outer shell, which possibly represents the outer more resistant layer of the red blood corpuscle. In the meantime there generally arises a sort of hernia 20 W. 8. Thayer and J. Hewetson. through the outer more resistant layer, which may take various forms; inside of this new spherules develop. This process of vacuolization Antolisei considers to be degenerative in nature, as does he also that of flagellation, which is seen to occur in large bodies exactly similar to those which undergo vacuolization. Furthermore, Antolisei believes that true segmenting bodies are rarely met with in the circu- lating blood. He asserts that these are not larger than a red blood corpuscle, whereas those forms which one often considers to be full grown tertian parasites are frequently considerably larger. He be- lieves that the majority of these large forms which appear in the circulating blood are over-grown organisms which are no longer capable of reproduction; they undergo only degenerative processes, vacuolization, fragmentation, and flagellation. Those pigmented forms which are capable of producing true healthy spores remain in the internal organs and are not to be found in the peripheral circulation; they never grow as large as these large free forms. Bastianelli and Bignami (152) have further studied tertian fever, comparing the blood taken from the finger with that from the spleen; they find that while during apyrexia there is no great difference between the character of the blood from these different parts of the circulation, at the beginning of the paroxysm a marked difference is noticeable. At this time the full grown segmenting bodies with their pigment clumps and new spores are rapidly accumulated in the spleen. These forms reach the spleen, they believe, just as do any foreign bodies which enter the blood current. This does not take place while the parasite is endo-globular, or so long as the red blood corpuscles are not gravely altered in their essential charac- teristics. They suggest that if this same distribution is not observed in quartan fever, it is probably because the red blood corpuscles are less deeply altered by the quartan parasite than they are by the tertian. They believe, as does Antolisei, that Golgi's possible third form of segmentation is a degenerative process. They found these bodies much more frequently in the blood of the spleen than in the blood of the finger, particularly toward- the beginning of the febrile paroxysm. They also note that in the irregular quotidian fevers and in anticipating tertians, they find, always in the spleen, and sometimes in the finger, small segmenting forms with five to ten small spores which are collected about possibly but a single pigment granule, The Malarial Fevers of Baltimore. 21 and contained in red blood corpuscles which are not so swollen as is usually the case in tertian fever; sometimes these forms may be free. They suggest, therefore, that in these cases the cycle of development of the parasite may be accomplished in a shorter time than under normal conditions. The large, free, pigmented bodies which may be observed to become fragmented, vacuolated, or to show flagella, they believe to be degenerate forms. They suggest that spon- taneous recovery may be associated with the frequency of these forms in the blood. The accuracy in the main of these descriptions of the tertian and quartan parasites has been confirmed in almost all malarial districts; by Grassi and Feletti(205) in Sicily, by Canalis/104' Patella, (14U Marchiafava and Celli/144' Terni and Giardina (145) in Italy, by Mannaberg(291) in Austria, by Kamen(242,243) in Germany, by Sacha- row,(153) Titow/177' Romanowsky/210' and Korolko/226' in Russia, by Remouchamps(321) in Holland, and by Dock/240' one of the authors/327' and Koplik (305) in the United States. The student of the literature can, however, hardly fail to notice the difference between these large pigmented bodies of tertian and quartan fever, and the small hyaline bodies-the " plasmodia "-to which Marchiafava and Celli ascribed so much importance, forms which have a likeness only to the very earliest stages in the cycle of existence of the parasites just described. It will also be noticed that the crescentic bodies which played so important a part in Laveran's first descriptions of the parasite, do not occur in the cycle of development of the organism of either tertian or quartan fever. And later observations have tended strongly to show that these organisms are associated with a different type of fever, a form of fever which is seen only in the more malarious districts, which is rare in Pavia where Golgi studied, but common in Rome and Algiers where Marchiafava and Celli, and Laveran made their observations. Golgi/49' in his first note on the quartan organism, mentions that in one case with irregular fever he found crescents and ovoid bodies in the blood, and he suggests that these forms may have a special cycle of existence differing from that of the organisms already described. One of the first observers to call attention sharply to the fact that the more irregular and continuous fevers were associated with a clearly different type of organism was Councilman/87' In 1887 he speaks as follows : "The character of these bodies " (the malarial parasite) " varies 22 IK & Thayer and J. Hewetson. in different forms of the disease. Although they seem in rare cases to run into one another, still, in general, we can say that where the plasmodia inside the red corpuscles are seen, the patient has inter- mittent fever, and where the crescentic and elongated masses are found he has either some form of remittent fever or malarial cachexia." At the conclusion of this paper he states that from the examination of the blood we are " not only enabled to diagnosticate the disease as such, but in most cases the particular form." In 1889 Marchiafava and Celli(100) and Pietro Canalis(104) pub- lished almost simultaneously more elaborate descriptions of the type of organisms associated with the "aestivo-autumnal" fevers observed in Rome. The preliminary note by Marchiafava and Celli appeared before that of Canalis, the article of Canalis before that of Mar- chiafava and Celli. Canalis gives a careful description of the organisms associated with this type of fever. He refers to the organism as the " semi-lunar variety." He traces the life-history and cycle of development with considerable care, dividing it into two phases: (1) a rapid cycle, and (2) a slower cycle associated with the development of crescentic bodies. He finds that Golgi's rule applies here just as in the more regular intermittent fevers; that each paroxysm corresponds to the matura- tion of a generation of parasites. (1). The rapid cycle is difficult to follow in that the blood usually contains several generations of parasites in different stages of develop- ment, which are associated with attacks following one another at varying intervals. He believes, however, that the cycle is generally of not less than two days' duration, though he has seen it as short as twenty-four hours. In the first three or four hours of the attack, one finds small hyaline amoeboid intracorpuscular bodies of about one- sixth the diameter of a red blood corpuscle. These bodies show a clear annular peripheral ectoplasm and a more shaded central endoplasm, which, from its shape and situation, resembles a nucleus. Sometimes, instead of one darker central point, one may see two or even four. When the body is in repose the ectoplasm is sometimes quite refractive. Often the blood corpuscles which contain them are shrunken and mis- shapen. Sometimes one sees free bodies in the plasma. The parasites gradually grow,and the amoeboid movements become more active, while in the peripheral, ring-like, often somewhat refractive zone, one notices The Malarial Fevers of Baltimore. 23 fine granules of a dark red or black pigment. The appearance of pigment begins sooner or later, depending probably upon the length of the cycle of development. Gradually the parasite increases in size while the pigment granules accumulate. At the end of the cycle there are usually but very few minute granules of pigment, rarely more than six or seven. These stages of development occupy the greater part of the cycle, while the later stages are more rapid in their course, and examples are much more rarely seen in the peripheral blood, the process taking place probably in the internal organs. The parasite increases in size and loses its amoeboid movement while the pigment granules collect in a group or in a small block at the centre of the parasite; sometimes they may be placed eccentrically. The organism has a more hyaline appearance, and the distinction between the ectoplasm and endoplasm is no more to be made out. The blood corpuscle in which the parasite lies loses its color which it had retained fairly well before. An indication of radial striation now appears in the protoplasm of the parasite which eventually breaks into from six to ten round or slightly ovoid segments which surround a group of pigment granules or a very small block. These segmenting forms are considerably smaller than those of tertian or quartan fever. By this time the substance of the red blood corpuscle may have wholly disap- peared, or the wholly decolorized body may form a pale ring about the parasite or at one side of it. A striking difference between these forms and those of tertian and quartan fever is the small quantity of pigment in the last stages of development. Canalis, however, has never observed segmenting forms without pigment. The segmenting bodies are but rarely seen in the peripheral circulation, though, at the time of segmen- tation, one may often see the small pigment blocks which have been derived from them, either free or in phagocytes. (2). The second cycle, that associated with the development of the crescentic bodies, occurs, sometimes, in association with the more rapid cycle, but, at other times, only after this more rapid course of develop- ment has been checked by the administration of quinine. He has never observed crescents at the beginning of the process; in one instance only, did they occur before the fifteenth day. He traces the gradual development of the crescents inside of the red corpuscles from the small amoeboid forms; these assume a long elliptical shape, with the pigment collected in the middle, and gradually take on a crescentic 24 W. S. Thayer and J. Hewetson. form, decolorize the corpuscle, and finally become free in the blood, showing a double outline which appears to be the evidence of a surrounding membrane. These crescents in turn change into long elliptical, ovoid, and finally into round forms, though the ovoid forms would appear to arise in some instances directly within the corpuscles, without having passed through the crescentic stage. While, in the ovoid and crescentic forms, the pigment is motionless in a clump or in a ring at the centre of the body, in the round forms it is often in active movement, and commonly arranged in the shape of a ring. The ovoid and round bodies show sometimes a double outline, sometimes not. Sometimes the crescents may change into round bodies before the red corpuscle is entirely destroyed. When the crescents have reached this stage sporulation may occur. These bodies, usually round or ovoid, have sometimes a double outline, and contain eight or ten small spherules. The pigment is sometimes in a solid clump in the middle, though more commonly arranged in the shape of a ring in the middle or at one pole. Sometimes the pigment is free, sometimes retained in a mass of hyaline protoplasm which may be extruded from the body. The fresh segments are round or slightly ovoid with an opaque central area and a clearer outer layer which suggests a double outline. The association of these bodies with the paroxysm and with the appearance of fresh hyaline forms in the red corpuscles, convinces him that this is a true sporulation. The process of sporulation must be, according to Canalis, sharply distinguished from certain degenerative processes which one some- times sees. " In this degenerative process " he says, " one meets with bodies which have lost their yellowish or ashy color and have become clearer, sometimes refractive, with a double contour much more marked than that of the ordinary parasite, while their substance is transformed into a mass of round or irregular bodies of various sizes, and with a single contour. If one continues the microscopical examination of one of these parasites during the course of several minutes, he may sometimes see that two or three of these spherules become united into a single body, forming, thus, irregular masses, which, continuing the process of fusion, give, finally, to the parasite an homogeneous aspect without traces of spherules. " The pigment is sometimes arranged as a central crown, sometimes scattered irregularly at an extremity or at one side of the body. The The Malarial Fevers of Baltimore. 25 points which distinguish this process from that of sporulation are: the refractiveness of the degenerating body; the inequality in size of the spherules; the absence in these spherules of a more opaque central area; their fusion into irregular bodies and finally into an amor- phous mass." These forms may also be seen in complete apyrexia, without being followed by a paroxysm or by the appearance of fresh hyaline bodies. The flagellate bodies are often observed here, though they cannot be proven to be a constant phase. They arise, always, from the round forms which do not show a double contour. They appear, generally, several hours before the beginning of the attack, sometimes during apyrexia at a distance from the attack. " They represent, assuredly, one of the last stages in the development of the parasite, for I have never seen them appear in the blood before the formation of the round bodies." The length of this cycle varies in different cases. The period from the beginning of the amoeboid stage to the appearance of the crescents lasts, probably, not less than three or four days; after the appearance of the crescents the round bodies may appear upon the following day, or later. Associated with this type of organism occur the more irregular and continued fevers, the pernicious fevers, as well as many cases of malarial cachexia and fever with long intervals. Marchiafava and Celli(100) state that where Golgi was dealing with fevers which pursue a regular cyclical course, are never pernicious, and yield, often without, and always with quinine, these cases of " aestivo-autumnal " Roman fever show, usually, an acyclical course; the attacks occur generally daily, following one another at intervals of twenty-four or thirty-six hours; the paroxysms themselves are often of long duration, so that one may be engrafted upon another without the temperature ever reaching the normal point. The chill is often lacking, the patient complaining only of symptoms of con- tinued fever. These cases often show a pernicious character; they rarely heal spontaneously, show frequent relapses, and are associated often with grave anaemia. Some of the most pernicious cases may show no rise in temperature. The examination of the blood at the acme of the fever, and, also, at the beginning of apyrexia, shows the small, round or actively motile bodies-their "plasmodia." A few hours before the attack begins, however, there occurs a change; 26 IF. & Thayer and J. Hewetson. there may be seen : (1) Small round bodies with a little mass of haemoglobin or pigment granules in the centre-ring-like forms; (2) small, more or less amoeboid bodies, with one or two extremely minute pigment granules; (3) larger, round, immovable parasites of a more glistening white color, with a round pigment block in the middle or at the periphery. The haemoglobin of the red corpuscle is, in some instances, concentrated about the parasite in the middle of the corpuscle, while the periphery is decolorized. Many of the corpuscles containing plasmodia are also shrunken, somewhat crenated, and of a color resembling old brass (globuli rossi ottonati). In quartan and tertian fever segmenting forms are commonly seen in the circulating blood; in this type of fever they are extremely rare. They are common, however, in the internal organs, particularly in the spleen and, in pernicious cases, often in the cerebral capillaries. Segmentation occurs while the parasite is yet in the red corpuscle which rapidly disintegrates. Pigmentation begins shortly before the paroxysm, and the discovery of pigment in the organisms is a sure sign that the paroxysm is near. The cycle of development appears to last about twenty-four hours or even less. With the paroxysms, and a few hours afterwards, appears the new group of young, fresh, hyaline bodies. They describe the crescents, admitting what they previously had denied, that these appear to have a double contour. They have seen intermediate forms between their plasmodia and the crescentic bodies. They find, as did Councilman, more crescents in the spleen than in the peripheral blood, and agree with Laveran that they are more common after continued attacks. They have, however, seen pernicious cases without crescents. They have never seen evidences of segmentation in the crescents; those bodies which are described by others they believe to be degene- rative forms, asserting that what Canalis has considered to be fresh segments, are only vacuoles. In some instances the parasite may run its entire course to segmentation without the development of pigment. They conclude that, in the malarial fevers of the summer and fall in Rome, there occur, generally, daily or frequently repeated paroxysms with a tendency to become pernicious. With this type of fever is associated the presence of a small amoeboid parasite in the red-blood corpuscles. This organism shows a short cycle unaccom- panied by the development of pigment, and a longer cycle, where a The Malarial Fevers of Baltimore. 27 few pigment granules are to be seen. This parasite differs from the larger tertian and quartan organisms, which are found only in particular regions, and cause the milder forms of fever. Different malarial parasites are, then, related to the different times of the year, to different malarial regions, and, finally, to the mild and severe forms of the disease. These observations have been confirmed in their main features by a large number of observers. Among the first were Gualdi and Anto- lisei,(U1) who proved the existence of this separate type of organism by inoculation experiments. Antolisei and Angelini(119,131) refer to this variety of the parasite as the " haematozoon falciforme." They believe that it may run through its cycle of existence quickly, reaching the stage of sporulation, in some instances, before the appearance of pigment, as described by Marchiafava and Celli. In other instances it pursues a longer course, developing into the ovoid and crescentic bodies. They confirm Canalis' observations concerning the sporulative and degene- rative forms observed in the crescents. The process of gemmation, however, they do not consider reproductive, likening the small, hyaline buds to the " corpuscles d'exudation " of Hayem. Golgi(94, U8) notes that some fevers with long intervals are associated with these organisms, and believes that they are particularly related to the crescentic forms which pursue a slow development, the paroxysms thus occurring far apart. Patella,(141) Terni and Giardina,(145) Bastianelli and Bignami/168,170) Sanfelice(190) in Italy, Grassi and Feletti022,205,221'^ in Sicily, Mannaberg,(291) von Jacksch(128) in Austria, Plehn(262) and Kamen(243) in Germany, Sacharow,(153) Korolko/226) and Titow(177) in Rus- sia, Dock,(207) one of the writers of this article,(327) and Koplik (305) in America have confirmed, in the main, these observations, in so far as they recognize a distinct type of organism associated with the aestivo-autumnal fevers, an organism which differs .from those observed in the regular tertian and quartan ague. Con- siderable difference of opinion exists, however, between these observers as to the significance of certain forms, particularly the crescentic bodies. Bignami,(179) Bastianelli/168'170) and Marchiafava and Celli/222, &0 ) in their later works, assert, in contradistinction to the views above expressed, that the crescentic and ovoid pigmented 28 W. S. Thayer and J. Hewetson. bodies are deviate and degenerate forms; that their presence in the blood has no influence on the condition of the patient. They deny the possibility of sporulation in these forms, but state that they can follow out processes of vacuolization, fragmentation (gemmation) and flagellation, all of which they believe to be degenerative pro- cesses. Certain authors have gone beyond this simple division, and have sub-divided the class of " aestivo-autumnal " organisms. Marchiafava and Bignami(218, believe that they can separate two distinct varieties of the aestivo-autumnal parasite. Each is represented in the beginning by a small, hyaline, amoeboid, or ring-shaped body, but the cycle of development, in the one instance, lasts about twenty-four hours, and in the other about forty-eight hours. In other words they recognize a true quotidian and a "malignant tertian" type of organism. The quotidian fever they say may be quite regular, the attacks being definitely intermittent and similar in most ways to those of the double tertian or triple quartan fever, lasting from six to eight, or rarely twelve hours. Usually, however, the attacks do not come at regular intervals, showing often a tendency toward anticipation or retardation, and varying in severity and duration; often a more or less continuous fever may result. The parasite of this quotidian fever passes a good part of its existence as a small, amoeboid, hyaline body. It may then pass on directly to segmentation with but little increase in size, though, generally, it develops a few fine pigment granules, in its protoplasm before this occurs. In either case the segmenta- tion occurs within the red blood corpuscle before this is definitely destroyed. Sporulation occurs almost entirely in the internal organs; the appearance of segmenting bodies in the circulating blood is rare. In the spleen, however, they may be found in great numbers. The corpuscles containing the parasites are often shrunken and of a brassy color; the retraction of the haemoglobin about the parasite, as described by Marchiafava and Celli, may be present. After a certain length of time crescentic and ovoid forms usually appear. The tertian type of organism is associated with a fever which, according to Marchiafava and Bignami, has a characteristic type, differing materially from the mild or spring tertian. The individual paroxysm lasts usually more than twenty-four hours, often from thirty to forty hours. There is a marked tendency toward aggrava- The Malarial Fevers of Baltimore. 29 tion, anticipation, and conjunction of the attacks which frequently follow one another in such a manner as to produce a continued fever. They believe, however, that they are able to distinguish certain char- acteristic points about the febrile curve; a rapid invasion, a status febrilis, with more or less marked oscillations, a slight pseudo-crisis, a pre-critical rise in temperature during which the maximum point of fever is often reached, and finally the crisis. The paroxysms are so long and the periods of apyrexia so short that the patient often believes that he is suffering from a continuous fever, while, from vari- ous modifications of the temperature curve, this may actually be the case. Generally the curve becomes more or less complex ; this may be brought about by various influences. (1). By modifications of the curve in the individual paroxysm ; (2). By modifications in the succession of the paroxysms. (1). The important modifications of the curve are the following : (a). The lack of a sharp initial elevation so that the curve rises in a progressive and continuous manner; (6). the exaggeration of the pseudo-crisis so that the attack tends to lose its individuality ; (c). the prolongation of the paroxysm, which is usually associated with an exaggeration of the thermic oscillations during the fastigium; (d). the lack of a sharp pre-critical elevation. (2). The modifications in the succession of the paroxysms may be: (a). The anticipation of the paroxysms, which can occur in the mild as well as in the severe forms; (6). the retardation, which can occur also in the grave infections; (c). the prolongation of the paroxysms, by which apyrexia is made incomplete; (d). the presence of slight oscillations in the temperature during the period which ought to be one of apyrexia; the reduplication of the attacks. Further irregularities in temperature may be caused by combined infections or by the use of quinine or other remedies. The parasite which is the cause of this type of fever pursues its cycle of development, according to their idea, in direct relation to the clinical course of the case, just as do the other varieties of the malarial parasite. Its development is very similar to that of the quotidian par- asite. It produces, however, a larger quantity of pigment, and, at the 30 IV. S. Thayer and J. Hewetson. time of its full growth, may be one-half the size of the red corpuscle. The reproductive processes take place in this form as well as with the parasite of quotidian fever, chiefly in the internal organs, and, at the beginning of the attack, it may be almost impossible for several hours to find any malarial parasites in the blood. One sees here, as with the quotidian parasite, the collection of pigment in a clump in the central part of the body which breaks up into segments while it is yet contained within the red corpuscle, which is almost invariably gravely altered-shrunken, crenated, brassy-colored or destroyed. The chief differences between these two varieties of the parasite, Mar- chiafava and Bignami state to be the following: (1). The length of the cycle of development, which, in the quo- tidian parasite, lasts about twenty-four hours, and often occurs with- out the development of pigment, while in the tertian it lasts forty- eight hours, and is always associated with pigmentation. (2). The size of the amoeba; in the same relative stage of devel- opment, the amoeba of tertian fever is generally larger and of a more transparent appearance. (3). The movements, which, in the tertian parasite, are retained for a longer time by the larger pigmented forms than in the quotidian parasite; they are also more active in the tertian organism. (4). The length of the amoeboid unpigmented stage, which, in the tertian body, may last more than twenty-four hours. (5). The time elapsing after the beginning of the new paroxysm, before the appearance of the new generation of parasites, which, in the tertian fever amounts to several hours, considerably longer than with the quotidian type. The differences between the malignant tertian parasite and that of the ordinary mild tertian fever are marked. (1). It differs in its size, which is considerably smaller than that of the organism of mild tertian fever. (2). In the appearance of the young forms, which, in the malignant tertian fever, are ring-shaped, a characteristic not observed in the mild tertian fevers. (3). In the character of the pigment, which, in the organism of mild tertian, is always active, which is not the case in this form; the quantity of pigment in the malignant tertian organism is also much less than in the spring tertian body. The Malarial Fevers of Baltimore. 31 (4). The manner of segmentation; the segmenting bodies in mild tertian parasites are larger and contain a greater number of spores than those of the malignant tertian organism; they are also found very frequently in the blood of the finger in the one instance, and very rarely in the other. (5). The changes occurring in the infected red blood corpuscles; in the spring tertian these become increased in size and decolorized, while in aestivo-autumnal fever they commonly assume a deeper brassy color and become shrunken and crenated. (6). Finally, with the amoeba of the aestivo-autumnal tertian is associated the appearance of crescents which never occur in the other form. A still more elaborate classification of the malarial parasite is that of Grassi and Feletti.(221,339) These observers separate the parasite into five distinct varieties : (1). The li Haemamoeba praecox," giving rise to quotidian fever with a tendency to anticipation. (2). The 11 Haemamoeba immaculata," which is similar to this, ex- cepting that it runs its course sometimes more rapidly without the development of pigment. (3). The " Haemamoeba vivax," giving rise to tertian fever. (4). The " Haemamoeba malariae," giving rise to quartan fever. (5). The " Laverania malariae," giving rise to the irregular fevers. They insist that the Haemamoeba praecox, which corresponds to the aestivo-autumnal parasite of Marchiafava and Celli, is an entirely separate organism from the crescentic and ovoid forms, to which they give the name of " Laverania malariae." They agree with Canalis, Golgi, Antolisei and Angelini in believing that segmentation may occur in these forms. They have made extensive studies, in the blood of birds, of the haematozoa which so closely resemble, the parasites of malarial fever, and they believe that the parasites of the bird and those of the human being are entirely similar, though inoculations from one to the other have proven unsuccessful. Sacharow/212-1 in Tiflis, describes a "parasite of irregular fever" which corresponds to the aestivo-autumnal type of organism, the only difference being in the greater frequency with which segment- ing bodies are to be found in the peripheral circulation. He believes, as do Grassi and Feletti, that the crescentic bodies form a separate 32 W. S. Thayer and J. Hewetson. type of the parasite; they are associated with irregular fevers. He adopts the following types :(276) (1). Haemamoeba praecox (Grassi). (2). Laverania (Grassi). (3). Haemamoeba febris tertianae (Golgi). (4). Haemamoeba febris quartanae (Golgi). Mannaberg(291) has pursued quite elaborate studies of the malarial parasites, and has reached results which are not uninteresting. He divides the parasites into two groups : (1). Malarial parasites with sporulation and without syzygia : (a). The quartan parasite. (b). The tertian parasite. (2). Malarial parasites with sporulation and syzygia: (a). The pigmented quotidian parasite. (6). The unpigmented quotidian parasite. (c). The malignant tertian parasite. It will thus be seen that he accepts the division of Grassi and Feletti into the pigmented and unpigmented quotidian para- site (the Haemamoeba praecox and the Haemamoeba immaculata). The descriptions which he gives of these bodies are exactly similar to those given by Marchiafava, Celli and Bignami. The great differ- ence, it will be seen, between Mannaberg's classification and that of the Italian observers, is due to his interpretation of the crescentic bodies. These bodies, he asserts, arise from a conjunction of two smaller, intra-corpuscular forms. This conjunction is followed by the development of a membrane about the body; more pigment is formed, and finally the full grown ovoid or crescentic body results. By his staining methods he believes that he obtains definite proof that the crescents represent two individuals. He has seen the division of a crescentic body into its original two constituents. Beyond this transverse segmentation, as he calls it, he has never seen any other evidence of segmentation of the crescents. He denies, however, the assertion of Bignami, Bastianelli and March- iafava that these are degenerate forms. Dock(240) has been able to satisfactorily distinguish the tertian, quartan and aestivo-autumnal organisms without any sub-division of the latter variety. Titow (177) confirmed in the main Golgi's divisions of the parasite, which Korolko(226) has also been able to do. The Malarial Fevers of Baltimore. 33 One of the authors(327) of this note has also been able to confirm the divisions into the tertian, quartan, and aestivo-autumnal varieties. Finally Golgi(309) has studied the aestivo-autumnal fevers at Rome, arriving at results somewhat different from those of most other observers. He asserts that " the doctrine of the nosogenic process of the malarial fevers is not yet entirely known." Marchiafava's and Bignami's ideas concerning the regular cycles of twenty-four and forty-eight hours are rather an hypothesis than a fact based upon actual observation. His own observations have led him to believe that: (1). The parasites which circulate in the peripheral vessels in aesti- vo-autumnal fever are nothing more than an index, " non necessarie," though almost constant, of the infection; they have of themselves little to do with the pathogenesis of the febrile process ; they represent the first phases of a cycle of development which is much longer than has been believed-of as yet undetermined duration. (2). The entire process of development occurs, not in the peripheral blood circulation, but in the internal organs; here these parasites go through their diverse stages of development. (3). The doctrine of the quotidian and tertian varieties is not borne out by his researches; "it is not justifiable to accept this classification." He confirms Baccelli's(263) observations that, in the first few days of the disease, comparatively few organisms may be found in the circu- lating blood; they may indeed be absent. Those forms which one does find represent only the earliest phases of development. He distinguishes three phases: (1). The small amoebae without pigment or with but a few granules -the forms seen in the circulating blood. (2). The small amoebae with central clumps or blocks of pigment, which are thought to be pre-segmenting forms, and forms of more advanced development which may have grown to a size as large as the red blood corpuscle which may have been wholly destroyed. This phase is doubtless longer than the first. (3). A phase represented by the parasites with marked endo- globular development or even free forms. These present different appearances depending on their ultimate development and particularly on the forms of sporulation which are various. 34 W. S. Thayer and J. Hewetson. There are three main varieties of segmenting forms: (a). Regular forms like those of the tertian and quartan organ- isms ; these may vary greatly in size, some being larger than the red blood corpuscles, with as many as forty or fifty segments. (6). Forms of endogenous segmentation, where a layer of substance looking like a membrane remains about the periphery, while within there are eight, to ten, to twelve small spherules with sharp contour, arranged irregularly about a pigment block. (c). Forms with a more advanced development. These may vary from one-third the size of a red blood corpuscle to a size even larger than the corpuscle itself. They always contain a pigment mass. They have an irregular, mulberry-like contour and can change their form ; they arrive at reproduction in various manners. Segmenting bodies are best found from three, to four, to five, to six hours before the paroxysm, but, as the organisms appear to be arranged in foci in the spleen-here a group in one stage of development, here in another-the puncture of the spleen gives uncertain results. Certain facts suggest that these organisms may continue to de- velop and even segment within the bodies of large macrophages in the spleen. This, however, and many other points, need further investigation. He divides the malarial fevers into two groups: (1). Fevers, the pathogenesis of which is connected with parasites which have their principal habitat in the circulating blood where, by preference, they accomplish the phases of their cycle of existence. (2). Fevers, the pathogenesis of which is connected with parasites which have their chief seat in the internal organs, particularly the bone marrow and the spleen, where, by preference, they accomplish their cycle of existence in conditions of relative stability. (1). The fevers of the first group are, unquestionably, associated with different species or varieties of the parasite: (a). The quartan parasite. (b). The tertian parasite. (2). " To the second group belong the fevers which appear clini- cally under multiform types, very often irregular, of which for the present it is impossible to make a grouping based upon an ascertained biology or cycle of development of the parasite. ... We are deal- ing, in these cases, with generations of parasites which, occurring in the The Malarial Fevers of Baltimore. 35 parenchyma of organs, in different stages of development, give origin, at periods of a certain regularity, or, in a more or less continuous succession, to colonies of young forms which, in large or small numbers, or in insignificant quantity, may escape into the blood current, permitting one to discover by microscopical examination of the blood the presence of the small endo-globular amoebae." He refers to the crescents as " forms the biology of which has not yet been well determined." Culture and Inoculation Experiments. Thus we see that all authors who have had sufficient material at their service, agree in the statement that malarial fever is always associated with the presence of these parasites in the blood. It is, however, unfortunately true, that this discovery fills but one of the classical stipulations of Koch, which go to prove the dependence of a disease upon a specific micro-organism. Attempts, by many observers, to cultivate the parasite, by the most varied methods, have proven uniformly unsuccessful. Coronado/273, alone, asserts that he has been able to cultivate the organisms in water from a source from which he believes many individuals had been infected. Sterilization of the water makes cultivation impossible. By introducing malarial blood into tubes containing some of this water with about one-third the volume of mud from the bottom, he obtains, in twenty-four hours, cultures in which, he believes, he can trace the entire development of the malarial parasite. He observes the development of flagella from the pigmented parasites; these become free, and, eventually, break into from eight to fifteen small segments which begin again the cycle of existence developing pigment (!) and arriving, finally, again at the stage of flagellation. These remarkable experiments have been repeated by Sacharow(324) without success. If, however, culture experiments have failed, some observers have, at least, succeeded in preserving the organism for a certain length of time, outside the human body. This was first accomplished by Sacha- row, (163) who was able to keep the parasites (aestivo-autumnal (?)) alive as long as a week in leeches which were kept on ice. Bosen- bach, (214) applying leeches to a case of tertian fever, was able to 36 W. 8. Thayer and J. Heweison. demonstrate apparently living organisms after forty-eight hours. He believed that the parasites showed signs of growth and, possibly, of multiplication. Sacharow(324) has repeated these experiments, in order to test the effect of cold on the parasites, with interesting results. He placed the leeches on ice, examining them at varying periods. With the aestivo-autumnal parasite he still found forms with actively amoeboid movements and normal staining reactions after seven days, while an inoculation experiment made on the fourth day was successful. In a case of double tertian fever he found, after forty-eight hours, only the small amoeboid initial stages of the parasite, the older forms being apparently less resistant to the cold. All experiments, then, directed toward the cultivation of the para- site, with the exception of the as yet unconfirmed work of Coronado, have failed. Experiments, however, with inoculations made, if not from pure cultures, at least from patients whose blood has l)een care- fully examined before and after the inoculation, have given results which tend, strongly, not only to show that these parasites are the specific cause of malarial fever, but also to uphold the view first introduced by Golgi, that certain definite varieties of parasites are associated with certain definite varieties of fever. Gerhardt(38) was the first to show that malarial fever could be transmitted by inocula- tion of one patient with the blood of another. His results, however, were obtained before the parasite itself had been discovered. In two instances, inoculations were made from patients with quotidian par- oxysms. In the first, quotidian paroxysms appeared in sixteen days; in the second, irregular paroxysms gradually becoming quotidian appeared on the sixth day. The inoculation consisted in the injection of a Pravaz syringe full of blood. In 1884, Mariotti and Ciarrochi,(39) and Marchiafava and Celli,(41) inoculated five patients with malarial blood, obtaining positive results in three cases. Unfortunately though, as, in all these instances, several inoculations were made, it is impossible to state the exact period of incubation. It is interesting, however, to note, that, in case I, chills developed eleven days after the first intra-venous inoculation, a sub- cutaneous inoculation having been entirely negative before; in the second case, twelve days after the first inoculation ; and in the third, thirteen days after the first inoculation. Though these facts were not interpreted in exactly this manner by the authors, it is in every way The Malarial Fevers of Baltimore. 37 probable, in view of what we have later learned, that this represented the true incubation period. The next experiments were reported by Gualdi and Antolisei(102) from Baccelli's clinic at Rome. Two patients were inoculated intra- venously with 3 ccm. of blood from a patient suffering with quartan fever, at a time when the blood showed the earlier stages of segmen- tation. In the first case an irregular fever appeared in ten days after the inoculation, the blood showing the organisms characteristic of aestivo-autumnal malarial fever. In the second case the inoculation was followed, in twelve days, by a mild irregular fever, the blood showing, as in the former case, aestivo-autumnal organisms, but, also a few quartan forms. These two cases have served and still serve as the strongest argument used by the opponents of the idea that definite types of organisms are associated with definite types of fever. For here are two cases of aestivo-autumnal fever with its characteristic organism, resulting from inoculation with the blood of an appar- ently pure case of quartan fever. It was, however, discovered, on more careful investigation/11^ that the patient from whom these inocu- lations were made, was not suffering from his first attack, but had previously suffered from irregular fever, and, later on, had had a relapse, the blood showing the characteristic organisms. In view of the results which have been obtained since then, one is certainly justified in accepting the opinion of the experimenters themselves, as expressed later, that this case was not one of pure quartan infection, and that the aestivo-autumnal organisms being more resistant had developed to the exclusion of the quartan parasites which were present at the same time. Later, Antolisei and Angelini(103) inoculated two patients with the blood from a case of tertian fever. In each instance, in eleven days, within a few hours of one another, the two inoculated patients showed a rise of temperature, and, in each instance, characteristic tertian organ- isms were found. In the first instance, however, the fever was of an anticipating character, and later on became quotidian, while in the second case, the fever was at first somewhat irregular, but later showed a tertian character. The irregularity of the fever in the second case they ascribed to the presence of more than one group of organisms. Gualdi and Antolisei(110) next report a typical case of quartan fever, in which the characteristic quartan paroxysms, with the usual 38 IF. S. Thayer and J. Hewetson. organisms appeared twelve days after the inoculation. The same authors(111) later made an inoculation from the blood of a patient who had had malarial fever of an irregular type, with small hyaline bodies and crescents in the blood; the hyaline bodies had, however, disappeared under quinine, and after two days' careful examination of the blood by Marchiafava and Celli, nothing but crescentic or- ganisms were found. Irregular fever began on the ninth day, ring- shaped and hyaline organisms were seen on the tenth day, and eight days later, after the administration of quinine, crescentic bodies were for the first time seen; 2 ccm. of blood were used in the inoculation. Di Mattei(202) injected, intra-venously, blood from a case of irregular fever where he found at first only crescents, into a patient who had suffered from quartan fever which had disappeared spontaneously. A few days after inoculation hyaline bodies without pigment were found. Sixteen days after inoculation irregular fever appeared, and nine days later, crescentic bodies were found in the blood. He then injected blood from a case of quartan fever into a patient whose blood showed crescents. In fifteen days the symptoms of quartan fever appeared, the blood showing typical quartan organisms, while the crescents diminished in number, and finally disappeared. Calandruccio(205) inoculated himself with blood from a case of quartan malaria, which, at times, had shown regular quartan paroxysms, and, again, evidences of a triple quartan infection. He injected about 1 cc. of blood, with a sterilized Pravaz syringe, into the subcu- taneous tissue of his left arm. Eighteen days later he developed a malarial fever, the blood showing organisms similar to those injected, the fever pursuing the same course. He had never had malaria previously, and had never lived in a malarious district. The case from which the blood came was also one of artificial infection. In two other cases Calandruccio obtained positive results from the in- oculation with blood containing only crescentic bodies. The time of incubation, was, however, not noted. Bein(228) made four experiments with tertian parasites. In the first instance, one of tertian fever, a quotidian ague with characteristic tertian organisms appeared on the twelfth day. In the second experi- ment, a case of quotidian fever with tertian parasites gave rise, in twelve days, to a similar fever with similar organisms. In the third instance a double tertian infection gave rise, in nine days, to a single tertian. The Malarial Fevers of Baltimore. 39 Blood from the same case, injected into a fourth patient gave rise, in nine days, to tertian paroxysms disappearing spontaneously and recurring, after six days, as quotidian fever. In this, as in all the other cases, characteristic tertian organisms were present. The blood, in these instances, was taken in leeches which were then placed in warm water, and opened with sterilized scissors in a sterilized dish ; the blood was taken up in a Pravaz syringe and injected intra-ve- nously in one instance, and in the other cases, into the subcutaneous tissue of the forearm. Baccelli(263) made intra-venous inoculations from a case of double tertian fever and from a case of quartan fever, reproducing, in each instance, the same type of fever and of organism. The period of incubation in the case of tertian fever was six days, in the quartan eleven days. Sacharow (324) performed an interesting experiment upon himself. He obtained blood in leeches from a case of pernicious, comatose malaria with large numbers of hyaline, ring-shaped and amoeboid, non-pigmented bodies. From one of these leeches, which had been kept on ice for four days, 1 ccm. of the blood was injected, subcu- taneously, into the arm. Twelve days later chills and fever appeared, two paroxysms occurring on successive days. On the second day characteristic ring-shaped hyaline bodies were found in the blood. On this date quinine was administered and the organisms and fever disappeared. The results of these inoculation experiments are certainly striking. In only two instances has the type of organism which was believed to have been introduced, failed to reappear in the blood of the infected individual. These were the first two cases of Gualdi and Antolisei; the probable cause of this variance has already been explained. In all other instances the same type of organisms has appeared, and, with the exception of the instances where infection from a case of apparently single tertian fever produced a double tertian infection, and the converse, the types of fever have been exactly what might have been expected. The average duration of incubation, estimated from these eighteen cases, would appear to be from 11 to 12 days. In individual cases there was a variance of from 6 to 18 days. The experiments of Di Mattei, showing the disappearance of one set of organisms upon the introduction into an already infected individual 40 W. S. Thayer and J. Hewetson. of blood from a patient suffering from a different variety of infection, are very interesting. They show the possibility of producing, experi- mentally, the presence of two varieties of organism at the same time, but they show also, how, in each of the cases, the symptoms were produced by one variety only, the growth and development of one set of organisms being associated with the disappearance or diminu- tion of the other. Bacteriologically occurrences similar to this are, of course, not uncommon. It will be interesting to note, further on, that in the 11 cases of combined infection which we have observed, one variety of organism has always been in great predominance, while the symptoms have appeared to be due to this set alone. We have never seen a combined infection with irregular fever which ap- peared to be due to the flourishing of two varieties of organisms at the same time. Dochman,(U) in 1880, reported some interesting results from inocu- lations with the contents of herpetic vesicles in cases of malarial fever. In three cases typical intermittent fever resulted; the fever was quartan in one instance, tertian in another, and quotidian in the third. In all instances, however, the fever began, either on the same day, or on the day following the inoculation; no examinations of the blood were made. These experiments have never been confirmed, while careful examinations have failed to reveal the presence of or- ganisms in the herpetic vesicles or in sweat. Methods of Examination of the Blood. The most satisfactory method, in many ways, of studying the mala- rial parasite, is in the fresh blood which contains the organisms while yet living. The preparation of such specimens is extremely simple. A minute drop of blood is taken upon a cover glass and allowed to fall upon a clean slide; no pressure is exerted upon the glass, and the specimen is immediately examined. Some observers surround the edge of the glass with vaseline or paraffine in order to prevent evapo- ration. Some make use of Hayem's special slide, in which a small area in the middle is surrounded by a slight circular depression. A more accurate description of the methods of examining fresh blood will be given later, when we speak of our own proceedings. The Malarial Fevers of Baltimore. 41 One method of examining fresh blood we will speak of here as interesting, and, possibly, of value. We cannot, however, speak from experience. Plehn(176) asserts that he has obtained the best results in the following manner: All examinations of the blood are made at body temperature, the microscope, as a whole, being placed within a specially constructed case made by Lautenschlager of Berlin. He makes use of an ordinary slide, in the middle of which an area about the width of a common cover glass is surrounded with a layer of shellac, thus forming a modified hollowed slide. A carefully-cleaned cover glass is then covered by a drop of fluid paraffine, while another drop is allowed to fall in the middle of the concavity of the slide. The well-cleaned finger-tip, from which he takes the blood, is then painted with pure vaseline in order to prevent the entrance into the blood of foreign substances which might injure its composition. Through this vaseline he makes his puncture collecting the blood, immediately, upon the fresh paraffine drop on the cover glass. This is then laid upon the slide so that the blood spreads out between the two layers of paraffine which protects it from outside influences. In this manner he has seen the blood well preserved for two or three days. The difficulties of this method, it is easy to see, would prevent its daily use in ordinary examinations for diagnostic purposes. Many different methods have been proposed for the staining of the parasite and for the preparation of permanent specimens. The parasite is well colored by all basic aniline dyes, in fact, by most nuclear stains; it is not colored by the acid aniline dyes. It would be a waste 'of space to enter into a careful description of all the methods which have been advised. We will take up here but a few of the more important. The most satisfactory color, upon the whole, for the staining of the parasite is generally acknowledged to be methylene blue, and most observers have obtained the best results by a combination of methy- lene blue and eosin, the eosin staining the red corpuscles, the methylene blue the parasites. For making permanent specimens, the blood is collected upon cover glasses and fixed, either by heat or by subjection to the influence of absolute alcohol or alcohol and ether combined in equal quantities. Chenzinsky(75) recommends the following method : A concentrated watery methylene blue solution, diluted one-half with water, is mixed 42 IF. £ Thayer and J. Hewetson. with an equal volume of a | per cent, solution of eosin in 60 per cent, alcohol. The dried and fixed cover glass specimens are allowed to remain four or five minutes in the staining fluid, and then washed in water, mounted in balsam, and examined. Celli and Guarnieri(93) recommend an ingenious method which gives, apparently, good results. They endeavored to stain the parasites while yet alive, their mixture consisting of a solution of methylene blue in fluid from a serous transudation. They collected ascitic serum in sterilized test tubes under aseptic methods. The tubes were filled about two-thirds full of serum to which a sufficient quantity of methylene blue was added. This, for a short time, floats upon the surface, and then sinks slowly to the bottom, coloring the fluid a deep blue. After filtering into another test tube, the solution will remain for a long time without changing. Neither microscopical examination nor cultures reveal, after several days, the presence of micro-organisms. To color the blood in the fresh state the finger of the patient is cleansed and punctured with a needle, while, with a glass rod, a drop of the staining fluid is placed upon the drop of blood which appears. From this mixture a drop is placed upon a cover glass and allowed to spread out upon the slide, a little pressure being exerted in order to spread out the red corpuscles and prevent the formation of rolls. The staining requires a little time, the best results being obtained by leaving the preparations from one to three hours in a moist chamber. These specimens are, of course, not entirely permanent. Feletti(171) advises the following method: A small dro"p of an alco- holic solution of methylene blue-one part to five-is placed upon a slide and allowed to dry by passing the glass over a flame. One drop of blood is collected upon a cover glass and placed upon the stained area; the cover glass is surrounded by paraffine. The methylene blue is redissolved in the blood serum and stains the parasites satisfactorily. Plehn(176) advises the following method. The solution which he uses is constituted as follows : Concentrated aqueous solution of methylene blue 60. One-half per cent, eosin solution in 75 per cent, alcohol 20. Distilled water 40. 20 per cent. NaOH gtt xii. The Malarial Fevers of Baltimore. 43 The cover glass specimens are allowed to remain in absolute alcohol for from three to five minutes, are then placed in this solution for from five to six minutes, washed in water, and mounted. The results obtained by this method are excellent, and specimens may be obtained as permanent as is possible by the use of eosin and methylene blue. Mannaberg(291) advises the following method : The dried specimens are allowed to remain for half an hour in a mixture of absolute alco- hol and ether of equal quantities, dried upon filter paper, stained in a concentrated watery solution of methylene blue for half an hour, washed with water, dried on filter paper, and colored for about half an hour in a 2 per cent, solution of eosin in 60 per cent, alcohol, washed in water, dried, and mounted in balsam. Romanowsky(210) advises the following method: He keeps two solutions on hand; a saturated aqueous solution of methylene blue, and a one per cent, watery solution of eosin. The older the methylene blue solution the better the results. The specimen is heated not less than thirty minutes at a temperature of from 105° to 110° C.; the staining mixture is then made just before it is to be used. To one part of the filtered methylene blue solution about two parts of the eosin solution are added. This is carefully stirred with a glass rod, blit not filtered, and poured into a watch glass. The cover glasses are allowed to float upon the top of this fluid, the specimens being covered by another inverted glass, and the whole by an inverted cylinder which is moistened upon the inside. In from one-half to three hours-best in two or three hours-good specimens are obtained. Romanowsky believes that he obtains thus three colors; the red corpuscles are stained red by the eosin, the malarial parasite of a Prussian blue color by the methylene blue, and the nuclear chro- matin of a violet color-a neutral stain. Malachowsky(211) advises the following method : The dried speci- mens are fixed by being placed in absolute alcohol for several minutes, and then allowed to remain twenty-four hours in Sahli's borax methylene blue solution: Concentrated aqueous solution of methylene blue 24. 5 per cent, solution of borax 16. Water 40. Filter after twenty-four hours. 44 W. 8. Thayer and J. Hewetson. Sacharow,(212j in studying the small hyaline bodies of aestivo- autumnal fever, advises the use of gentian violet on account of the intense color which the parasites take. Sforza(288) has used the method of Canon and Pielicke with good results. The dried specimen is fixed by being placed for from five to ten minutes in absolute alcohol. It is then allowed to remain for from six to twenty hours in the following solution at 37° C., washed in water, and mounted. The solution is as below: Concentrated aqueous solution of methylene blue 40. | per cent, solution of eosin in 75 per cent, alcohol 20. Distilled water 40. Laveran(229) advises the following simple method: The dried speci- men is fixed in a mixture of alcohol and ether, equal parts, stained for thirty seconds in a concentrated aqueous solution of eosin, washed in distilled water and dried. It is then stained for about thirty seconds in a concentrated aqueous solution of methylene blue, washed again, dried and mounted, either dry or in Canada balsam. Good results may be obtained by the use of haematoxylin, Manna- berg/29^ hi particular, advising this method. His method he describes as follows : " The dried specimen is allowed to float at first for about five minutes upon distilled water, dried between filter paper, and washed in a very dilute solution of acetic acid (acetic acid gtt. j; dis- tilled water 20 com.) until complete disappearance of the haemoglobin. The entirely colorless preparation is then floated for two hours upon the fixing solution : Concentrated aqueous solution of picric acid 30. Distilled water 30. Glacial acetic acid 1. From this it is placed in absolute alcohol for about two hours. This is followed by staining for twelve to twenty-four hours in alum hae- matoxylin ; then by differentiation by means of 0.25 per cent. HC1 alcohol (alcohol 75 per cent.) and ammonia alcohol (3 drops of ammonia to 10 ccm. 75 per cent, alcohol), washing in 8 per cent, alcohol, mounting in Canada balsam. The washing of the prepara- tion with water and acetic acid causes the removal of all albuminous substances which would otherwise give rise to annoying precipitates The Malarial Fevers of Baltimore. 45 with the subsequent treatment with picric acid. The preparations made by this method show the parasites as well as the leucocytes of a blue color. The red blood corpuscles remain perfectly colorless. In satisfactory preparations the finer structure of the parasite stands out very beautifully." Mannaberg uses a solution of haematoxylin (10 grammes of hae- matoxylin to 100 of absolute alcohol) which is as old as possible. Before use, one part of this is mixed with two parts of a | per cent, ammonia alum solution. The fixing of specimens with osmic acid and a large number of other methods which have been advised will not be entered into here. References may be found in the table of literature at the end of the article. The Finer Structure of the Malarial Parasite. Celli and Guarnieri(93) were the first to make a careful study of the intimate structure of the malarial parasite. In the fresh state definite signs of a nucleus are not to be made out. In their speci- mens colored with methylene blue dissolved in ascitic fluid, they were able to distinguish a deeply colored ectoplasm and a more palely stained endoplasm. The bodies which appear to be ring- shaped, are not really rings, the part within the ring being represented by the endoplasm which is but faintly colored and allows the corpuscle to show through. In the youngest bodies they noticed a deeply staining spot at a point on the border between the endo- and ectoplasm. In the endoplasm, in some specimens, they were able to make out a palely stained body or sometimes one or more sharply stained points or a net-work, which they believed to be the nucleus. They describe the double contour of the crescents and note that these bodies stain more deeply toward the extremities, while the middle is pale; often there is a spot under the pigment in the middle of the crescent which takes a deeper color. Grassi and Feletti,(122) in their studies of the quartan parasite, go further, stating that the parasites possess a large, clear, bladder-like nucleus, corresponding apparently to the entire endoplasm described by Celli and Guarnieri. This is usually eccentric, with a delicate, often invisible nuclear membrane. The nuclear juice they believe 46 IK S. Thayer and J. Hewetson. to be " halbfest; " while the nuclear net-work consists of a more or less eccentric nucleolus-like mass of varying form, sometimes round, sometimes almost triangular or quadrangular, from which three or four very delicate fibres which are almost invisible in the smaller forms, stretch out toward the membrane. The plasma is generally hyaline, but often shows a fine granulation which stains readily with methylene blue; it also shows the granules of melanin. There are sometimes one or more non-contractile vacuoles. As the body grows the nucleolus grows larger and almost fills the nucleus; it often has a rod-like shape. This divides into two parts, and each daughter section again dividing, there results, finally, an amoeba with numerous nucleolus-like granules. Eventually nuclear juice collects, and a thin, delicate membrane forms about each nucleus. Later on the plasma divides in a manner not yet entirely cleared up, the pigment remain- ing behind, leaving the fresh segments, which they believe to be gym- nospores, probably simply young amoebae. The crescents have a similar nucleus in the middle, about which the pigment is usually collected. The crescent is surrounded by a membrane which, they believe, arises from the blood corpuscle in which it has developed, as does the delicate membrane surrounding the segmenting bodies. The plasma (ectoplasm) alone is concerned in the formation of flagellate bodies, the nucleus taking no part; this fact, they believe, is sufficient to prove that these forms are not regenerative in nature. Celli and Sanfelice(l90) likewise describe the pale, non-staining nucleus. Romanowsky(188,210) studied the tertian parasite on dried cover glass specimens stained, by a particular method, with eosin and methylene blue. He separates, always, two distinct parts of the organism ; one of irregular shape of a Prussian blue color; and one entirely uncol- ored of an ovoid or round form lying within the blue colored rim. In this central area, always close to the periphery, he found a small body of a dark carmine-violet color. Because these minute bodies were present in every parasite, and because they showed a coloring similar to that of the nuclei of the leucocytes, and because, also, they showed at times signs of a fibrillary metamorphosis, he believed that these represented the chromatic part of the nucleus while the rest of the clear central area was the clear nuclear fluid. He believes that at The Malarial Fevers of Baltimore. 47 the time of segmentation he can distinguish karyokinetic figures in the chromatic substance of the nuclei. Sacharow/212, 324) studying the aestivo-autumnal organism, notes also the pale central area-nucleus-with the deeply staining granule -nucleolus. He states that as the organism approaches segmenta- tion, with the collection of the granules into a central mass, the nucleus disappears. Mannaberg(203,291) states that the nucleus is represented in the unstained specimen by a refractive body which takes up the greater part of the spore; that the small, more refractive point within it represents the nucleolus; the clear space which one occasionally sees in the large free forms represents the bladder-like nucleus which Grassi and Feletti described in stained specimens. The nucleus is represented as a relatively large, more or less round, bladder-like affair which lies, generally, excentrically. It is colorless or only very slightly colored, and shows at a point on the periphery a deeply staining body about which one sometimes sees a more palely stained zone. This body, which contains the greater part of the chromatin substance, is the nucleolus, while the clear substance represents the nuclear juice. As the parasite grows one can distinguish an outer layer of protoplasm taking a deeper stain and showing the granules of melanin, and an inner clearer layer free from granules, lying about the nucleus. The nucleus is usually excentric. The nucleolus grows with the organism, but before segmentation it disappears, passing out apparently into the substance of the parasite. The nucleus at this stage has a diffuse pale blue color, and is only to be distinguished from the parts outside by its lack of pigment; at this time one may speak of a " plasma part " and a " nuclear part " of the parasite. With segmentation we begin to see, in the nuclear part, the appear- ance of new nucleoli which finally form the centres of new spores. He cannot confirm Romanowsky's views concerning the karyokinetic division. He divides the life of the parasite into a vegetative and a reproductive stage. The reproductive stage begins with the dis- appearance of the nucleolus. More recently Bastianelli and Bignami(331) have studied minutely the structure of the aestivo-autumnal parasites. They fixed their specimens with alcohol, and stained with eosin and haematoxylin. According to them the young parasite consists of two substances; 48 W. S. Thayer and J. Hewdson. an outer colored and an inner uncolored cytoplasm. In the former one sees one or more granules of chromatin though no real nuclear structure is to be recognized. The ectoplasm is in functional ac- tivity during the entire life of the parasite. During the further development of the body these three portions remain quite clear and distinct, while granules of melanin begin to appear in the cytoplasm. As the increase in size progresses the small granules or masses of chromatin substance disappear, entering probably into solution in the cytoplasm. The cytoplasm increases in quantity and shows a slightly granular or homogeneous appearance. At this time the endoplasm develops a slight staining propensity. The pigment then begins to leave the chromophilic zone and tends to collect toward the middle or at one side of the parasite; thus arise the small bodies with central pigment, bodies one-fourth to one-fifth the size of a red blood corpuscle. These bodies consist of an apparently homogeneous substance more deeply colored in its outer part than in the middle, but without sharp boundaries between the two substances. In this stage the phase of reproduction may suddenly take place, but often the bodies keep on growing, the chromophilic substance ever increasing in quantity; the largest individual forms however are always smaller than a red blood corpuscle. The largest forms which one sees free in the plasma and, especially, in the spleen show changes which lead the authors to believe that they are degenerative, and incapable of reproduction. The reproduction begins with the formation of very small, deeply colored points of thickening of the chromatin substance; these increase steadily in size, becoming, finally, round or slightly ovoid in shape. Later on each one of these chromatin bodies becomes surrounded by a fine border of chromophilic protoplasm. A small amount of faintly stained protoplasm remains apparently unused. These spores differ from the young parasites in (1) that they have a regular, constant form ; (2) that they possess no apparent achromatic cytoplasm (with occasional exceptions); (3) that they are immovable. The authors conclude that one cannot recognize in this variety of parasites, any body which has the various constituents of a true nucleus. The granular bodies of chromatin which form a part of the cytoplasm and become dissolved in it when the body is ready for reproduction, bodies which form the most important part of the young spore, represent that part of the parasite which performs the The Malarial Fevers of Baltimore. 49 function of the nucleus. The phase of a resting nucleus is wanting in this organism, probably because of its rapid cycle of development. The crescents, they say, stain faintly and usually take a diffuse color; often they have no chromatin granules. They have no mem- brane, and show, usually, no differentiation of the protoplasm. These facts convince the authors all the more that these are sterile forms of the parasite. It will be seen in this description that the chromophilic granule or granules are said to exist in the ecto-plasm of the parasite, while most of the above mentioned authors have assumed that it lies upon the border of the endoplasm. No one has been able to distinguish with certainty a membrane about the malarial parasite. Antolisei(126) has described a double outline about the spores, while, as has been stated, numerous observers inter- pret the more refractive outline of the crescentic and ovoid bodies as representing a distinct membrane. Antolisei and Angelini(119) believe that this contains haemoglobin. In summary, then, the substance of the parasite has, by careful study, been shown to consist of a more deeply staining outer part, which contains the pigment granules, and an inner part which is pale and non-staining, excepting for a small, more deeply colorable body which is usually situated close at one side on the border line between this area and the more deeply staining outer layer. This colorless area is generally interpreted as a bladder-like nucleus, the dot at one side representing the chromatin substance or the nucleolus. Bastianelli and Bignami can distinguish no body in the aestivo-autumnal organ- isms which has all the characteristics of a nucleus. While Grassi and Feletti, Mannaberg, Bastianelli and Bignami have been unable to dis- tinguish characteristic karyokinetic changes at the time of division, Romanowsky believes that he has done so. Manner of Reproduction. Most observers agree that reproduction may take place by sporu- lation, and even Laveran is inclined to-day to accept the process first described by Marchiafava and Celli(45) as one of the modes of repro- duction. Some observers, Laveran,(229) Mannaberg,(291) Dock,(161) and Manson,(347) believe that the flagellate body may represent another method of reproduction. The fragmentation of the large, extra- 50 IK & Thayer and J. Hewetson. cellular bodies, and the budding of certain crescentic and ovoid forms, which were thought, at first, to represent reproductive processes, are now believed by most observers to be rather degenerative than regenerative processes. The spores resemble very closely the young individuals, differing from these chiefly in their lack of motility and in their regular form. Plehn(176) believes that they possess one or more flagella and asserts that he has seen them move about actively among the blood corpuscles. Antolisei(126) describes a double contour. Classification of the Parasite. Much has been written concerning the classification of the malarial organism and its position among the protozoa; it will be, however, scarcely worth while in a paper of this nature to enter too closely into the literature upon this point. Laveran,(25) without definitely suggesting the biological position of the parasite, proposed the name " Oscillaria malariae " for the organ- ism, believing that the flagellate bodies represented the more important stage. But later on,(60) wishing to hold himself aloof from any too early conclusions as to the nature of the parasite, he accepted the term " Haematozoon " used by Osler.(55) In his last publication he has accepted the classification of Metchnikoff.(59) Osler,(55) in 1887, believed that until further studies had been made it should be classified as belonging to the genus " Haematomonas," species " Haematomonas malariae." Metchnikoff,59 in 1887, places the parasite in the class of Sporozoa, to which class it has been, generally, since then referred. Metchnikoff believes that the organism should be considered among the Coccidia, and proposes the name " Haematophyllum malariae." This classifi- cation has been accepted by Laveran. Danilewsky also inclines toward this view in so far as he ranks the parasite among the Sporozoa. He proposes, however, a new group, "Haemosporidia," in which he would place these organisms as well as the similer parasites observed in birds. With this view Celli and Sanfelice(190) and Mannaberg(291) agree. Celli and Sanfelice(190) with Kruse(1M) distinguish in this subdivi- sion, three genera: The Malarial Fevers of Baltimore. 51 (1). Haemogregarina (Danilewsky) (Frogs and Keptiles). (2). Haemoproteus (Kruse) (Birds). (3). Plasmodium (Marchiafava and Celli) (Man). Kruse(251) later separates the Sporozoa into four orders: Gregarinida. Sarcosporidia. Myxosporidia. Microsporidia. The Gregarinida he divides into the following subdivisions : (1). Polycystideae. (2). Monocystideae. (3). Coccididae. (4). Haemogregarinidae. The Haemogregarinidae are separated into four genera: Haemogregarina (Tortoise-Lizard). Drepanidium (Frog). Haemoproteus (Birds). Plasmodium (Man). A few authors have objected to the inclusion of these parasites among the Sporozoa. Among others, Antolisei(139) considers them to belong to the Gymnomyxa (Ray Lankester) or more exactly to the Proteomyxa, while Grassi and Feletti(122) include them among the Sarcodinia, more especially the Rhizopodia, in the division of Amoebae. Similar Haematozoa in other Animals. It is scarcely worth while in this article to enter into the subject of the haematozoa of certain other cold and warm-blooded animals which so closely resemble the malarial organism. Following the earlier work of Lewis,8) Gaule/10,20) Osler,* and others, extensive studies, more particularly of the blood of birds from malarial regions, have been made by Danilewsky/44,52,53, &0) Chalachnikoff/79) Kruse/164, 251) Celli and Sanfelice,(190) Grassi and Feletti,(205,221) Laveran,(227,229) Labb&(298'310,318) and Sacharow.(300) It has been clearly shown that birds may suffer from a malarial infection very similar to that in man. * Canadian Naturalist, Vol. X, No. 7. 52 W. 8. Thayer and J. Hewetson. Danilewsky(232) divides the parasites of birds into : (a). The Haemocytosporon malariae, which is the cause of acute malaria; this may be seen to grow, to develop pigment, and to divide into spores just as does the malarial parasite in man. (6). The parasites of chronic infection, which are represented by the Polimitus and the Laverania malariae. He is not yet certain as to whether the parasites are the same in man and in birds, but he finds a close resemblance between the organisms of acute malarial fever in man and the Cytosporon in birds, and a similar resemblance between his Polimitus and Laverania in birds, and the flagellate and crescentic bodies in man. Celli and Sanfelice(190) find three forms of the parasite in birds: (a). A parasite with slow development which corresponds to the quartan organism in man. (6). One with a more rapid development corresponding to the ter- tian organism in man. (c). A third with the most rapid development, corresponding to the quotidian * in man. They believe, however, that the identity of the parasites of man and birds is not, as yet, established. Grassi and Feletti{205,221) go farther and believe that the malarial parasites of birds are the same as those seen in man; they identify in birds all the forms which they have distinguished in man. They have, however, been unable to successfully transfer organisms from man to birds or from birds to man. Inoculations from bird to bird have proven unsuccessful, excepting in a very few instances, and then only when birds of the same species were used. Laveran(227, has also made careful studies of the organisms in the blood of birds. While he recognizes the great similarity in many instances between the parasites of birds and those of the human being, he is not yet convinced that they represent the same organism. Labbe (298, divides the parasites of birds into : (a). The Proteosoma Grassii; this corresponds to the Amoeba of Grassi and Feletti. Labbe describes, however, but one species. * At this time the Roman authors had not subdivided the aestivo-autumnal para- site into a quotidian and a tertian variety, but considered that the parasite had a cycle of development lasting about twenty-four hours. The Malarial Fevers of Baltimore. 53 (6). The Halteridium Danilewskyi (Grassi and Feletti) ; this cor- responds to the Laverania of the Sicilian authors. Danilewsky/185) Sacharow,(300) and Labbe,(345) all describe haematozoa which develop in the leucocytes of birds, " Leucocytozoa." ♦ Form in which the Parasite exists outside of the Body. Manner of Infection. Notwithstanding all the studies which have recently been made concerning the malarial parasite, we have, as yet, no knowledge as to the form in which it exists outside of the body, nor have we gained any positive information concerning the manner in which it enters the system. The contagium of malaria has been supposed to enter the system in various ways; the most important points of entry which have been suggested are: (1). The respiratory tract. (2). The digestive tract. (3). The skin (insect bites, etc). (1). That infection may take place through the respiratory tract there can be little doubt, though it must be said that we have as yet no, positive proof of its occurrence. Celli and Sanfelice(190) assert that they have succeeded in transfer- ing a malarial infection from one bird to another by intra-pulmonary inoculations. Their results, however, have been disputed by Grassi and Feletti,(221) who have been quite unable to accomplish the same thing. Grassi and Feletti,(205) have however, found certain small amoebae in very large numbers in malarial regions. One of these, the Amoeba guttula, is readily encysted and easily carried about by the wind. This amoeba they found in the nostrils of young doves which they had placed in cages which were hung for two nights in a malarial region about two metres above the ground. In nine days these birds showed Laverania in their blood. This suggestive observation has never been repeated. More recently, Labbe(345) asserts that he has succeeded in transferring the infection by intratracheal injections of blood. 54 W. 8. Thayer and J. Heweison. (2). Many observers still believe that the parasite is intro- duced chiefly through the digestive tract. Among these is Coro- nado/273, We have, however, no positive evidence in favor of this idea, and much against it. Celli(46) allowed six individuals to drink large quantities of water from the Pontine marshes without ill effects, while Marino(172) had similar results from like experiments. Zeri,(132) in Baccelli's clinic, experimented in thirty cases with inhalations, drinking and enemata of water from malarious dis- tricts without a single positive result. Grassi and Feletti(205) allowed healthy individuals to drink dew collected from malarious regions without ill effects. The same observers caused healthy men to drink blood from malarial patients, and fed birds of prey on infected birds, but in no instance did they obtain positive results. Labbe's(345) experiments with frogs and birds were also unsuccessful. (3). Inoculation experiments have given positive proof that infec- tion may take place through the skin, which renders more plausible the old idea that insect bites may serve to convey the contagion. Particularly interesting in this connection are the remarkable re- searches of Theobald Smith,* who has shown that the haemocytozoon of Texas fever in cattle (Pyrosoma bigeminum) is conveyed from animal to animal by means of the cattle tick (Bodphilus bovis). Experimentally, then, it has been shown that while infection through the alimentary tract is improbable, subcutaneous infection is possible, as is also •intra-pulmonary infection, if we can accept Celli's and San- felice's and Labbe's observations on birds. There is much room for further experimentation in this field. Relation of the Parasites to some of the Main Symptoms of Malarial Fever. (1). The Intermittent Fever. Laveran,(23) in 1881, suggested that the parasites which during apyrexia remain largely in the internal organs, enter finally into the general circulation, and by an irritating influence on the nervous * " Investigations into the Nature, Causation and Prevention of Texas or Southern Cattle Fever," Theobald Smith and F. L. Kilbourne. U. S. Department of Agri- culture, Bureau of Animal Industry, Bulletin No. 1, Washington, 1892. The Malarial Fevers of Baltimore. 55 centres bring about the febrile paroxysm. The afebrile period, which is often so constant and regular, may represent the time which the nervous system requires to recover from the exhaustion following the paroxysm. Richard(33) believes that the rapid multi- plication of the parasites produces the fever which represents the reaction of the organism against the invaders; "they " (the parasites) " excite the fever, the fever destroys them and falls in its turn; " with apyrexia the parasites multiply again. With the more exact knowledge which we have gained concerning the cycle of development of the parasites, the coincidence of the paroxysms with the segmentation of groups of organisms has been made out. Golgi(49) first attributed the paroxysm to the invasion of the red blood corpuscles by a new group of parasites, and asserted that the severity of the paroxysm depended on the number of fresh organisms which attacked the red corpuscles. Antolisei(126) later called attention to the fact that it was not upon the number of new organisms which invaded the red blood corpuscles, but rather upon the number of segmenting bodies, that the paroxysms depended. Quinine given before a paroxysm may entirely prevent the development of a new group of parasites, but it cannot prevent the segmentation or the chill. Baccelli(263) speaks of the importance of chemical poisons in pro- ducing the symptoms of malarial fever. He says that the symp- toms of malarial fever depend upon, (a) a morphological hae- modyscrasia; (6) a chemical haemodyscrasia. The former depends upon the progressive destruction of the red blood corpuscles by the parasites which live at their expense. The latter manifests itself in a much more intense and rapid manner, and depends upon the entrance into the circulation of as yet undetermined chemical poisons which are set free at the time of sporulation, poisons due either to the act of spor- ulation or to substances set free from disintegrated red blood corpuscles. These poisons are injurious to the nervous system and specially to the vasomotor ganglia ; it is to their liberation that the febrile paroxysms are due. During the paroxysm many spores are destroyed, but a certain number remain to begin again their cycle of existence. Golgi(274) in 1892, accepts this conception of the toxic origin of the fever. Plehn(262) asserts, also, that the febrile manifestations are due 56 IF. & Thayer and J. Hewetson. to the circulation of toxic substances in the blood, and makes the interesting suggestion that in some instances the febrile paroxysms occurring in individuals immediately after exposure to severe malari- ous influences, may be dependent upon the absorption of a quantity of these toxic substances produced by the parasite, sufficient to cause a single paroxysm. He relates two cases where individuals showing a paroxysm of this nature, developed, nine to twelve days later, charac- teristic malarial fever with organisms in the blood. Mannaberg(291) likewise adheres to Bacelli's theory, which is proba- bly accepted to-day by most observers. Strongly in favor of the idea of the toxic origin of the febrile manifestations of malaria are the observations of Brousse * and of Roque and Lemoine,(174) who have demonstrated an increased toxicity of the urine following malarial paroxysms, and of Queirolo,(108) who has shown that the same increased toxicity is observed in the sweat obtained during the paroxysm. Even more striking evidence in favor of this view is the occur- rence of the disseminated areas of necrosis in the liver described by Guarnieri,(66) Bignami,(179) and noted by Barker in another part of this fasciculus. These changes which are so characteristic of various severe infectious processes may be produced, as first shown by Welch f and Flexner, as well by soluble toxines as by actual infection. It must be said, however, that Laveran (277) in his last work does not speak with any degree of certainty on these points. He states that toxic products may have an influence on the febrile manifesta- tions, but that at present this is a mere hypothesis. He says " the degree of irritability of the nervous system which varies with indi- viduals and with the date of the infection, seems to play an important role in the determination of the form and type of the fever. If the case be one of a robust individual who has the fever for the first time, the nervous system reacts vigorously against a pathogenic agent to which it is not accustomed, and one observes a continuous or at least a quotidian fever. If the patient be anaemic, reduced in strength by repeated attacks of fever, the nervous system having become less impressionable, the result is a fever with long intervals." *Soc. de M^d. et de Chir. pratiques de Montpellier. 14 Mai, 1890. Quoted by Laveran. C229) t The Johns Hopkins Hospital Bulletin, No. 20, March, 1892. The Malarial Fevers of Baltimore. 57 (2). 1 he Anaemia. Red Corpuscles.-All observers agree that the anaemia is due primarily to the actual destruction of the corpuscles by the parasites; this may be excessive. Kelsch(6) has seen as small a number of red blood corpuscles as 500,000 to the c. m. m. A reduction in corpuscles follows each paroxysm; these reductions are more marked after the early paroxysms than in those occurring later. When a certain degree of anaemia has been reached, the losses per paroxysm are much less. When the number of corpuscles is reduced to 2,000,000, or 1,000,000, there is little tendency toward a further fall; sometimes there may be slight rises in the curve between the paroxysms-often, however, the number of corpuscles remains stationary for weeks. In pernicious cases the number of corpuscles may fall between paroxysms. Kalindero,(92) from 400 blood counts made in fifteen cases, con- cludes that the number of red corpuscles is greatly diminished in malarial fever. This diminution is greater the longer the disease lasts, and the more intense the manifestations. During the paroxysm the number of red corpuscles as well as of the white tends to increase. These changes are particularly notice- able during the first paroxysms. When, on the other hand, the anaemia is profound, the number of corpuscles tends to fall to a nearly constant number which does not appear to be modified by the par- oxysm. If the paroxysms are suppressed before they have lasted long, and before the spleen is much hypertrophied, the number of red and colorless corpuscles returns to the normal. If the fever has lasted long and the spleen is much hypertrophied, while the general condition of the patient is bad, the diminution tends to become permanent. There is no intimate relation between the enlargement of the spleen and the diminution in the number of the corpuscles. Dionisi(173) made a careful study of the variations in the number of the red blood corpuscles during malarial fever with the following results: (1). In aestivo-autumnal fever, the reduction in the number of red blood corpuscles bears a direct relation to the number of organisms. 58 W. S. Thayer and J. Hewetson. Where the parasites are numerous there is a constant reduction of from 200,000 to 1,000,000 with each febrile paroxysm ; where the parasites are scanty the reduction is less. (2). When crescentic bodies are present in addition to the other forms, they seem to exert no influence on the blood changes. (3). When, after a paroxysm, the number of corpuscles has suffered a sudden and very marked diminution, the succeeding paroxysms may be followed by but a slight reduction only or even by an increase. (4). In relapses the reduction per paroxysm is less than in a pri- mary infection. (5). In infections determined by the amoeboid forms (acute aestivo- autumnal infection) there is, during apyrexia, no complete return of the red corpuscles to their normal number. Some attempts at resti- tution may be seen during the first several days of apyrexia, while after this, during perhaps eight to fifteen days, there may be a steady reduction of from 1- to 500,000 red blood corpuscles without the appearance of any parasites in the blood. (6). Only after marked and continuous reductions following each paroxysm does there occur in the afebrile period a relative restitution of the red blood corpuscles; this may be slow or rapid. (7). If the increase in the corpuscles has begun, the presence of crescents has no deleterious effect. (8). In tertian and quartan fevers the same changes are observed, excepting that in the afebrile period there is a rapid and almost com- plete restitution of the red blood corpuscles. (9). The colorless corpuscles follow the same course as the red, both in apyrexia and fever. In later periods, however, when the red corpuscles have increased, there may still be a marked diminution in the colorless elements. Bastianelli(246) noted the association of the anaemia of cachetics with actual changes in the marrow produced by the infection. Bignami and Dionisi(332) distinguish four types of post-malarial anaemia: (1). Anaemiae in which the examination of the blood shows alter- ations similar to those observed in secondary anaemiae, from which they differ only in that the leucocytes are diminished in number. The greater part of these cases go on to recovery; a few, without any further change in the haematological condition, pursue a fatal course. The Malarial Fevers of Baltimore. 59 (2). Anaemiae in which the examination of the blood shows alter- ations similar to those seen in pernicious anaemia-presence of gigan- toblasts. These cases end fatally. (3) Anaemiae which are progressive, as a result of the lack of com- pensation by the marrow for losses brought about by the infection. At autopsy the marrow of the long bones is found to be wholly yel- low, while the marrow of the flat bones is also poor in nucleated red corpuscles. (4). Chronic anaemiae of the cachectic, which differ from the above mentioned types by clinical and anatomical characters in that the special symptoms of malarial cachexia prevail, while one observes post-mortem, a sort of sclerosis of the bone marrow. The marrow of the long bones is red and of an increased consistency; the giant cells are very numerous and many are necrotic; the nucleated red blood corpuscles are very rare, and the colorless polymorphonuclear * corpuscles are present in small numbers. Colorless Corpuscles.-Kelsch(7) noted that the leucocytes were dimin- ished during the paroxysm more than the red blood corpuscles, an absolute diminution sometimes to one-half or one-third the normal number. From this they may show a slight increase just at the beginning of the paroxysm. Usually the number of leucocytes returns to normal much more slowly than that of the red corpuscles. The minimum of the leucocytes corresponds to the maximum of the splenic enlargement. In cachexiae with chronic splenic tumor he found, generally, a diminution in the number of leucocytes, though in some pernicious cases there was a leucocytosis. Hayem f noted the absence of increase in the colorless corpuscles. Kalindero(92) noted a marked diminution in the number of the leucocytes, especially in the more acute cases. During the paroxysm there is a tendency toward an increase in the number. Dionisi,(173) as has been stated, noted that the colorless corpuscles show the same variations in number as do the red, excepting that in some long continued anaemiae the white corpuscles remain sub- normal in number for a longer time. * This term first used by Cabot (Boston Med. and Surg. Journal, March 20, 1894), a translation of the German term " Polymorphkernige " appears to me the best which we have in English. t Le Sang, Paris, 8°, 1889. 60 IF. S. Thayer and J. Hewetson. P6e* remarked the absence of any leucocytosis in intermittent fever. Bastianelli(246) noted also a diminution in the number of leucocytes during the attacks; this he thought might depend on the active phagocytosis with subsequent necrosis. He noted colorless elements in karyokinesis in the spleen and sometimes in the circulating blood- a regenerative process, he believed, to compensate for the active destruc- tion which had occurred. He made a series of differential blood counts in specimens stained according to Ehrlich's methods, showing that in these cases with a diminished number of leucocytes the relative pro- portion of the small mononuclear elements remained normal, while that of the large mononuclear leucocytes was much increased, and the polymorphonuclear neutrophiles appreciably diminished; eosinophilic cells were generally scanty in number. The striking similarity of these counts to the condition seen in typhoid fever will be noted. Billings,(338) in this clinic, made a series of observations confirming, in the main, these results. He notes that the leucocytes, which are generally sub-normal in number, show a slight increase at the begin-* ning of the febrile paroxysm. Following this increase there is a rapid diminution continuing throughout the paroxysm. The smallest number of leucocytes is seen at the end of the paroxysm when the temperature is sub-normal. From this time the number shows a gradual slight increase, which, as has been said, is slightly accentuated just at the beginning of the paroxysm. The changes in the relative proportion of the different varieties of leucocytes he found to be just as noted by Bastianelli. In four cases of post-malarial anaemia, Billings found quite a marked leucocytosis. Haemoglobin.-Rossoni(106) studied the variations in the percentage of haemoglobin in,association with blood counts, and arrives at the following conclusions: (1). No acute infection results in as active a deglobulization as does malarial fever. (2). In all cases of malarial fever there is an immediate diminu- tion in the number of corpuscles and the amount of haemoglobin. This loss generally bears a direct relation to the duration of the infec- tion. In pernicious cases, however, a diminution of as much as two- thirds of the total amount may take place in from one to three days. * Diss., Berlin, 1890. The Malarial Fevers of Baltimore. 61 (3). The gravity of pernicious cases does not always bear a direct relation to the extent of the loss in haemoglobin. (4). The destruction of haemoglobin and corpuscles bears, generally, a direct relation to the number of parasites in the blood. Occasion- ally, however, cases with high fever and marked losses in haemo- globin and corpuscles, may show but few parasites in the circulating blood. A long-continued diminution of haemoglobin is often asso- ciated with the presence of crescents. (5). The loss in haemoglobin and corpuscles is rarely evident during the paroxysm, but begins with apyrexia and may continue for several days afterwards. (6). Recovery from malarial anaemia is slower than from the other acute anaemiae. (7). Usually the haemoglobin and corpuscles are equally dimin- ished, but sometimes the haemoglobin is reduced disproportionately. (8). The rapid diminution in haemoglobin is sometimes a valuable point in differential diagnosis between malarial fever and enteric fever or pneumonia. (9). The restitution of the haemoglobin in malarial anaemia is often incomplete, and individuals living in malarious districts have often a slightly smaller percentage of haemoglobin than those living elsewhere. (3). Other Symptoms. The pathogenesis of a number of the other important symptoms of malarial fever has been much elucidated by the knowledge we have gained concerning the parasites. The coma in some pernicious cases has been shown by many observers to be associated with enormous collections of malarial parasites and pigment in the cerebral capillaries. The parasites may be free and are often in the process of segmentation; they may be contained in red corpuscles; they may form actual thromboses. The endothelial cells of the capillaries are often swollen and degener- ated, while in many places perivascular punctate haemorrhages may be seen. These so-called " pigment thromboses " were first noted as long ago as 1854, by Planer(4) who attributed to them the coma- tose symptoms. 62 W. 8. Thayer and J. Hewetson. In one case of pernicious fever with symptoms of bulbar paralysis Marchiafava(167) demonstrated the special localization of similar changes in the region of the bulbar nuclei. While these local conditions may be reasonably supposed to account for many of the cerebral symptoms in pernicious fever, it must be acknowledged that we cannot deny a possible toxic cause for some. It is also interesting to note the hypothesis of Guarnieri,(66) who, finding enormous accumulations of large macrophages blocking many intra- lobular capillaries in the liver, and extensive areas of necrosis, called attention to the similarity between the cerebral symptoms in these cases and those produced artificially in animals by ligature of the portal vein. In cases with choleriform symptoms, enormous accumulations of the parasites have been noted in the gastro-intestinal mucosa, produc- ing marked secondary changes. Marchiafava(330) has recently devoted a paper to this point. MELANIFEROUS LEUCOCYTES-PHAGOCYTOSIS-SPONTANEOUS Recovery. The presence of melaniferous leucocytes in the blood of patients suffering with malarial fever has, as has already been said, been known for years. Laveran/29'60) in his earlier articles, noted their appearance, especially during and just after paroxysms. Marchi- afava and Celli(61) early noted that they might contain the red blood corpuscle as well as the pigment and parasite. Golgi,(49) in his first article on the quartan organism, noted that phagocytosis was most marked during the paroxysm, from its height on to the period of apyrexia, the leucocytes taking up the pigment left free by the sporulating forms. Metchnikoff(59) lays much stress on phagocytosis as an active pro- tective process. The malarial organisms are engulfed and destroyed particularly by the macrophages of the spleen and liver, and to a lesser extent, by the ordinary leucocytes. Guarnieri(66) asserts that the process has one of its most important seats in the capillaries of the liver, the slow current and the relatively large size of the vessels affording a particularly good opportunity for the engulfing of the parasites by the macrophages. The endothelial cells of the capillaries have also a phagocytic action. The Malarial Fevers of Baltimore. 63 Golgi,(78) in 1888, devotes a special study to the phagocytosis in the tertian and quartan fevers. In these fevers phagocytosis takes place periodically as a regular function of the leucocytes. This process occurs in connection with certain distinct phases in the cycle of exist- ence of the parasite, and at a regular period in each paroxysm. In fresh blood one first notices phagocytosis with the beginning of the paroxysm; the process becomes more marked several hours later, and ends several hours after the paroxysm, lasting altogether from eight to twelve hours. At the beginning of the attack, the leucocytes contain either the whole segmenting forms, fragmenting bodies, or the free pigment blocks left after segmentation. The simple pigment-bearing forms are the commonest. Toward the end of the paroxysm the forms containing the whole parasite are rare, probably because the engulfed bodies have been digested leaving only the fine granules. Punctures of the spleen show that a much more active phagocytosis is carried on there than in the circulating blood. Golgi believes that all this supports Metchnikoff's theories of phagocytosis; he inclines to believe that it is largely through the action of the phagocytes that any given attack of malarial fever is prevented from becoming per- nicious, though he acknowledges that it remains to be definitely proven that the parasites which are taken up are at the height of their func- tional activity, and not forms which are already of somewhat dimin- ished vitality. Bignami(179) in 1890 in his studies of the pathological anatomy of pernicious fever, describes the extensive phagocytosis which takes place in the spleen, liver, and bone marrow, and notes also the fact that the phagocytes may contain not only whole parasites but the red corpuscles, usually degenerated, in which the organism may lie. He is inclined to ascribe considerable importance to phagocytosis as a protective process. He notes, however, degenerative changes in some large macrophages-loss of the staining power of the nucleus, fragmentation of the nucleus-and suggests the possibility that in these instances spores which have been taken up may preserve their vitality and later, after the death of their host, escape and become the cause of a relapse. While these observers rather incline to regard the phagocytosis in the sense of Metchnikoff, as an active warfare against the parasites, other observers take a rather more sceptical view. 64 IF. 8. Thayer and J. Hewetson. Osler,(91) in 1889, believes that we have, as yet, insufficient evidence to prove an aggressive warfare of the part of the leucocytes against the malarial parasites. Bastianelli/246) in 1892, published an elaborate study of the leucocytes in malarial infection. He confirms Golgi's observations concerning the phagocytosis in tertian and quartan fevers, and devotes himself especially to the aestivo-autumnal fevers. Here, as in the regularly intermittent fevers, there are indications of a periodicity in the phago- cytosis, but this periodicity is by no means as well marked. The pigmented leucocytes are more numerous at the time of sporulation, beginning to appear with the paroxysm, and increasing to a maximum at the precritical elevation (malignant tertian fever), during the crisis, or in the first hours of apyrexia. At the beginning of the attack, owing to the small number of parasites in the circulating blood, the pigmented leucocytes may be the chief evidence of the malarial nature of the process. These phagocytes may not, however, disappear dur- ing apyrexia, owing, in part, to the great frequency of the shrunken and brassy colored red corpuscles which are readily taken up. Again, owing to the irregularity and multiplicity of the paroxysms, phagocytes dating from a former access are often present at the beginning of a second. Sometimes the number of phagocytes is enormous. In the milder cases one sees only a few ordinary leucocytes with pigment granules, and a few macrophages containing blood corpuscles as well as para- sites. These latter forms are much more frequent in severe infections; they may show various degenerative changes in their protoplasm. Large endothelial cells containing pigment and parasites may also be seen. These often show degenerative changes. The following, in order of frequency, are the bodies which are more commonly found included in phagocytes: (a) pigment; (6) sporulating forms and spores; (c) red corpuscles, normal or decolorized, containing sporu- lating forms or bodies with central pigment clumps; (d) red corpus- cles, decolorized or brassy colored and shrunken, containing parasites; (e) free bodies with central pigment clumps; (/) more rarely red corpuscles of normal appearance containing parasites in the amoeboid stage, or free amoeboid bodies; (^) crescentic bodies. Sometimes one may see entire phagocytes engulfed by macrophages. The phagocytes themselves often become necrotic, showing vacuolic and fatty degen- The Malarial Fevers of Baltimore. 65 eration of their protoplasm, and fragmentation or loss of affinity for coloring matters in the nucleus. " The phagocytic action of the leucocytes occurs at all moments in the life of the parasite in this class of fevers, as well in the pyrogenic as in the non-pyrogenic * cycle : it occurs whenever parasites or pigment become free, or when the red corpuscles are profoundly altered (necrosis with 'brassy color, decolorization). Therefore one cannot say absolutely that the phe- nomena of phagocytosis are associated with a definite phase of the cycle of evolution of the parasite." With this the observations of Marchiafava and Bignami *245) agree. Bastianelli disputes Golgi's assumption that the phagocytosis is the chief element which prevents the ordinary tertian and quartan infec- tions from becoming malignant. In cases of spontaneous cure there is no particular increase in the phagocytosis-rather the opposite. In the severe cases, on the other hand, there is no evidence of a lack of activity on the part of the phagocytes; indeed, the process here is much more active; it is not upon the absence of phagocytosis that the severity of a paroxysm depends, but rather upon the amount of toxic material which is set free in the circulation. It is not evidence of increased phagocytosis which one observes in the cases of sponta- neous recovery, but rather an increased number of fragmenting and degenerating parasites-parasites the vitality of which has been in- jured by some other cause (Celli, Bastianelli and Bignami, Antolisei). Furthermore, Bastianelli notes the rhythmic course which un- treated malarial infections often pursue; a gradual increase in the severity of the paroxysms; a period of oscillation; a spontaneous recovery; a relapse after one or two weeks, which pursues the same course, and so forth. It is difficult to see why, if phagocytosis alone be the cause of these spontaneous cures or rather arrests, they should always occur after a certain number of paroxysms and not at the beginning of the infection. It would seem more probable that after a certain time some other factor comes into play which diminishes the vitality of the parasites and makes them an easy prey for the phagocytes. The important element in spontaneous recovery is the oscillation in the virulence of the parasite and not the phagocytosis. The parasite may die in the blood current without the intervention of * Crescentic and ovoid forms (?) (W. S. T.). 66 W. S. Thayer and J. Hewdson. the phagocyte. " If, however, the phagocyte is not the preponderant factor in determining the course of the infection, it maintains always a most important position in malarial processes; its constant action is exercised in eliminating a large number of pathogenic elements and in facilitating the return of the organism to its normal functions by freeing it from all extraneous injurious substances." With Bignami, he agrees in suspecting the possibility that some spores may remain living in the macrophages of the spleen, liver, and bone marrow, whence they may later escape, causing a relapse. Mannaberg(291) asserts that the febrile paroxysm, either from the high temperature or from the circulating pyrogenic substance, exerts an injurious action on both the half- and full-grown parasites. He concludes: " The spontaneous cure of malaria depends upon three factors, namely: the activity of the macrophages of the spleen and the bone marrow (to a lesser extent of the endothelial cells of the cerebral vessels); on the circumstance that numerous parasites remain sterile; finally, on the destructive action of the febrile paroxysm which is manifested by the fragmentation of numerous half- and full-grown parasites." Action of Quinine. The specific action of quinine in malarial fever cannot be dis- cussed here. Its direct action on the parasite has, however, been studied of late with interesting results. As long ago as 1867, Binz* concluded that the efficacy of quinine in paludism depended upon its action as a protoplasmic poison on some lower organism which he assumed to be the cause of the process. Laveran,(23) in 1881, asserted that "it is because it destroys the parasite that quinine causes the disappearance of the manifestations of paludism," a statement which has received abundant confirmation since. He showed that by allowing a 1-10,000 solution of quinine to run under the cover glass, the movements of the parasite were immediately arrested. Marchiafava and Celli(45) showed that the same results could be obtained by using an 0.5 or 0.75 per cent, salt (NaCl) solution, and also with distilled water or Pacini's solution, while Grassi and *Centralblatt fur die Med. Wise., 1867, p. 308. The Malarial Fevers of Baltimore. 67 Feletti(221) showed that after shaking malarial blood with distilled water for an hour, inoculation experiments remained negative. Binz,(323) however, asserts that these latter experiments are no evi- dence that quinine does not act in this manner, as both salt and dis- tilled water are protoplasmic poisons. Rosin(3n) alone, on testing the action of 1-5000 solutions of quinine on the tertian parasite, found active movements of the pigment granules forty-eight hours afterwards. Further proof as to the manner of the action of quinine on the parasites has been obtained by a study of the organisms found in the circulating blood after its administration. Golgi(274) studied the action of quinine on the tertian and quartan organisms. The quartan parasite in its endoglobular stage shows a coarser granulation with a metallic reflex, while the protoplasm shows a certain cloudiness; at times one may see abortive segmenting forms which are smaller than the normal, with a lack of regularity and fewer segments; the pigment, also, may not collect as sharply in a clump in the middle of the parasite. In the tertian parasite the changes are more marked, owing to the greater normal activity of the organism. The body is round and immovable, and shows a sharper outline than usual, while the pigment has a peculiar metallic reflex and tends to collect in clumps. Full grown tertian forms may show the large transparent swollen condition with very active movements of the pigment. Sometimes the pigment collects toward the periphery and a hyaline space is left in the middle. Mannaberg(291) asserts that three hours after the administration of 0.5 of quinine the amoeboid forms of the tertian parasite show a marked diminution in their activity. In several hours more the number has greatly diminished, while many of those present are fragmented (" zerrissen "), so that they form several separate spher- ules in the red corpuscle. The full grown forms show a cessation of the movements of the pigment, the body showing a somewhat refractive homogeneous appearance. The large hydropic forms with active pigment may also be seen. Both of these forms, according to Golgi and Mannaberg, may be seen normally during the paroxysm ; they are probably degenerate forms. The segmenting forms are sometimes imperfect. 68 IT. S'. Thayer and J. Hewetson. Baccelli(263^ noted that in aestivo-autumnal fever there was at first after quinine, an increase in the activity of the small amoeboid forms which shortly-often in twenty-four hours-disappeared without showing any outward signs of degeneration. Marchiafava and Bignami(245) also studying the aestivo-autumnal fevers, note that the administration of quinine is followed by an increase in the number of shrunken, brassy colored corpuscles; they believe that the included parasites are incapable of further development. More direct proof of the destructive action of quinine on the malarial parasite is offered by the researches with stained specimens by Romanowsky(201,210) and Mannaberg/208,201) Both of these observers note the loss of staining properties in the chromatin substance of the nucleus. They note also that in the sporulating forms, after quinine has been given, the greater part of the segments show no nucleolus. These changes in the nucleus they believe to be evidence of a necrotic process; the spores without nucleolus Mannaberg terms " still-born." Romanowsky studied the tertian parasite; Manna- berg both tertian and quartan. All observers agree that the crescentic bodies are affected slowly, if at all, by quinine. Golgi(274) asserts that in tertian and quartan fever quinine acts most markedly on the young free spores, less upon the more advanced forms where the red corpuscle is in greater part destroyed, and least upon the young endoglobular forms. If quinine be given several hours before a paroxysm it will not prevent segmentation, but it destroys the new group of organisms- the fresh segments. Segmentation taking place and toxic substances escaping, the chill occurs, being at most a little modified and retarded; further development of this group of organisms is, however, cut off. This, then, is, according to Golgi, the best time to administer the drug, though continued doses may be needed to wholly eradicate the infection. By giving single doses in this manner a double tertian infection, or a double or triple quartan may be changed at will into a single tertian in the one instance, or into a single or double quartan in the other (vide page 113). Marchiafava and Bignami,(245) studying the aestivo-autumnal para- site, conclude that "the maximum and most rapid action of the remedy is exercised on that phase of the extraglobular life of the para- The Malarial Fevers of Baltimore. 69 site which follows the completed segmentation." They note, as does Golgi, that the segmentation cannot be prevented if quinine be given when the parasite has reached the preparatory stages. " Quinine acts on the amoeba of malaria," they say, " during those phases of its life in which it absorbs nourishment and develops; when the nutritive activity comes to an end, the transformation of haemoglobin into black pigment being accomplished, and the phase of reproduction begins, then quinine becomes inefficacious against this process." They agree with Golgi that to best combat the development of the infection, quinine should be in solution in the blood at the time of the setting free of the spores: i. e., it should be given several hours before the paroxysm. III.-GENERAL ANALYSIS OF 616 CASES OF MALARIAL FEVER. During the period between June 14th, 1889, and January 1st, 1894, 616 cases of malarial fever were observed in the wards and at the out- patient department of the Johns Hopkins Hospital. Of these, 333 were treated in the wards of the hospital, while 283 were treated at the out-patient department. Relapses of cases occurring in the hospital, treated later in the out-patient department, have not been counted in the list. Two of the 333 cases treated in the hospital were relapses of cases already on the list, and have therefore been left out in some of the tables.* Age. Of 614 cases in which the ages were obtained, there were: Between 1 and 10 years of age 18 " 10 " 20 " " " 146 " 20 " 30 " " " 204 " 30 " 40 " " " 130 " 40 " 50 " " " 65 " 50 " 60 " " " 36 " 60 " 70 " " " 11 " 70 " 80 " " " 3 " 80 " 90 " " " 1 Total 614 * Relapses of cases treated in the out-patient department are not counted as new cases. 70 IF. S. Thayer and J. Hewetson. Below is a table with the ages of 614 patients selected at random from the admissions to the hospital and the out-patient department- 331 from the hospital, and 283 from the dispensary. Between 1 and 10 years of age 14 " 10 " 20 " " " 92 " 20 " 30 " " " 207 " 30 " 40 " " " 114 " 40 " 50 " " " 84 " 50 " 60 " " " 59 " 60 " 70 " " " 33 " 70 " 80 " " " . 11 " 80 " 90 " " " 0 Total 614* A comparison of these two tables shows clearly the greater fre- quency of malarial fever among children and young adults. This is probably due not so much to a greater susceptibility as to the fact that the young adult is more exposed to malarial influences-remain- ing out of doors in malarial districts at night, etc. Sex. Of these 614 patients there were-males, 493; females, 121. A table of 614 admissions to the hospital and out-patient department for the same time shows males 396; females 218. The differences in the number of women depends, probably, largely on the fact that the men are so much more likely to be employed in malarious dis- tricts : boating on the bay; farming; fishing; while the women, remaining in the house, are spared. Race. Of these patients there were: white, 585; colored, 29, or 4.7 per cent. In the hospital and dispensary, taking the cases at random, there were: white, 539; colored, 75, or 12.2 per cent. These figures would tend to uphold the generally accepted view that the negro is relatively insusceptible to malarial infection. * As there is no children's ward in the hospital, while the cases treated in the children's room at the out-patient department did not come under our observation, the statistics as regards children under ten years of age are of no value. The Malarial Fevers of Baltimore. 71 Relation of the Cases to the time of Year. The following table shows the relation of the occurrence of these cases to the various months of the year. Jan. Feb. Mar. Apr. May. June. July. Aug. Sept. Oct. Nov. Dec. Total. 12 8 18 28 35 33 74 67 129 137 45 28 614 From this table it appears that while in the winter months, De- cember, January, February, and March, malarial fever is at a mini- mum, with the month of April the number of cases begins to increase, as a general thing, showing a gradual steady rise until the climax which occurs in the months of September and October. In Novem- ber and December, a well-marked fall begins. This table, while it gives a good general idea of the distribution of the malarial infection throughout the year, is, however, a trifle misleading if taken too strictly. The cases during the latter half of the year 1889 were few, as the hospital was new and the clinics had not yet developed, while the cases from January to August of 1894 represent a much larger clinic. The proportion of cases occurring in the first seven months is thus over-represented, while the second half-year suffers, the under- representation of the cases in August being especially marked. The following table, dealing with the cases during the four years from January 1st, 1890, to January 1st, 1894, gives a more accurate repre- sentation of the variation of malarial fever with the seasons : Jan. Feb. Mar. Apr. May. June. July. Aug. Sept. Oct. Nov. Dec. Total. 9 8 8 17 21 18 38 66 122 120 38 25 490 It may thus be seen that more than five-sixths of the cases of ma- laria observed by us occur in the second half-year; nearly one-half occur in the months of September and October. It has seemed to us, however, a matter of interest to make another table, which appears below, showing the time at which the patient observed the first symptoms of the affection; this shows several inter- esting variations from the other tables : Not Jan. Feb. Mar. Apr. May. June. July. Aug. Sep. Oct. Nov. Dec. Stated. Total. 8 2 21 21 44 23 83 103 156 69 16 8 60 614 72 W. S. Thayer and J. Hewetson. We see thus that the smallest number of cases occurred in the months of December, January, and February, only two cases begin- ning during the month of February. From this time on there is a fairly steady increase until the month of May which shows the spring maximum. In July again an increase begins, reaching the climax in September, when 156, or more than one-fourth of all the cases, appear to have shown their first symptoms; 103 cases originated apparently in August, while only 69 appear to have originated in October; in 60 cases the date of onset could not be obtained. Thus, nearly one- half of all the cases originated in the months of August and September, and whereas 137 cases were first admitted to treatment in October, only 68 dated their symptoms from that time. Of these 616 cases, there were: Primary attacks 396 Relapses or new infections 166 Uncertain 52 Relapses of cases already classified 2 General Summary of some of the more important Symptoms and Complications. The following tables deal with some of the more important symp- toms noted in these 616 cases taken en masse without regard to type. Chills.-There were : Chills in 479 cases. Chilly sensations in 41 " Vague symptoms of headache, anorexia, muscular pains, etc., in... 90 " No history in 6 " Vomiting.-Vomiting was noted in 84 cases, though it is probable that it occurred in many more. Epistaxis occurred in 19 instances. Condition of the Bowels: Diarrhoea occurred in 80 cases. Constipation occurred in 161 " Alternate diarrhoea and constipation 5 " The bowels were regular in 157 " No note was made in 213 " The Malarial Fevers of Baltimore. 73 Urine.-The analysis of the urine in the 335 cases occurring in the hospital shows the following results : The urine was normal in 151 instances. Albumin was noted in 133 " Casts of the renal tubules were found in 31 " The diazo reaction was present in 18 " Acute haemorrhagic nephritis was present in 3 " Severe subacute diffuse nephritis was present in 1 " No note was made in 51 " In not a single instance of malarial fever observed in the hospital or in the out-patient department, was haematuria present, with the exception of the three cases of acute nephritis, where the blood was present merely in the shape of altered red corpuscles, giving a smoky color to the urine. Condition of the Blood.-In 94 cases pallor was noted ; in 21 cases there was grave anaemia. Cutaneous manifestations.-In 61 cases, herpes labialis was noted ; in 3, a petechial eruption ; in 3 instances an eruption suggesting the rose spots of typhoid fever was found; in one case, general erythema; in one, a rash resembling measles; in one, eczema ; in one, a varioli- form eruption ; urticaria was present during the paroxysm in 3 cases ; herpes zoster was present in one case. Respiratory Organs.-In 16 cases, bronchitis was noted, while in a number of others a slight cough, without physical signs, was present. Complications.-A mong the chief complications, the following may be mentioned : Chronic valvular disease of the heart 5 Arterio-sclerosis 1 Pregnancy 2 Secondary syphilis 3 Congenital syphilis 1 Incontinence of urine 1 Epilepsy 2 Pleurisy 2 Pneumonia 2 Asthma 1 Cancer of the uterus 1 Cancer of the jaw 1 Subacute rheumatism 1 Tonsillitis 1 74 W. S. Thayer and J. Hewetson. Amoebic dysentery.., 1 Entero colitis 2 Typhoid fever 1 Chronic nephritis 1 Acute nephritis 2 Anasarca 1 Keratitis 1 Furunculosis 1 Parotitis 1 Adenitis 1 Acute mania 1 Alcoholism 1 Cases of Pneumonia associated with Malarial Fever.-Two cases of malarial fever in the hospital were complicated by pneumonia. Case 9424-C. J., aged 30, a laborer, native of the United States, admitted March 16th, 1894, complaining of loss of appetite and cough. Family and personal history bear no relation to his present trouble, excepting for the fact that he had malarial fever a year ago; chills at uncertain intervals. He has been living recently in a very malarious district. The mistress of the house in which he lives and her three children are all suffering from chills and fever at present. For several weeks, has not been feeling well; appetite poor; has been languid and easily tired; gave up work three weeks ago. Two days ago the patient began to complain of a very severe headache, nausea and vomiting, and thinks that he has had fever since this time; no chills; diarrhoea, three or four movements daily; slight cough for several weeks. Hasty examination of the blood on admission showed no malarial organisms. Urine normal, yellow, cloudy, acid, 1020, trace of albumen, distinct diazo reaction, no sugar nor bile; microscopically, leucocytes and epithelial cells; one doubtful granular cast. The temperature on admission was 102°, reached 105.2° at 10 p. m., and was 101.8° at 8 a. m. the next morning. 17-3-94. Patient was in bed ; well nourished; tongue coated ; pulse, twenty-five to the quarter, regular in force and rhythm; heart and lungs negative; abdomen negative, excepting for an increased area of splenic dulness. At 10.30 a. m. the blood showed half- and full-grown malarial organisms of the tertian type with fine, dancing, brownish pigment; one intracellular hyaline body; one early segmenting form. Temperature steadily elevated. At 4 p. m. no malarial organisms seen in two slides. Leucocytes, 10.000. 18-3-94. "Last night the patient complained of pain in the right axilla-a "stitch "; respiration at the right base appeared somewhat enfeebled, and the resonance was slightly impaired. Though the malarial organisms were few in number, the patient was ordered quinine, gr. x (0.65), at nine and twelve, and gr. v (0.32), every four hours afterwards. Patient passed a restless night, the temperature this morning being 102.3°. Pulse is rapid, over 130, rather soft." Well marked evidences of consolidation were found at the right base. The Malarial Fevers of Baltimore. 75 Leucocytes at 10 a. m., 14,500; at 4 p. m., 17,000. From this time on, the patient went through a very serious attack of pneumonia, the temperature falling by lysis. The quinine was continued only three days, gr. Ixxxv (5.32) in all. The tempera- ture reached the normal on the 26th of March. No malarial organisms were seen after the 17th. On the afternoon of the 9th of April, the patient complained of having a headache, and the temperature was found to be 103.6°. It fell at midnight to 99.2°. On the 10th, the temperature rose between 12 and 4 p. m. to 103.8°, falling gradually to 99.2° at 8 a. m. on the following morning. Examination of the blood on the 10th showed tertian parasites. Quinine, gr. v (0.325), three times a day, was ordered; the patient made an uninterrupted recovery. This case is of interest in that it is the only one which has occurred, since the opening of the hospital, where malarial organisms were found in the blood during the actual existence of a pneumonia. It is in every way probable that the patient had had for a week or two a tertian infection which had not yet reached a sufficient intensity to pro- duce actual chills; that during this time the pneumonia also developed. During the convalescence, twenty days after the omission of quinine, a relapse of the tertian fever occurred. So far as could be made out, the presence of the malarial infection caused no essential modification of the chart of the pneumonia. Case 9963.-W. B., aged seven, admitted on May 24th with single tertian malarial fever, though indications of a second group of organisms were present. As the chart shows, the patient had an abortive paroxysm on the 26th, the temperature remaining normal afterwards until the 30th. Quinine was given on the 26th, and no malarial organisms were seen afterwards. On the 30th the patient had a chill at 4 a. m., associated with some vomiting. The blood showed a slight leucocytosis. The temperature remained continuously elevated until the 3rd of June. Nothing could be made out on physical examination until the 2nd of June, when evidences of consolidation at the right apex appeared. Crisis on the evening of the 3rd. Quinine was discontinued on the 1st of June. On the 18th of June the patient had a chill, temperature rising at 1.30 p. m. to 103.8°, blood showing one group of organisms. Quinine was begun on the 19th. A few fragmented, extra-cellular bodies were seen on the 20th, when the patient was dis- charged with a prescription for quinine, the temperature having remained normal. In this case it will be seen that the pneumonia developed during the malarial infection which was never quite eradicated, a relapse occurring twenty-three days after the last organisms had been seen. In neither of these instances did the pneumonia show anything remarkable in its course, nor is it likely that the malaria exerted any 76 W. S. Thayer and J. Hewetson. influence upon the pneumococcus infection, excepting in so far as it may have prepared the soil. Case of Typhoid Fever combined with Malarial Fever.-In one instance malarial fever was associated with typhoid fever. The patient, J. D , aged 20, Irish, was admitted on the 16th of October, 1891, com- plaining of chills, fever, headache, cough, and occasional bleeding from the nose. The temperature on admission, was 100°; it fell on the morning of the 17th to 96°. The blood on the 17th showed fairly numerous, non-pigmented, intracellular, hya- line bodies. Physical examination was negative. On the 17th, as the chart will show, the patient had a chill, the temperature remaining elevated for nearly twelve hours. During the next several days, there were slight oscillations in the tempera- ture, which remained nearly normal. Quinine, 0 26 three times a day, was ordered on the 17th. The last malarial organism seen in the blood was an ovoid body, with coarse pigment granules, which was seen on the 23d. The temperature began to rise on the 22d, reaching 104.8° at 4 p. m. on the 23d, the patient passing through a long, severe attack of typhoid fever. Quinine was omitted on the 26th. The patient made a good recovery, leaving the hospital on the 19th of January. No malarial organisms nor symptoms of malarial fever were noted. In this instance, the typhoid fever unquestionably developed dur- ing the course of a malarial infection, organisms still being present in the blood at the beginning of the rise of temperature. The case demonstrates the possibility of the co-existence of the two affections. IV.-THE VARIETIES OF THE HAEMATOZOA OB- SERVED IN THE MALARIAL FEVERS OF BALTIMORE. Methods of Examination of the Blood. Almost all the examinations of the blood upon which this article is based, were made with fresh specimens. In a number of instances we have used different staining methods, but the examination of the fresh blood, when carefully carried out, has always seemed to us simpler and more satisfactory. The steps toward the preparation of the specimen are simple, but certain precautions must be rigidly adhered to. The cover glasses and the slides must be carefully washed in alcohol, or alcohol and ether, in order to remove all fatty sub- stances. They should always be washed immediately before use. The blood may be taken from any part of the patient's body, though The Malarial Fevers of Baltimore. 77 in our practice we prefer the lobe of the ear, inasmuch as it is less sensitive and more easily approached than the finger tip, while a smaller puncture will draw more blood. This method is also more satisfactory than the puncture of the finger in that the patient cannot so readily observe the proceeding, a point of considerable importance in nervous patients and children. The ear is at first thoroughly cleaned; the lobe is then punctured with a small knife or lancet. The first several drops of blood are wiped away. The freshly cleaned cover glass is then taken in a pair of forceps and allowed to touch the tip of a minute drop of blood; it is then placed immediately upon the perfectly clean slide. It is well, if a third person be present, to allow the slide to be vigorously rubbed with a clean linen cloth just before the application of the glass. The spreading out of the drop of blood will thus be considerably facili- tated. If the slide and the cover are perfectly clean, the blood will immediately spread out between them, and unless the drop of blood has been too large, the corpuscles may be seen lying side by side, entirely unaltered in their main characteristics. The drop of blood which is taken should be very small, unless the patient is very anaemic, and care should also be exercised that the tip of the drop only should touch the cover. If the cover be placed rudely against the drop, and pressed, perhaps, also against the ear, the blood may so far spread out that the process of drying may have begun before the glass is laid upon the slide. If this be the case, the immediate spreading out of the blood between the slide and the cover does not occur. No pres- sure whatever should be exerted upon the cover which should not be pushed or allowed to slide. We have not, in our examinations, used the prepared slides of Hayem, nor have we endeavored to preserve our specimens for a longer time by the application of vaseline or paraffine about the cover glass. The specimens will remain in good condition for a considerable length of time, an hour or more, long enough to be thoroughly examined. For the examination of fresh blood, a good oil-emersion lens is almost necessary. It should not be forgotten, however, that in the absence of such optical assistance, we may yet study the organisms with some satisfaction, for Laveran made his discovery and the majority of his researches with ordinary dry lenses of moderate power. As has been said, however, for satisfactory work a A oil-immersion lens, with a 4 eye-piece, is advisable, and, indeed, 78 IP. £ Thayer and J. Hewetson. if the lens be good, eye-pieces as high as 8, or even more, give satis- faction. * For the preparation of permanent and stained specimens, we have had best results with eosin and methylene blue. In the prepara- tion of these specimens we rather prefer fixing by means of abso- lute alcohol, or absolute alcohol and ether, to the methods of heating. A specimen hardened for half an hour in absolute alcohol and ether, may be stained with a concentrated aqueous solution of methylene blue for from half a minute to a minute with excellent results. A good contrast stain may be obtained by the following method : The specimens are placed for thirty minutes in absolute alcohol and ether, dried, and stained for from thirty seconds to five minutes in a J per cent, solution of eosin in 60 per cent, alcohol, washed in water, dried, and placed for from thirty seconds to a minute in a concen- trated aqueous solution of methylene blue, washed, dried between filter paper, and mounted in Canada balsam. The methylene blue stain may not be very intense, but at times beautiful pictures may be obtained. The most satisfactory results which we have obtained have been with a modification of Romanowsky's method. Romanowsky's(210) (vide p. 43) directions are carried out strictly, excepting that the specimens, instead of being fixed by heat, are placed for from ten to twenty minutes in absolute alcohol. By this method beautiful specimens may sometimes be obtained inside of half an hour, while in other instances it may be necessary to stain longer. The Parasite of Tertian Fever. The earliest forms of the tertian parasite begin to appear in the blood during the latter part of the paroxysm or just after it. They are small colorless bodies (Plate I, 1, 2, 3, 4) which fill but a small part of the corpuscle. They have appeared to us to lie within the corpuscle, and not upon it, as Laveran believes. We have never seen hyaline bodies which were engaged in the process of entering the corpuscles or which appeared to be attached to them previously to the probable entry, as Mannaberg believes he has observed. When in the resting stage they are round and apparently disc-shaped, this form being very possibly due to the shape of the corpuscle in which they lie. The Malarial Fevers of Baltimore. 79 When one examines the fresh blood, they appear as pale bodies which, while they seem to have no color of their own, do not show the com- plete lack of color and the sharp outline which is characteristic of certain vacuoles commonly observed in some of the red corpuscles in fresh preparations, particularly in the blood of anaemic patients. On examining carefully one of these bodies, one gains the impression that he is looking through a thin layer of haemoglobin containing sub- stance with which the body is covered; that is, it would appear to lie in rather than upon the corpuscle. In this stage the organism is usually actively amoeboid. It suddenly changes its shape, often assum- ing rapidly the shape of a cross or of a star with four or more arras, becoming then often even more irregular, and finally, perhaps, return- ing again to its original disc-like shape. In the fresh specimen there is, at this stage, no indication whatever of a nucleus, unless, perhaps, the centre of the body, where the nucleus probably lies, has a more trans- parent and paler appearance than the outer part, which seems a trifle thicker and more refractive. Sometimes the small body may assume the shape of a ring, owing generally to the meeting and fusing of the pseudopodia (Plate I, 5). In the middle of this ring lies apparently a bit of the corpuscular substance. As time passes on, this small body increases in size and begins to develop reddish brown pigment granules (Plate I, 5, 6, 7). These granules are at first very minute. They are irregular in size and shape, appearing sometimes as small, irregular fragments, sometimes as minute rods. They are generally in very active motion, a motion much more marked than the ordinary Brownian movements. This activity would appear to be communicated by lively undulations of the protoplasm in which the pigment granules are con- tained. At this stage in the development of the organism, one com- monly sees, on looking at a specimen of fresh blood, what, at the first glance, would appear to be collections of minute granules scattered throughout different parts of certain corpuscles, and the first impres- sion is usually that the corpuscle contains several distinct haematozoa. Almost invariably, however, upon careful search, it may be noted that these little groups of pigment granules are contained in the bulbous extremities of the pseudopodia of a single extremely amoeboid organ- ism. The pigment tends to collect at the extremities of the pseudo- podia) while the index of refraction of the protoplasm of the organism differs so little from that of the surrounding corpuscle, that it is some- 80 W. S. Thayer and J. Hewdson. times almost impossible to distinguish the outlines of the body. With the growth of the organism and the development of pigment, the red corpuscle which harbors the body becomes paler and usually expands, showing a diameter appreciably larger than that of its unaffected neigh- bors. As the organism increases in size, and pigment accumulates, its amoeboid properties become less marked while the pigment, which may still be extremely active, tends to seek a peripheral arrangement (Plate I, 7, 8). Before the end of forty-eight hours the organism has usually completely filled the red corpuscle, the pigment granules are greatly increased in number, and about the full grown body which is now about the size of the normal red corpuscle, may be traced only the pale shell-like outline of the expanded red disc (Plate I, 9). Sometimes all indications of the red corpuscle disappear. When this stage is reached, indications of segmentation begin to be seen (Plate I, 10-14). The pigment, which has formerly been so very active, becomes almost motionless, and tends to collect in the centre of the body, in the form either of a single block of pigment or a close collection of granules. The substance of the organism about this central clump assumes a finely granular, more refractive, appearance. Shortly after this, one may notice distinct indications of a radial shading or striation which begins to appear in the peripheral part of the protoplasm and becomes steadily more marked until, finally, the central pigment clump is sur- rounded by from twelve to twenty or even more separate segments arranged in a characteristically rosette-like form. Each of these segments shows, usually, a central spot, which is more refractive, having been sometimes mistaken for pigment. It often looks like a central depression, and probably represents the nucleus. A little later than this we may see the central pigment clump surrounded by a mass of entirely separate round, hyaline bodies (Plate I, 14), which are in every way similar to those already described as the first stages in the development of the organism. At this time, also, one begins to notice the appearance of similar small hyaline bodies in some of the red corpuscles. We have thus a very suggestive chain of evi- dence in favor of the view that this is a reproductive process; that these hyaline segments resulting from the division of the organism are identical with the fresh hyaline forms that appear in the red cells. Commonly, however, segmentation does not occur with quite such regular figures. The smelting, so to speak, of the granules into a The Malarial Fevers of Baltimore. 81 solid block may not occur, and the segmentation may take place before the granules have all collected in the centre. Again, instead of the regular radial arrangement of the segments, we see the organ- ism break up throughout its substance into a number of round, hyaline bodies, with central refractive points (Plate I, 13), while later on we find the central pigment mass surrounded by a group of separate hyaline bodies. We have never seen figures corresponding exactly to Golgi's first form of segmentation, where he shows the pigment left in a central protoplasmic body, while a peripheral layer of pro- toplasm alone segments. We have not been able to make out a distinct double outline in the case of the spores, as Antolisei asserts that he has done. Not infrequently, at the time when we observe full-grown organisms in the blood, as well as during the days when only half-grown forms are to be seen, occasional pigmented bodies may be found outside the red corpuscles free in the plasma. Some of these represent entirely full-grown bodies which have destroyed the surrounding corpuscle (Plate I, 18), while in other instances the half-grown forms may actually leave their host (Plate I, 21). This process may be occasionally observed under the microscope. The cor- puscle containing the parasite suddenly collapses like a bladder, its color becoming immediately diffused into the surrounding plasma, while the parasite at the same moment bursts out of the corpuscle into the serum. Almost immediately after its escape from its host, the free parasite becomes irregular in outline, or fragmented. The pale decolorized expanded shell of the corpuscle may sometimes be distinguished for a short time after the escape of the parasite. This bursting of the half-grown form from the corpuscle has been well described, also, by Bastianelli and Bignami. The budding or break- ing up of the extra-cellular forms into several small bodies, is very commonly observed (Plate I, 19-20). The large extra-cellular forms are often several times the size of the normal red corpuscle. They have generally a pale, transparent, swollen look. The outlines are indistinct, while the pigment is commonly extremely active. After observing these bodies for a time, certain changes are often seen to take place. (1). The pigment remains for a considerable time extremely active, while the outlines of the body become very indistinct and somewhat irregular, and the whole parasite becomes more and more expanded 82 W. S. Thayer and J. Hewetson. until it reaches almost the size of the ordinary polymorphonuclear leucocyte. Gradually the motion of the pigment becomes less active, the outlines more irregular, till finally there remains only a misshapen mass of protoplasm containing fine brown motionless granules, a pic- ture very similar to that drawn by Laveran in his description of the swollen, cadaveric forms. (2). The large extra-cellular forms very often become fragmented. A small prominence will be noted upon one side of the body, which rapidly becomes shut off from its mother form, forming a separate circular pigmented body. In this manner, one large form may give rise to four or five smaller bodies. The motion of the pigment may be quite active, but very commonly after a short time it becomes less marked, the outline of the bodies becoming indistinct, until they remain as pale shadows in the field. Not infrequently one sees several of these small bodies, the results of fragmentation, connected together by thread-like processes in which pigment granules may be seen (Plate I, 21). This process of budding and fragmentation we believe to be degenerative in nature. (3). Not uncommonly, one of these large, swollen, extra-cellular bodies may be seen to develop a pale vacuole-like area usually of a disc-shape, in which sometimes one or two bodies resembling segments may be seen. About this area, a number of small irregular vacuoles develop, while the pigment between them is often very active. As time goes on, and the vacuoles increase in number, the pigment gen- erally becomes motionless, lying as small brown or black specks between the vacuoles (Plate I, 23, 24). Often one of these bodies, filled with vacuoles, may assume a most irregular shape. These elements we believe, with Antolisei, to be degenerative, and not, as Golgi suggested, regenerative forms; for, notwithstanding the fact that the round bodies seen in the large clear area are not dissimilar to the segments seen in the other forms of segmentation, as one observes them in the fresh specimen, the vacuolization of the rest of the substance, the irregularity of the shape, and, more important than all, the fact that these bodies do not stain in a characteristic manner, leads us to believe that they are degenerative. (4). Another change often noted in these large, extra-cellular organ- isms, is the development of the so-called flagellate forms. Here the pigment assumes at first a particularly active motion. It dances The Malarial Fevers of Baltimore. 83 with surprising rapidity, while now and then at the periphery of the organism we may note marked wave-like protrusions and undulations. Suddenly the granules assume a more central position, still being extremely active, while at the same moment one or more thread-like processes, several times the length of the organism, break out from different parts of the periphery (Plate I, 22). These flagella show often a slight swelling at their extremity, and occasionally other olive- shaped swellings at one or more points in their course. Sometimes granules of pigment may be seen in the flagella. Often the body from which the filaments come gives off buds, or fragments into several smaller pigmented bodies, all of which are moved about with great activity by the mobile flagella. The length of time during which these motions may exist varies; sometimes they may be observed for as long as half an hour. Sometimes the flagella may break off from the main body; but with the breaking off of the flagellum, its power of individual motion does not cease, and free flagella are not infrequently seen, making their way about among the red corpuscles. They have in this stage quite the appearance of spirilla, such as occur in relapsing fever. Phagocytosis, as pointed out by Golgi, occurs, generally speaking, at stated intervals in tertian fever; that is, at the time of the par- oxysms. Wherever segmenting bodies are seen, we may observe pig- mented leucocytes, and the pigment in these leucocytes is generally in the form of large blocks, similar to those left after the segmentation of the parasite. But this free pigment is not the only constituent of the malarial parasite which is taken up. Commonly, the small, extra- cellular bodies, which result from the breaking up of the large, full- grown, swollen, extra-cellular organisms, are also taken up, a process which may be observed under the microscope. Again, the same fate may befall the half-grown bodies which break out from the corpuscles, so that at times pigmented leucocytes may be seen at a considerable distance from the paroxysm. The very best opportunity which we possess for studying phagocytosis under the microscope is offered us, however, in the presence of the flagellate bodies. Wherever flagellate bodies develop, we may almost invariably observe the active process of phagocytosis. The appearance of flagella seems to be, in most instances, the signal for an attack upon the parasite by the surround- ing leucocytes. Not all the varieties of leucocytes appear to take part 84 IK & Thayer and J. Hewetson. in this warfare. While pigment granules are very commonly found in mononuclear elements in the circulating blood, we have never seen a mononuclear leucocyte attack a flagellate body under the microscope. The a multinuclear " neutrophiles appear to monopolize this function in the fresh specimen, and at times we have seen a single flagellate body attacked by as many as three leucocytes at once. We have never seen a lymphocyte or small mononuclear form containing pigment, nor have we ever seen any indication of phagocytosis among the eosinophilic leucocytes. We believe, then, that we can trace in the blood the life-history of the tertian organism, beginning with the hyaline body directly after segmentation, and ending, after nearly forty-eight hours, with the full- grown form which has destroyed the red corpuscle, while the process of reproduction is represented by the segmenting forms of Golgi. The segmenting bodies, as has been noted by Antolisei(l29) and Bastianelli and Bignami,(152) are disproportionately scanty in comparison to the number of adult forms seen some hours before the paroxysm, a fact which is doubtless explained, as pointed out by these observers, by their greater frequency in the spleen. The segmenting bodies are usu- ally at first surrounded by the pale rim of a decolorized red corpuscle. This is often so pale that it is overlooked; it shows more distinctly in colored specimens. In the more advanced forms this rim may be no longer distinguishable. The segmenting bodies which are observed in the peripheral circulation are usually about the size of a red blood corpuscle, sometimes larger, sometimes smaller. Occasionally we have found smaller segmenting bodies contained in red blood corpuscles which show relatively little decolorization (Plate I, 16, 17). We have not been able to definitely associate these forms with anticipating fevers, as Bastianelli and Bignami(l52) have done to their satisfaction. The large extra-cellular forms, with pale protoplasm and dancing granules, are probably, in some instances, degenerative forms, but we do not feel that there is as yet sufficient proof to warrant the assump- tion that this is true in all instances. We have seen segmenting bodies develop from some quite large forms. There are, also, some reasons which would suggest that the flagellate forms are, as so many persons believe, degenerative in nature, but we do not feel at present quite ready to accept that view. The Malarial Fevers of Baltimore. 85 We find that the fever keeps pace with the development of the organism, the paroxysm being invariably associated with the segmen- tation of the full-grown bodies and the appearance of the fresh group of young individuals. The presence of segmenting forms is always, in our experience, an indication that the paroxysm is impending or has already begun. Not infrequently these forms may be seen several hours before the onset of the paroxysm, but never have we seen segmenting bodies in tertian fever without their being definitely connected with a paroxysm. Double Tertian Infection. Multiple Infections. Such, then, is the course of development of the tertian parasite as we observe it in studies of the fresh blood. More commonly, how- ever, we have a somewhat more complicated picture: namely, the presence of two instead of one group of parasites. Thus, for example, if we examine the blood during the paroxysm, we find not only full-grown segmenting forms, and perhaps fresh hyaline bodies, but also another set of organisms which show the development characteristic of about twenty-four hours' growth; in other words, there is a double infection, two sets of organisms, becoming mature on successive days, and, as one might be justified in expecting, the clinical picture in these cases is one of quotidian fever. It is probable that in some instances there may be still further complications by infection with more than two groups, or by infections with organ- isms which are not so sharply distinguished into separate generations as in the great majority of instances. The Parasite of Quartan Fever. This parasite, in its earliest stages of development, is scarcely dis- tinguishable from the organism of tertian fever. The youngest forms are small hyaline, amoeboid bodies, filling but a small part of the red corpuscle. The very earliest forms are quite indistinguishable from the tertian parasite, but as they begin to grow, certain differences are readily made out. In the first place, they show a much sharper outline than the tertian parasite, while the protoplasm has a somewhat more refractive character, and the amoeboid movements are slower W. S. Thayer and J. Hewdson. 86 and much less extensive (Plate I, 26). The first forms, as in tertian fever, appear with the paroxysm, and shortly afterwards begin to develop pigment granules (Plate I, 27). These granules, however, differ a little in appearance from those in the tertian parasite. They are generally a little larger and also a little darker in color. While the pale, yellowish-brown granules of the tertian parasite are always in very active motion, these larger darker granules lie almost motionless, arranged generally about the periphery of the somewhat refractive, colorless parasite. In these young pigmented forms, there is still a certain amoeboid movement, but it is slow and lazy as compared to the rapid changes of outline which are seen in the tertian parasite. As the parasite grows and the pigment increases in quantity, the red cor- puscle does not become decolorized and expanded, as does the corpuscle containing the tertian parasite. On the other hand, the infected cor- puscles are usually a trifle smaller than their unaffected neighbors, while the color is, if anything, a little darker than the normal. They are also more refractive and sometimes there is a distinctly greenish, brassy appearance (Plate I, 28-34). At the end of from 64-72 hours, the parasites have reached their full development. They are then round or ovoid bodies, somewhat smaller than the normal red corpuscle; about them may be seen a very thin layer of still colored, refractive, haemoglobin-containing substance. In this stage, the amoeboid movements of the bodies are entirely lost, while the pigment, which tends to be peripherally arranged, is coarser and darker than in the tertian parasite, the individual granules differing also more markedly in size; these pigment granules are almost motionless. The index of refraction of the protoplasm is quite high, and the picture is quite different from that presented by the tertian parasite, so much so that the organisms may be readily distinguished by the skilled observer on the first examination. At this time some of these bodies may seem to have entirely destroyed the corpuscle, remaining appar- ently free in the serum (Plate I, 35). On staining, however, most bodies show evidence of a slight layer of corpuscular substance about them, and it is a question of doubt in our minds as to whether any true segmenting bodies are not, in the beginning, contained in the shell of the red corpuscle. Six to eight to ten hours before the febrile par- oxysm begins, some of these full-grown bodies begin to show certain striking changes (Plate 1,36-39); the pigment granules which, though The Malarial Fevers of Baltimore. 87 scattered throughout the body, have tended toward a peripheral arrangement, begin to collect at the centre. The process of the accumulation of the pigment in the centre of the quartan organ- ism gives pictures which one does not see in the case of the tertian parasite, namely: the arrangement of the pigment in a star- shaped form, as though it tended to arrive at the centre of the body through certain definite currents which flow inward from the periphery. Finally, the pigment is collected in a central clump or solid block, while the protoplasm of the organism becomes some- what more refractive and of a slightly granular appearance. A radial shading begins to be evident, similar to that observed in the tertian parasite, and finally the protoplasm divides into from six to eight to ten to twelve small pear-shaped leaflets, each containing a central more refractive point. The regularity of the arrangement of these leaflets is decidedly more marked than in the case of the tertian parasite, most exquisitely symmetrical marguerite forms being at times observed. Later on, these pear-shaped leaflets separate from the central mass and are seen as small, round or ovoid bodies surrounding the central pigment clump. Simultaneously with this we may note the appearance of fresh hyaline forms in certain of the red blood corpuscles. Some of the full-grown parasites do not segment on reaching their complete development, but undergo certain changes similar to those observed in full-grown tertian organisms: (1). The pigment granules, which have previously been extremely lazy in their movements, may take on a considerable activity, while the body may expand, equalling or even slightly exceeding the size of a normal red corpuscle (Plate I, 40). These bodies are very transparent, and closely resemble the analogous forms of the tertian parasite. Eventually, the movements of the pigment become less marked, the outlines of the body become irregular and indistinct, and a motionless cadaveric form remains. (2). Forms similar to those just described may undergo a further change, namely: fragmentation into a number of small bodies, which eventually become indistinct and deformed, just as in the case of the tertian parasite. (3). Vacuolization of these forms we have also observed (Plate 1,42). (4). These bodies may develop flagella just as in the case of the tertian parasite (Plate I, 41). The granules become suddenly very 88 W. S. Thayer and J. Hewetson. active, collecting at a given moment more toward the centre of the body, while long, thin, flagella burst from the contour, making active, serpentine movements among the surrounding corpuscles. These forms differ from those of the tertian parasite in their smaller size and in the greater coarseness of their granules. The movements of the flagella are not, so far as we can make out, essentially slower than those in the tertian organism. As the parasites are smaller, and the granules darker and larger, the complete bodies resemble much more closely the forms about to be described in the aestivo-autumnal para- site, than those developing from the tertian organism. Flagellate bodies were observed in two of our five instances of quartan fever. Phagocytosis is observed in quartan infection with the same extreme regularity as in tertian fever. It begins with the paroxysm and lasts during it and for several hours afterwards. The forms taken up, as in the case of tertian fever, are the central pigment clumps, the small, fragmented, extra-cellular forms, the flagellate bodies, and not infrequently the segmenting bodies. In a number of instances we have been able to follow, under the microscope, the engulfing of an entire segmenting body by a " multinuclear" leucocyte. In other words, the extra-cellular forms alone are usually taken up by the phagocyte. Double and Triple Quartan Infections. As, in tertian infection, two or more groups of parasites, showing different stages of development, may be present in the blood, so in quartan infection, this is a very common occurrence. Sometimes we may see two groups of quartan organisms which reach maturity on successive days. As the febrile paroxysm is always associated with the segmentation of a group of parasites, we see, in these instances, par- oxysms on two successive days, with one day of intermission,-double quartan fever. Again, with considerable frequency, we may see three groups of organisms, which, reaching maturity on successive days, cause daily paroxysms-triple quartan infection. Three of our five cases of quartan fever were triple infections. It is probable, as has been noted in the summary of the literature, that infection with multiple groups of parasites may take place, causing irregular febrile manifestations, though this we have not, in our limited number of The Malarial Fevers of Baltimore. 89 cases, been able to observe. We have, then, distinguished a parasite which differs from the tertian organism in several distinct manners: (1). The length of the cycle of development, which lasts forty-eight hours in the one case, and seventy-two in the other. (2). The appearance of the organism itself; pale and indistinct in the tertian ; sharply outlined and somewhat refractive in the quartan; actively amoeboid in the former; slightly amoeboid in the earlier, and motionless in the later stages in the latter. (3). Character of the pigment; often a reddish-brown in the one; coarser, more irregular in size, and darker in the other; actively motile in the former; lazy and almost motionless in the latter. (4). The volume; reaching the full size of the red blood corpuscle in the tertian; never reaching so large a size in the quartan; the large, full-grown, free (degenerative ?) forms being sometimes twice as large as the red blood corpuscle in the former; rarely larger than the red corpuscle in the latter. (5). The segmenting forms; usually as large as the red corpuscle in the one; not as large in the other; the segments numbering usually from fifteen to twenty in the former; from six to twelve in the latter; the whole organism breaking not infrequently into irregu- larly arranged segments in the former; typical rosette forms almost always in the latter. (6). Behavior of the infected corpuscle: The corpuscle becomes ex- panded and decolorized in the tertian infection; shrunken and often brassy-colored in the quartan. It is not just, as some of the critics have done, to assert that the chief difference between the quartan and tertian parasites consists in the number of their segments. There are differences which the skilled observer can detect in every stage of development, unless it be in the very earliest forms,-those immediately following segmentation. In tertian infection, while many full-grown and nearly full-grown forms are .to be found some hours before segmentation, at the time of segmentation the bodies observed in the peripheral circulation are distinctly less frequent; the explanation is, probably, that segmenta- tion takes place for the most part in the internal organs. This is, however, not true of the quartan parasite. Here all stages are seen with equal frequency in the peripheral circulation, and segmenting bodies may be found where very few organisms are present. In IF. 8. Thayer and J. Hewetson. 90 tertian fever, for instance, it is extremely rare to see segmenting bodies in cases where they are not associated with a definite febrile paroxysm. In quartan fever, on the other hand, one may follow the entire life-history of a single group of parasites for weeks, where the number of organisms is so slight as to produce little or no visible febrile reaction. The Parasite of tEsti vo-autumn a l Fever. The third type of organism which we have been able to distinguish, is identical with that which has been described by Sacharow as the organism of Febris irregularis, the Haematozoon falciforme of Anto- lisei and Angelini, the aestivo-autumnal parasite of Marchiafava and Celli. This type of organism shows quite marked differences from the forms above described. The youngest forms of the parasite are quite similar to those observed in tertian and quartan fevers; they are small hyaline bodies. There are, however, certain differences which may be striking. The hyaline forms are usually smaller than those of the tertian parasite, while they are generally more highly refractive. They often have a decidedly ring-like appearance (Plate II, 1, 2), which is probably in most instances only apparent. These ring-shaped bodies are very small-the smallest seen. The outer layer of the parasite shows quite a sharp glistening refraction, while the central part is shaded, appearing as though it were thinned, the coloring of the corpuscle, showing through. While observing one of these very small, refractive, ring-like forms, we not uncommonly see it become suddenly expanded, more homogeneous, and paler (Plate II, 3-6). The outer rim no longer seems more refractive and thicker than the centre, and the ring-shaped appearance is lost. A wavy undulation of the border is commonly to be seen, while, very frequently, most active amoeboid movements develop, similar in every way to those of the tertian parasite. Sometimes, in this stage, we may see two pseudo-podia join one another, enclosing a central piece of corpuscle, thus causing a true ring. While in the organisms of tertian and quartan fever we have been able to follow out and to trace the length of the cycle of development with perfect clearness, we have not been able to do this with the same accuracy in the case of the aestivo-autumnal organisms. This difficulty is due, in part, to The Malarial Fevers of Baltimore. 91 the fact that the earlier stages of development only are found in the peripheral circulation, the later stages in the cycle occurring in the spleen, marrow, and other internal organs, and, in part, to the fact that in most cases, when they come under observation, several groups of organisms are present at the same time. We are inclined to believe from our observations that the length of the cycle is subject to great variations, amounting, in some instances, to twenty-four hours or less, and in others to forty-eight hours, or even more. The small hyaline forms above described, appear, usually, during and shortly after the paroxysm. In a variable length of time after this, pigment granules begin to make their appearance. These are not, however, numerous and active as in tertian infection, or coarse as in the quartan. Often, only one or two most minute dark granules appear in the periphery of the homo- geneous, disc-shaped organism (Plate II, 7-12); sometimes, in the more ring-shaped refractive variety, they may be situated at the inner edge of the more refractive border, close to the central pale area, though more commonly they are observed, as in the more expanded forms, just at the periphery. The pigment granules show but little movement. Before the appearance of the pigment, the organism increases some- what in size; rarely, however, does its diameter exceed a third that of the red corpuscle itself. The corpuscles in which these bodies lie, show no indication of decolorization. Not infrequently, however, they are shrunken, often crenated or spiculated, and of a deeper brassy color ("globuli rossi ottonati"), an alteration indicating, probably, degenerative changes in the corpuscle (Plate II, 7,16). In some cases we may see corpuscle^ containing small, refractive, ring-like bodies, with or without pigment, where the haemoglobin seems to have left the outer part of the disc and collected about the parasite, leaving the outer part decolorized though still showing the outline of the original corpuscle (Plate II, 13). The haemoglobin here shows generally the brassy green color. Later on we may see in the larger forms of the organism a small collection of non-motile or slightly motile pigment granules about the centre of the body (Plate II, 13, 16-19). This is seen only in the larger forms, forms which may have a diameter more than one-third the size of that of the red corpuscle. The pigment, however, in these instances is never as profuse as in the tertian form. With these bodies, which occur only before and during the paroxysms, certain still more characteristic forms may be 92 IK & Thayer and J. Hewetson. seen in the circulating blood, forms which we have never seen except- ing in association with the paroxysm. Here, in similar bodies, those which are, perhaps, a trifle more than one-third the size of the cell in which they are contained, a few pigment granules may be seen to have gathered together near the centre, and to have become smelted, as it were, into a solid clump, while the surrounding body has a peculiarly homogeneous, refractive appearance (Plate II, 14, 15, 20). These forms, as we have said, have only been noted just before or during the paroxysms. They are always associated with pigment-containing leu- cocytes, while the pigment in these leucocytes is usually in the form of similar blocks. Occasionally these bodies may reach nearly the size of a normal red corpuscle. From the fact that these forms are observed only during the paroxysms, from the fact that we have never seen these solid blocks of pigment in tertian or quartan fever, excepting in segmenting forms, from the fact that they are always associated with leucocytes containing similar blocks of pigment, we might easily conclude, even had it not been proven by the examina- tion of the splenic blood, that these are early or pre-segmenting forms. We have never seen actual segmenting forms in the circulating blood, as described by Sacharow,(212) possibly because we have not had so large a number of severe cases to deal with. During the early part of the paroxysm, indeed, and for several hours before, very few organ- isms are to be found in the peripheral circulation. In several instances at this stage we have been unable to find any, while some hours later the organisms were present in large numbers. We have not carried out a systematic study of the splenic blood, though in several instances we have found, on puncture, segmenting forms similar to those de- scribed by Marchiafava, Celli, and Bignami. Examination of the splenic blood at the beginning of the paroxysm reveals always a large number of intracorpuscular parasites with central pigment blocks, as well as a certain number of similar organisms, which are free. The advanced segmenting forms, which we have seen, have showed no traces of the surrounding blood corpuscle (Plate II, 21-24). Both in the number of segments and in the manner of division, the seg- menting aestivo-autumnal parasite resembles closely the similar stage of the tertian organism. It is, however, much smaller, as is shown in the plate. The Malarial Fevers of Baltimore. 93 As has been said above, we have not been able to sharply define the length of time required for this cycle of development. We be- lieve, however, that it varies considerably from twenty-four hours, or even less, to forty-eight hours, or somewhat more. In a majority of instances, where the fever has lasted more than one week, other char- acteristic bodies may be noted in the blood. Here, at first, one may notice more of the larger rounded bodies with central pigment granules. Commonly, these assume an elongated or ovoid shape. Occasionally, forms may be seen nearly as large, or larger, than the corpuscle. These show a peculiarly refractive appearance, the pig- ment granules become more numerous, coarser, and show a tendency to a ring-like arrangement in the centre. The bodies lie usually at one side of the red corpuscle, the remains of the cell forming a bib- like attachment, as it were, upon the other side (Plate II, 26-33). Often the red cell becomes much decolorized; sometimes it shows a crenated outline. Finally, we see still larger forms, which are usually ovoid or crescentic in form, the remains of the red corpuscle forming a convex bib, connecting the two horns of the crescent, or attached to one side of the ovoid form. Sometimes the crescentic or ovoid bodies may lie in the middle of the cell (Plate II, 25); more often, the remains of the cell are attached to them as a bib. Some of the apparent separate ovoid bodies are, probably, simply crescentic forms which are viewed through the microscope from the convex side of the crescent. This may at times be clearly shown by the revolving of one of these bodies on the slide. These forms are highly refractive, so much so that the outer border has been described as a double outline, and interpreted as a cap- sule. Whether this apparent double outline represents an actual cap- sule, or only a thickening of the outer parts of the body, we do not feel quite certain. We have never been able to observe that this so-called double outline showed a coloring with haemoglobin, as described by Antolisei and Angelini.(119) The pigment granules are coarse, often in the form of rods collected about the centre in a clump, or not in- frequently in a ring. Finally, we see large crescentic or ovoid bodies, averaging eight to nine micromillimetres in length; the red corpuscle in which they have developed is represented by but a small, faintly- colored attachment upon one side of the ovoid, or at the concavity of the crescent, while, in some instances, all trace of the corpuscle may be absent. At times one may observe actual changes from 94 W. S. Thayer and J. Heweteon. the ovoid bodies into the crescentic forms, or the converse, beside the occasional picture of the revolving crescent before referred to. Often, in association with these crescentic and ovoid bodies, we may also see a number of somewhat smaller round bodies (Plate II, 34, 35, 38); indeed, at times, we may trace the change from a crescent or an ovoid form into one of these round elements. The round bodies do not as often show a " double outline," nor are they, as a rule, quite as refrac- tive. In the crescents and the ovoid and round bodies, we see, occa- sionally, changes which show a certain analogy, as Antolisei and Angelini(119) have pointed out, to processes occurring in the large full- grown tertian forms: (1). Sometimes, for example, one of these bodies may show one or more small protrusions from the surface, which may, indeed, be cut off from the rest of the body as small, clear, hyaline droplets (Plate II, 30, 36). This is the gemmation which, by some of the earlier observers, was supposed to be a reproductive process. (2). Again, we may see the development of a large number of small vacuoles of different sizes; the parasites at the same time lose their sharp refraction, becoming pale and more indistinct (Plate II, 37); this process is clearly degenerative in nature. (3). Lastly, whenever these round bodies occur, flagellate forms may be seen to develop (Plate II, 38-40). These flagellate bodies are dis- tinctly smaller than those of the tertian parasite, being much more simi- lar to the quartan forms. The pigment collects frequently in the shape of a ring in the centre of the organism, and assumes the same active movements that one sees in tertian fever, while the periphery of the body shows the same violent undulations which suggest so strongly that some body within the parasite is trying to escape; and just as in the tertian parasite, one or more active flagella eventually break forth. The same breaking off of the flagella, the same budding and frag- mentation of the body, the same phenomena of phagocytosis, are noted here as in tertian infection. The small hyaline and slightly pigmented forms disappear quite rapidly after the administration of quinine, though they are consider- ably more resistant than the similar forms of the tertian or quartan parasite. The crescentic and ovoid bodies, however, may remain for a very long period, notwithstanding large and continued doses of quinine. In cases where quinine is given during the first week of the disease, The Malarial Fevers of Baltimore. 95 the organisms disappear in the majority of cases without the occur- rence of crescentic bodies, a fact which would tend to show that the formation of the ovoid and crescentic forms does not occur before the end of the first week. In the cases where we have found crescentic and ovoid bodies alone in the blood, fever has rarely been noted, the febrile paroxysm always being associated with, or followed by the presence of small hyaline and amoeboid bodies. In our studies, then, which have been mainly conducted with fresh blood, we find a type of organism quite separate from that of ordinary tertian or quartan fever. The cycle of existence of this parasite begins with a small hyaline body which, when it has reached its full development, is rarely half the size of the red corpuscle. During its growth, marked changes (crenation, brassy color, retraction of haemoglobin) are often caused in the red cor- puscles. The advanced segmenting forms are rarely seen in the blood current, though pre-segmenting bodies (bodies with central pigment) are not infrequently observed. The process of segmentation, and probably the greater part of development, goes on in the internal organs. We have been unable to trace a constant length of the cycle of development, and we have been unable further to separate two or more types of the parasite depending either upon the length of the cycle of development or upon any other morphological or biological differences. We believe that the length of the cycle varies greatly in different cases, lasting usually from twenty-four hours or even a little less, to forty-eight hours or more. After the infection is five days or a week old, certain of the organisms, instead of segmenting, pursue a further growth, developing into the hyaline, refractive, ovoid and cres- centic bodies which show a particular resistance to quinine, having been considered by many to be encysted forms. Do these crescentic bodies represent forms with a longer cycle, giving rise to fevers with long inter- vals between the paroxysms, as Canalis,(104) Golgi,(118) Antolisei,(131) and others believe? We do not feel justified in making positive state- ments concerning this point. We have never observed segmentation of the crescentic, ovoid or round bodies, though the frequency of relapses in cases where they are found suggests the possibility of its occurrence. We have, on the other hand, seen processes of vacuoliza- tion and of gemmation, which we believe to be degenerative in nature. 96 W. 8. Thayer and J. Heweteon. We have met with nothing in our observations suggesting that the crescents are conjugate forms, as is believed by Mannaberg.(291) Phagocytosis we have observed here, as in tertian and quartan fevers, particularly at the time of the paroxysm, though pigmented leucocytes are found occasionally at all stages of the cycle. The presence of the large mononuclear macrophages, described so well by Bastianelli,(246) we have found very rarely in the peripheral circulation. While mononuclear elements with pigment are not uncommon, we have never seen the act of phagocytosis performed under the micro- scope by a mononuclear leucocyte, while we have many times seen the engulfing of flagellate bodies by the polymorphonuclear neutrophiles. V.-GENERAL ANALYSIS OF 544 CASES IN WHICH THE TYPE OF ORGANISM WAS CLEARLY DISTINGUISHED. Of these 616 cases, in 542, not including the two relapses, the type of parasite was definitely differentiated. The following table shows the number of cases of each type observed in the hospital and out- patient department: Hosp. Disp. Total. Infection with the tertian parasite. { terliu" infection .. 57 93 150 1 I Double " .. 116 72 188 r Single quartan infection...., .. 2 0 2 Infection with the quartan parasite, j Double " " .. 0 0 0 1 Triple " .. 3 0 3 Infection with the aestivo-autumnal parasite .. 104 84 188 Combined infection with aestivo-autumnal and tertian parasites.. .. 9 291 2 251 11 542 It is interesting to note the greater frequency with which single tertian infection was seen in the dispensary than in the hospital- 93 cases occurring in the dispensary from a total of 251, and 57 in the hospital out of a total of 291. This is doubtless due largely to the fact that the cases of mild malarial infection are unwilling to enter the hospital, while the double tertian cases and the aestivo-autumnal infections, which are more severe, are more ready to enter the wards. The Malarial Fevers of Baltimore. 97 The tables below show the relation of the different types of malaria to the time of year : Jan. Feb. Mar. Apr. May. June July. Aug. Sept. Oct. Nov. Dec. Tot'l. § Single.... 5 1 7 16 20 14 27 14 17 19 7 3 150 Double... 2 5 8 9 12 13 23 27 30 43 10 6 188 .Total 7 6 15 25 32 27 50 41 47 62 17 9 338 Single.... 0 0 0 0 0 0 0 0 0 0 1 1 2 Double... 0 0 0 0 0 0 0 0 0 0 0 0 0 5 Triple.... 0 0 0 1 0 0 2 0 0 0 0 0 3 - . Total 0 0 0 1 0 0 2 0 0 0 1 1 5 Aestivo- 1 autum... J 1 0 1 0 1 2 17 18 65 55 18 10 188 Combined 1 Aestivo- I aut. and I Tertian. J 0 1 1 0 0 1 2 0 0 5 0 1 11 Total 8 7 17 26 33 30 71 59 112 122 36 21 542 Thus in the first half-year there were : Tertian infection. - Single 63 Double 49 112 Quartan infection. - Single 1 Double 0 Triple 0 1 Aestivo-autumnal infection 5 Combined infections 3 Total 121 While in the second half-year there were: Tertian infection. Single 87 Double 139 226 98 W. S. Thayer and J. Heweison. Quartan infection. Single 1 Double 0 Triple 3 4 Aesti vo-autumnal infection 183 Combined infections 8 Total „ 421 These tables show in an interesting manner how the severity of the type of infection increases as the summer and fall approaches; thus, in the first half-year we have more single than double tertian infec- tions, while in the second half-year, when malarial fever assumes a more severe type, we have nearly twice as many cases of double ter- tian as of single tertian infection. The increase in severity of the malarial fevers becomes more evident when we observe the course of the aestivo-autumnal cases. While in the first half-year only 5 cases were noted, a little less than one twenty-fourth of the total num- ber of cases observed, in the second half-year we see 183 cases, or nearly an half of all the cases which occurred. Thus, it may be seen that with the earliest cases of malarial fever in the year, the mildest types of infection are met with,* the single tertian type predominating. As the season advances, and the months approach which are richest in malaria, the single tertian cases become less frequent and the double tertian infections more common, while at the height of the malarial season a majority of the cases are of the aes- tivo-autumnal, the most severe type in this climate. Marchiafava and Celli(144) have, in some of their writings, been inclined to believe that a patient suffering from one malarial infection may show the organisms and the fever characteristic of aestivo-autumnal malaria during the fall, and later, in the spring, without a new infection, simply as a relapse, show the regular types of fever, tertian or quartan, with their char- acteristic organisms. In a number of our cases, patients who had * This is an old observation, dating back to Hippocrates and Sydenham. In fact, not only were the spring tertians known to be mild, but they were even thought to be beneficial. Thus a contemporary of Sydenham, Richard Morton, whose chapters on malaria (Pyretologie Opera Medica, 1696) are unequalled at that date, says (p. 51) : " Quod Febris Intermittens verna sit liemedium Regium ; h. e., saluteferum & certe- rorum morborum prophylacticum, &c." The Malarial Fevers of Baltimore. 99 suffered, for instance, with aestivo-autumnal malaria during the fall, have, in the following spring, had a characteristic tertian or double tertian infection, or the converse. In none of our cases, however, has it appeared to us that these were true relapses, all of them giving histories, and having been subjected to circumstances which would wholly justify the assumption that a second infection had occurred. Against this view, also, speaks the course of the infection in cases of aestivo-autumnal fever, which, having arisen in tropical climates, come to Baltimore in the spring months. This was the case in two of the five instances of aestivo-autumnal fever admitted in the first half-year. One of these cases originated in Jamaica, the other in Cuba. In neither instance did the organisms or the progress of the case differ in any way from the ordinary aestivo-autumnal in- fections, though they occurred at a time of year when the milder tertian infections formed the vast majority of all cases observed. Particularly striking is the history of one of the three cases of combined aestivo-autumnal and tertian infections. This man arrived in February with a fever which he had contracted in Cuba. His symptoms at the time of his arrival appeared due rather to the tertian organisms, which were preponderant, than to the aestivo- autumnal. Under quinine the fever disappeared, and the organisms were no more seen in the peripheral circulation. Seven or eight weeks later, in April, he had a relapse while still in the hospital where he had undergone an operation for the radical cure of hernia; but in this relapse only aestivo-autumnal forms-small hyaline amoeboid bodies, ovoid and crescentic forms-were seen. The less resistant tertian parasites had yielded to quinine, while the aestivo-autumnal forms persisted. Surely no better opportunity could have been offered for the change in the type of the parasite were this really possible. While, in our experience, we have seen nothing which would justify us in positively denying the possibility of the change of an organism from one type into another according to the influences to which it is subjected, we have seen nothing whatever to suggest that this does occur, and we are decidedly inclined to believe that the tertian, quartan, and aestivo-autumnal parasites are permanently different varieties of closely allied sporozoa. 100 W. S. Thayer and J. Hewetson. Relation of the Different Types of Infection to Race. We have seen that the colored, as compared with the white race, pre- sents a marked relative insusceptibility to malarial infection. Should we then expect to see, in the colored race, only the more severe types of malarial fever, or should we rather expect to find that infection once taking place in relatively unfavorable ground, the disease would pursue a milder course? Among the 27 cases of malarial infection in the colored race, where the type was clearly differentiated, there were: Single tertian infections 9 Double tertian infections 7 Aestivo-autumnal infections 9 Combined infections 2 That is, 59.2 per cent, of the cases occurring in colored patients were tertian infections, and 33.3 per cent, aestivo-autumnal; while among the white patients, 62.5 per cent, were tertian, and 34.7 per cent, aestivo-autumnal infections. There would then appear to be no essential difference between the susceptibility of the white and the colored patient to the various types of malarial fever. On further analysis of these cases, one point is, however, rather striking. While, among the white patients, only 43.7 per cent, of the tertian infections were single,-56.3 per cent, being double-in the colored we find 56.2 per cent, of single tertian infections, and 43.8 per cent, of double. The explanation which would naturally suggest itself is that the negro, having a certain relative immunity from malarial infection, is more resistant against the organism when the infection has once taken place; the process is thus much more likely to remain a single infection than to increase in intensity and develop, as it does so frequently in the white race, into a double infection. The Malarial Fevers of Baltimore. 101 VI.-ANALYSIS OF THE TYPES OF FEVER ASSO- CIATED WITH THE DIFFERENT TYPES OF ORGANISMS. In considering the 544 * cases in which the types of fever were definitely made out, we shall take up separately those cases occurring in the hospital and those cases occurring in the dispensary, noting finally what conclusions may be drawn from the combination of the cases from both sources. The studies of the ward cases were much more satisfactory. In certain ways, however, the addition of the dispensary cases makes the note more complete. Tertian Infections. There were 339 cases in which typical tertian organisms were observed. Of these, there were: Single infections..... 151 Double infections 188 (1). Single Tertian Infections. Of the 151 single tertian infections, 58 occurred in the hospital and 93 in the dispensary. Cases of Single Tertian Infection Observed in the Hospital.-Of the 58 cases showing typical tertian organisms, one was a relapse of a case previously treated. Of these 58 cases, 52 showed, either outside or within the hospital, typical tertian paroxysms. Of the remaining 6 cases, one gave a his- tory of having taken a few doses of quinine whenever a paroxysm appeared, with the resulting occurrence of a chill about every ten or eleven days. Treatment was begun in this case immediately, so that it could not be studied further. One case complained of chills at intervals of about seven or eight days. One case gave a history of having had tertian and quotidian chills, which became irregular after the spasmodic use of quinine. There was but one paroxysm in the hospital. * This includes the two relapses above referred to. 102 IK /S'. Thayer and J. Heuetson. One case had a single chill the day before entrance, the fever dis- appearing spontaneously after admission. One case gave a vague history of occasional chills, headache and vomiting for two weeks, but showed no further fever or symptoms after the paroxysm during which he was admitted, excepting a slight rise in temperature on the fourth day. One case, where there had been daily paroxysms before entrance, showed no symptoms after the chill during which he entered. This case was probably one of double tertian infection which was dying out; it was classified among the tertian cases because but one set of organisms was seen on entrance. Of the 52 cases showing typical tertian paroxysms, five had had quotidian attacks sometime before entrance. Of these 58 cases of tertian infection, 11 showed a spontaneous disappearance of the fever after admission. In 3 of the 47 remain- ing cases, the fever disappeared after one or more paroxysms without the administration of quinine. The average duration of the paroxysms from the beginning to the end of the rise in temperature (above 99°) was between eleven and twelve hours (11.8). Out of 24 cases with multiple paroxysms, ten showed, perhaps, a slight tendency toward anticipation, three toward retardation ; eleven showed paroxysms occurring at the same hour. Of these 58 cases of tertian fever, 55 cases had had, in or outside of the hospital, "shaking" chills. The other 3 had chilly sensations. Organisms.-In all of these cases typical tertian organisms were found. In 15 of the cases segmenting bodies were noted during the paroxysm. In 5 cases flagellate bodies were noted, in three instances during the paroxysm, in the fourth a few hours before the paroxysm, and in the fifth case during apyrexia, eleven hours before the paroxysm. Cases in the Out-patient Department.-There were 93 cases in the out-patient department in which typical tertian organisms were found. Of these, 75 gave a history of having had tertian paroxysms. Of the 18 who gave no history of tertian paroxysms, 3 showed their first chill on the day of consultation or upon the day before; in 3 the his- tory was not noted; in 2 the first chill had been followed by quinine, the symptoms afterward being indefinite; in 2 there were vague gen- eral symptoms-headache, pains in the back and limbs, and other The Malarial Fevers of Baltimore. 103 symptoms characteristic of any acute infectious process; in one case the only complaint was of haemoptysis; in the remaining 7 cases chills and chilly sensations occurred, but the patients were unable to give definite statements as to the type. In these 93 cases, there were noted : Chills in 79 Chilly sensations in 8 " Paroxysms " in 2 Haemoptysis in 1 Vague febrile symptoms in 1 No note in 2 In the 75 cases giving a history of having had sharply-defined ter- tian paroxysms, four had had, at one time or another, quotidian par- oxysms. Organisms.-In five of these cases segmenting bodies were seen during the paroxysm; in one a flagellate body was also noted. Summary of the Cases of Tertian Fever in the Hospital and Dispen- sary combined.-Thus in the hospital and dispensary together there were 151 cases showing single tertian infection; one of these was a relapse. Of these 151 cases, 127 had tertian paroxysms. Of the 127 which had had tertian paroxysms, 9 had had at some time* quotidian paroxysms. In the 151 cases, there were noted : Chills in 134 Chilly sensations in 11 "Paroxysms" in 2 Vague febrile symptoms in 1 Haemoptysis in 1 No note in 2 151 The average duration of the paroxysms was between eleven and twelve hours (11.8). Organisms.-Segmenting bodies were noted in 20 cases, always at the time of the paroxysm; flagellate bodies were noted in 6 cases,- in four instances during the paroxysm, in one shortly before it, in one eleven hours before it. 104 W. S. Thayer and J. Hewetson. Cases. Case 4934 is an illustration of typical tertian fever with regular paroxysms. Man, aged 24, English, a laborer; admitted March 25th, 1892, complaining of headache and fever. Family and personal history negative; has been living in a very malarious dis- trict. He has had chills and fever ofl' and on for six months; gives no clear history as to type; says that he would go to bed for several days at the beginning of his attack; would then get up, and in about two weeks would have another attack. His last paroxysm occurred the day before entry. Physical examination negative, barr- ing a large, palpable spleen, the border reaching nearly to the median line. The blood on the day of entry showed a large number of half-grown tertian organisms. The chart shows three typical tertian paroxysms, with a remarkable regularity as to the degree of fever, and the time of onset. The following case (10089) is an interesting example of the so-called fever with long intervals, which, as has been shown, may depend upon the presence of any of the three main varieties of parasites. The patient, a man aged 30, German, was admitted to the hospital on June 14th, 1894, complaining of headache and chilly sensations. Four years ago he had two chills a week apart, which were immediately stopped on the beginning of treatment. Four weeks before entry he had a shaking chill, followed by fever and sweating. A week later he had a second attack, and a week after that a third; yesterday a fourth. Examination of the blood yesterday in the dispensary, while the patient was in the sweating stage, showed two or three large, extra-cellular pigmented organisms, characteristically tertian in type, with the pigment in active motion. On entrance to the hospital, the examination showed a well-nourished man, complexion sallow, herpes about nose and lips, spleen readily palpable. Sonorous and sibilant rales heard occasionally on inspiration. Examinations of the blood in the hospital were negative. The temperature remained normal until the 18th, with the exception of a rise to 99.4° on the 16th. On the 18th, at 11.30 a. m , the patient had a chill, exactly eight days after the last. The blood during the chill at 11.30 a. m. showed one hyaline, intra-cellular parasite in active motion; two large, extra-cellular, full-grown bodies, with actively moving pigment. 19-6-94. The blood showed a small number of half-grown intra-cellular pig- mented parasites of the tertian type. The patient insisted upon leaving the hospital, and was discharged with a pre- scription for quinine. This is clearly an instance of tertian infection, where, with each paroxysm, the greater part of the new group of parasites was destroyed, the patient passing, as it were, through a fresh incubation period of seven or eight days between each attack. The Malarial Fevers of Baltimore. 105 The examination of the blood on the day of discharge makes it probable that in this attack there would have been a paroxysm on the following day, a considerable number of half-grown bodies having been found. Nb./oosj jyLicheid ffire,ie,v (2). Double tertian Infections. There were 188 cases of double tertian infection. Of these, 116 occurred in the hospital, and 72 in the out-patient department. Cases of Double Tertian Fever occurring in the Hospital.-116 cases in the hospital showed typical double tertian infection. Of these, 114 showed characteristic quotidian paroxysms, either in the house or out- side. The two which did not have quotidian paroxysms, had tertian fever. The first of these cases was a man 28 years of age, who gave a vague history of headache, thirst, and general debility for 106 W. S. Thayer and J. Hewetson. five days. This patient showed a slight paroxysm on the day of admission. On the following day the temperature varied between 97.1° and 100.7°. On the third day there was another slight par- oxysm, the fever disappearing spontaneously after this. The blood showed on entrance two distinct sets of parasites, one group being much more numerous than the other. The case was probably one of developing double tertian infection, which recovered spontaneously in the hospital. The other case had had regular tertian chills for two weeks. On admission, the examination of the blood showed two dis- tinct groups of organisms. There was, however, spontaneous disap- pearance of the fever in the house, no distinct paroxysms occurring after that during which the patient entered. This case was probably, also, one of developing double tertian malaria, which was interrupted in its course by the favorable change of surroundings. Of the 114 cases which had quotidian paroxysms, 20 had had tertian paroxysms at some time before entrance, while 9 gave a his- tory of irregular paroxysms before entrance. Two cases gave no distinct history of paroxysms before entrance. One of these cases gave a history of general pains in the back and limbs, weakness, diar- rhoea, and vomiting; the other gave a history of headache, abdomi- nal pain, and diarrhoea. One of these was a foreigner, who spoke English with difficulty, and was not able to give a clear account of himself. Four patients, who gave a history of quotidian fever outside, showed tertian fever after entrance into the hospital. One patient showed in the hospital two tertian paroxysms, the first severe, the second very mild. After this quinine was given, and recovery followed. Though the paroxysms in the hospital were tertian in character, two sets of organisms were found on entrance, and the case was, doubtless, either a double tertian infection which was dying out, or, what is not im- probable, the patient's history of daily chills was incorrect, as he spoke but little English, and we were dealing rather with a beginning double tertian infection. The second case was one of a dying-out infec- tion, only a few half-grown organisms being found on the day of entrance. No paroxysm was observed on the following day, and but a feeble one on the third. One case had an abortive paroxysm on the day of entry and ter- tian attacks later, the second group of organisms disappearing. The Malarial Fevers of Baltimore. 107 One case was changed to a tertian infection experimentally (see page 113). Of these 116 cases, three showed marked irregularity in the par- oxysms. One case showed daily abortive paroxysms, with a ten- dency toward continuity. The irregular temperature followed several doses of quinine. One case was complicated with an abscess of the thigh, which probably accounted for the slight irregularity. One case was that of a child ten months of age, whose chart showed con- siderable irregularity in the temperature. The examination of the blood in this case showed organisms in nearly all stages of develop- ment, and it is probable that the irregularity of the temperature may be accounted for by the lack of the ordinary arrangement in groups. Two cases showed a more or less steady elevation of temperature with daily exacerbations. The first showed rather irregular daily paroxysms, the temperature remaining elevated on one occasion for thirty-six hours. This was one of the earlier cases, and as the notes concerning the organisms are not as satisfactory as could have been wished, one cannot state whether in this case the presence of organ- isms in different stages of development may have had any relation to the irregularity of the symptoms. The second case showed at first a more or less continuous tem- perature, with daily exacerbations; it was mistaken for a case of typhoid fever. After five days' treatment with cold baths, the tem- perature became quite regularly intermittent. The case is of enough interest to cite more particularly. W. Y., aged 29, German, was admitted to the hospital on the 8th of August, 1892, complaining of loss of appetite, general malaise, and fever. His family and personal history bore no relation to his complaint at that time, which began four days before admission with loss of appetite and fever. He had had no chills, no abdominal pain, no nose bleed. He complained of shortness of breath, some cough, occasional nausea, no vomiting. There was constipation at first; later diarrhoea. The examination of the blood, which, unfortunately, was very superficial, showed no malarial organisms. Physical examination. The patient was a large, well-nourished man; thorax and abdomen were negative on examination, except for a palpable spleen. The urine showed a trace of albumen; no casts seen; diazo reaction absent. Between the 8th and 10th of August the temperature ranged between 99° and 104.5°, being continu- ally elevated. The case was believed to be one of typhoid fever, and cold baths were ordered. After the 10th of August, the patient had an irregularly intermittent tem- perature, ranging between 97.6° and 105.8°. He was given, in all, ten tub baths. On the 14th, by which time, as the chart will show, the temperature had become more 108 W. S. Thayer and J. Hewetson. regular in character, the examination of the blood showed typical full- and half- grown, intra-cellular bodies, a number of hyaline, amoeboid, intra-cellular bodies, and one segmenting body. The examination was made during the paroxysm. Qui- nine, live grains every four hours, was begun at 4 p. in. on the 15th, after which date there were no further paroxysms. The case is of considerable interest on account of the rarity of irreg- ular and remittent fevers in association with tertian infections. The probability is, that we were dealing here with an infection with several groups of the parasite in different stages of development, though it may be that the regular course of the fever was somewhat interrupted by the treatment with cold baths. It is of interest, that at the time when the organisms were discovered, two groups only were found. At this time, however, it will be noted that the temperature, which had previously been irregular, had assumed a more regular course. On the whole, the consideration of the case, and the inspection of the chart, would suggest that the probable course of events had been as follows; primarily, severe infection with multiple groups of the ter- tian organism, modification of the infection by rest in bed, and the treatment with cold baths, until finally, at the time when a thorough examination of the blood was first made, only the two stronger groups of organisms remained. It will be noted, by consulting the chart, that the paroxysms on the 10th, 12th, and 14th occurred in the morning; while those on the 11th, 13th; and 15th occurred in the afternoon. In 3 cases there was no fever in the hospital. In 13 cases with fever on entrance, there was a spontaneous dis- appearance of the fever in the hospital. In two of these cases apparent spontaneous recovery was followed later by a relapse, the fever recurring in the first in six, in the latter in three days. In the 116 cases, there were noted: Chills in 107 Chilly sensations in 4 Vague general symptoms in 5 116 One of the instances in which no chill was noted was a child ten months of age. JTO sjos The Malarial Fevers of Baltimore. 109 The average duration of the paroxysms was about eleven hours (10.7). Organisms.-In all these instances characteristic tertian organ- isms were seen, arranged distinctly in two groups. In 10 cases flagellate bodies were noted; in 7 instances during the paroxysm; in 2 just before the paroxysm ; in 1 between paroxysms when the temperature was normal. In none of these instances had the patients had quinine. Segmenting bodies were noticed in 42 cases, always during the paroxysm. Cases of Double Tertian Infection in the Dispensary.-There were 72 cases of double tertian infection treated at the dispensary. Of these, 58 gave a history of having had quotidian paroxysms; 8 gave a history of tertian paroxysms, all showing, however, a double set of organisms; 3 cases gave a history of having had tertian paroxysms becoming irregular after quinine; 2 gave a vague uncertain history of quotidian fever; one case had had but one chill, the day before entry. Of the 58 cases having had characteristic quotidian paroxysms, 14 had had tertian paroxysms at one time or another. Of the cases giv- ing vague uncertain histories, one complained simply of anorexia and vague general pains. The other was a Slav, who was unable to make himself understood, further than that he complained of chills. In the 72 cases, there was a history of: Chills in 65 instances. Chilly sensations in 3 " Fever only in 1 " Headache in 1 " " Paroxysms " in 1 " No note in 1 " 72 " In 5 of the 72 cases, segmenting organisms were noted; in 2, fla- gellate bodies were seen, in each instance at the time of the paroxysm. Summary of the Cases of Double Tertian Fever in the Hospital and Dispensary.-There were 188 cases of double tertian infection seen in both hospital and dispensary. Of these, 172 gave a history of having had quotidian paroxysms. Thirty-six had had, at one time or another, tertian paroxysms. There were : 110 W. 8. Thayer and J. Heweison. Chills in 172 cases. Chilly sensations in 7 " No chills in 7 " "Paroxysms" in 1 " No note in 1 " 188 " Organisms.-Segmenting bodies were noted in 47 instances, always during the paroxysm. Flagellate bodies were noted in 12 instances, in all during or just before the paroxysm, with one exception, where the temperature was normal, between paroxysms. Cases. A good example of the double tertian infection is the following: Case 2998.-J. F., aged 37, German, admitted July 28th, 1891. Has had frequent attacks of malarial fever during the last seven years in Texas; has been in Baltimore seven weeks. About a week ago he began to have chills in the afternoon, which have occurred daily. Temperature on admission 97°. Physical examination negative, excepting for the palpable spleen. The blood showed typical intra-cellular tertian organisms, full and half grown, and extra-cellular fragmenting forms. The chart shows three characteristic paroxysms. It is interesting to note that the paroxysms on the 28th and 30th began at about 2 p. m., while that on the 29th occurred between 4 and 5 p. m. This point is one of considerable interest, as it serves, some- times, to demonstrate very clearly the fact that the daily chills depend upon two different sets of organisms. Sometimes it is possible to observe, through a considerable length of time, the regular difference between the time of onset of chills following one another on alternate days, those on the first and third day occurring at one time, while those on the second and fourth occur at another. Case 6101.-L. K., single, aged 16, native of the United States, admitted October 18th, 1892. The present is his first attack of malarial fever. It began six days ago with creeping chills. Yesterday he had a severe shaking chill. The spleen was readily palpable. The blood showed two sets of tertian organisms. The chart in this case shows a regular quotidian intermittent fever, with paroxysms occurring at almost exactly the same hour daily. The fact that these cases depend on the action of two groups of tertian parasites is demonstrated not only by the examination of the organisms, and by the fact that one may trace in the temperature curve The Malarial Fevers of Baltimore. 111 the similarity of the chills on alternate days one with another (hour of onset, severity, duration); it is often possible to demonstrate this point with great clearness by the use of quinine. Golgi has shown John that the parasites are most successfully combated with quinine at the time of segmentation, before the new group of young parasites has entered the red corpuscles. After segmentation, only very large doses of quinine will destroy the organisms. Thus, one dose of quinine, 112 IK & Thayer and J. Hewelson. ^o. 6101 J/pnisf Petvv ^Diepota-. 77ie Malarial Fevers of Baltimore. 113 given just before or early in the paroxysm, will, at times, almost destroy an entire group of organisms which has reached its perfect development and has begun to segment, while a half-grown set of parasites will continue in its course of development. In this way, then, we should be able to change a quotidian into a tertian malarial fever by the administration of quinine in a single moderate dose before or early in the paroxysm. This is the fact, as may be shown very clearly by the following case. This case was modified experiment- ally before the ward class. Case 9047.-P. D., male, aged 36, German, laborer, admitted May 8th, 1894, com- plaining of cough, fever, thoracic pains and weakness. Family and personal history bear no relation to his present trouble, excepting that two years ago he had an attack of chills and fever of unknown type. Present illness began a week before entry. Chills on the third, on the fifth, sixth and seventh, and also at noon on the day of entry. Physical examination was negative, excepting for the palpable spleen. Urine normal. Temperature 103.6° on entry. 8-5-94. Blood at 4.15 p. m. showed a number of nearly full-grown typical tertian organisms, a few amoeboid, intra-cellular, hyaline forms, two fragmented extra-cellu- lar bodies, pigmented leucocytes. 9-5-94. A chill being expected, five grains of quinine were given at 11.15 a. m.; chill at 12. The blood at 9 a. m. showed a few large, full-grown, extra-cellular bodies and a number of half-grown forms. 10-5-94. Chill again about eleven o'clock. Blood at twelve showed a number of typical segmenting parasites, a few large, full grown forms, several amoeboid, intra- cellular, hyaline bodies, one large, fragmenting, extra cellular body, pigmented leuco- cytes, no half-grown forms. 11-5-94. No paroxysm. 12-5-94. Paroxysm about ten o'clock. Blood at eleven showed a few segmenting bodies, several full-grown and large fragmenting, extra cellular forms, no half-grown forms. Quinine gr. X (0.65) at the height of the paroxysm; gr. II (0.13) three times a day afterwards. The organisms disappeared almost immediately afterwards; no further fever. Surely no better proof than this case could be asked to demon- strate the dependence of these quotidian paroxysms upon a double tertian infection. The same point is sometimes brought strongly to one's notice in the case of an individual who enters the hospital with one strong and one weaker set of organisms. Placing the patient in bed and upon a good diet is often sufficient to bring about the spontaneous disap- pearance of one group, so that the quotidian paroxysms are succeeded by tertian fever. 114 IK S. Thayer and J. Hewetson. Case 4889.-C. M., single, aged 34, Pole, admitted March 16th, 1892. Second attack, possibly a relapse of an attack for which he was treated by methylene blue in the hospital. Daily chills for five days. Patient had paroxysm in the dispensary. The blood showed characteristic seg- menting bodies of the tertian type, with fifteen or more segments; large, transparent forms, with actively-moving pigment granules; a very large number of fragmenting, extra-cellular, pigmented forms; a few half-grown, intra-cellular forms; no fresh hya- line bodies. At 4 p. m., a number of half and nearly full-grown intra-cellular, pigmented forms, fragmenting extra-cellular bodies, no hyaline bodies. 17-3-92. Paroxysm at noon. Blood at 3.45 p. m.; occasional large, full-grown, tertian bodies, a certain number of extra-cellular, fragmented organisms, small, actively amoeboid, hyaline forms, only an occasional half-grown organism. 18-3-92. Temperature normal. An occasional fully-developed, intra-cellular para- site, numerous extra-cellular, fragmenting bodies, no hyaline bodies, a number of half-grown forms. Paroxysms on the 19th, 21st, 23rd, the blood, showing characteristic single tertian infection. At 8 p. m. on the 22nd, and 8 a. m. on the 23rd, eight grains of quinine were given, having no influence whatever upon the paroxysm of the 23rd. After this, quinine was given regularly without further fever, the organisms rapidly dis- appearing. This case shows, in an interesting manner, the association of large numbers of extra-cellular, fragmenting bodies with the spontaneous disappearance of one group of organisms. It also demonstrates clearly the inefficacy of moderate doses of quinine in preventing a paroxysm, if given when the organisms have already entered into the red corpuscles; the paroxysm on the 23rd, it will be seen, occurred just as if nothing had been done. Quartan Infections. There were five cases of quartan infection, all occurring in the hospital. Of these there were : (1). Single quartan infection 2 (2). Double " " 0 (3). Triple " " 3 5 (1). Single Quartan Infections.-Of the two cases of single quartan infection, both showed characteristic quartan paroxysms. The par- oxysms lasted between 10 and 11 hours (10.6). In both instances there were chills. fjris yi^rvfeirv. The Malarial Fevers of Baltimore. 115 Organisms.-The organisms in both instances were of the char- acteristic quartan type described by Golgi. Segmenting bodies were noted in one case; in the other, the examination of the blood was imperfectly made. Flagellate bodies were not seen. (2). Double Quartan Infections.-There were no cases of double quartan infection noted. (3). Triple Quartan Infections.-1There were three cases of triple quartan infection admitted to the hospital. Of these, the types of fever were as follows : Abortive quotidian elevations of temperature 1 Slight quartan paroxysms 1 One paroxysm on day of entry, afterwards normal 1 3 Chills occurred in all these instances. The duration of the paroxysms averaged about ten hours. Organisms.-All of the cases showed three groups of character- istic quartan organisms. Segmenting organisms were seen in all cases during the several hours preceding the paroxysms; in several instances they were found as much as eight hours before the paroxysms. In a number of instances where there were but few parasites, seg- menting bodies were seen on days when no paroxysm occurred. In two cases, flagellate bodies were seen. Cases of Quartan Fever Occurring in the Hospital. Case 1.-L. G., male, sixteen years of age, admitted to hospital November 29th, 1890. Family history good. Has always been in good health, excepting for an attack of tertian ague in July, 1889. For two weeks he had chills every other day; then a period of rest would follow, lasting two or three weeks. This lasted until October, 1889. After Christmas he had chills off and on until July, 1890. The day before entry he had a chill lasting about half an hour, followed by fever and sweating. Throughout the last year he has taken quinine in broken doses, omitting treatment usually as soon as the chills disappeared. The examination of the blood showed "a few intra-cellular organisms, no crescents or flagellate bodies." The physical examination was negative, excepting for a greatly enlarged spleen. The urine was dark yellow, clear, acid, 1028, no albumen, no casts, no diazo reaction. At 8 p. m. on the 29th the temperature was 100.5°. 30-11-90. Temperature practically normal throughout the day. 1-12-90. Paroxysm in the afternoon, temperature reaching 104.2° at 4 p. m. 2-12-90. Temperature normal. 116 IF. 8. Thayer and J. Heweteon. 3-12-90. Temperature normal. 4-12-90. Chill in the afternoon. A chill occurred also on the afternoon of the 7th, and on the 10th, the temperature being perfectly normal between. On the 11th, treatment with one grain of quinine, three times a day, was begun, the temperature remaining quite normal thereafter until the 29th of December, when the patient was discharged, the examination of the blood being negative. The organ- isms throughout showed rather coarse pigment. On the day of the chill, segmenting bodies were always observed ; these bodies were very numerous during the morning hours, from three to six hours before the chill. They were most beautifully sym- metrical rosettes, showing, in all instances where the leaflets were counted, from six to eight segments. Case 2 (4368).-Male, aged 52, German. The family history was negative; per- sonal history good. Present illness began on the 8th of December, when he had a severe chill, lasting for about an hour, followed by fever and sweating; none on the two following days. The physical examination was negative, excepting for the palpable spleen; the urine was normal. The blood showed fairly numerous rounded and ovoid, coarsely pigmented, intra-cellular bodies, which did not quite fill the cor- puscle. The markedly greater refraction and the sharper outline of the body, as compared to the ordinary tertian forms, were noted. The amoeboid movements were very slight, and the pigment was almost motionless; in some bodies no motion could be made out. The pigment granules appeared coarser than those in the ordi- nary tertian form of the parasite, and of a slightly different color. As the chart shows, the patient had two paroxysms, four days apart. The examination of the blood was, however, not carefully made at the time of the paroxysms, and segment- ing bodies were not noted. The fully-developed organisms, however, were not as large as those in ordinary tertian fever. On the 15th of December methylene blue, 0.1 four times a day, was ordered. No organisms were seen after the 18th. There were no further attacks of fever. The patient died of an attack of influenza, with extensive broncho-pneumonia, on the 9th of January. Case 3 (9773).-J. S., single, aged 10, Pole, admitted April 30th, 1894. She speaks but little English, and the history is not satisfactory. Chills and fever last fall; also two months ago. For two or three weeks chills at uncertain intervals. On entry, 8 p. m., the blood showed one half-grown intra-cellular body, with a small amount of very dark pigment which was rather larger than that seen in tertian parasites, and very slightly motile, while -the body was round and scarcely at all amoeboid; several fragmented, extra-cellular parasites. 1-5-94. Physical examination negative, excepting for the palpable spleen. Blood, 9 a. m. A few organisms seen this morning, nearly filling up the body of the corpuscles. These corpuscles are not expanded, as one ordinarily sees in tertian infection; on the other hand, they appear to be rather smaller than the others about them, as if contracted about the body. The pigment is rather dark and coarse. The movements of the pigment granules are slow, while the surrounding protoplasm is quite refractive. One form, which w'as slightly elliptical in shape, a little smaller than an ordinary red corpuscle, with almost non-motile, black pigment, showed a jL/clit i'eiice: (xavtunA Temp. 109 |08 107 106 105 104 103 403 ioi too 09 98 97 96 Temp Pulse Resp .No. wcr The Malarial Fevers of Baltimore. 117 suggestion of a double contour; it was very similar to the ovoid aestivo autumnal forms in appearance, except for the irregular arrangement and the quantity of pig- ment. A number of fragmenting and vacuolating, extra-cellular forms, and several bodies nearly, but not quite filling up the red corpuscle, with almost non-motile pigment and quite refractive protoplasm, were seen; also other smaller bodies, about one third the size of a corpuscle, quite refractive, with very slow amoeboid movements and slightly motile pigment granules. Several early segmenting forms were found. At 2 p. m. a number of characteristic segmenting bodies, with from six to ten seg- ments, were seen. Paroxysm in the afternoon. During and just after the paroxysm, small, amoeboid, intra-cellular forms were seen. 2-5-94. Temperature, at 8 p. m., 100.1°. 3-5-94. Temperature normal. 4-5-94. Temperature 100.5° at 8 p. m. 7-5-94. Temperature 99.8° at 8 p. m. 10-5-94. Temperature 99.8° at twelve, midnight. 13-5-94. Temperature 101.5° at 8 p. m. Examination of the blood revealed a characteristic triple quartan infection, seg- menting bodies being observed during the first four days, notwithstanding the slight rises in temperature. The strongest group of organisms reached maturity on the 1st, 4th, 7th, 10th, and 13th, causing slight abortive paroxysms. The patient was removed from the hospital by her parents on the 13th, when she was given a pre- scription for quinine. Case 4 (10429).-A. K., single, aged 12, Pole, entered the hospital on July 19th, 1894. Does not speak English; history imperfect. 20-7-94. Examination of the blood, at 12 m., showed typical quartan organisms, a number of early segmenting forms, other small bodies just beginning to develop pigment, other more advanced bodies nearly filling up the shrunken, brassy-colored corpuscle, a few' extra-cellular, fragmenting bodies; one small pigmented form was seen to burst from the corpuscle which became immediately decolorized; the escaped parasite became immediately deformed. Temperature, at 6 p. m., 99.6°. 21-7-94. Temperature subnormal during the night; 100.6° at 8 p. m. Blood, 2 p. m., showed a few segmenting bodies. 9 p. m.; a number of characteristic quartan organisms, nearly filling the shrunken corpuscle, with almost immobile pigment; a few hyaline, amoeboid, non-pigmented forms. 22-7-94. Temperature subnormal during the night; 99.2° at 8 p. m. Blood, 3 p. m. A few intra-cellular, hyaline bodies, one or two larger pigmented bodies, several nearly full-grown pigmented bodies, large and fragmented extra- cellular bodies with active pigment granules, pigmented leucocytes. 23-7-94. Temperature subnormal during the night; 99° at 10 a. m., 2 p. m. and 8 p. m. Examination of the blood unfortunately not noted. 24-7-94. Temperature subnormal during the night; 103.8° at 6 p. in., to-day. Blood at noon showed segmenting bodies. 8 p. m.; a few intra-cellular, apparently half-grown and some nearly full-grown bodies, several swollen, extra-cellular forms with active pigment, one flagellate body. 118 IF. <8. Thayer and J. Hewetson. 25-7-94. Quinine, two grains (0.13) every four hours. Temperature normal on the 26th. Slight paroxysm on the 27th and 28th. Normal on the 29th and 30th, when the patient was discharged with quinine. The organisms were present in the blood until the day of discharge. On that date none were to be seen. The case was one of typical triple quartan infection, the organisms showing characteristics entirely different from those of the tertian parasite. It is interesting to note how, with the abortive paroxysms, the whole life history of the parasite could be traced in the circulating blood. The inefficacy of the quinine in stopping the paroxysms on the 27th and 28th is what might have been expected, the administra- tion of the drug having been begun when the parasites had already entered the corpuscles. Case 5 (10431).-19-7-94. A. K., single, aged 15, Pole, complains of chills and fever; no further history obtainable. Is a sister of the last patient. Physical examination negative, excepting for the palpable spleen. Temperature 102.2° at 8 p. m.; no marked paroxysms after this, though slight rises in temperature were noted on the 25th and 28th. Quinine begun on the 25th. Examination of the blood showed a dying out triple quartan infection. Flagellate bodies noted on the evening of the 23rd. Segmenting bodies were observed on the day of entry and on several other occasions, notwithstanding the slight abortive rises of temperature. It is interesting to note that, in these dying out quartan infections, we observed, as has Antolisei, extra-cellular forms with active pig- ment granules, fragmenting forms, and flagellate bodies, just as we have noted in tertian fever. The large, extra-cellular forms, how- ever, are materially smaller than those of the tertian variety; they are not as frequent; they are not as transparent; the pigment is larger and coarser. There was no question in any of these cases of a combined infection, not an organism having been observed which was not quite distinctively of the quartan type. A sixth case may probably be added to those above mentioned : A girl, aged 15, a German, was admitted to the hospital on the 26th of January, 1892. The family history was negative. She had never had previous illnesses, excepting two years before, when she had malarial fever of unknown type The illness of which she then complained began in August with chills which occurred, she said, about twice a week. At times she did not have regular chills, but " felt badly." This continued until October, when regular chills began, which were stopped by quinine. After two weeks the chills recurred, and for the past two weeks patient had had a chill every fourth night, the chill, associated with severe headache, lasting The Malarial Fevers of Baltimore. 119 an hour. This was followed by fever and sweating. Bowels regular. The physical examination was negative, excepting for the palpable spleen. The patient showed no paroxysms in the hospital. She had had quinine outside before entrance. The blood showed a very few organisms similar to those observed in the other quartan cases, but, owing to the imperfect entry made concerning them, we have not felt justified in including this case among those where the type was definitely made out. We have little doubt, however, that this also represented a case of quartan malaria. JESTIVO-AUTUMNAL INFECTIONS. There were in all 189 cases of aestivo-autumnal fever observed in the hospital and dispensary. Of these, 105 cases were treated in the hospital, and 84 in the dispensary. Cases of Aestivo-autumnal Infection Observed in the Hospital. In the 105 cases of aestivo-autumnal infection observed in the hos- pital, one of which was the relapse from a case previously treated, the types of fever may be divided as follows: Quotidian intermittent paroxysms 38* Daily paroxysms, with a tendency to become continuous 16 f Continuous fever, with quotidian exacerbations 13 Tertian intermittent paroxysms 6 Continuous fever, with no sharp paroxysms 9 Normal or subnormal temperature 8 Moderate irregular fever 8 Indefinite 7 J 105 Thirteen of these cases which did not show tertian fever in the house gave a history of having had tertian paroxysms before entrance. Thus, of the 105 cases, only 38 showed sharp quotidian intermittent paroxysms, though 67, or not quite two-thirds, showed a distinct * In several instances the patient was admitted during the paroxysm, and showed only one or more slight daily rises of temperature on the following days, with a normal temperature afterwards; so clear a history was, however, given of sharp paroxysms before entering the hospital that the cases were placed in this list. fUnder this heading are classed those cases which showed several distinct par- oxysms, where, on one or more instances, the temperature failed to reach the normal point before the beginning of the following paroxysm, " subintrant, fever." t Cases showing but one paroxysm in the house, with a vague, indefinite history. 120 IF. S. Thayer and J. Hewetson. tendency toward quotidian exacerbations. Six showed tertian par- oxysms, while 20 gave a history of having had tertian paroxysms at some time. On the other hand, 38, or more than one-third of all the cases, showed a more or less continuous fever. Of these 105 cases, 68 either showed, in the hospital, or gave a clear history of having had, before entrance, distinct chills, and 7 chilly sen- sations ; 30 complained only of headache, pains in the back and limbs, etc., the symptoms ordinarily accompanying an acute infection. The duration of the paroxysms in these cases differed considera- bly from those in the tertian and quartan infections, averaging between twenty and twenty-one hours, while in the tertian and quartan fever it averaged from ten to twelve hours. In many instances the paroxysm lasted considerably longer-in one case, for instance, for thirty-eight hours, while in a number of instances long paroxysms which would probably have brought up the average duration considerably, could they have been reckoned among those on which this calculation is based, were followed by a second par- oxysm before the fall to normal occurred ("subintrant" cases), so that the length of each paroxysm could not be estimated. It will also be noted that, while in 97.2 per cent, of the cases of tertian and quartan infection in the hospital, chills or chilly sensations were present, in only 71.4 per cent, of the cases of aestivo-autumnal fever were these symptoms noted. While in some cases with quotidian paroxysms the periods of sub- normal temperature during the attacks were similar to those observed in double tertian fever, there were many instances where the over- lapping of paroxysms caused a continuous fever, thus showing a chart quite different from that observed in the common double tertian intermittent. In some cases a continuous elevation of temperature, most suggestive of typhoid fever, was noted. In 5 cases where there was fever on admission, the temperature disappeared spontaneously. Organisms.-These 105 cases all showed the presence of the organ- isms characteristic of aestivo-autumnal infection. In all the cases in which fever was present during the stay in the hospital, the small, hyaline, ring-shaped and often actively amoeboid bodies described in an earlier section were noted. In several of the cases where no fever was present, only the crescentic and ovoid bodies were found. The Malarial Fevers of Baltimore. 121 In 35 cases, only these small, hyaline bodies, with or without a few minute granules of pigment, were seen. Of these, 27 were primary attacks, 8 were repeated attacks or relapses. In 70 cases ovoid and crescentic bodies were found. Of these cases, 46 were primary attacks, 24 were repeated attacks or relapses. In 5 cases nothing was found in the blood on admission, while later ovoid and crescentic forms were seen. In 29 cases hyaline bodies alone were present on admission, ovoid and crescentic forms appearing later. Of these 29 cases in which hyaline bodies alone were found on admission, with the development of the crescents later, the crescentic forms appeared before the begin- ning of treatment in 11 instances, while in 18 cases the treatment had been begun previously. In these 18 cases, the treatment was begun in the first week in only 4 instances. Of the 70 cases in which crescentic and ovoid bodies were seen, in only two instances were these bodies noted before the eighth day of the disease. The first case was that of a man who had had previous attacks, and had been living in Jamaica, having left for Baltimore two weeks before entering the hospital. He dated his symptoms, however, but two days back. It is highly probable that in this case the disease had lasted longer than the patient fancied, the crescents being the remnants of a previous attack, from which complete recovery had never occurred. The second case was a patient who had recently arrived from Cuba. He dated his quo- tidian chills, fever and delirium but five days back. It is somewhat striking that both of these patients had been living in the tropics, and that one had had already several previous attacks. In 28 of these 70 cases the crescents were noted before the fourteenth day. In all the remaining cases the patients had been ill at least two weeks. In 5 cases the patients had taken quinine from five to nine days before the appearance of crescents. Hyaline amoeboid bodies were found alone on entrance in 64 instances. In 29 of these instances crescents appeared later ; while in 35, hyaline bodies alone were seen throughout. Of the 35 cases in which hyaline bodies alone were seen, in one case the disappearance of the organisms before the beginning of qui- nine is noted. Case 8268 entered on the fifth day; no organisms were seen after the sixth; quinine given on the 14th day. It should 122 W. S. Thayer and J. Hewetson. be said, however, with regard to this case, that the discovery of hya- line forms is so delicate a matter that it is not impossible that a more careful, continued search would have shown these bodies. Out of the 35 cases where hyaline bodies alone were seen, 19, or about one-half, lasted over two weeks before the disappearance of the organisms; 16 lasted over twenty days. In two of these 16 cases there is considerable probability that the real attack may have been of much shorter duration than would appear from the history. With the exception of these two cases, the longest period during which symptoms existed, with the presence of hyaline bodies alone in the blood, occurred in case 6289, where the duration of the case was from eight to nine weeks, and in case 8105 which lasted six weeks. Of the 19 cases, where hyaline bodies existed alone for more than two weeks after the onset, 15 were first attacks. Of the 35 cases, in 17, treatment was begun in the first week; in 3 in the second. In 2, the duration of the case was not known, while in 13, with the exception of two cases in the tenth week, treat- ment was begun all the way from the third to the ninth week; in 2 instances, as noted above, the cases had existed from nine months to a year. Out of 64 cases, where hyaline bodies alone were present on admis- sion, in 21, treatment was begun in the first week, crescents appear- ing in only 4, or 19 per cent.; in 8, in the second week, crescents appearing in 5, or 62.5 per cent.; in 35, where the treatment was begun after the second week, the crescents appeared in 20 instances, or 57.1 per cent. In these 105 cases, flagellate bodies were noted in 18. In 6 of these cases quinine had been previously administered ; in one case there was some question as to whether the patient had, or had not had qui- nine. In 10 instances these bodies appeared before quinine was given. The earliest period at which they were noted was on the eighth day. They were, in all instances, associated with the presence of crescentic, ovoid, and round bodies. In 9 of the 18 cases the temperature was normal at the time when the flagellate bodies were found; in 4, they were found during the paroxysm; in 3, during the mild continuous fever; in one instance they were found after death in the spleen. In one case in which the organisms were found during the paroxysm, early in the course/they were found The Malarial Fevers of Baltimore. 123 again five days later, when the temperature was normal, after the administration of quinine. In another case they were found, first, ten days after the administration of quinine, and nine days after the temperature was normal; they remained present here till the thirteenth day. Cases of Aestivo-autumnal Infection observed in the Out-patient Department.-There were 84 cases of aestivo-autumnal fever ob- served in the dispensary. There were: Quotidian paroxysms in 35 Tertian paroxysms in 7 "Paroxysms" in 5 Irregular paroxysms in 8 Vague general complaints in 29* 84 Of the 29 cases complaining of vague general symptoms, one com- plained of tertian paroxysms, but stated that he believed his fever had been continuous. Of the cases showing quotidian paroxysms, nine had, at one time or another, had tertian attacks. In only 59 cases were chills or chilly sensations noted. Organisms.-Among the 84 cases, crescentic and ovoid forms were found in 35 instances; of these, 25 were first attacks; 5 were repeated attacks or relapses; 5 were uncertain, probably relapses. Hyaline bodies alone were noted in 49 instances; of these, 35 were first attacks; 13 were repeated attacks or relapses; 1 was uncertain. Of the 84 cases, 21 were seen during the first week, and of these only 3 (14.2 per cent.) showed crescents. In two of these cases they were noted on the seventh, and in one on what the patient believed to have been only the fourth day of his disease. 15 cases were seen in the second week, and in only 3 of these (20 per cent.) were cres- cents found. 46 cases were seen after the second week, and in 27 (58.6 per cent.) of these, crescents were seen. Out of 33 cases ad- mitted or seen later than the third week, crescents were found in 20 (60.6 per cent.). Of 2 cases, where the duration of the disease was doubtful, crescents were seen in one. Of the 13 instances in which hyaline bodies alone were found after the third week, in 3 the patients had had quinine before, with * Headache, pain in the back and limbs, and the symptoms generally associated with acute infections. 124 IF. S. Thayer and J. Hewetson. a temporary relief of the symptoms. In 4 of the instances where crescents were found, quinine had been administered before their appearance. Flagellate bodies were noted in two instances, on both occasions after the administration of quinine and during normal temperature. Cases of Aestivo-autumnal Infection in the Hospital and Out-patient Department.-There were 189 cases which showed the organisms characteristic of aestivo-autumnal fever. One was a relapse of an attack previously included in the classification. If we combine the observations of the temperature in those cases which were in the hospital with the most reasonable deductions that may be drawn from the statements of the out-patients concerning their attacks, we obtain the following result: Quotidian intermittent fever 73 cases. Tertian fever 13 " Continued fever, generally associated with daily paroxysms. 66 " Moderate irregular fever 21 Normal or subnormal temperature 8 " Indefinite 8 " 189 Organisms.-In 117 cases there were chills; in 17 chilly sensations; in 55 vague general symptoms only. In the 189 cases of aestivo-autumnal fever seen in the hospital and out-patient department, Hyaline bodies alone were found in 84. Of these there were : Primary attacks 62 Relapses or repeated attacks 21 Uncertain 1 84 Crescentic bodies were found in 105. Of these there were: Primary attacks 71 Relapses or repeated attacks 29 Uncertain 5 105 The following table shows, graphically, the time at which crescents generally developed in the hospital, and, so far as could be made out, in the dispensary cases. The Malarial Fevers of Baltimore. 125 1st week: Admitted to Hospital 36; crescents 2 " " Dispensary 21; crescents 3 57 5 8.8 per cent.* 2d week; Cases admitted to the Hos- pital, or present without having previously shown crescents 35; crescents 27 Cases consulting at Dispensary 15; crescents 4 50 31 62 per cent. After the second week: Cases admitted to the Hospital, or still remaining, without having shown crescents... 48; crescents 35 Cases in Dispensary 46; crescents 26 94 61 64.8 per cent. Cases of doubtful duration: House 8; crescents 5 Dispensary. 2; crescents 2 10 7 70 per cent. Relapses, House 1; crescents 1 100 per cent. Actual advanced segmenting bodies were never seen iu the circu- lating blood, though forms with a central pigment block were noted in a number of instances. Flagellate bodies were seen in 20 cases. In 8 cases quinine had been previously administered. In 1 case they were found both before and after the administra- tion of quinine. In 11 cases the temperature was normal at the time when the flagellate bodies were noted. In 4 cases the bodies were found during paroxysms. In 3 cases the bodies were found during mild continuous fever. In 1 case the bodies were found first during a paroxysm, and again, five days later, when the temperature was normal, following quinine. In 1 case they were found in the spleen after death. * This rather high percentage is explained by the fact that of the two cases show- ing crescents in the hospital during the first week, one, as has been stated, had had numerous previous attacks, so that it is uncertain as to whether the case may not have been a relapse, while the other came from a most malarious district (Cuba) and had probably had his disease longer than he stated-five days. Of the three cases in the out-patient department, the crescentic bodies were noted on the 7th day in two, whrle in the other the patient asserted that it was but the 4th day of the disease. 126 IT. £ Thayer and J. Hewetson. Cases. The following cases will serve to illustrate some of the different varieties of fever which were found associated with aestivo-autumnal organisms. The first case shows a chart very similar to that of ordinary double tertian or triple quartan fever. Case 8115.-Patient, a man aged 24, colored, entered the hospital at 8 a. m., September 5, 1893. He had had previous attacks of malarial fever, the last attack a year ago; had been ill seven days with headache, general depression, anorexia; no chills, no vomiting, no marked sweating, no nose bleed; has taken no medicine. On the day before entrance, the sixth day after the beginning of the symptoms, the blood showed fairly numerous intra-cellular, non-pigmented, hyaline, malarial organ- isms, small, many of them ring-shaped with sharp outlines. The temperature on entrance was 100.5°. Physical examination was practically negative, excepting for herpes at the corner of the mouth, and a palpable spleen. The urine showed a faint trace of albumen; no casts. The course of the temperature is shown in the chart. The paroxysms were fairly sharp in onset, and associated with chilly sensa- tions, though there were no actual shaking chills. For the first four days only small, hyaline, ring-shaped and amoeboid bodies were seen, which showed, between the paroxysms, one or two very fine pigment granules. Just before and during the early part of the paroxysms the organisms were very scanty in the peripheral circu- lation, a note having been made on the afternoon of the sixth that no organisms were to be seen at all. The forms seen shortly after the paroxysms were always free from pigment. No segmenting bodies were seen at any time. On the ninth, for the first time, one pigmented crescent was seen, and after this the crescentic and ovoid bodies became very numerous. On the tenth, flagellate bodies were seen for the first time, and while, after the beginning of quinine on the ninth, the small, hyaline forms dis- appeared with great rapidity, and the temperature returned to normal, the ovoid, crescentic and flagellate bodies were found continually, in considerable numbers, up to the date of discharge, the 14th. In this case, it will be seen that the paroxysms were very similar to those observed in the ordinary spring tertian fever. There was a tendency towards spontaneous recovery, and the administration of quinine was followed by the immediate disappearance of the fever. The examination of the blood suggested that this was a case of true quotidian malaria, only one set of organisms, apparently, being present. Case 7767.-G. E., single, white, aged 29, ship carpenter, admitted to the hos- pital July 22nd, 1893. Was in the hospital last year, during the latter part of August, with double tertian fever. He has been well since September, 1893. Three days ago he started to work in the morning, when he was seized with an intense frontal headache, anorexia, fever and sweating; the next day he had a The Malarial Tevet's of Baltimore. 127 8//^ C'aesar J!G>ore 128 W. S. Thayer and J. Hewetson. "dumb chill " To-day, has had a shaking chill lasting forty-five minutes, accom- panied by vomiting; complains of constipation. The patient entered at 7.30 p. m. with a temperature of 104.6°. The physical examination was negative, excepting for the considerably enlarged spleen. The urine showed a trace of albumen; no casts were found. The entry on the morning of the 23rd is as follows: " Last night, at 8 p. m., the blood contained a very considerable number of the smallest variety of hyaline bodies, some of them homogeneous in appearance, others more or less ring- shaped, some of them amoeboid; no other organisms found. There was no leuco- cytosis; indeed, rather a small number appeared to be present." The following morning the bodies were less numerous, a trifle larger, and some contained a few fine pigment granules lying at the periphery of the body. July 23rd, 3.30 p. in., the blood showed relatively few organisms. Those which were found were for the most part small, hyaline discs, some of which showed one or two extremely minute particles of pigment at the periphery. 4.15 p. m., tem- perature about 103°; the blood from the spleen showed a number of pigment clumps, which appeared to be free. Many others contained in large mononuclear, colorless cells. There was a considerable number of apparently free organisms a little larger, or about the size of the bodies with central pigment clumps, which were filled with very active, brown pigment granules. They resembled the extra-cellular pigmented forms seen in the spring tertians, excepting for the greater abundance and activity of the pigment. A number of apparently free bodies were seen ; some others within red corpuscles, in which there was a small central pigment clump, the surrounding protoplasm being somewhat granular in appearance, with a slightly "scalloped" out- line. These were probably early segmenting forms. 11 p. m.; more of the smaller, hyaline bodies present, but still forms with occasional pigment granules. July 24th; in the morning, a majority of the organisms had one or two fine pig- ment granules. At 11 p. in., at the beginning of the decline of the fever, the blood showed only a few organisms ; none were seen which contained pigment. 25-7-93. 10.30 a. m. Hyaline forms are rather larger, and about one-third con- tain a few fine pigment granules in the periphery. Several similar bodies, extra- cellular, hyaline, rather refractive, with a few granules grouped in the centre. Qui- nine, five grains (0.325) every four hours. 27-7-93. 10.15 a. m. The blood showed a few organisms, one or two ring-like forms, a few larger amoeboid; no pigmented forms were seen. The temperature, as the chart shows, was normal after the 25th. In this case, it is seen that two paroxysms overlapped one another, the fever having been continuous for thirty-seven hours after entry. The paroxysms occurring in the house were wholly unassociated with chills. The impression that one obtained from the examination of the blood was that there was but one main group of organisms, though all pigmented forms did not, always, disappear with the paroxysms. Case 8024.-E. B., female, single, aged 13, adinittted to the hospital on the 24th of August, 1893. This was the first attack of malarial fever. It began about ten days before entry with abdominal pain and diarrhoea which has continued until The Malarial Fevers of Baltimore. 129 George 130 W. S. Thayer and J. Hewetson. the day of entry. She complains now of pain in the left side, slight cough, con- siderable headache, anorexia, no chills. The child was well-formed and nourished; lips and mucous membranes of good color; tongue coated ; pulse dicrotic ; marked typhoidal appearance. Thorax negative; hepatic border just palpable; splenic border to be felt 5j cm. below the costal margin. Abdomen negative on palpation, not distended, no rose spots. Examination (rather hasty) of the blood on the after- noon of the 23d, and at 8.30 p. m., showed no malarial organisms, no pigment-con- taining leucocytes; a distinct increase in the large mononuclear leucocytes,-five out of twenty-five. The appearance of the child was characteristically typhoidal, and sponge baths were ordered, and continued for twenty four hours. The irregular, continued course of the temperature is shown by the chart, no distinct paroxysms occurring while the patient was in the hospital; no chills at any time during the course of the fever. On the 26th, for the first time, the examination of the blood showed small, amoe- boid, and ring-shaped hyaline bodies. On the 27th, the fourteenth day of the disease, beside the hyaline bodies, cres- centic forms were noted. The hyaline bodies, at 10.20 a. m., when the temperature was 101.8°, contained no pigment. At 7.30 p. m., the temperature 103.8°, the blood showed numerous hyaline bodies a trifle larger than in the morning, some with a few pigment granules at the periphery, one larger body with a few pigment granules collected in the centre. At 8.30 p. m., several more bodies with small central col- lections of pigment granules were to be seen. A number of the organisms were con- tained in crumpled, refractive, brassy-colored corpuscles; the hyaline bodies were mostly of medium size, a number with a few pigment granules; one free ovoid body ; pigmented leucocytes. 28-8-93. 11 a. m. Temperature 100.4°. Organisms perhaps a trifle smaller than last night; very few forms with pigment; one ovoid, refractive, pigmented body. At 3 p. m., the temperature 100.2°, very few organisms; only a few amoeboid and non-pigmented forms were seen. R. Quinine, gr. v (0.325) every four hours. 29-8-93. Temperature nearly normal; a few hyaline bodies, and several ovoids and crescents were seen. The hyaline bodies disappeared rapidly, though the cres- cents remained for some time, none, however, being seen on discharge, 19th of Sep- tember. This is a fairly good example of continued fever. There were no sharp paroxysms in the house, though there were slight rises daily. It would seem quite impossible to say whether we were dealing in this case with one group of organisms with overlapping paroxysms,* or with an infection with organisms in different stages of development, where, perhaps, different groups were segmenting through consider- * If so, should it be interpreted as a quotidian case, or, perhaps, as a tertian, show- ing two long paroxysms, beginning respectively on the 24th and 25th ? The examina- tion of the blood, in view of the few stages of development which we see circulating, is insufficient to clear up this point. The Malarial Fevers of Baltimore. 131 able periods of time. The first crescents were seen here on about the fourteenth day. Case 10480.-F. P., female, aged 28, German, admitted 25-7-94, complaining of headache and pain in the back and limbs. Family history negative. Personal history bears no relation to her present trouble. The present illness, her first attack, began two weeks before entry with severe headache, a feeling of giddiness, aching pains in the back and limbs, anorexia, occa- sional vomiting; bowels regular. On July 20th, had chilly sensations, lasting for about half an hour to an hour, fol- lowed by fever and profuse sweating; no nose bleed. 25-7-94. Temperature on entry 98°; 100.7° at 8 p. m.; 101.8° at 10 p. m. Blood at 8 p. m.: Numerous actively amoeboid hyaline bodies, some containing one or two minute pigment granules, also numerous ring- and disc-shaped bodies. Urine; dark amber, hazy, acid, 1013, faint trace of albumen, no sugar; diazo reac- tion present. Microscopically; epithelial cells and leucocytes ; no casts found. 26-7-94. Temperature remains elevated. " Patient is in bed, on her back ; tongue clean ; pupils equal, respond to light and accommodation ; lips and mucous membranes of good color; no herpes; pulse full, regular in force and rhythm, rather soft, 96, no thickening of the vessels. Thorax; well formed, costal angle wide, expan- sion good; fronts, axillae and back clear on percussion and auscultation. Heart. Position, area of dulness, and sounds normal. Border of the liver not palpable; right kidney just palpable ; splenic dulness obliterated by abdominal tympany ; border is not felt. Abdomen, not distended, generally tympanitic, negative on palpation. No rose spots, no glandular enlargements. Blood, 2 p. m. Large numbers of hyaline bodies, many actively amoeboid, some ring-shaped, a few showing pigment granules. 8 p. m. A few hyaline and ring-shaped bodies. 27-7-94. Temperature remains elevated, no sharp paroxysms. Blood, 9.30 a. m. Numerous, rather large, hyaline bodies, about a quarter the diameter of a red corpuscle. 2 p. m. A number of smaller bodies, some actively amoeboid, some showing occa- sional pigment granules. 8 p.m.; a few actively amoeboid hyaline bodies. 28-7-94. Patient is dull and drowsy ; temperature remains elevated. The blood at 9 a. m. showed a few hyaline forms. At 3 p. m., negative; at 8 p. m., negative. R. Quinine, gr. v (0.325) every four hours. 29-7-94. Temperature has remained continuously elevated since entrance, the course much resembling typhoid fever. Patient has the same dull look, the same dry coated tongue. Blood, 10 a. m. One amoeboid, hyaline body, several pigmented leucocytes. 3 p. m. Two crescentic, pigmented bodies,, several pigmented leucocytes. 8 p. m. One hyaline body with a few pigmented granules, one- crescent. 30-7-94. The temperature has remained elevated and uninfluenced by quinine ; spleen not palpable; no rose spots. Blood, 8.45 a. m. Several ring-like bodies; a few hyaline, amoeboid forms, one containing pigment; one large, ovoid, pigmented body. 132 UK Thayer and J. Hewetson. 2 p. m. Negative. 8 p. m. Several crescentic bodies.' 31-7-94. Temperature has been steadily Calling since the 29th ; no great change in the condition. This afternoon the left parotid gland is very tender, and some- what swollen; temperature at 8 p. m., 101.6°* Blood at 9 a. m., negative; at 2 p. m., negative. 1-8-94. Temperature in the morning was 104.6° ; at night, 102.6°. Whole left parotid gland greatly swollen, red and tender. Blood. No organisms seen, excepting an occasional crescent. Leucocytes, 5000 to the cu. m. m. From this time on, no hyaline organisms were noted in the blood. The parotid swelling gradually disappeared, the temperature reaching normal on the 4th of August. The patient insisted on leaving the hospital on August 8th, when she felt perfectly well. This case is of remarkable interest, in that it simulated typhoid fever so closely. The temperature showed a continuous elevation without intermissions; the tongue was dry and coated ; the patient was, at first, in a drowsy typhoidal condition. The urine showed throughout a diazo reaction. There were no chills and no sweating while she was in the hospital. The presence of the amoeboid bodies in the blood alone revealed the true nature of the case. Moderate doses of quinine, begun on the 28th, showed, on the 30th and 31st, a slight influence upon the fever. No hyaline forms of the parasite were observed in the blood after the 31st. The appearance, however, of the parotitis on the evening of the 31st caused an elevation of tem- perature, which would lead one to believe, on superficial examination, that the process had not reacted to quinine. This is one of those cases which shows the importance of the ex- amination of the blood in all doubtful cases of fever. It is also of interest in that it was quite impossible to distinguish any separate groups of the parasites in the blood. No examples of the later stages of development were ever found. It is probable that here the spleen and internal organs contained multiple groups of organisms in all stages of development, while continuous segmentation and liberation of toxic substances was occurring throughout the course of the fever. The question may arise whether it is not possible that the case was one of typhoid fever combined with malarial fever. We see no reason to believe that this was the case. On entrance to the hospital, the patient's temperature was normal. She had had chills on at least one instance before entry. We are not justified in taking the patient's statements as indicative that the temperature before entry had been jVo. Jammer iVi/fo S' reihricq The Malarial Fevers of Baltimore. 133 continuously elevated. It is not at all unlikely that it had been, at first, somewhat intermittent. As soon as the fall in temperature began, the patient was given a full diet, which was perfectly well borne. She was, also, able to be out of bed and about within two days after the time the temperature reached normal, without showing the debility which one would expect following typhoid fever. There were never, at any time, any abdominal symptoms. The following case is an interesting example of that class of cases in which the existence of malaria is often unsuspected, owing to the absence of any acute febrile symptoms. Case 7677.-The patient was a female, single, aged 23; mentally rather feeble; has never had malaria before. She was admitted on the 8th of July, 1893, com- plaining of an illness of six days' duration, of pain in the abdomen and vomiting; severe headache and general muscular pains; slight cough, anorexia; the vomitus was at times blood-stained; constipation; slight oedema of the feet and ankles. Physical examination showed a fairly well-nourished girl; tongue slightly coated ; color good; thorax negative; abdomen negative; splenic border easily palpable. Patient was very nervous, and marked vaso-motor disturbances were seen on the skin. She was given, at first, a light, later a general diet; tincture of mix vomica. The urine was negative, barring a faint trace of albumen; no casts were found. An hasty examination of the blood showed no malarial organisms. The temperature, on entry, was 100°, but was never again above 99.5°, and, during the eight days that the patient was in the hospital, was, for the greater part of the time, sub-normal. The girl com- plained, however, bitterly and continually, of headache. On the 16th of July the patient, owing to a misunderstanding, was discharged. She returned five days later, July 21st, complaining of the same symptoms. She was very dull and heavy; tongue thickly coated. Temperature 99.2° on entry; rose to 101.3° at twelve midnight, but was normal afterwards. Examination of the blood, on the 22nd, showed a few ovoid and crescentic pigmented parasites. On the 23rd there was a moderate number of pigmented crescentic and ovoid bodies, with an occasional hyaline, intra-cellular form, amoeboid or ring-shaped. On the 25th, the temperature still being normal, and the patient complaining bitterly of headache, she was given five grains of quinine every four hours. For several days after this the temperature was sub-normal. On the 27th no hyaline forms were to be seen, though numerous ovoids and crescents were present. On the 18th of August no malarial organisms were to be seen. The following cases, 6 in number, are the only ones of surely ter- tian fever which we observed, though there are many in which this had existed, if we are to believe the statements of the patients. Case 5922.-S. S., single, aged 26, Pole, was admitted on the 15th of September, 1892. Patient could speak no English; he was a laborer, in a very malarious dis- 134 W. S. Thayer and J. Hewetson. trict. So far as could be made out, there had been no previous attack. Present illness began, two days before entry, with a shaking chill, accompanied by headache, fever and sweating. He had no chill yesterday, though he feels badly to-day. The patient was admitted with a temperature of 101°. By midnight it was sub-normal, and there was no fever till the evening of the 16th, when it began to rise gradually until, at 9.45 a. m. on the 17th, it had reached 104.2°. There was a fall after this time to 101.2° at noon. At 4 p. m., the temperature being 102°, the patient was Stephen- Sti •'vste-rts discharged for insubordination. The blood on the 16th and 17th showed a few small, intra-cellular, hyaline bodies. Case 5923.-C. R., single, aged 25, Pole, admitted to the hospital on the 15th of September, 1892. He was a companion of the last patient, working with him in the same place. He has always been a healthy man; no serious illnesses previously. Present illness began two days before entry, when patient complained of chilly sen- sations, headache, fever and sweating. His symptoms came on at almost exactly the same time as those of his companion who lives in the same house and works at the same place. On entry the physical examination was negative, excepting for the palpable spleen. The urine contained a trace of albumen; no casts seen. As may The Malarial Fevers of Baltimore. 135 be seen by consulting the chart, the temperature, which was 101° at 8 p. m. on the 15th, was normal by 10 p. m., and remained so nearly all day, until the evening of the 16th, when it began again gradually to rise, reaching 102.4° at 6 a. m. on the 17th. It fell then to 100° at 8 a. m., rising gradually after this to 104° at 4 p. m., and reaching normal only between ten and twelve midnight, the paroxysm having lasted over thirty-eight hours. During the morning of the 18th, the temperature was normal, rising to 105.7° at 4 a. m., and falling to 102.8° at 8 a. m., with a second rise to 105° at noon on the 19th. There was another break in the fever between noon and 2 p. m., the temperature falling, in two hours, five degrees, and rising, gradually again, with chilly sensations, but without a shaking chill, to 103.8°, reaching normal by 2 a. m. on the 20th. Quinine, gr. ij (0.13) three times a day, was begun on the 17th. There was but a slight paroxysm on the 20th and the early morning of the 21st; a normal temperature afterwards. The examination of the blood showed, on the morning of the 16th, a very few small, intra-cellular, hyaline forms. At 8 a. m. on the 17th the same organisms were to be seen, still scanty. On the 18th and 19th the same forms were noted; at 8.30 a. m. on the 19th one form showed one or two fine pigment granules. The organisms disappeared rapidly under quinine, none being seen on the 21st and 23rd. This case corresponds, well, to Marchiafava and Bignami's aestival- tertian fever, the paroxysm of the 16th and 17th showing, rather strikingly, the pseudo-crisis and the precritical elevation. The follow- ing paroxysm, however, was not so characteristic, showing several oscillations. The organisms, however, showed no apparent differ- ences from those in the quotidian cases. It is of considerable interest that these two cases of tertian fever should have occurred in companions, subjected to the same influences. The attacks began on the same day, and, in the hospital, the patients showed almost simultaneous paroxysms, both entering with fever on the 15th, the temperature reaching normal, in each case, between ten and twelve p. m., with a rise in temperature beginning, almost simul- taneously, on the evening of the 16th in each instance. Case 8147.-J. C., colored, aged 39, laborer, admitted on September 11th, 1893; first attack. Illness began five days ago with pain in the back, headache, some abdominal pain, constipation; no chill, no nose bleed. Physical examination nega- tive, excepting that the spleen was palpable. The patient entered during a par- oxysm, the temperature at 2.45 p. m. having been 103°, reaching 106° at 6.30 p. m., and falling to normal by 6 a. m. The temperature remained normal during the 12th and the greater part of the 13th, starting to rise again between 3 and 4 p. m., and reaching 104.3° at 8 p. m., from which time it fell gradually, reaching the normal point at about 6 a. m. on the following morning. Quinine, gr. x (0.65), was given at the height of the paroxysm ; gr. v (0.325) every four hours afterwards, the temperature remaining normal or sub-normal until discharge on the 20th. On 136 B7. 6'. Thayer and J. Hewetson. 2^0. Ooutray The Malarial Fevers of Baltimore. 137 admission the blood showed a few small, hyaline malarial organisms. On the following day similar amoeboid, ring-like bodies were seen, but no pigmented forms were made out. During the 13th a few forms with occasional pigment granules were seen. On the 15th no malarial organisms were to be made out, and none were seen afterwards. This would appear to be an undoubted example of a retarding ter- tian infection, though the temperature does not show the oscillations described by Marchiafava and Bignami as characteristic. s^j Oc/n ret A- cpi * Case 8427.-C. D., aged 54, stevedore; first attack; admitted October 17th, 1893. About a month ago had a shaking chill, followed by headache and fever, which continued through several days. Has had headache and fever most of the time 138 IK S. Thayer and J. Hewetson. since, with periodical sharp paroxysms, associated with shaking chills. On admis- sion, the temperature was 99°. On the following day, shortly after midnight, there was a gradual rise in temperature, reaching 102.4° at 5 p. m., and reaching normal at about 4 a. m. on the 19th. Quinine, gr. v (0.325) every four hours, was ordered on the 19th, when the temperature was normal. On the morning of the 20th, be- tween eleven and twelve o'clock, there was a sharp chill, the temperature reaching 105° at 1.30 p. m., and falling to 99° at about midnight. The patient left, early on the morning of the 21st, against advice. The blood on entry showed actively amoe- boid, intra-cellular, hyaline bodies, several ovoid forms, one of which was filled with vacuoles of different sizes, apparently a degenerative form. At 8.30 p. m., two cres- cents and only one small hyaline, intra-cellular, ring-like form was seen. These small hyaline bodies, and crescentic forms, were seen throughout the patient's stay in the hospital; no segmenting forms, and no flagellate bodies were seen. It is inter- esting to note, that on the 20th, at 8.30 a. m., only one hyaline form was seen, after long search, while at 3 p. m., none were to be seen. Ovoid and crescentic forms were, however, noted. Case 10465.-U. S. G., male, single, aged 25, laborer, admitted July 24th, 1894, complaining of headache, pain across the back, and chills. Has been ill for four days with headache and general pains; no chills ; no nose bleed ; some abdominal pain. On entry, the temperature was 103.4°; rose to 105° at 4 p. m.; was normal at 6 a. m. on the following morning. Blood, 2.30 p. m. A large number of amoeboid, hyaline, non-pigmented bodies; also smaller, more refractive, ring-like forms; two bodies with pigment collected in a central block ; no actual segmenting forms. 8 p. m. Numerous amoeboid, hyaline organisms, ring-like forms, bodies with one or two grains of pigment, pigmented leucocytes. The course of the temperature is shown by the chart on the opposite page. It will be seen that the patient showed two paroxysms in the house; one beginning on the evening of the 25th, and one on the evening of the 27th, each showing the initial rise, the pseudo-crisis, and the pre- critical elevation described by Marchiafava and Bignami. The following are the notes of the blood and the urine, which may be compared with the temperature on the chart. 25-7-94. The urine showed a faint trace of albumen ; no diazo reaction ; no casts seen. Blood, 8.45 a. m. Parasites appear a trifle larger than they were last night. There are not so many of the small ring-like forms, while a majority show an occa- sional pigment granule at the periphery. The amoeboid movements are less marked than they were last night. Several bodies contained in shrunken, crumpled, brassy corpuscles were seen ; leucocytes containing pigment blocks. 2.30 p. m. Numerous ring-like hyaline bodies, many amoeboid forms, some pig- mented. 8 p. m. Temperature is beginning to rise. Examination of the blood showed nothing beyond one non-pigmented, ring-like form. 26-7-94. Blood, 9.30 a. m. Negative; no organisms seen. 2 p. m. A few ring-like bodies. 8 p. m. Numerous ring-like, amoeboid, hyaline bodies. No J0^6^ & § fir tin* 140 IK. & Thayer and J. Hewetson. 27-7-94. The blood shows a few actively amoeboid, hyaline bodies; a few ring- like forms ; a few bodies showing occasional pigment granules. 2 p. m. Numerous larger ring-like forms, one showing two quite active pigment granules; one larger body with a clump of pigment in the middle; two leucocytes containing pigment blocks. 7.45 p. m. Blood showed a few hyaline, amoeboid, bodies. At noon, quinine, gr. x (0.65), were given, to be followed by gr. v (0.325) every four hours. 28-7-94. 8.30 a. m. Blood negative. 2 p. m. One crescent and one ovoid body, with coarse pigment granules in the middle; two pigmented leucocytes. 8 p. m. Crescentic bodies and numerous pigmented leucocytes. 29-7-94. Temperature normal. Blood at 10.15 a. m., negative. At 3 p. m., ovoid and crescentic bodies. At 8 p. m., the same. 30-7-94. Crescents still visible. There was a slight abortive rise in tempera- ture on the evening of the 29th; temperature was normal on the 30th, when the patient insisted upon leaving the hospital. This case shows, as far as the clinical chart goes, the closest ap- proach to Marchiafava's and Bignanii's aestival-tertian fever that we have seen. While the examination of the blood revealed, apparently, but one set of parasites, the few stages of development, however, which were visible, makes it impossible for us to say with certainty whether this was the case. There was, so far as we could discover, no difference between the morphological characters of these parasites and those associated with quotidian fever. Case 10534.-M. R., female, single, colored, aged 29; first attack. Duration? Entered the hospital July 31st, 1894, in an hysterical attack; opisthotonos, grind- ing of the teeth, tossing about, complaining of general soreness and pain, particu- larly in the left breast. Temperature, 100.1°; 101° at 8 p. m.; nearly normal the following morning; the blood not examined. 1-8-94. Patient is better, complaining only of headache; examination negative. Temperature, as noted on chart, beginning to rise during the evening. 2-8-94. Temperature elevated. Blood at 10 p. m. showed a considerable number of small, ring-shaped and amoeboid hyaline bodies. 3-8-94. Temperature normal during the morning, beginning to rise in the after- noon. Blood, 3 p.m., showed a large number of hyaline bodies, many showing distinct spots of pigment, some smaller ring-shaped forms; pigmented leucocytes. 8 p. m. Numerous ring-like bodies, several hyaline forms with pigment granules; pigmented leucocytes. 4-8-94. Temperature elevated. Blood at 9 a. m. showed a few ring-like bodies with one or two hyaline forms; some pigmented leucocytes. 2 p. m. Several hyaline bodies ; pigmented leucocytes. 7.30 p. m. A few ring-like bodies. 5-8-94. Quinine, gr. v (0.325), every four hours. Temperature normal. jVo The Malarial Fevers of Baltimore. 141 9 a. m. A few ring-like bodies; one or two amoeboid forms. 3 p. m. A few ring-like bodies with one pigment granule ; pigmented leucocytes. 7.20 p. m. A few ring-like bodies. Temperature beginning to rise. 6-8-94. Temperature normal. Blood negative at 9 a. m. and 2 p. m. 7, 8, 9, 10, 11-8-94. Temperature normal and blood negative. 14-8-94. Temperature normal. No blood examinations for several days. To-day, ovoid and crescentic forms are seen. 15-8-94. Ovoid, crescentic, round and flagellate bodies; pigmented leucocytes. 16-8-94. Crescents and ovoids; no flagellate bodies to-day at 2 and 8 p. m. 17-8-94. Crescents, ovoids, and flagellates; pigmented leucocytes, the pigment being in fine granules. 18-8-94. Blood examined at 9.30 a. m., 2 and 8 p. m.; only crescents and ovoids were seen. 19-8-94. Crescents, ovoids and flagellates. 20-8-94. Crescents and ovoids. 21-8-94. Crescents and ovoids. From this time on the blood was negative. The chart here shows two anticipat- ing tertian paroxysms; one of them shows the pseudo-crisis and pre-critical elevation described by Marchiafava and Bignami. Examination of the blood, in this case, is particularly interesting, in that it shows the development of flagellate bodies ten days after the beginning of quinine, nine days after the temperature had been normal. These were found as late as the fourteenth day of normal temperature. The following case is included as a possible instance of aestival- tertian fever, though the temperature was, for some time, continuous. Case 7753.-J. W., married, aged 38, laborer, admitted 21st July, 1893. He says that he had intermittent fever at fifteen; has been, otherwise, always well. His present illness began four days before entry with a shaking chill in the morning, followed by fever and sweating. This was repeated two days ago, and to-day, July 21st, the patient entered the hospital with a temperature of 102.6°. The physical examination was negative; the spleen was not palpable. The urine showed a slight trace of albumen; no casts were found; a faint diazo reaction was present. t The blood, on entry, showed only a few very small, ring-shaped, hyaline bodies. The chart shows the course of the fever. On the 22nd, at 3.45 p. m., the blood showed but a few small, hyaline, ring-shaped bodies. On the morning of the 23rd, at 9.45 a. m., the blood contained a very considerable number of hyaline organisms, some very small and often ring-shaped, others a trifle larger and amoeboid; no pigmented forms were seen. At 3.45 p. m. numerous hya- line bodies, slightly larger, but no pigmented forms. At 11 p. m. about the same appearance. On the evening of the 24th the blood showed a similar appearance; still no pigmented forms. 142 IF. 8. Thayer and J. Hewetson. On the 25th, at 10.30 a. m., the organisms were much more numerous than the night before, mostly a little larger than last night, and a few contained one or two very fine pigment granules. On the 26th very few organisms; no pigmented forms. Quinine, gr. v (0.325), every four hours. On the 27th, at 10.15 a. m., no pigmented forms seen. The organisms are less numerous. . 28-7-93. Temperature normal; patient leaves at his own request. In this case, a history of tertian paroxysms before entry was given, though the examination of the blood did not allow us to follow out the cycle of development of the organism. The temperature, how- ever, is a good example of the more or less continuous variety of fever which is sometimes seen with this form of malaria. We have not included the case among those with tertian paroxysms, though we are inclined to think that Marchiafava and Bignami would place it under that heading. Does the continuous fever from the 22nd to the 24th and from the 24th to the 26th represent one or two paroxysms? The examination of the blood, not as complete as might have been wished, does not wholly clear up the matter. The following case, though it is included, in our classification, among the combined infections, would, perhaps, be better mentioned among the aestival-tertian cases. Case 10529, male, single, aged 29, admitted July 31st, 1894, complaining of chills and fever; first attack. He has been feeling poorly for a month, having had chills and fever, he believes, at irregular intervals; general soreness, vomiting, variable appetite. On entrance, temperature was 103.8°, reached 104.3° at 8 p. m., and was normal by early the following morning. The appended chart will show the course of the fever. Blood, 6 p m., showed a few amoeboid, non-pigmented, hyaline bodies. 1-8-94. Physical examination showed a coated tongue, herpes on lips; spleen not palpable. Blood. One amoeboid, hyaline body, with two spots of pigment, at 8.30 a. m.; at 9 a. m., the same; at 2 p. m., a few rather large ring-like bodies, more hyaline forms, several having distinct blocks of pigment. 8 p. m. Hyaline bodies a little larger, some ring-shaped, one nearly full-grown parasite, apparently of the tertian variety, the red corpuscle being expanded and decolorized, pigment granules in the body being brown, fine, and in active motion. 2-8-94. Blood, 9 a. m. Negative. 2 p. m. Numerous small ring-shaped bodies, few hyaline forms, several with distinct pigment granules, two larger bodies nearly filling the blood corpuscle, with a clump of pigment in the middle. Corpuscles were not expanded, but were rather pale. 3k 77^^ 7%, JOS'&j Sfettn SAerman^ The Malarial Fevers of Baltimore. 143 8 p. m. Numerous small ring-shaped bodies, a considerable number of hyaline forms. The patient had two distinct chills, one at 2 a. m. and one at 2 p. m. At 3 p. m. the patient was given quinine, gr. v (0.325), which was vomited. At 10 p. m., gr. x (0.65), afterwards gr. v (0.325), every four hours. During the after- noon, a most profuse urticarial eruption appeared over the whole body. About 7 p. m. patient suddenly sat up in bed ; his eyes became fixed and staring, he fell back again muttering to himself, apparently quite unconscious; profuse sweating; face livid; pulse uncountable at the wrist; no biting of the tongue; no involuntary micturition or defecation ; no rigidity of the limbs. In fifteen minutes the attack had passed off. 3-8-94. Temperature normal. Blood, 8.30 a. m., showed a fair number of amoe- boid, hyaline bodies in unaltered corpuscles, some ring-like forms, occasional bodies with one or two minute pigment granules; pigmented leucocytes, the pigment being for the most part in fine granules. 3 p. m. A few ring-like hyaline bodies, several forms having minute pigment granules; pigmented leucocytes similar to those in the morning. 8 p. m. A few ring-like forms, two bodies having minute pigment granules. 4-8-94. The temperature rose early this morning with chill, another chill occur- ring at 4 p. m. Blood, 9 a. m. A number of small hyaline bodies, one with a pigment granule, a few ring-like forms, one large, full-grown, swollen, extra-cellular tertian parasite, with pigment in active motion. 2.45 p. m. One body filling about two-thirds of the red corpuscle, containing a central clump of pigment in active motion; several pigmented leucocytes. 5-8-94. Temperature normal. Examination of the blood at 9 a. m., 3 and 7.20 p. m., showed a few ring-like bodies and pigmented leucocytes. The blood of the 6th and 7th of August showed no organisms. 8-8-94. One pigmented leucocyte with scattered granules. 8-9-94. No organisms seen; patient discharged. This case is interesting from several standpoints. As with all the other cases of combined infection which have been noted, while organ- isms of both tertian and aestivo-autumnal types were present, one of these types-in this case the aestivo-autumnal-was preponderant, causing all the symptoms. It is an interesting question as to how we should regard the chart. Was the elevated temperature between the early morning of the 2nd and the morning of the 3rd a single paroxysm, and the case one with intervals of about fifty-two hours, or are we to assume that we were dealing with multiple groups of parasites? We do not feel that the examination of the blood justifies a conclusion. It is an interesting point, that on the 2nd there were two chills, one at 2 a. m., and another at 2 p. m. ; while on the 4th there were also two chills, one at 6 a. m., and one at 4 p. m. The marked irregularity of the temperature between the 2nd and 3rd 144 IP. S. Thayer and J. Heweison. is striking. It may, also, be noted that there was a slight rise of temperature at noon on the 1st. The presence of occasional pre- segmenting forms during the paroxysms is of interest. The curious nervous manifestations, during the paroxysm on the second, may have been dependent upon some interference with the intra-cerebral circu- lation on the part of the parasites. Cases of Pernicious Malarial Fever. Only three cases of pernicious fever have been admitted to the hospital since its opening. Of these, two resulted fatally, and one recovered. The first two cases we will quote from Dr. Osler's note in the Johns Hopkins Hospital Bulletin, December, 1891. Case 131.-Lewis K., admitted July 18, 1889, complaining of pains in the head and of coldness and numbness of the feet and hands. He has enjoyed fairly good health, and, for his age, is a vigorous, healthy-looking man. On the 9th, while picking berries in a field in Anne Arundel county, he had a heat stroke; was un- conscious for two hours, and had to be carried home. He was up the next day and was able to work; has not felt well since, and has had headache and occasional feel- ings of sensation of cold. On the 18th the following note was made: Healthy-looking, much sun-burnt, pulse full, vessel-walls soft, no oedema of feet. The lungs are clear in front and behind; respiration is a little prolonged. The apex beat of heart is neither visible nor palpable; the sounds are weak, the second is scarcely audible at base. The area of liver dullness is reduced; the spleen not enlarged. The urine is light yellow in color, specific gravity 1010; no albumen or casts. I saw the patient only during the first four days of his stay at the hospital, and thought that he was suffering from the effects of a sun-stroke. He was given a tonic mixture. The patient's temperature was normal, but on the 20th and 21st the morning record was 97.6° and 97.8°. On the 25th, at 11.30, he had a chill, and the temperature rose to 105° and remained high all afternoon. At 7.30 p. m. it was again 105°, and he had a gradu- ated bath. Throughout the 26th the temperature fell, but did not get below 101°; the pulse was rapid and feeble. On the 27th the temperature at 8 a. m. was 100.5°; rose in the afternoon to 103°, and in the evening was 100.3°; pulse 104, extremely irregular and intermittent. There were feeble rales, with a high-pitched percussion note in right in fra-scapular region. Towards evening the patient sweated profusely, and the breathing was of the Cheyne-Stokes type. On the 28th the temperature fell rapidly, sinking from 103° at 4 p. m. of the 27th to 97.3° at 8 a. m. of the 28th, and to 95.5° at 10 a. m. The pulse is extremely feeble and irregular. He vomited twice; no expectoration. There was marked The Malarial Fevers of Baltimore. 145 feebleness of breathing at the right base. Throughout the afternoon of the 28th the temperature rose, and at 8 p. m. was 100°. 29th. Cheyne-Stokes respiration persists; has had slight diarrhoea. He speaks with difficulty, but appears to be conscious. Throughout the 30th and August 1st he gradually sank, and died on the morning of the 2d. I did not see this patient from the date of his chill until the morning of the 2d, just before his death. The case was regarded as one of low anomalous pneumonia. The day after the chill it is stated in the note that the blood was examined with nega- tive results; but there is no initial to indicate by whom the examination was made. The following note of the microscopic examination was appended to the post- mortem report by Dr. Welch: "Blood from the finger shows in small numbers malarial organisms, namely, spots of the shape and size of the red blood corpuscles with pigmented plasmodia. free round pigmented corpuscles, varying in size from blood plates to twice that size, and pigmented crescents, the pigments in a ring in the middle. I found in one specimen of splenic pulp two actively free flagella. In the capillaries of the brain are a few pigmented corpuscles." Case 1769.-J. B., aged 34, admitted September 10th, 1890. 1 saw him in the dispensary at 1.30 p. m. He was very weak and tremulous, with eyes congested and cheeks flushed, and with a dazed, stupid appearance. The tongue was swollen, heavily furred and indented. He looked like a man who had been drinking, and I told his brother that it would be impossible for us to admit him to the wards in his present state. He assured me, however, that he had not been drinking to excess, and on ascertaining that there was not the slightest trace of alcoholic odor in the breath, I signed the order for his admission. The following history was obtained. Family and personal history good. The patient is a sailor by occupation, and has enjoyed excellent health ; he left Boston for Savannah five weeks ago; spent a week in the latter place, and as the weather was oppressive he, with several of his shipmates, was in the habit of sleeping upon the grass all night. He remained well on the voyage to Baltimore, where he landed August 31st. He was about the house all week, not feeling quite himself, but the present illness dates from Sunday the 7th, when, without any chill or fever, he began to have vomiting. He felt extremely weak and prostrated, so that he could not get up on Monday morning. Throughout Monday and Tuesday the vomiting continued at intervals, and he was completely prostrated. He had no chills, but on Monday and Tuesday he took some quinine pills. In the dispensary, after failing to detect any alcoholic odor in his breath, and on learning that he had recently come from the South, the blood was at once examined ; large numbers of Laveran's organisms were found, which rendered the diagnosis clear. His temperature on admission in the ward was 101° ; pulse 104, small; tension not increased ; radials not stiff. The abdomen was soft; nowhere tender. The edge of spleen was just palpable on deep inspiration ; upper border of dulness at the ninth rib. Apex beat of heart in 5th interspace within nipple line ; sounds clear; examina- tion of the lungs negative. Blood. Small intra-corpuscular forms in extraordinary abundance, often 6 or 8, to be seen in the field of the im. The majority of them are not pigmented, and undergo very rapid changes in outline. The pigmented forms have the granules 146 W. S. Thayer and J. Hewetson. more concentrated than is usual in this stage of the evolution of the parasites. An unusual number of the leucocytes presented pigment granules. 11th. Very bad night; much vomiting; temperature sank to 98.6° at 10 a. m., and to 98.2° by 8 a. m. At the morning visit the patient looked depressed ; tongue heavily furred; pulse 80, small and thready; respirations 20. Has no headache, and complains chiefly of profound weakness. At noon the temperature began to rise, and at 4 p. m. reached 102.2°, and for six or eight hours remained about 102°, gradu- ally falling through the early morning hours, and at 8 a. m. reaching 98.5°. The blood condition remains practically the same. 12th. 10 a. m. Patient passed a better night. The vomiting has stopped, but the tongue is still furred ; no increase in splenic dulness. The bowels have been freely opened. He still looks depressed and dull, and complains of a feeling of great prostration. 13th. Temperature has been about 98° for the past twenty-four hours, pulse 72, small. The vomiting has not been so distressing, and he has taken the milk and brandy better than on any day since admission. The blood examination shows a marked diminution in the number of corpuscles containing the plasmodia, doubtless under the influence of the quinine. 14th. Temperature has been sub-normal, not rising above 97.5° all day. The vomiting has returned, and for the first time it contained blood, not in large amount, but sufficient to color the fluid. His mind is perfectly clear, and his sole complaint is of the extreme depression. 15th. 10 a. m. Patient's condition is worse since 8 p. m. last evening. The temperature has been below 97°, and at 12 midnight sank to 96°; pulse 64, respira- tions 20. Tongue still swollen, heavily furred and indented. Note on the blood to-day is: "Plasmodia very much diminished in number; leucocytes still show much pigmentation." The urine is amber colored, specific gravity 1010, acid and contained a slight amount of albumen. At 9 p. m. I made the following note: patient is in a very peculiar condition; is drowsy, dull, roused with difficulty, and does not answer clearly. He has behaved oddly all day, and has been very restless. There has been very little vomiting; temperature has been sub-normal, and is now 96.5°. For the first time the tongue is distinctly dry. 16th. Through the night the patient was very restless, and had much hiccough ; was not delirious, but acted queerly. The temperature sank through the night, and at 2 a. m. was 96°; at 4 a. m. the thermometer could not be made to register more than 95°, and remained at this point until 10 a. m. The vomited matter last night contained flakes of blood enough to tinge the whole fluid. He had retention of urine, and this morning 1500 cc. were withdrawn, which showed a narrow ring of albumen and contained hyaline and granular tube-casts. The nurse says that he does not understand questions, but he seemed to recognize me, and gave fairly rational answers, but complained of great oppression in the abdomen. The pulse is 72, and, considering his condition, the volume and tension were remarkably good. At 6 p. m. I made the following note: temperature has risen through the day, and is now 97.2°. The tongue is dry, pulse 96, regular and of very fair volume. He is extremely rest- less, and his face has a dusky hue; the respirations are at times gasping, 24 to the minute. He answers questions, but talks and rambles in an incoherent way. To-day very few red blood corpuscles containing plasmodia have been found ; the leucocytes The Malarial Fevers of Baltimore. 147 are still much pigmented. Patient became much more restless, threw himself about on the bed, then became unconscious, and died at 8 o'clock. The treatment consisted of half drachm doses of quinine every six hours, which was given hypodermically when the vomiting became excessive. The drawings made from the blood in this case showed most characteristic aestivo- autumnal parasites. A further comment upon the anatomical lesions in these cases will be found, in another part of this fasciculus, in the article by Dr. Barker. The first of these cases is a very interesting example of death with a sub-normal temperature, occurring after the number of malarial parasites had been materially reduced by quinine. Case 10419.-F. O., single, aged 40, commercial traveller, admitted to the hospital July 19th, 1894. The patient, on entrance, could give no history, but from friends, and, later on, from himself, the following notes were obtained: Since the 11th of June the patient has been travelling for the greater part of the ime in very malarious districts further south, having been "on the road" all the way from Maryland to Florida. For three weeks before entrance patient had not felt well, having, he believes, had fever off and on, but never chills nor sweating. His appetite was poor; he had considerable headache and, at times, nausea. He took to bed on the 16th, and became dull and stupid, recognizing no one after the morning of the 18th; no diarrhoea; troubled much with hiccough for six days before admission. Immediately after admission the patient was seen and the following note was made: "Large, well-formed man, rather corpulent; is lying on his back in bed; respirations quiet, ten to the quarter; pulse regular and full, twenty-seven to the quarter, rather soft. The patient is quite comatose; the eyes are closed, the mouth open. A clonic spasm of the lower facial muscles on the left side is frequently noted, the mouth being drawn a trifle to the left. Pupils are equal, of moderate size, react readily to light on raising the lids. There is a well-marked sub-icteroid tint to the skin and to the conjunctivae, and the urine, which has been passed involun- tarily, stains the bed clothing a markedly yellow color. Thorax; negative on auscultation and percussion. Heart; point of maximum impulse in the fifth space a little inside the mam- millary line; relative dulness at the fourth rib; does not pass left sternal margin; sounds clear, of normal relative intensity. Hepatic flatness begins at the fifth space, and reaches about to the costal margin; the border is not palpable, possibly because of the lack of deep respirations. Splenic flatness begins at the eighth space and reaches anteriorly to the costal margin. The border is not distinctly palpable. The extremities are relaxed ; there is no increase of the reflexes. While the patient does not answer questions, and pays no attention to sharp requests to put out the tongue, he occasionally moves an ex- tremity, and when one grasps his hand, he makes a slight effort to close his fingers." Examination of the blood at the bedside showed a considerable number of the smallest ring-shaped, intra-cellular, hyaline bodies, situated-, for the most part, in 148 W. S. Thayer and J. Heweison. JVo. The Malarial Fevers of Baltimore. 149 crumpled, brassy-colored corpuscles. In one of these the haemoglobin was noted to have retracted from the outline of the corpuscle about the ring-shaped organism. No apparent leucocytosis; no pigmented parasites nor pigmented leucocytes. Muri- ate of quinine and urea, gr. xx (1.3), was immediately given hypodermically. Sur- prised by the hypodermic injection, the patient started for a moment, opened his eyes, and turned over in bed. Afterwards he had a slight attack of hiccough, lasting not more than a minute. The urine, on admission, was of a mahogany brown color, bile-stained, clear, acid, 1021, faint trace of albumen, no diazo reaction, no sugar, microscopically, negative. Temperature rose to 103.8° at 2 p. m. Blood. 11 a. m. A considerable number of small ring-shaped and amoeboid hyaline bodies. Almost the majority of these were contained in crumpled, brassy- colored corpuscles. In many the haemoglobin was retracted about the organisms. At 12 m.; the same appearance, excepting that in one parasite a few minute pig- ment granules were seen. At 2.15 p. m.; organisms much more scanty, almost all ring-shaped, in crumpled corpuscles. From 3 to 5 p. m., various examinations showed similar appearances. At 8.30 p. m.; organisms very scanty, mostly ring-shaped and amoeboid hya- line bodies. One was seen about one-quarter the diameter of a red corpuscle, with several pigment granules in the middle, ft was lying in a crumpled, brassy colored, corpuscle with retracted protoplasm. During the afternoon the patient became more restless and a little brighter, tossing about much in the bed. He opened his eyes when spoken to, and occasionally answered a question, but was confused and wandering. Muriate of quinine and urea, ten grains, (0.65), hypodermically, at 5 p. m. and 11 p. m. 20-7-94. Temperature 101.4° at 8 a. m. This morning, is tossing about in bed and restless, occasionally mumbling to himself. He answers sharp questions in a confused manner. Patient was fed yesterday entirely by enemata; to-day takes liquids. R. Sulphate of quinine, gr. v (0.32), every four hours. Temperature, by evening, had fallen to 100°. The blood, in the morning, showed a number of intra-cellular hyaline forms, amoe- boid and ring-like ; no pigmented forms ; no crescents. Late in the afternoon, but a few hyaline bodies were seen in two specimens. 21-7-94. The following note was made: " The temperature, which on entry was 101.2°, rose, on the afternoon of the 19th, to 103.4°, since when it has steadily fallen, until 8 a. m. to-day, when it is 98.3°. Throughout the day yesterday the patient became gradually clearer mentally, and to-day is quite rational. Ever since the afternoon of the 19th the patient has had obstinate hiccough for the greater part of the time. The slight jaundice still persists ; pulse and respiration are slow and quiet. The spleen is readily palpable on inspiration. He is taking quinine, gr. v (0.325), every four hours. The blood shows only an occasional intra-cellular hyaline body." 22-7-94. Temperature normal. The speech, which has been a little thick before this, is quite clear. The blood showed but one hyaline body after long search. The urine is normal in color, free from bile, no albumen. 23-7-94. No hiccough since yesterday. From this time onward recovery was steady ; no further organisms were found in the blood. 30-7-94. Leaves to-day, well. 150 IT. S. Thayer and J. Hewetson. This case is one of considerable interest in as much as it is the only example of comatose pernicious fever which we have had in the hospital. A particularly interesting point is the fact that, notwith- standing the severity of the symptoms, but few organisms, and those almost entirely the very small hyaline forms, were found in the peripheral circulation. The hiccough and the spasm of the lower facial muscles on the left side, as well, also, as the slight thickness in enunciation, are interesting points. It will be noted that all these cases showed the aestivo-autumnal organisms, and, while severe symptoms may occur during the paroxysms in cases of tertian fever (delirium, etc.), true pernicious fever we have only observed in aestivo-autumnal infection, an observation which agrees entirely with those of the Italian and Russian authors who have dealt particularly with such cases. The analysis of the types of fever in these cases certainly justifies us in distinguishing, sharply, the fevers associated with the aestivo- autumnal organisms, from those seen in the ordinary tertian or quartan infections. While, as has been previously noted, certain cases show charts not unlike those of tertian or quartan infections, the majority show distinctly longer paroxysms, lasting, on an average, at least nineteen or twenty hours, and frequently overlapping one another, causing continuous fever. The proportion of continuous and irregular fevers is much greater than in tertian infections. The individual paroxysms differ further from those in tertian or quartan fever, in that, in many, the rise of temperature is more gradual, fre- quently occurring without the sharp initial rigor.* Acknowledging, then, these differences between the regularly intermittent and the aestivo-autumnal fevers, can we distinguish any ground type or types among the latter? We have learned to recognize, in the regularly intermittent fevers (tertian and quartan infections), that the febrile symptoms bear a distinct, direct relation to the life history of the specific parasite; that the paroxysm is always associated with the arrival of a group of organisms at maturity and with their segmenta- tion. The observations of numerous students, particularly in Italy, make it probable that this paroxysm is due to toxic substances set free * The term initial rigor, however, it should be remembered, is not always correct, as neither in tertian nor in aestivo-autumnal fever, can the chill be regarded with certainty as the initial step in the paroxysm. The Malarial Fevers of Baltimore. 151 by the parasites at the time of their segmentation. Do these rules, which apply so accurately to the regularly intermittent, tertian and quartan fevers, hold also for the aestivo-autumnal infections. If they do, how are we to account for the great variation in the febrile manifestations ? The cycle of development of the tertian and quartan organisms is easily followed out by the examination of the blood taken from peri- pheral vessels. We find the organism, in all stages of its develop- ment, in blood from the capillaries of the finger or the ear, and it has been shown, in a most interesting manner, that, just as in certain tertian and quartan fevers the paroxysms anticipate one another slightly, or show a tendency toward retardation, so the parasites, particularly of tertian fever, may, in certain instances, show a tendency to earlier segmentation, bodies being found in the process of sporulation which have not yet reached the ordinary full develop- ment, showing a smaller number of segments than is usually seen. In other words, it has been shown that while, regularly, the cycle of development of the tertian organism lasts approximately forty-eight hours, we may, not infrequently, see a parasite which matures every forty-six hours, or indeed, in some instances, every forty-four hours, or perhaps, in forty hours, while in others the cycle may take a somewhat longer time than the ordinary two days. And in all these instances the febrile manifestations follow the same course as the para- site, anticipating or retarding as the case may be. Now are we to explain the irregularity of the aestivo-autumnal fevers by assuming a variability in the length of time required for the development of the parasite, recognizing, also, the frequency of infections with multiple groups of organisms? Must we assume that one of the chief characteristics of these infections is the extreme variability in the length of the cycle of development of the parasites, a variability dependent, perhaps, upon the malignity of the organism or upon the resistance of the individual affected; in other words, that this type of fever is essentially irregular? Or must we assume that there are two or more ground types of aestivo-autumnal fever depend- ent upon two or more varieties of the parasite? From the observations which we have made, we feel that it is prob- able that there are aestivo-autumnal infections with but one group of organisms, which show daily paroxysms. Likewise, it appears to be 152 W. S. Thayer and J. Hewetson. true that there are other fevers which, with one group of organisms, show paroxysms occurring at intervals of forty-eight hours or even more. It may also be stated that in most of the cases with longer intervals the paroxysms have been rather unusually long, while, in some instances, paroxysms strongly resembling those described by Marchiafava and Bignami as dependent upon their aestival-tertian organisms, have been seen. In some of these, however, as in Case 7753, it is most difficult to say whether we are really dealing, in each instance, with a single or with multiple paroxysms, while, owing to the few stages of development of the parasite which are found in the peripheral circulation, and to the small number of parasites which we see altogether in some cases, we do not receive the same assistance from examination of the blood that is given to us in the tertian and quartan fevers. Moreover, in these cases with quotidian and tertian chills, we do not see the same regularity in the hour of development of the paroxysms that we note in tertian and quartan infections; the variations are so great that it is not at all clear that we can draw a distinction between the two forms. Do we not rather see every inter- mediate stage between the two? We have certainly been unable to make any sharp distinction between the cases with tertian paroxysms, and other cases where the paroxysms occurred, instead of, perhaps, at intervals of forty-eight hours, rather at intervals of between twenty- four and forty-eight hours, suggesting, thus, a connecting link between the two forms of fever. Had we been able to distinguish, in these cases, any marked differences between the organisms observed in each, such as exists between the organisms of tertian and quartan fever, we might have been led to suspect that there were, in reality, two distinct types of infection. But this is not the case. As a matter of fact, the organisms, in our few cases with tertian paroxysms, have had all the characteristics of those observed in the other forms of aestivo-autumnal infection. We have not, unfortunately, been able to study carefully the later stages of development of the segmenting bodies, but the dif- ferences pointed out by Marchiafava and Bignami in the development of the organisms and in their segmentation, appear to us too slight to justify the division that they have made. These differences appear to us to be scarcely greater than those between the ordinary tertian parasite and the tertian parasite which assumes a slightly more hasty development, and undergoes precocious segmentation. The differences The Malarial Fevers of Baltimore. 153 consist almost entirely in the size of the adult forms, in the quantity of pigment which is present, and in the number of segments found, the organism which .has taken longer to develop growing slightly larger, showing slightly more pigment, and a greater number of segments. In conclusion, then, we have been able to distinguish, in infections with the aestivo-autumnal parasite, fevers with paroxysms occurring at intervals of about twenty-four hours, as well as others with inter- vals of about forty-eight hours, more or less. But we find, also, intermediate forms which constitute a connecting link between these two varieties of fever. The fevers with longer intervals show, gen- erally, longer paroxysms. There is a large class of cases showing a more or less continuous fever where it is impossible to distinguish any ground type. We have been unable to distinguish any morpho- logical or biological differences between the parasites associated with these various types of fever. In most cases, owing to the fact that but the earliest stages of development of the parasites are to be found in the peripheral circulation, and, sometimes, owing to the very small number of parasites which is to be found altogether, we are quite unable to distinguish whether we are dealing with one or with more groups of parasites. In a few cases, however, with characteristically intermittent fever, the examination of the blood, taken in connection with the course of the fever, has suggested to us tha^ we were dealing with single groups of parasites whose cycle of development lasted from twenty-four hours or less, to forty-eight hours or a little more. The fever in these instances, as in the case of the tertian and quartan intermittents, we believe to be due to some toxic substance set free at the time of sporulation; it is essentially intermittent, and it is un- doubtedly the fact that this intermittency is more evident in those cases which areobserved at the beginning of their course. Though our studies of the parasite have been made almost entirely in the circulating blood, and do not justify a positive conclusion, we are, however, inclined to believe that the irregularity in the febrile manifestations is due chiefly; to the tendency on the part of the parasite to irregularities in the length of its cycle of development; to the fact that the period of time required for the sporulation of one group of organisms is materially greater than in the regular infections, owing to the fact that the arrangement of the parasites in definite sharp groups, sporulating 154 W. S. Thayer and J. Hewetson. nearly at the same time, is much less distinct than in the tertian and quartan intermittents; to the fact that, frequently, organisms in all stages of development are present at one time, segmentation occurring almost continuously. We do not believe, then, that we can, as yet, separate the aestivo- autumnal fevers into two or more distinct types. With regard to the relations of the crescentic and ovoid bodies to the febrile manifestations, we shall speak later on. We are not, as yet, inclined to accept the view of Bignami, Marchiafava, et al., that they are degenerative forms, though we have never been able to trace their sporulation. Much, however, remains to be done in the study and analysis of these fevers; a systematic study of the splenic as well as the periph- eral blood should be carried out. Combined Infections. The cases of combined aestivo-autumnal and tertian infection observed were eleven in number. Of these nine were seen in the hospital, and two in the dispensary. Case 1.-The first case was that of a man, single, aged 17, admitted to the hospital October 27th. Family history good; no previous illnesses. This is the first attack of malarial fever. Illness began fourteen days ago with chill, followed by fever and sweating. This has been repeated every day, chills occurring at about ten in the morning. The physical examination was negative, excepting for the palpable spleen; urine, negative. The blood showed numerous large, amoeboid, pigmented, intra-cellular organisms, characteristic of tertian fever, and the case was considered one of double tertian infection. The chart showed characteristic quotidian par- oxysms with periods of subnormal temperature. The patient was treated with methylene blue, 0.1 five times a day, beginning on October 29th. After November 3rd the temperature was nearly normal, rising, however, slightly above 99° every day. The tertian organisms disappeared rapidly from the blood, but on November 3rd, five days after entrance, nineteen days after the beginning of the paroxysms, the patient showed crescentic and ovoid bodies characteristic of aestivo-autumnal malaria. On November 7th a few actively motile, small, hyaline bodies were also to be seen. Four days later the patient was discharged, the blood showing at this time no organisms. Eleven days later the patient returned to the dispensary, complaining of headache, loss of appetite, and thirst. The blood showed again crescentic and hyaline bodies, no tertian organisms. The patient was given quinine and was lost sight of. The Malarial Fevers of Baltimore. 155 Case 2 (4847).-A little girl, aged 7, admitted to the hospital on the 10th of March, 1892. For five or six months before entrance the child had suffered from quotidian paroxysms. She had had treatment, off and on, ever since then, the chills being at times tertian, and again irregular, according to the history. At other times she complained only of continued fever, headache, and sweating. On entering the hospital, tertian organisms were found in the blood, one strong group, and one group less developed. The temperature chart showed typical paroxysms on the 12th and 14th of March, the temperature being slightly elevated on the days between, but showing no sharp paroxysms. On the 14th, beside the typical tertian organisms, one crescent was seen. Quinine was given eight days after entrance, the paroxysms having disappeared on the sixth. The tertian organisms disappeared quite rapidly, but crescents were found in the blood for some time afterwards, while small, hyaline, actively amoeboid bodies, in association with the crescents, were noted for some time after the tertian forms had ceased to appear. The last date on which organisms were seen was on the 22nd of March, three days after the beginning of quinine. On this date a small, ring-like hyaline body was noted. This case is interesting in that it showed a spontaneous disappear- ance of the tertian infection after rest in bed and tonic treatment, while the small organisms characteristic of aestivo-autumnal fever, being more resistant, continued present in the blood, only to disappear after the beginning of quinine. Case 3 (5387).-A colored man, aged 32, admitted to the hospital June 15th, 1892. He had had his first attack of malarial fever during the fall before, no chills having occurred since January. Six days before entrance he had a shaking chill, lasting two hours, followed by fever, headache, and sweating; another, two days after this, and a third, two days later, the last occurring the day before entrance. The patient was a well formed man. Physical examination; negative, excepting for the palpable spleen. On the day of entrance the patient had a typical tertian paroxysm, lasting twelve hours, the temperature remaining below 99.8°, after this, without the admin- istration of quinine. The blood showed, in the hospital, at the time of the chill, typical tertian organisms. Numerous segmenting bodies were seen, all showing from twelve to twenty segments. One of the,se bodies was of unusually small size, not having entirely filled the corpuscle. One typical crescentic body was seen. The tertian organisms disappeared entirely during rest in bed, and, after the 13th, only ovoid and crescentic forms were found. The patient was discharged on the 15th with a prescription for two grains (0.13) of quinine three times a day. In this instance the symptoms appeared to be entirely due to the tertian organisms. It was probably a case of fresh tertian infection engrafted upon an old, attenuated aestivo-autumnal infection dating from the previous fall. Case 4 (6090).-Male, aged 20, Pole, first attack of malaria, admitted to the hos- pital October 9th, 1892. He dates his illness back five weeks before entrance, having 156 W. S. Thayer and J. Hewetson. had, at first, daily paroxysms, which had continued, off and on, up to the time of entry. The patient was anaemic, but otherwise the physical examination was negative, barring the palpable spleen. He showed a well-marked paroxysm on the day of entrance, and a slight rise on the following day. Quinine was given immediately, and the temperature was normal afterwards. The blood showed, at first, typical tertian organisms. On the second day after entrance crescents were found. On the 15th no organisms were to be seen. He remained in the hospital, taking quinine, until the fifteenth day of the next month, and was discharged well. This case occurred at the season of the year when aestivo-autumnal malaria is particularly common; the patient had had paroxysms off and on for a number of weeks before entrance. It was doubtless a case of double infection. Case 5 (6748).-A man, aged 23, admitted February 9th, 1893. He had arrived, a month before entrance, from Cuba, where he had had various malarial attacks. He showed, on entrance, a typical double tertian infection. The paroxysms dis- appeared immediately after the administration of quinine on the 11th, and no organ- isms were seen on the 15th. Nearly a month later, while in the surgical ward, where the patient had been operated upon for hernia, typical crescentic bodies were found in the blood. On April 4th, the patient returned, complaining of headache, ano- rexia and slight fever. The blood showed a typical aestivo-autumnal infection ; hyaline bodies, ovoid and crescentic forms. Doubtless the crescents, here, were the remnants of an old aestivo- autumnal infection. The tertian infection yielded readily to quinine, while the more resistant aestivo-autumnal parasites remained, causing a relapse. Case 6 (8302).-A young man, aged 30, admitted to the hospital October 2d, 1893; first attack. Two weeks ago, after working on the Shell road for about a week, he complained of headache and general lassitude, slight chill and vomiting. Since then he has had nearly daily chills, with headache, fever and sweating. In the hospital the patient had a paroxysm on entry and one on each of the following days, lasting respectively 19 and 10 hours. The blood showed great numbers of aestivo-autumnal organisms, small, hyaline, amoeboid bodies, some showing occasional minute pigment granules, and also a certain number of tertian forms. Ten days later crescents were seen. Quinine was begun on entry, the tertian organisms disappearing rapidly, and the temperature remaining normal after two days. In this case, also, there were clearly two distinct sets of organisms; the paroxysms here were apparently due to the aestivo-autumnal rather than to the tertian infection. The Malarial Fevers of Baltimore. 157 Case 7 (8317).-Female, married, aged 27, admitted to the hospital October 4th, 1893; first attack. Present illness began about a month before entry with a shaking chill, followed by fever and sweating, which was relieved by quinine. For four days the legs have been swollen. The patient was in the seventh month of pregnancy. The temperature was never above 99.5°; the spleen was readily palp- able. There was well-marked aortic insufficiency. The blood contained numerous ring-shaped and amoeboid hyaline bodies, and crescents; one tertian organism was also seen. Quinine was given on the day of entrance, and, after three days, no organ- isms were seen. The patient had been living in a very malarious district, and had undoubtedly suffered from a combined infection. r Case 8 (8454).-Man, aged 23, admitted October 25th, 1893; first attack. He had been living in an extremely malarious district. His complaint, on entrance, was of general weakness and chilly sensations, with constant fever for two weeks, head- ache, and pain in the back. The blood showed hyaline bodies, crescentic and ovoid forms, and a few half-grown intra-cellular organisms of the tertian type. On the following day flagellate bodies were seen. The temperature was irregular, showing slight daily rises for several days. Quinine was given on the 21st, five grains every four hours, and, after this day, no tertian organisms were seen; only crescents and ovoid bodies were noted. The temperature was subnormal after the 23rd. Case 9 (10529) has been mentioned under the cases of aestivo- autnmnal fever. See page 142. Cases of mixed Infection with Tertian and Aestivo-autumnal Organisms Observed in the Dispensary. There were two cases of mixed infection observed in the dispensary. Case 7546.-A colored woman, aged 17, admitted to the dispensary on December 2nd, 1890. She complained of having had quotidian chills during August and September. Quinine was followed by relief, but, after a month, the paroxysms returned, and have recurred, she says, nearly every morning for the last six weeks. The blood showed a considerable number of typical tertian, intra-cellular organisms. Quinine, two grains three times a day, was given. Five days later the patient returned, stating that she had had no chills, but complained of feeling " terrible funny" at about the time when she ordinarily had the chill. The blood showed crescents and pigmented leucocytes. This patient, who lived in an excessively malarious district, had probably been subjected to repeated malarial infection. Small doses of quinine readily overcame the tertian infection, while the aestivo- autumnal bodies resisted for a much longer time. 158 W. S. Thayer and J. Hewetson. Case 10351.-A. man, aged 53, admitted to dispensary July 7th, 1891. He dated his symptoms back for four or five days, complaining of headache, vomiting, general lassitude, and occasional chills, fever, and sweating. The temperature at the time of admission was 102°. The blood showed typical aestivo-autumnal, hyaline bodies. Three months later the patient returned, giving a history of a return of his symptoms several weeks back, with daily chills for three or four days. Typical tertian organisms were found in the blood. Four days later, after the administration of quinine, five grains, three times a day, the patient said that he felt perfectly well. The blood showed no tertian parasites, but one ovoid aestivo- autumnal body. It is probable that this case was one of fresh tertian infection on top of an old aestivo-autumnal fever. In all these cases, then, it will be noted that, while two varieties of organisms were made out, the fever and the clinical symptoms appeared, in each instance, to be due to one particular set, that which was most strongly represented. In no case have we seen complicated temperature charts as a result. In cases 2, 3, 4, and 5, it would seem that there was probably a fresh tertian infection engrafted upon an old aestivo-autumnal fever; while in cases 6, 7, 8, and 9, the aestivo- autumnal organisms appeared to be the important group. It is inter- esting, in connection with this, to remember the experiments of Di Mattei, who found that on injecting blood from a case of quartan fever into one of aestivo-autumnal, the organisms injected increased in number, giving rise to clinical symptoms, while those already present showed a tendency toward diminution and disappearance. The converse was noted when aestivo-autumnal organisms were in- jected into a quartan case. In neither of his cases did a complicated fever chart result. Most of these patients had been in very malarious districts, and had probably been again and again subjected to infections, and it is not unlikely that the predominating organism in each instance rep- resented the fresher infection. Some may be inclined to use these cases as an argument in favor of the complete unity of the malarial organisms ; as an argument that the tertian parasite may give rise to crescentic and ovoid forms. It is interesting, however, that, in most of these cases, not only the crescents were found after the disappearance of the tertian organisms, but also the other forms of the aestivo- autumnal parasite, forms which are notoriously more resistant to qui- nine than the tertian parasites. We have never seen any transitional The Malarial Fevers of Baltimore. 159 stages between tertian parasites and crescentic or ovoid bodies, while every stage can be readily followed out in the aestivo-autumnal group. We have never seen any transitional stages between tertian, quartan, or the aestivo-autumnal organisms, nor have we met with observations which would give sufficient ground for the assumption that this could occur. General Conclusions with Regard to Types of Fever. In conclusion, then, we believe that we can distinguish three dis- tinct types of malarial fever : (1). Tertian fever. 1 „ . . . , .x, x „ ; ' „ , - > Regularly intermittent levers. (2). Quartan jever. j (3). Aestivo-autumnal or irregular fever. (1). Tertian Fever. The tertian type of fever depends upon the presence, in the blood, of a parasite which passes through its cycle of existence in about forty-eight hours. The segmentation of this organism is always associated with a febrile paroxysm ; these paroxysms occur, with con- siderable regularity, at intervals of forty-eight hours, though, in many cases, there is slight anticipation or retardation. The duration of the paroxysm is ordinarily from ten to twelve hours. The onset of the fever is generally sudden, associated, in the great majority of cases, with a distinct shaking chill or marked chilly sensations. The febrile period lasts for a variable length of time, while the fall of tempera- ture is accompanied, generally, by profuse sweating. Frequently, owing to the presence of two sets of organisms, there are quotidian paroxysms. More rarely, probably owing to the presence of more than one group of organisms, or to the fact that the organisms are not arranged sharply in groups, a more irregular, somewhat continuous fever may be seen ; in these cases rest in bed and general treatment will often reproduce a true intermittent type of fever. During the period between the paroxysms the temperature is generally sub-normal. The single tertian infections, representing the mildest forms of the disease, occur, more commonly, in the earlier months of the spring and summer; the double tertian infections, which are more severe, form the 160 IF. & Thayer and J. Hevoetson. majority of the cases later on. Spontaneous improvement is very common, though it is not generally permanent; more commonly, in the course of ten to fourteen days, a relapse occurs. (2). Quartan Fever. More rarely in this climate, we see fevers dependent upon the presence, in the blood, of a parasite which passes through its cycle of existence in seventy-two hours. As in tertian fever, the paroxysms are definitely associated with the segmentation of groups of the para- site. The paroxysms resemble, strongly, those observed in tertian infections, both in the manner of their onset and in their duration. Not infrequently, double or triple quartan infections may be observed, with resulting variations in the febrile manifestations. As in tertian fever, the symptoms yield rapidly to quinine, the organisms disap- pearing quickly from the blood. (3). Aestivo-autumnal Fever. Thirdly, we see a type of fever, occurring in the late summer and fall, dependent upon the presence in the blood of the aestivo-autumnal organism of Marchiafava and Celli. The cycle of existence of this parasite has not been followed out in an entirely satisfactory manner. We are inclined to believe that its duration may vary under different circumstances (malignity of the special parasite, different conditions in the infected individual, etc.) between twenty-four hours or slightly less, and forty-eight hours or more. This type of fever, in its pure form, is intermittent, while the paroxysms may be very similar to those of tertian or quartan fever. Commonly, however, the paroxysms show material differences'; their length averages over twenty hours; the onset occurs often, without chills or chilly sensations; the rise in temperature is frequently gradual and slow, instead of sudden ; the fall, likewise, occurs, often, by lysis instead of by crisis. The tend- ency toward anticipation and retardation of the paroxysms is much greater than in tertian or quartan fever, while, frequently, from the lengthening of one paroxysm, or the anticipation, perhaps, of another, the chart may show a more or less continuous fever. Sometimes there occurs a continued fever without sharp paroxysms. We believe that The Malarial Fevers of Baltimore. 161 these phenomena on the part of the temperature are due to irregu- larities in the duration of the cycle of existence of the parasite, to the presence of multiple groups of the organism, and, often, to the fact that segmentation is going on almost continuously in the internal organs. It is in these fevers that haematuria and haemoglobinuria are seen. These infections include, also, the pernicious fevers as well as the so-called " remittent " fevers, though we believe that the great majority of cases of " remittent fever " referred to as such in this country, are not malarial in nature. These fevers are much more resistant to quinine than the tertian and quartan infections, though, when given in sufficient doses, the specific action is always manifest, unless the case be one of pernicious fever resulting fatally before the drug has had time to act. VII.-CONCERNING THE NATURE AND SIGNIFI- CANCE OF THE CRESCENTIC BODIES OF LAVERAN. The general results of our observations of the organisms in the aestivo-autumnal fevers have been stated in our description of the parasite, in an earlier part of this paper, and, in this section, we wish more particularly, to discuss the significance of the so-called crescents, which, though they are never found at the beginning of the process, appear, in most of the cases of aestivo-autumnal fever, after a certain length of time. It will be remembered that Laveran,(15) in his origi- nal articles, believed that these crescents represented a species of cyst containing the developing parasites, which, at their full growth, were represented by motile filaments, the flagella which might frequently be seen to break forth from the round bodies into which the crescents changed. With these views Richard (26, 33) and Dani lewsky(194) agree. Richard(26) suggested that the crescentic bodies represented cor- puscles containing malarial organisms which, before they had reached full development, had been caught in capillaries through which they passed with difficulty, and moulded into this shape during their passage. Marchiafava and Celli, as late as 1884,(36) denied that these were parasites, but later on, when they had recognized the organism, their 162 IF. & Thayer and J. Hewdwn. descriptions were similar to those of Laveran, excepting that (1885)(45) they denied that they were able to see a double contour. They did not agree with Laveran's conception of the nature of these bodies, denying that they were cystic in character. Celli and Guarnieri,(93) however, describe the double contour, and note that often, on staining with methylene blue, a round body which is more deeply colored, may be seen near the middle, surrounded by the pigment, while the area about this is pale; the poles of the cres- cents show a marked affinity for the coloring matter. They note, also, for the first time that these crescentic and ovoid forms may show small round bodies-buds, as it were-about the periphery, one or more in number. The development of these minute round bodies, they suggest, may represent a method of reproduction. They also note the vacuolic degeneration of these crescentic forms, a process which had been previously described by Laveran. Canalis/1W) in 1889, described the aestivo-autumnal organisms in an elaborate article which has already been referred to. He believes that there are two distinct cycles of development, the first lasting for a short time-about twenty-four hours-the parasite developing but a very small quantity, or, indeed, no pigment, and then segmenting in the ordinary manner; the second cycle lasting considerably longer- a variable length of time-and ending in the development of these crescentic and ovoid bodies. He also describes the double contour, suggesting a membrane, and notes that this is best seen in preparations several hours old, or fixed by osmic acid. He asserts that he has seen unquestionable evidences of sporulation in these crescentic and ovoid forms. He has seen round forms with or without double contour, containing eight or ten round or slightly ovoid bodies, each with a more obscure central part, while the periphery has the appearance of a double outline. Sometimes the pigment mass is in the middle, more frequently arranged in the shape of a crown at the centre or at one of the poles; at times the pigment appears to be retained in a small corpuscle; it may be seen to be extruded, contained in a protoplasmic mass; sometimes one sees groups of small bodies regu- larly arranged about a central pigment clump. He has never seen the whole process of segmentation, but he believes that these bodies are sporulating forms, both on account of their appearance and on account of their relation to the paroxysm. He also mentions the The Malarial Fevers of Baltimore. 163 possibility that gemmation, as described by Celli and Guarnieri, may likewise occur as a reproductive process. After sporulation we have, again, small, hyaline, amoeboid bodies. The cycle of development varies in length, lasting generally three or four days, at least, before the appearance of crescents. He notes the constant appearance of young hyaline bodies after the paroxysms, slight though they may be. Canalis insists that this sporulation must be sharply distinguished from the processes of degeneration which one may often observe. " The evidence of this degeneration consists in the presence of bodies which have lost their yellow or ashy color, and have become more clear, sometimes refractive, having a double contour much more distinct than that of the ordinary parasites, and a substance trans- formed into a mass of round or irregular bodies, generally of different size, and with a single contour. If one prolongs the microscopical examination of one of these parasites, he may observe, sometimes, in the course of several minutes, the fusion of two or three of these bodies into a single globule, forming, finally, irregular masses which eventually unite, giving to the parasite an homogeneous aspect with- out any further trace of the small bodies. The pigment is sometimes arranged in a central crown, sometimes irregularly placed at one extremity or at one side of the body. The characteristics which dis- tinguish this process from that of sporulation are; the refraction of the degenerating body; the inequality in the size of the spherules; the absence, in these, of a more obscure central part; their fusion into irregular masses, and finally into one amorphous mass." These forms may also be found during complete apyrexia without any following rise of temperature, or any subsequent appearance of amoeboid forms ; they represent a cadaveric state. Marchiafava and Celli,(100) in their article on the aestivo-autumnal fevers, note the double outline of the crescents, and assert that it represents a distinct membrane, though they say that, at times, it may not be very evident. They have seen pernicious forms of fever without the development of crescents. They have never seen sporu- lating crescents, and do not definitely commit themselves as to the nature of these parasites. They insist, however, that the crescents filled with small round bodies are simply forms undergoing vacuolic degeneration, and that sporulating forms, as described by Canalis, do not exist. 164 W. S. Thayer and J. Hewetson. The theory of Canalis concerning segmentation of the crescentic forms is accepted by Golgi,(U8) though he states distinctly that he has never seen the actual process of segmentation. He believes, however, that in patients whose blood contains these bodies, paroxysms occur at long intervals-intervals of ten, twelve, fifteen days-which are doubtless associated with the development of new forms from the crescents. He regards their presence in the blood, as does Canalis, as a constant menace of further paroxysms. Antolisei and Angelini/119,130 in the clinic of Baccelli in Rome, state that they, also, have observed the segmentation of the crescents, asserting that the spores of the segmenting bodies have a distinct double outline, in contra-distinction to the simple outline of the degenerate vacuolating forms which represent the death of the para- site. Vacuolization occurs as well in the crescentic, as in the ovoid, fusiform, and round bodies. The sporulation, they say, they observed before Canalis, though Canalis anticipated them in his article. The bodies show eight or ten segments with double contour, similar to those of the parasite of quartan fever. There is no doubt, they say, as to the nature of the process. They describe the crescents in a somewhat different manner from the previous observers, believing that they possess an outer layer of varying thickness, which is colored with haemoglobin ; this, they think, represents a membrane similar to that observed about the red blood corpuscle. The outer border of the double outline is the only smooth sharp line; the inner part shades gradually into the substance of the crescent. This membrane does not stain with methylene blue. The crescents, they believe, are very resistant forms which do not disappear readily with quinine, the parasite pursuing a sort of latent life and reviving again later, going on to sporulation. Korolko(275) believes that the double outline represents a membrane derived from the red corpuscle; he states that it may be stained with eosin. The view that sporulation occurs in the crescentic bodies is also held by Grassi and Feletti.(221,339) They believe that the crescents, how- ever, are a totally different variety of parasite from the small hyaline forms which appear so frequently with them; they describe them as a distinct species of organism under the name of Laverania, a divi- sion which is accepted by Sacharoff.^12,2765 They believe that the The Malarial Fevers of Baltimore. 165 * crescents are surrounded by a membrane which, like the membrane surrounding segmenting bodies, arises from the substance of the red blood corpuscle. The segmentation, they say, is similar to that in the Haemamoebae, but the resting stage is much longer, from eight to ten days, while the appearance of segmenting forms in the peripheral blood is abnormal. They doubt, seriously, whether the forms observed by Canalis, in the peripheral circulation, were true segmenting bodies. They believe that they have seen crescents with two nuclei. Later on, Antolisei(l39) asserts that the crescents are not really encysted, but that there is a cutinizing or thickening of the peripheral layers of protoplasm, the same process which they believe to exist in the spores, giving them the double outline. Thus it may be seen that, while, between Canalis, Golgi, Antolisei and Angelini, Grassi and Feletti, and Sacharoff there are some differ- ences of opinion as to the development of these crescentic organisms, all believe that they may undergo a reproductive process-segmenta- tion. The persistence of these bodies under quinine has been noted, and various of these observers have suggested that it is to the resist- ance of these encysted or, at least, protected forms of the organism that the long continuance of this type of malaria and the liability to relapses is due. Bignami,(179) however, in May, 1889, in his work on the patho- logical anatomy of the pernicious fevers, suggests that this form of parasite is not a living body performing its normal functions, but merely a deviate and degenerate form which does not go on to repro- duction. Bastianelli and Bignami(170) discuss this question at length. They conclude that the crescents belong to the same type of organisms as do the smaller hyaline bodies, not forming, as Grassi and Feletti and Sacharoff believe, a separate group of parasites. If quinine be given early, at the beginning of an attack of fever, the organisms may disappear before the appearance of crescents, while, if quinine be begun later on, the crescents, which appear ordinarily at about the end of the first week, may be present in the blood for a considerable length of time. In these crescents one frequently sees evidences of vacuolization, which is a degenerative and not a regenerative process. Flagellate bodies, which they believe to be also degenerative forms, develop, often, from the round bodies. They call attention to the fact that, at the time of segmentation in, for instance, the tertian parasite, 166 W. S. Thayer and J. Hewetson. not all the organisms fulfil this process, but, as is well known, a considerable number of large swollen forms, which are usually extra- cellular, occur. When one observes these bodies, they may be traced through various changes; sometimes they undergo vacuolization; sometimes they break up into a number of smaller, extra-cellular forms, in which the pigment is usually seen after a while to become motionless, while the outlines of the body become indistinct and often irregular; sometimes they develop into flagellate bodies. These changes, they believe, are sufficiently proven to be degenerative. They note the remarkable analogy between these processes occurring in the crescentic, ovoid and round bodies in aestivo-autumnal fever and those which are seen in the large swollen tertian parasites. Here, as in the large tertian forms, one not infrequently sees vacuolization, deformation, and also gemmation or budding which they consider analogous to the fragmentation of the tertian parasite. In these forms, alone, do we see the development of flagellate bodies. When crescents exist alone in the blood they have no influence upon the temperature or the general condition of the patient. Con- valescence may have begun and may continue, after the administration of quinine has been omitted, while these bodies are yet present in the blood. The attacks occurring at long intervals, they believe to be true relapses, in no way connected with the slow maturation of the crescents. They note, with apparent reason, that these relapses are commonly separated by the time ordinarily required for the incubation of the disease; they believe that they are due to spores which have remained living in the internal organs. These views, first set forth by Bignami and Bastianelli, have been accepted and elaborated by Marchiafava and Celli,^'M5) both of whom insist that the presence of crescents, alone, in the blood has no influence upon the health of the patient. Dionisi,(173) also, in studying the blood cor- puscles, notes that the presence of the crescents appears to have no influence in producing anaemia. Mannaberg 290 takes an entirely new view of the origin and significance of the crescentic bodies. He calls attention to the fact that many observers have noticed the not infrequent presence of sev- eral small hyaline bodies inside of one blood corpuscle. He insists that, in many instances, the two parasites thus included move toward one another and finally become joined together. It is a process of The Malarial Fevers of Baltimore. 167 conjunction, of copulation. After joining together in this manner, a membrane is developed about them. The nuclei of the two small corpuscles which enter thus into copulation are close to one another, forming in this manner a pale, unstained area in the centre of the parasite, while the outer, more deeply staining part of the ecto-plasm constitutes the more deeply staining poles of the crescent. Not infre- quently one may see the two small nucleoli present in the middle of the body, though these are very often hidden from view by the pig- ment, becoming evident only after treating the specimens in such a manner as to dissolve the pigment. Mannaberg mentions four reasons which he believes form a convincing argument in favor of his views : (1) The fact that the crescent possesses a membrane; (2) the structure of the parasite as revealed by staining ; (3) the formation and arrange- ment of the pigment; (4) the segmentation. (1). This is, according to Mannaberg, the one variety of the mala- rial parasite which possesses a membrane, a fact which proves the biological difference between these bodies and the other forms. With the other protozoa, the formation of syzygia is, also, always followed by encystment. (2). With regard to the structure of the crescent, Mannaberg insists that when one carefully examines the body, two distinct component parts may always be made out. Celli and Guarnieri first noted that only the poles, and sometimes one or two granules toward the middle of the crescent, take on a deep color with staining fluids. Mannaberg states that " the young crescents-that is, those in which the pigment is scattered in fine granules along the whole of the body- take, on staining, a general pale color, while the poles and the zones about the border are of a slightly deeper hue. In fully developed crescents, which one recognizes by the concentration of the pigment in one or two clumps, sometimes in the middle, sometimes more toward a pole, one sees, almost without exception, the evidences of duality, in that, beside the colored poles and the border, a transverse part also, over which the pigment lies, which divides the crescent into two symmetrical halves, takes on a deep stain. It is, moreover, to be noticed that the inner parts of both constituent bodies remain almost colorless, while beneath the pigment, in the transverse bridge before mentioned, there appear two deeply-stained points. These points one rarely sees in ordinary preparations, because they are generally hidden 168 IF. S. Thayer and J. Hewetson. by the pigment; but, if one dissolves this by allowing the specimen to remain several hours in weak ammonia, they may be seen in many fully-developed forms, though they may stain more faintly as a result of this treatment. Such a ripe crescent, freed from pigment, appears very like the early stages of conjunction. The slight differences between the two pictures consist in the fact that, in the • crescent, the plasma mass at the point of conjunction between the two individuals (the transverse bridge) has become more marked, while the nucleoli have diminished in size and in staining propensity." (3). With regard to the origin and arrangement of the pigment in the crescentic bodies, Mannaberg is of the opinion that " by the con- junction of the two copulating parasites, an appreciably increased vital activity develops in both of them, which manifests itself in the rapid development of pigment and the coincident decolorization of the red blood corpuscle. While the amoeboid forms are very slightly, or, indeed, not at all pigmented, there is always more or less pigment in crescents. This pigment appears in separate distinct granules and rodlets, just as in parasites of the tertian and quartan type. In fresh specimens these separate pigment granules within the crescent show slight vibratory movements. Owing to currents in the plasma they change their place slightly, and form, as a result, ever-changing group- ings. In the already concentrated pigment one never sees any motion. As in the parasites of the regularly intermittent types of fever, the pig- ment, in the ripe crescents, becomes concentrated, but often this occurs in a manner which speaks for the duality of the crescent. Granules move from the two limbs toward the middle in such a manner that, at a certain point of time, they take an aster-like form. If the concentra- tion proceeds yet further, we then see two clumps of pigment corres- ponding to the two limbs, which very frequently remain separated from one another, or finally run together into a single mass. This aster-like arrangement of the pigment is so very common that one cannot doubt that, in the two halves of the crescent, there are inde- pendent currents which cause this grouping; from this process also, then, the dual nature of the crescent makes itself evident. In those crescents in which the concentration of the pigment occurs, not in the middle of the body, but at one or the other pole, one may assume that they have arisen from the conjunction of two forms dissimilar in size." The Malarial Fevers of Baltimore. 169 (4). The transverse segmentation of the crescents, which has also been noted by Grassi and Feletti, Mannaberg has been able to con- firm. Segmentation occurs, frequently, through the middle of the body, and, before the total separation of the two halves, these bodies may hang together like a pair of sausages. With either half, a part of the pigment remains. These segmenting bodies possess a deeply- staining granular contents. He believes that the segmentation and the deeply-staining granules which are often present in great numbers, suggest a reproductive process, yet this is not definitely proven. He believes that from the transverse segmentation of the bodies, only one conclusion can be drawn, namely, that the crescents are dual in nature. The size of the crescents, their somewhat delayed appearance in the blood, their resistance against quinine, the difference in their internal structure, are, he believes, to be explained by this view. The process, he believes to be a pseudo-conjugation. He has not been able to determine the fate of the segmenting bodies. He does not believe in the hypothesis of Bastianelli and Bignami, that the cres- centic bodies are degenerate forms. Against this argument he brings forward the fact that they are so rarely seen included in phagocytes. Van der Scheer(356) and Laveran(350) have been unable to confirm Mannaberg's observations. The former is sceptical as to the existence of a membrane about the crescentic bodies, inclining, rather, toward the view that the double outline is due to changes occurring in the parasite after the preparation of the microscopical specimen. Manson(347) believes that the crescent " is intended to carry on the life of the species outside the human body." Coronado(146) holds a view different from all of the above-mentioned authors; he asserts that the crescents are empty cysts left after the escape of the flagella. Sforza,(313) recently, in staining the parasites by Canon's method,* notes that the crescents, instead of taking up the methylene blue, show a pale rose color resembling the hue which is shown by degenerating * Harden in alcohol abs., 5-10 minutes. Stain in; Methylene blue (cone. aq. sol.) 40. Eosin (0.25/70 per cent, alcohol 100) 20. Aq. dest 40. for twenty-four hours. Wash in distilled water and mount. 170 W. S. Thayer and J. Hewetson. red blood corpuscles. He concludes that, in the crescentic bodies we are dealing with a degenerative form of the parasite " which, dur- ing its cycle of development, invades but in part the red blood cor- puscle, and that the greater part of the crescentic body is nothing more nor less than the degenerate red corpuscle." Laveran, in November, 1892,(280) and again in 1894,(350) reiterates his views concerning the crescents. He denies vigorously that they can be empty cysts, stating that he has, many times, watched the bodies after the disappearance of the flagella without ever seeing them take a crescentic form. On the other hand, he has frequently observed the transformation of crescents into round bodies, and, in turn, into flagellate forms. He says, also, that he has frequently seen febrile symptoms in patients whose blood contained crescents alone. He has never been able to see anything which would lead him to believe that Mannaberg's theories are true. He suggests an interest- ing explanation of the development of crescents. The malarial para- site, he says, "is found in the blood in two principal forms; (1) amoeboid bodies in different stages of development, free in the serum, or attached to red corpuscles ; (2) encysted bodies in the red corpuscles,* presenting first a spherical form, then a crescentic form. We have seen, above, that the encystment of the parasitic elements in the red corpuscles explains, very well, this singular crescentic form. The existence of a cystic membrane appears indubitable. These modifi- cations of the haematozoa of paludism are more easily understood when one considers that this parasite lives in a medium the composi- tion of which is variable; the blood of a patient who is profoundly anaemic and cachectic is very different, from the point of view of the number and the resistance of the red corpuscles, of the composition of the serum, and of the activity of the leucocytes, from the blood of an individual who, having recently arrived in a malarious district, is attacked by fever for the first time. I have shown, in my preceding communication, that crescents are seen, almost always, in individuals who are cachectic or who are, at least, markedly anaemic. It seems to me easy to comprehend that in such cases the haematozoon may develop differently than in those patients where the blood has not yet undergone profound alterations. Its presence in the form of amoeboid * Laveran acknowledges that the crescents may develop in the red corpuscle. The Malarial Fevers of Baltimore. 171 bodies, in the blood of these latter patients, excites a lively reaction, and the parasites, which become the prey of the leucocytes, or which are destroyed by the quinine, have not the time to become encysted. On the other hand, with the cachectic individual, the parasites develop without encountering the same obstacles. The impoverished blood is more easily overcome and the parasites become encysted." He believes that those cases where the crescents are found during what the patients believe to be the first few days of the illness, are really instances of old latent infection. The resistance of these forms against quinine, Laveran believes to be due to their encysted condition, the encysted parasites remaining a long time latent. He sums up his views concerning the crescents as follows : " The parasite of paludism develops first in the blood in the form of amoeboid bodies which live in the free state in the blood, or which adhere to the red corpuscles; generally the development of these parasitic elements in the blood provokes a lively reaction and one is obliged to interfere early and to give quinine. In these conditions the haematozoon does not arrive at its phase of encystment. On the contrary in cachectic individuals the economy, accustomed to the presence of the parasites, reacts but little, anti the haematozoon can go through all its phases, penetrate the red blood corpuscles, and become encysted, all the more, because, as the patient has not had violent attacks, one delays considerably the administration of quinine." To sum up, then, the various views held to-day with regard to the nature of the crescentic bodies: Many observers believe that the double outline of the crescent is due to the presence of a membrane. Antolisei suggests that this is rather a condensation of the external part of the body, and not a true membrane. Laveran believes that the crescents represent an encysted form of the parasite; that they are active, indeed unusually virulent parasites, resisting, more than the others, the action of quinine; that while their mode of reproduction is not known, their presence in the blood is always the menace of a relapse ; that frequently, without the presence of other forms, they may cause active febrile symptoms. Canalis, Antolisei, Angelini, and Golgi believe that these represent a more resistant form of the aestivo- autumnal organism, a form which has a cycle of development longer than that of the smaller variety, from which, however, they are directly derived. They believe that sporulation occurs in a manner similar 172 W. & Thayer and J. Hewetson. to that in the case of the quartan parasite; that, in the blood con- taining this form of organism alone, the paroxysms occur at long intervals, ten, twelve, fourteen days, or even longer. Grassi and Fe- letti and Sacharoff believe that the crescent represents a separate and distinct type of the parasite, which they call Laverania. The former assert, also, that they have observed segmenting forms. Bignami, Bastianelli, Marchiafava and Celli believe that they are deviate and degenerate forms of the parasite. Mannaberg believes that they are encysted forms following a pseudo-conjugation of two individuals; that they can again segment into two bodies similar to the original. He does not believe that they are degenerate forms, though he has been unable to follow out their further development. Manson believes that the crescents are forms a intended to carry on the life of the species outside the human body." Coronado believes that the crescentic bodies are empty cysts from 'which flagella have escaped. All agree that the crescents do not appear at the beginning of the infection. Bastianelli, Bignami, Antolisei and Angelini, who have more carefully followed out their development, have shown clearly that they appear, generally, in the spleen from the fifth to the eighth day; in the blood from the seventh day on. Our own observations with regard to the nature of the crescents have been, for the most part, already stated in the preliminary section concerning the organisms. We have noted, as well as the other observers, that, in the fresh specimen, the crescent has a somewhat refractive protoplasm, while the border shows a greater refraction, similar to that which, as Antolisei states, one observes about the border of the red corpuscle. Whether this has the significance of an actual membrane, or whether it is simply the indication of a slight cuticular thickening of the outer part of the body, we do not feel clear, though we incline rather to the latter view. We have never noted that this more refractive border or double outline showed the color of haemoglobin, though, during a considerable part of its existence, the body is probably surrounded by some corpuscular substance. In stained specimens we have never seen any tendency on the part of this outer border to take up eosin or acid coloring matters, as is the wont of bodies containing haemoglobin. We have observed, also, the fact that the poles of the crescents stain more deeply than the central part, in which there exists a clear area, and, at times, we have also made out The Malarial Fevers of Baltimore. 173 darker staining spots beneath the pigment. We have not, however, carried out studies of stained specimens with regard to the finer structure of the parasite, with sufficient system to speak positively concerning Mannaberg's observations. We can only say, from what we have seen, that the idea that the crescent is formed as a result of conjugation, appears to us to lack confirmation. From a consid- erable experience in the study of fresh specimens, we can say that, while the presence of two parasites in one corpuscle is occasionally seen, it is a rather rare occurrence; that while we have seen two parasites lying side by side, as is shown in Plate II, No. 19, this has been extremely rare. On the other hand, we have been able, again and again, to trace what we believe to be every step in the formation of crescents from the bodies with pigment gathered in the centre, such as one occasionally sees at the time of the paroxysm, and we feel that there can be little doubt that the crescent develops from these bodies. With regard to the time of their ap- pearance, the tables, which have been already given, show, in an interesting manner, how thoroughly our results agree with those of Bastianelli, Bignami, Antolisei and Angelini; these forms are not seen during the first days, but appear generally during the second or third week. Taking, for instance, the cases which were observed in the hospital, as those in which the observations were most reliable, the following table shows : Cases observed in the first week 35 ; crescents 2; * 5.7 per cent, Cases observed during the second week, where crescents had not been previously observed 35; crescents 27; 77.1 per cent. Cases observed after second week, where crescents had not been previously observed Cases of doubtful duration. 48 ; crescents 35 ; 72.9 per cent. 8 crescents 5 ; 62.5 per cent. Relapse of a case where crescents had been previously seen 1; crescents 1 ; 100 per cent. It will thus be seen that, in these instances, the percentage of cases showing crescents in the second week is even a trifle higher than in * In both of these cases the patient had had previous attacks of malaria, and, while they stated that their symptoms had lasted only two days, it is not at all improbable that the process was a relapse from a previous attack. 174 W. S. Thayer and J. Hewetson. the later weeks, showing, quite clearly, the time at which these bodies first appear. They are, indeed, found with nearly equal frequency from the beginning to the end of this week. Another point that is clearly shown by our tables is the fact that, in those cases where the treatment with quinine is begun during the first week, the organisms may often disappear without being followed by the appearance of crescentic forms; thus it may be remembered that in twenty cases where hyaline bodies alone were present on ad- mission, and treatment was begun in the first week, crescents appeared in only four-20 per cent.; in six cases, where treatment was begun in the second week, crescents appeared in three-50 per cent.; in thirty-one cases, where treatment was begun after the second week, crescents appeared in seventeen instances-54 per cent. This, again, is good evidence that crescentic bodies are not formed during the early part of the first week. The question concerning the significance of the crescents is a much more difficult matter to decide. As we have stated, we do not believe that they are conjugate forms, as asserted by Mannaberg. They do not appear to us, from what observations we have been able to make, to represent cysts, as we cannot persuade ourselves that there is any direct evidence of their possession of a membrane. What, then, is their relation to the other organisms of this group, and what influence do they exert upon the fever? With regard to their influence upon the fever, we can only state that in 3 of the 8 afebrile cases, crescents alone were found ; that while in many cases, during an afebrile period, we have been unable to find other forms in the blood than crescents, we have always, when the patients have shown febrile relapses, seen small hyaline bodies associated with them. Are we, then, to consider this a proof, as do Golgi and his followers, of the segmentation of these crescents? Are we to consider the small, fresh, hyaline bodies as the offspring of these; and are we to ascribe the febrile paroxysm to reproductive processes going on in these crescentic organ- isms ? Or are we to believe with Bignami, Bastianelli, and others, that these resistant bodies-for resistant they surely are-are deviate and degenerate forms of the parasite ? Segmentation of the crescents we have never observed. We have, however, occasionally seen the much discussed vacuolization, as shown The Malarial Fevers of Baltimore. 175 in the plate. This vacuolization, in the instances in which we have observed it, has been, clearly and unmistakably, a degenerative rather than a regenerative process. We have also observed the development of the small peripheral bodies, the gemmation, which has been so fre- quently described, a crescentic or ovoid body occasionally showing, on one side, a smaller, round, clear protrusion of the protoplasm, which may be sometimes drawn in or again cut off, so as to lie separately beside the body; this process is particularly common in the flagellate forms. We have not supposed that this was a regenerative process. And lastly, we have seen the crescents, as well as the ovoid forms, change into the round bodies, which often develop flagella. The round forms show a distinctly less sharp index of refraction, while the so-called double outline is less noticeable. We have seen, then, in the crescents, what we believe to be evidences of degeneration (vac- uolization, gemmation), and we have seen, further, the change into the ovoid and round forms which we have learned to recognize as the precursors of flagellation, concerning the nature of which we shall next speak. We have never seen the transverse segmentation of Mannaberg, nor, indeed, have we ever seen any indications of segmen- tation, as is described by Canalis, et al. We have seen the crescents present in both the febrile and afebrile periods. When seen alone, they are rarely or never associated with fever; with the fever we always see the advent of small, hyaline, amoeboid forms. The small hyaline forms disappear quickly after the administration of quinine, while the crescentic forms remain much longer-often for weeks, some- times for months. From practical observation, then, we can say that the crescents represent a very resistant form of the organism; that their presence in the blood alone is often unassociated with fever; that in many instances where they have previously been seen without fever, relapses have occurred, but always in association with the presence of small, hyaline and amoeboid forms; that in connec- tion with these attacks of fever, we have never seen reproductive forms, while we have occasionally seen what we believe to be degen- erating bodies; that it is clearly demonstrated that the crescents may change into the round bodies from which flagellation is frequently observed. We feel that our observations do not justify a definite con- clusion with regard to the significance of these bodies. 176 IF. S. Thayer and J. Hewetson. VIII.-THE FLAGELLATE BODIES. Concerning the significance and nature of the flagellate bodies there has been a continual dispute since the first note by Laveran.(18) Their extreme activity, the remarkable manner in which they agitate the surrounding corpuscles, the power of individual motion which the separate filaments possess, led Laveran to assume that they repre- sented the highest stage of development of the malarial parasite. He described them in his first article somewhat as follows: In repose they are represented by a spherical body about six micro-millimetres in diameter, containing a ring of rounded pigment granules of equal size. In motion they are surrounded by, usually, three to four fine filaments in active, serpentine motion. The length of these filaments is three or four times that of the red corpuscle, possibly longer; the ends are slightly swollen. They may arise from one or from various points on the periphery of the body. The central mass, at the same time, may be in active motion, while the granules change position. The movements of the central body are like those of an amoeba. He saw filaments break loose from the body, and found them moving about free in the blood. This original description by Laveran was, at first, quite generally discredited, notwithstanding the fact that Richard, shortly afterwards, confirmed his observations. Marchiafava and Celli/34,36,3® not having seen the bodies, insisted, at first, that they were not parasites but simply degenerative changes in the red corpuscles, similar to those produced by subjecting blood to a high temperature. In 1885,(41) however, when they had found flagellate bodies in four cases out of 42, they recognized their parasitic nature. Later in the same year/4® they expressed the opinion that the flagellate forms rep- resented a further stage of development which the parasite rarely reached. lu 1886/55) Osler described them clearly, and, in 1888", Councilman (81) noted the fact that they were much more frequent in the blood of.the spleen than in the circulating blood. Excellent drawings of flagellate bodies may be found in Vandyke Carter's^® article in 1888. Since then most observers who have been able to study the blood in malarial fever have noted these forms. They have been seen in all types of malaria, though they appear to be less common The Malarial Fevers of Baltimore. 177 in quartan fever than they are in tertian or in aestivo-autumnal infections. Canalis,(104) in 1889, studied the flagellate bodies with care, and notes that, in aestivo-autumnal fever, they are developed only from the full grown round forms, which, in turn, come from the crescents and ovoid bodies. He believes that they are seen, usually, several hours before the febrile paroxysm, though they may occur in apyrexia. They are more commonly found in the internal organs than in the circulating blood. They are smaller than the flagellate forms occurring in tertian and quartan fever, which, particularly in the former, may be double the size of the red blood corpuscles. They show a scant collection of granules in the centre, with a fairly clear peripheral zone, from which the filaments burst forth. After a certain length of time the movements of the pigment cease, while the gran ides collect in a small, dense, irregular mass; the movements of the flagella become slower and finally cease. The distinction between the more clear peripheral zone and the pigmented central area of the parasite, begins to disappear, while the entire substance of the body becomes more refractive. This is probably a cadaveric state of the flagellate body. Canalis does not commit himself as to the significance of these forms. Golgi(118) believes that the flagellate bodies are a passing phase in the development of crescents, and rather suggests that they are degen- erate forms. Antolisei(129) believes that flagellation is a degenerative process similar to fragmentation and vacuolization. In studying the tertian parasite, Antolisei noted that the flagellate bodies develop only from the large, swollen, fully-grown forms of the organism, which either fragment, become vacuolated, or develop flagella-never segmenting. The flagella, he believes, are sarcodic prolongations of the protoplasm. He(139) states that he has seen the flagellate bodies themselves become vacuolated. Grassi and Feletti(221) call attention to the fact that they never have observed flagellate bodies until the blood has remained twenty minutes or more on the slide. They do not believe that they are reproduc.- tive forms, but, rather, that they represent involutive or degenerative changes. They note that the nucleus does not take part in the pro- cess, neither dividing nor entering into the flagella. They mention what Councilman(8I) and Marchiafava and Celli(41,45) have also noted, 178 IF. S. Thayer and J. Hewetson. that certain of these ovoid, crescentic, or round forms may show an extremely rapid undulation of the outline without the presence of flagella. They liken the process of flagellation to the development of filaments from degenerating red corpuscles. Sacharoff,(2,2) in his studies on the "parasite of irregular fever" (the aestivo-autumnal parasite), is inclined to believe that the flagellate bodies develop only outside of the organism ; they represent changes provoked by exposure of the blood to a low temperature. He notes, as do Grassi and Feletti, that they are not observed until about a quarter of an hour after the preparation of the blood is made. Their appear- ance begins, nearly simultaneously, at different points in the prepara- tion. He has succeeded in staining the flagella by the following method : He collects a series of drops of blood on cover glasses, some of which are placed immediately in a moist chamber, while one is placed upon a slide, with vaseline at the borders of the glass, and is submitted to microscopical examination. He is able to follow the transformation of the crescents into ovoid and round bodies, the arrangement of the pigment in the shape of a crown, and, shortly afterwards, the appearance of movable filaments. After waiting a short time to allow the number to increase, he removes the cover- glasses from the moist chamber, spreads out the blood, dries, fixes, and colors with gentian violet. The filaments are intensely stained of the same color as the protoplasm of the parasite, which takes so deep a stain that the pigment granules are no longer distinct. He has published photographs(276) of these forms. Terni and Giardina(145) observed flagellate bodies in twenty-five out of sixty-two cases of aestivo-autumnal fever; they were noted, generally, just before febrile attacks. They were always accompanied by the round bodies, from which they had doubtless developed. Bastianelli and Bignami,(152) in their studies of the tertian and quartan infections, agree with Antolisei in believing that the flagellate bodies, as well as the large, swollen, extra-cellular forms from which they develop, are degenerative in nature. They find them most numerous toward the beginning of the paroxysm. They compare the changes in the crescents (fragmentation, gemmation, vacuoliza- tion, and flagellation), as does Antolisei, to the changes occurring in the large swollen forms of the tertian parasite, believing them all to The Malarial Fevers of Baltimore. 179 be degenerative changes. This standpoint lias since been taken by Marchiafava and Bignami.(245) Recently(300,301'324) interesting studies of the flagellate bodies have been made by Sacharoff. He notes that after a short exposure to lower temperature than that of the body, the crescents rapidly change into round forms, and then into flagellate bodies. In coloring flagellate bodies after the manner of Romanowsky, and studying their structure, Sacharoff has convinced himself that "the process of formation of the flagellate bodies consists in a perversion of the karyokinetic nuclear division, in a breaking up of the nucleus into the chromatin filaments, and in the escape of these from the parasite; these filaments, which are in lively motion, represent the flagella." This, he believes, is, undoubtedly, a degenerative process, the rapidity with which it occurs showing that the crescent cannot be long exposed to cold without dying. The same process, he states, may occur in the full-grown tertian parasites and in the parasites of chronic malaria in birds, which divide in the same way-by karyokinesis. Opposed to these views, that the flagellate forms are degenerative in nature, are a number of observers, the more important of whom are Laveran,(229) Danilewsky,(194) Dock,(151) Mannaberg,(291) Coronado(273) and Manson.(347) Laveran (229) believes that these bodies are cysts con- taining the fully developed flagella, which represent the parasites at their most perfect stage of development. He denies that the flagel- late forms have any relation to the similar appearances produced by the action of heat upon the red corpuscles. "The differences," he says, " which exist between the flagella of paludism and the sarcodic prolongations of the normal red corpuscle, submitted to the action of heat, are numerous: firstly, the flagella of the haema- tozoa of paludism are seen at the ordinary temperature of the Laboratory. I have seen them frequently at a temperature not above 15° C. The sarcodic prolongations of the red corpuscle do not develop until one heats the blood to 56° or 57°. Secondly, the haematozoa have never been observed excepting in patients suffering with malaria. In the blood of these patients they are always associated with other parasitic elements, spherical pigmented bodies, from which they appear to arise. Flagella never arise from the red corpuscles, as do, always, the sarcodic prolongations which one can bring about by heating the blood strongly. Thirdly, the flagella of paludism 180 IK S. Thayer and J. Hewetson. differ from the sarcodic prolongations by their form and their dimen- sions, which are much more regular, and in the vivacity and the variety of their movements. None of the observers who have, them- selves, seen the flagella go through their various motions, rolling and unrolling upon themselves, causing the most varied movements among the surrounding red corpuscles, which they sometimes seem to seek to pierce, woidd venture to assert that one could confound these move- ments with those of the sarcodic prolongations produced by heat. The flagella move, sometimes, so rapidly that they cause changes in the position of the spherical body to which they are attached. When they are free, they preserve the same vivacity, the same variety of movement." (Page 87.) Dani lewsky(194) holds similar views concerning these bodies. Dock(15I) suggests that the flagellate bodies "represent resting states of the organism, capable of existing independently, perhaps even of reproducing themselves, but also able, under favorable circumstances, of reproducing the typical growth of the parasite." Mannaberg(29I) takes an interesting view not dissimilar to that of Dock. He writes as follows : " In my opinion, these forms, as has been already said, are by no means to be regarded as phenomena of death (' agonieproducte'). It could hardly be explained why only a relatively small number of the parasites present show these changes when all the bodies in the preparation die in a short time. Moreover, one ought to see, here and there, flagella in the circulating blood, in which, as I shall later show, there occurs, at the time of the paroxysm, a great mortality among the parasites, dying forms being present in numbers. The same would be expected after the giving of quinine; but none of these things actually occur. Finally the remarkable activity of the movements is a convincing argument against the idea that the process is a phenomenon of the agony. My idea is, that we have, in the flagella, organs which permit the parasites to enter into a saprophytic existence. I suspect that the flagellate bodies enter upon the first steps of a cycle of existence outside of the human body, and that, as a result of the unfitting culture medium, the death of the young spores occurs." He notices, also, that they do not develop until the blood has been outside of the body for some little time. Manson(W) believes that . . . " the flagellated organism which proceeds from the crescentic body is the first stage in the life of the The Malarial Fevers of Baltimore. 181 malarial organism outside the human body, and the living moving flagella, into which it breaks up, the second stage. The central sphere to which the flagella are at first attached, and from which they are derived, must be looked on as residual." Lastly, Coronado,(273) as has been stated above, in his cultivation experiments, believes that he has seen the longitudinal segmentation of free flagella into young individuals, a fact which, if true, would demonstrate that the free flagellum was a fully-developed, perfect individual. Which of these several views are we to take? This is a very difficult matter to decide. We have observed flagellate bodies in all varieties of malarial fever. In the tertian and double tertian fevers the flagellate bodies were always noted a little before or during the paroxysm. In tertian infection, out of 174 cases observed in the hospital, flagellate bodies were noted 15 times. In quartan infection, flagellate bodies were noted in 2 out of 5 cases. In 105 cases of aestivo-autumnal fever observed in the hospital, flagellate bodies were noted 18 times. In the cases of tertian fever the flagellate bodies were noted, always, during or shortly before the paroxysm. In one instance, only, was a body seen eleven hours before the chill, and once when the temperature was normal between paroxysms. In the eighteen cases of aestivo-autumnal fever, in four cases they were seen during the paroxysm; in nine cases the temperature was normal; in three the fever was continuous; in one case the organisms were found in the spleen after death. In quartan fever the parasite was observed once several hours before a paroxysm, and once in association with degenerative forms during an abortive paroxysm. In quartan fever the flagella developed from full-grown, extra-cellular forms. In tertian fever the flagellate bodies developed, always, from the large, full-grown, extra-cellular forms, forms which are often considerably larger than the red corpuscle. In aestivo-autumnal fever the bodies developed, invariably, from the round, pigmented bodies which, in turn, could be traced to the crescents. We have never seen the appearance of flagella in bodies still contained in the red blood cor- puscles. In tertian and quartan fever, then, the process of flagellation was observed, invariably, at the time when full-grown organisms were found in the blood, at the time when segmenting organisms were to 182 IE /S'. Thayer and J. Hewetson. be seen-reproductive forms-but also at the time when degenera- tive processes - vacuolization, fragmentation-were most common. In one instance a flagellate body was seen during apyrexia, at a time when only occasional large swollen forms were seen, beyond the half developed forms within the red corpuscles, from which we have never seen flagellate bodies develop. The tertian flagellate bodies were materially larger than the quartan forms which resembled much more, the flagellate bodies in aestivo-autumnal infection. We have seen nothing which would lead us to believe that the development of flagellate bodies in aestivo-autumnal fever had any connection whatever with the paroxysm. On the other hand, in the majority of cases these forms were noted after the paroxysms had ceased, when the temperature was entirely normal. In 6* of the 18 cases of aestivo-autumnal fever quinine had been previously administered, and in seven of these instances flagellate bodies were observed for days after the fever had entirely disappeared. These statistics give us little particularly definite, then, with regard to the nature of the bodies. Their appearance, their activity, the regularity of outline, the shape of the flagella are very much against their being com- pared to the sarcodic prolongations of degenerating red corpuscles, which are certainly very dissimilar in appearance. Their occurrence in tertian and quartan fevers, generally in association with segmenting forms at the time of the paroxysm, might lead us to lean toward the opinion of Dock and Mannaberg, that they represent a reproductive process differing from that which usually takes place. On the other hand, the arguments of Bignami, Bastianelli, Marchiafava, Celli and others, who call attention to the fact that, in tertian fever, the flagella develop, regularly, from the large, swollen forms which otherwise end, apparently, only in vacuolization and fragmentation, and draw so interesting an analogy between these forms and the crescentic, ovoid, and round bodies, from which the flagella develop in aestivo-autumnal infections, have, also, much to say in their favor. The most suggestive point in our analyses is, it appears to us, that concerning the time at which the flagellate bodies in aestivo- autumnal infections appear. In an half of the cases the paroxysms *In both of the two additional instances in the dispensary where flagellate bodie were noted, quinine had been previously administered. The Malarial Fevers of Baltimore. 183 had ceased; in 8 out of 20 instances quinine had been previously given; that is, for days and, sometimes, for weeks after the activity of the infection had certainly been overcome, we were able to see flagellate bodies in association, sometimes, with other unquestioned degenerative changes. There is another point which has been, singu- larly enough, very little, if, indeed, at all, noted in the literature. Whatever our opinion may be concerning the primary influence of phagocytosis on the cure of malarial or other infections, it is an undoubted fact that any lifeless or dying foreign material in the blood current is attacked with particular activity by the phagocytes. The young intra-cellular parasites in the midst of relatively normal red corpuscles are almost never engulfed. What forms, or what con- stituents of the malarial parasites are most commonly attacked ? (1). Most commonly, we see the engulfing of the free pigment clumps which are left after segmentation-the lifeless pigment. (2). Again we see the small, extra-cellular bodies, the result of fragmentation from large tertian or from quartan forms, or those half- grown forms which have burst from the corpuscle and become deformed and immovable in the field. (3). Next in frequency, perhaps, do we see the engulfing of seg- menting forms. (4). Again, we may, in aestivo-autumnal infection, see small forms, contained in crumpled, brassy colored (necrotic) corpuscles, taken up together with the corpuscle. All of these forms, with the exception of the segmenting parasites, are generally considered to be degenerative in nature. It is, how- ever, to be remembered that it is at the segmenting stage that the parasite is most vulnerable, as proven by the experimental admin- istration of quinine, while it is an accepted fact that many of the segmenting forms are, normally, destroyed in the blood serum at the time of each paroxysm. (5). But the one form of malarial organism which one may clini- cally observe to be invariably, or almost invariably, attacked, is the flagellate body. Where a flagellate body is seen to develop in the field, the writers have, again and again, seen one, two, or even three leucocytes crawl into the field of the microscope and attempt to engulf the parasite, and, in many cases, the attempt is not unsuccessful. Often, to be sure, the flagella escape and the central body alone is engulfed, 184 W. S. Thayer and J. Hewetson. but in many instances the whole parasite is taken up. It is true that this argument might be used by others as indicating a special virulence on the part of the flagellate body, which would call forth an imme- diate attack from the protectors of the economy, but it would be interesting to find that the forms most commonly attacked were, in the one instance, the undoubted degenerative forms, and in the other the most perfectly developed full grown bodies. Another argument in favor of the degenerative nature of these forms of the parasite is the fact of the rarity of their appearance immediately after the formation of the specimen. In our observa- tions they appeared, always a few minutes, usually five, to ten, to fifteen, after the preparation of the specimen. We have never found them in the first few minutes of observation. The nature, then, of the flagellate bodies does not appear to be entirely understood. There are rather strong arguments which speak in favor of the view that they are degenerative stages of the parasite, and others which speak against it. No observations have, however, been made, with the exception of the as yet unconfirmed work of Coronado, which suggest a possible function, or which tend to clear up their relation to the cycle of existence of the parasite. While our observations concerning the time at which these bodies appear, their association with undoubted degenerative forms, their persistence after the disappearance of fever and after the administra- tion of quinine, the manner in which they are engulfed by the phago- cytes, are all, it seems to us, suggestive evidence that these bodies are degenerative in nature ; on the other hand, the extreme regularity in the shape of the flagella, their extraordinary activity, their power of individual motion, cause us to hesitate seriously in accepting this view. We believe that the nature of the flagellate bodies is not yet clearly understood, and must be decided by future research. The Malarial Fevers of Baltimore. 185 IX.-THE ACTION OF QUININE ON THE MALARIAL PARASITE. We have not made a systematic study of the action of quinine upon the fever or upon the parasites, and in this article we will only touch upon the subject. Suffice it to say that our observations have all tended to support the views first advanced by Golgi, that the time at which the malarial organism is best attacked is just at the period of segmentation. In dealing with the tertian organism, we have found that a moder- ate dose of quinine, given just before the paroxysm, so that the drug may be in solution in the blood at the time of the segmentation of the organisms, is always followed by an almost complete obliteration of the group of parasites then undergoing segmentation. An excellent illustration of the effect of quinine has been shown in Case 9047, page 113. Ordinarily, quinine, gr. v-x (0.325-0.65), given at any time during the paroxysm, will be sufficient to prevent the appearance of the next chill, though not generally to completely obliterate the group of parasites. When the parasite is in the endo-globular stage (be- tween paroxysms) quinine has relatively little effect, though in many mild tertian cases it will succeed, even in this stage, in preventing an approaching chill, if given ten to twelve hours before a paroxysm. In quartan infections the same rules appear to hold true. In most of the tertian infections, as they occur in Baltimore, very small doses of quinine are sufficient, if the patient be kept in bed, to eradicate the fever. Thus, in most cases of tertian and double tertian fever, sev- eral days' rest in bed and two weeks' treatment with as little as gr. ii (0.13), three times a day, is followed, generally, by a permanent recov- ery. The organisms usually disappear from the blood within the first four days. In the aestivo-autumnal infections, our observations concerning the time at which quinine is most efficacious are too few to justify us in expressing any opinion. We have seen no cases where, as in tertian or quartan fever, a single large dose of quinine, given at the proper time, has appeared to almost destroy the infection-at least to cause the disappearance of the fever for a considerable length of time. Here 186 IK /S'. Thayer and J. Hewetson. the doses of quinine must be materially larger. In most instances we place the patient simply upon quinine, gr. v (0.325), every four hours, keeping him in bed for three or four days; in the hospital for from one to two weeks. Under these circumstances permanent recov- ery is usual, after two or three weeks' treatment. In the same manner the cases in the dispensary, so far as we could follow them, recovered under similar doses continued through a proper length of time-two or three weeks. In severe and pernicious cases much larger doses of quinine may be necessary. In our cases we have used, generally, the muriate of quinine and urea which we have given, hypodermically, in doses as high as gr. xx (1.3). We have had no experience with the intravenous administration of the drug, as advised by Baccelli. It will not be worth while to discuss, in this paper, the value of other remedies against malaria. The only drug which deserves any serious consideration, beyond quinine and the other cinchona derivatives, is methylene blue, the value of which has been shown, by many observers, to be very slight. We see no reason to depart from the conclusions reached by one of the writers several years ago-that, while methylene blue has a certain definite action upon the malarial parasite, it is materially less efficacious than quin- ine, failing to accomplish its purpose where quinine acts satisfactorily ; that it has no advantages over quinine which would warrant its further use. X.-GENERAL CONCLUSIONS. Malarial fever is rare in Baltimore during the winter months, but becomes more frequent as the season advances, reaching a maximum in the month of September, the majority of all the cases occurring in August, September, and October. Any differences between the susceptibility of individuals of differ- ent ages, and of the two sexes, depend, apparently, only upon the varying chances of exposure to infection. The relative susceptibility of the negro is, by nearly two-thirds, less than that of the white population. We have distinguished three varieties of the malarial parasite: 1. The. tertian parasite. 2. The quartan parasite. 3. The aestivo-autumnal parasite. The Malarial Fevers of Baltimore. 187 (1). The tertian parasite requires about forty-eight hours to accom- plish its complete development, and is associated with relatively reg- ular tertian paroxysms, lasting, on an average, between ten and twelve hours, associated, almost always, with the three classical stages-chill, fever, and sweating. Frequently, infection with two groups of ter- tian organisms gives rise to quotidian paroxysms; rarely, infection by multiple groups of organisms gives rise to more irregular, sub-con- tinuous fevers. (2). The quartan parasite is an organism requiring about seventy- two hours for its complete development. It is rare, in this climate, and is associated with a fever showing regular quartan paroxysms, similar, in nature, to those associated with the tertian organism. In- fection by two groups of the parasite causes a double quartan fever (paroxysms on two days, intermission on the third). Infection, with three groups of the parasite, is associated with daily paroxysms. (3). The aestivo-autumnal parasite passes through a cycle of devel- opment, the exact length of which has not, as yet, been determined ; it probably varies greatly from twenty-four hours or under, to forty- eight hours or more. But few stages of development of the parasite are found, ordinarily, in the peripheral circulation, the main seat of infection being, apparently, in the spleen, bone-marrow, and other internal organs. Infection with this organism is associated with fevers varying, greatly, in their manifestations. There may be quotidian or tertian intermittent fever, or, more commonly, more or less continuous fever with irregular remissions. The individual paroxysms last, on an average, about twenty hours. The irregularities in temperature depend, probably, upon variations in the length of the cycle of devel- opment of the parasite, or upon infection with multiple groups of organisms. We have not been able to separate two distinct varieties of the aestivo-autumnal parasite, though we feel that more investigation is needed upon the subject. The cases of malaria in the spring and early summer are of the milder, more regularly intermittent varieties (tertian and quartan fever), the severe aestivo-autumnal infections beginning to appear only in the later summer, and reaching their maximum in September. The colored race, while showing a relative insusceptibility to malarial infection, is equally susceptible to the various forms. The 188 IK & Thayer and J. Hewetson. infections which occur are, however, more apt to take a simpler, milder course-the single tertian cases, for instance, outnumbering the cases of double tertian fever. The majority of all the cases of malarial infection in this climate depend upon the tertian parasite; these tertian infections form the vast majority of all the cases in the first half year, but occur through- out the malarial season. The majority of infections during the height of the malarial season depend, however, upon the aesti vo-autumn al parasite. The earliest cases of tertian infection are more commonly single in nature, while as the season advances double tertian infections become more common. Nothing, in our experience, has led us to believe that these varieties of the parasite are interchangeable. They are, we believe, distinct varieties, though closely allied to one another biologically. Combined infections, with parasites of different varieties, may occur, but they are rare-forming less than 2 per cent, of all the cases which we have observed. The crescentic bodies, associated with the aesti vo-autumnal parasite, develop from the small hyaline forms. We have seen nothing to support the views of Mannaberg that they are the result of conjuga- tion. We have never seen sporulating forms which we believe to have developed from crescents. We are not, as yet, inclined to accept the view that these are degenerate forms; we believe that their true nature is still undetermined. The nature of the flagellate bodies which may develop in all types of malarial fever, is not yet determined. The specific action of quinine upon these three varieties of the parasite is undoubted. It exerts its influence most strongly when the parasite is undergoing the process of segmentation, before the entrance of the fresh segments into new red corpuscles. It is best administered, then, just before the beginning of a paroxysm, if we wish to obtain the greatest effect with a single dose. The action is much more rapid and certain in the tertian and quartan fevers than in the aestivo-autumnal infections. XI.-TABLE OF REFERENCES* TO THE MAIN WORKS TREATING OF MALARIAL FEVER SINCE THE RECOGNITION OF ITS PARASITIC ORIGIN. (1). Meckel. Uber schwartzes Pigment in der Milz und dem Blute einer Geistes- kranken. Zeitschrift fur psychiatrie, 1847, 198. (2). Virchow. Zur pathologischen Physiologie des Blutes. Virchow's Archiv, 1849, II, 587. (3). Hischl. Uber Pigmentbildung nach Febris intermitttens. Zeitschrift der k. k. Gesellschaft der Aertzte in Wien, 1850, 338. (4). Planer. Uber das Vorkommen von Pigment im Blute. Zeitschrift der k. k. Gesellschaft der Aertzte in Wien, 1854, 127; 280. (5). Ray Lankester. On Undulina. Quarterly Journal of the Microscopical Sciences, Lond., 1871, XI, 387. (6). Kelsch. Contributions it l'anatomie pathologique des maladies palustres endemiques. Arch, de Physiologie, 1875, 690. (7). Kelsch. Nouvelle contribution a l'anatomie pathologique des maladies palustres endemiques. Arch, de Physiologie, 1876, II serie, t. Ill, 490. (8). Lewis. Flagellated Organisms in the Blood of Rats. Quarterly Journal of the Microscopical Sciences, 1879, 109. (9). Klebs and Tommasi-Crudeli. Studien fiber die Ursache des Wechsel- fiebers und fiber die Natur der Malaria. Arch. f. Exper. Path. u. Pharmak.. 1879, XI, 311. (10). Gaule. Uber Wfirmchen welche aus den Froschblutkorperchen auswandem. Archiv. fiir Physiologie, 1880, 57. (11). Dochmann. Zur Lehre von der Febris Intermittens. St. Petersburger Med. Woch., 1880, no. 20,164. (lla). Tommasi-Crudeli. Studi ulteriori sul Bacillus malariae. Bull, del R. acc. med. di Roma, 1880, VI, 9-12. (12). Tommasi-Crudeli. Der Bacillus Malariae in Erdboden von Selinunte und Campobello. Arch. f. Exp. Path. u. Pharm., Leipz., 1880, XII, 225. * The table is arranged, as far as possible, chronologically. A number of Russian articles of which good abstracts could be obtained were not consulted in the original. All other instances where the original articles were not consulted are mentioned in the table of literature. A few other references, unavoidably omitted from this list, will be found in foot notes. In a number of instances one article has been reproduced in several different journals or in translations without essential change. References to all these reproductions or translations will be found under that to the original article. 189 190 W. S. Thayer and J. Hewetson. (13). Tommasi-Crudeli. Malarial fever. The Practitioner, Lond., Nov., 1880, XXV, 320. (14). Laveran. Note sur un nouveau parasite, &c. Bulletin de l'acad&nie de m^decine de Paris, stance du 23 Nov., 1880. (15). Laveran. Un nouveau parasite trouvd dans le sang des malades atteints de fievre palustre. Origine parasitaire des accidents de 1'impaludisme. Bull, et m&n. de la soc. med. des h6p. de Par., 24 Dec., 1880. Also, L'union m^d., Par., 10 July, 1881, no. 95. (16). Laveran. Deuxieme note, &c. Bull, de l'acad. de m^d. de Par., sA du 28 Dec., 1880. (17). Cuboni and Marchiafava. Neue Studien iiber die Natur der Malaria. Arch. f. Exper. Path. u. Pharmak., Leipz., 1880-81, XIII, 265. (18). Afanassiew. Beitrag zur Pathologic der Malaria infection. Virchow's Archiv, Apr. 8, 1881, LXXXIV, 13. (19). v. Wittich. Spirillen im Blut von Hamstern. Centralbl. f. d. med. Wiss., 1881, no. 4, 65. (20). Gaule. Die Beziehungen der Cytozoen (Wiirmchen) zu den Zellkernen. Archiv. f. Physiologic, 1881, 297. (21). Tommasi-Crudeli. Malaria and the ancient Drainage of the Roman Hills. The Practitioner, 1881, XVII, 295. (22). Gaule. Kerne, Nebenkerne und Cytozoen. Centralbl. f. die Med. Wiss., 30 July, 1881, 561. (23). Laveran. De la nature parasitaire des accidents de 1'impaludisme. Compt. rend, des sA de l'acad. des sciences, 24 Oct., 1881. Also, France M^dicale, Par., 1881, II, 617-620. (24). Laveran. Troisieme note relative & la nature parasitaire des accidents de 1'impaludisme. Bull, de l'acad. de m^d. de Par., 25 Oct., 1881. (25). Laveran. Nature parasitaire des accidents de 1'impaludisme. Description d'un nouveau parasite trouv^ dans le sang des malades atteints de fievres palustres, 8°., Paris, 1881. (26). Richard. Sur le parasite de la malaria. Compt. rend, des sA de l'acad. des sciences, 20 Febr., 1882. Also, Gaz. mAi. de Par., 1882, 6 s., IV, 252. (27). Ziehl. EinigeBeobachtungen uber den Bacillus Malariae (Klebs). Deutsch. Med. Woch., 1882, VIII, 647. (28). Marchand. Kurze Bemerkungen zur Aetiologie der Malaria. Virch. Archiv., 1882, LXXXVIII, 104. (29). Laveran. De la nature parasitaire de 1'impaludisme. Bull, et mAn. de la soc. mAi. des hop. de Paris, 28 Apr., 1882, XIX, 2 s., Also, Revue Scientifique, 29 April, 1882, 527. Also, L'Union m^dicale, 12 June, 1883, 1033; 1051. (30). Laveran. Des parasites du sang dans 1'impaludisme. Compt. rend, des sA de l'acad. des sc., Paris, 23 Oct., 1882, XCV, 737. (31). Mitrophanow. Beitriige zur Kenntniss der Haematozoen. Biolog. Cen- tralblatt, 1883-84, III, 35. (32). Ceci. Dei germi ed organismi inferior! contenute dalle terre malariche e comune. Arch, per le sc. med., 1883, VI, 8. The Malarial Fevers of Baltimore. 191 ((32). Ceci.) Also, Arch. Itai, de Biologie, 1882, II, 1541 (good summary). (33). Richard. Le parasite de 1'impaludisme. Rev. Scientifique, Par., 1883,113. (34). Marchiafava and Celli. Nuove osservazione sulle alterazioni prodote dalla infezione malarica. Gaz. d. Osp., 1883, 652. (35). Marchiafava and Celli. Die Veranderungen der rothen Blutscheiben bei Malariakranken. Fortschritte der Med., Leipz., 1883, I, 573. (36). Marchiafava and Celli. Sull' alterazioni dei globuli rossi nella infezione da malaria e sulla genese della melanaemia. Mem. del. R. Acc. dei Lincei, 1883. Also, Arch. Itai, de Biol., 1884, V, 147. (37). Laveran. Traite de fievres palustres. 8°., Paris, 1884. (38). Gerhardt. Uber Intermittens Impfungen. Zeitschr. f. Klin. Med., 1884, 375. (39). Mariotti and Ciarrochi. Sulla transmissibility dell' infezione da malaria. Lo Sperimentale, Dec., 1884, s. IV, t. LIV, 263. (40). Councilman and Abbott. A Contribution to the Pathology of Malarial Fever. Am. Journ. of the Med. Sci., Apr., 1885, n. s., vol. 89, 416. (41). Marchiafava and Celli. Nuovericerchesull'infezione malarica. Annali d'agricoltura, 1885, 96-104. Also, Arch, per le Sc. med., 1885, IX, no. 15. Also, Fortschritte der Med., 1885, III, nos. 11, 14. (42). Danilewsky. Die Haematozoa der Kaltbluter. Arch. f. Mikr. Anat., 1884-5, XXIV, 588-598. (43). Laveran. Du paludisme, de sa nature parasitaire et de ses microbes. Bull, et m^m. soc. m^d. d. hop. de Paris, 24 July, 1885, 3 s., II, 287-292. (44). Danilewsky. Biologisches Centralblatt. 1885, V, 529. (45). Marchiafava and Celli. Weitere Untersuchungen uber die Malaria infec- tion. Fortschritte der Med., 1885, III, no. 24, 787. Also, Annali d'agricoltura, 1886. Also, Arch, per le sc. med., 1886. Also, Arch. Itai, de Biol., 1887. (46). Celli. L'acqua potabile e malaria. Bull. d. soc. Lane. d. Roma, 1886, VI, f. 1, 39 (5 Dec., '85). (47). v. Sehlen. Uber die Aetiologie der Malaria. Virchow's Archiv, CIV, 1886, 319-352. (48). Sternberg. The Malarial Germ of Laveran. The Medical Record, N. Y., May 1 and 8, 1886, 489; 517. (49). Golgi. Sull' infezione malarica. Arch, per le scienz. med., X, 1886,109-135. Also, Arch. Itai, de Biol., VIII, 1887. (50). Golgi. Ancora sull' infezione malarica. Boll. Med. chirurg. di Pavia, 1886. Also, Gaz. d. Osp., 4 July, 1886, n. 53, 419. (51). Councilman. On certain Elements found in the Blood in Cases of Malarial Fever. Transactions of the Assoc, of Amer. Phys., 1886, I, 90. Prelim, notice, Maryland Med. Journal, Oct., 1886, 441. (52). Danilewsky. Mat^riaux pour servir a la parasitologic comparee du sang. 8°., Kharkoff, 1887. Reprints from articles in Arch. Slaves de Biol., 1886-'87. 192 W. S. Thayer and J. Hewetson. (53). Danilewsky. Zur Frage iiber die Identitat der Pathogenen Blutparasiten des Menschen und der Hamatozoen der Gesunden Tiere. Cent. f. die Med. Wiss., Oct. 9 and 16, 1886, 737; 753. (54). Crookshank. Flagellated Protozoa in the Blood of Diseased and appar- ently Healthy Animals. Journal of the Royal Mier. Soc., Dec., 1886, 913. (55). Osler. An Address on the Haematozoa of Malaria. Phila. Med. Times, 1886. Also, British Med. Journ., 1887, I, 556. (56). Arcangeli. Le ricerche moderne intorno l'agente dell' infezione malarica. (Rivista Sintetica.) Ri vista Clinica di Bologna, 1887, 9. (57). Councilman. Further Observations on the Blood in cases of Malarial fever. Med. News, Phila., 1887,1, 59-63. (58). Marchiafava and Celli. Sui rapporti tra le alterazioni del sangue di cane introdotto nel cavo peritoneale degli uccelli e quelle del sangue dell' uomo nell' infezione malarica. Bull. d. R. acc. med. di Roma, 1887, 417. (Sitting of 29th May). (59). Metchnikoff. Zur Lehre von den Malariakrankheiten. Russkaja Medi- cina, 1887, n. 12, 207. (Russian). Ref. in Centralbl. f. Bact. u. Par., I, 1887, 624. (60). Laveran. Des h^matozoaires du paludisme. Annales de 1'Institut Pasteur, Paris, 25 June, 1887, I, 266. (61). Marchiafava and Celli. Sulla infezione malarica-memo ria quarta. Atti della R. accad. med. di Rom., 1887, s. II, III, 277 (Session of June 26). Also, Arch, per le scienz. med., 1888, XII, 153. Also, Arch. Itai, de Biologie, 1888, A, IX, f. 3. Prelim, note, Bull. del. R. acc. med. di Rom., 1887, XIII, 489. (62). Mosso. Die Umwandlung der rothen Blutkorperchen in Leucocyten und die Necrobiose der rothen Blutkorperchen bei der Coagulation und Eiterung. Virchow's Archiv, CIX, 1887 (2 August), 205. Also, Rend. d. R. acc. dei Line., Ill, fasc. 7 and 8. (63). Cohn. Uber die Aetiologie der Malaria. Centralblatt fiir Backt., 1887, II, 363. (64). Maragliano. Uber die Resistenz der rothen Blutkorperchen. Berliner Klin. Woch., 24 Oct., 1887, no. 43, 797. An address made at the R. accad. med. di Genova. (65). Tommasi-Crudeli. Die Ursache der Malaria. Deutsch, med. Woch., Nov., 1887, no. 46, 992. (66). Guarnieri. Ricerche sulle alterazioni del fegato nell' infezione malarica. Atti della R. accad. med. di Roma, 1887, serie II, v. Ill, 247-266. (67). Marchiafava and Celli. Sui rapporti tra le alterazioni del sangue di cane introdotto nel cavo peritoneale degli uccelli e quelle dell' sangue dell' uomo nell' infezione malarica. Bull, della R. accad. med. di Rom., 1887, f. 7, 417. Reference repeated by mistake; vid. (58). (68). Pfeiffer. Das Vorkommen der Marchiafarva'schen Plasmodien im Blute Vaccinirten und von Scharlachkranken. Zeitschrift fiir Hygiene, 1887, II, 397. The Malarial Fevers of Baltimore. 193 (69). Maurel. Contribution a 1'etiologie du paludisme, Arch, de med. nav., Par., 1887, 28 ; 182 ; 257 ; 329. Also (Recherches microscopiques sur I'etiologie du paludisme.) Paris, 1887, 8°. (70). Vandyke Carter. Note on some Aspects and Relations of the Blood Organisms in Ague. Scientific Memoires by the Medical officers of the Army of India, Part 3, 1887 ; 4°., Calcutta, '88, 139. Summary in Lancet, June 16, 1888, 1201. (71). Sacharoff. Untersuchungen fiber den Parasiten des Malariafiebers. 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Grassi and Feletti. Malariaparasiten in den Vbgeln. Centralblatt fiir Backt., 1891, IX., 403; 429; 461. A collection of articles, most of which had appeared in the journals of Italy, during 1890 and 1891, as follows: (1) Bolletino mensile dell' accademia gioenia di scienzi natural! in Ca- tania, f. XIII, 23 March, 1890 (also, Arch. Itai, de Biol., 1890, 297). (2) Boll. mens. &c., Catania, June, 1890. (4) Communication by Grassi alone. Boll. mens. &c., Catania, Dec., 1890. (6) Boll. mens. &c., Catania, Feb., 1891. (206). Koch. Uber die Malariaamobe und das Chinin. Biolog. Centralblatt, XI, 1891, no. 23. (207). Dock. Further Studies in malarial Disease.-The Parasites and the Forms of Disease as found in Texas. Medical News, 30 May and 6 June, 1891, 602; 628. (208). Bignami. Sulle febbri intermittenti cosi dette a lunghi intervalli. Bull. d. Soc. Lane. d. Osp. d. Rom., 6 June, 1891, XI, 211. (209). Torti and Angelini. Infezione malarica cronica coi sintomi della sclerosi a placche. 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Hewetson. Types of malarial fever observed in Baltimore. Remarks at XI Internal. Med. Cong., Rome, March, 1894. British Med. Journal, 1894, vol. I, 854. (334). Atkinson. The malarial fevers of Hong Kong. The Lancet, April 28, 1894, no. XVII, 1054. (335). Capitanio. Le amebe rispetto alia patologia. Nota critico storica. Basi, Feb., March, April, May, 1894, 29; 61; 99. (336). Thompson. Note on the Observations of Malarial Organisms in connection with Enteric Fever. Transactions of the Assoc, of Amer. Phys., May 30, 1894, 110. (337). Coronado. Remittentes paludicos de larga duracion. (Unica memoria premiada por la Real Academia de Ciencias en el certamen den 1894, habiendo obtenido Mencion Honorifico.) Archivos de la Policlinica, June, 1894, t. II, no. 9, 189-254. Also, An. r. acad. de cien. m^d. de la Habana, 1894-5, XXXI, 62; 135. (338). Billings. The Leucocytes in Malarial Fever. J. H. H. Bulletin, 1894, no. 43, 105. (339). Feletti. I parassiti della malaria e le febbre da esse prodotti. Osservazioni Cliniche. Arch. Itai, de Clin. Med., Milano, 1894, XXXIII, 207- 265, 1 pl. (340). Thermopoulos. La presence des infusoires dans le sang des palustres, &c. Communication faite & la soc. m^d. d'Athenes, Athenes, 1894, 120. (341). Gammon. Some Clinical Observations on Haematozoa Malariae. Tr. Texas Med. Assoc., Galveston, 1894, XXVI, 387-403. (342). Ozzard. Note on the Haematozoa of Malaria. British Guiana Med. An- nual, Demerara, 1894, VI, 167-172. (343). Botazzi and Pensuti. Sulla tossicitii dell' orina dei malarici. Lo Speri- mentale, Firenze, 1894, XLVIII, 232, 254. (344). Cutler. Two unusual cases of Malaria. Boston Med. and Surg. Journal, Sept. 6, 1894, CXXXI, no. 10, 237. (345). Labbe. Recherches zoologiques et biologiques sur les parasites endoglobu- laires du sang des vert£br&. Arch, de zoologie experim. et gen., s^r. Ill, t. II, 1894, 55-258. (346). Manson. A Malaria Chart. British Medical Journal, Dec. 1, 1894, v. II, 1250. (347). Manson. On the Nature and Significance of the Crescentic and Flagellate Bodies in Malarial Blood. British Med. Journal, Dec. 8, 1894, v. II, 1306. (348). Graves. The Aetiology of Malaria with Remarks upon the Diagnosis. Proc. Conn. Med. Soc., Bridgeport, 1894, 79-88. (349). Hehir. Malarial Melanaemia. Indian Med. Gazette, Calcutta, 1894, XXIX, 246-8. (350). Laveran. L'aetiologie du Paludisme. Rev. Scientifique, Par., 1894, 4 s., II, 449-455. 208 W. S. Thayer and J. Hewetson. (351). Cousin. Sue spleniqueet cachexie paludienne. N. Montpelier M&i., 12 Oct, 1894, HI, 814. (352). Langovoi. Malarial Parasites in Malarial Fever. Med. obozr, Mosk., 1894, XLI, 1138-1149. (353). Williams. The Temperature as a Guide in the Administration of Quinine in Malaria. Boston Med. and Surg. Journal, 1894, CXXXI, 478. (354). Ross. A List of natural Appearances in the Blood which have been mistaken for Forms of the Malarial Parasite. Ind. Med. Gazette, Dec., 1894, vol. XXIX, no. 12, 441. (355). Burleigh. Malariae Plasmodiae observed in a Case of Jungle Fever. Modern Medicine, Battle Creek, Mich., Jan., 1895, v. IV, no. 1, 21. (356). Van der Scheer. Uber tropische Malaria. Virch. Archiv, 4 Jan., 1895, CXXXIX, 80. (357). Billet. Sur les h^matozoaires des ophidiens du Haut Tonkin. Compt. rend. hebd. des sA de la soc. de biol., Par, 25 Jan, 1895, X s., t. II, no. 2, 29. (358). Bastianelli and Bignami. Studi sulla infezione malarica. Bull. d. R. acc. med. d. Roma, 1893-1894, anno XV, vol. XX, 151. (359). Di Mattei. Beitrag zum Studium der experi mentellen malarischen Infec- tion am Menschen und an Thieren. Archiv. fur Hygiene, 1895, 191- 300. APPENDIX. After the greater part of this article had already gone to the press, there appeared two communications, which are of too much import- ance to pass over in silence. The first of these, by Di Mattei of Catania,(359) treats of the experimental malarial infections in man and animals. He publishes several new inoculation experiments in man. In his first experiment he inoculated four individuals, hypodermically, with blood from a case of quartan fever. In the first two instances, where 2 cc. were injected under the skin of the forearm, a typical quartan ague, with the characteristic parasites, appeared after an incu- bation period of 17 days in the first instance, and 11 in the second case. In two cases where, respectively,/!, and 0.5 cc. were injected, the result was negative. In the second experiment, a healthy indi- vidual was inoculated with blood from a case of aestivo-autumnal fever. Hyaline bodies and crescents were found in the blood at the time of inoculation. The patient suffered from epistaxis, and the blood flowing from the nose was collected in a vessel containing ster- ilized water at 37°. 4 cc. of a mixture containing equal quantities of blood and water were injected hypodermically. On the 15th day after the inoculation an irregular fever began, the blood showing hya- line aestivo-autumnal parasites. Eight days later crescentic bodies were found. The author then reviews the literature of experimental malarial infection and concludes: " That the malarial parasites may be divided into several species, though in certain stages these resemble one another from a morphological point of view; that each species has for itself a special biological cycle; and that one variety never merges or changes into another. That between the several varieties of the malarial para- sites and the types of fever, there exists an undeniable (unverwisch- bares) relation of dependence, for the former " (the parasites) " are to 209 210 W. S. Thayer and J. Hewetson. be recognized as the cause, the latter" (the fever) " as the effect; that, thus, one type of fever does not change into another because it is caused by a distinct variety of parasite. That in those forms of malarial fever where no ground type is to be made out, we have often to do with, so to speak, impure cases, with individuals whose system is invaded by different varieties of malarial parasites at the same time." The author then speaks of the results of an elaborate series of studies on the experimental infection of birds with the haematozoa which so closely resemble the malarial parasites in man. Careful estimations of the temperature in infected birds appear to show that there is no change from the normal. Quinine, bichloride of mercury, arsenic, have no effect on the course of the infection. In 83 attempts to transfer the infection by inoculation, intra-venous, hypodermic, intra-abdominal, intra-pulmonary, the results were all negative. He examined the blood of doves from malarious and non-malarious districts, and studied healthy birds kept in various localities, at vary- ing altitudes, and during the different seasons of the year, and con- cludes that, while infection with the haematozoa is rather commoner in summer than in winter, and in birds kept close to the ground rather than in those whose cages are hung in lofty positions, yet there appears to be no difference between the frequency of infection in malarious and non-malarious districts. The close association of healthy with infected birds does not appear to be followed by infection; nothing in his observations suggested the possibility of hereditary infection. In 16 cases, inoculation of birds with the blood of malarial men gave negative results. In 4 instances the hypodermic injection of the blood of infected birds into healthy men was without effect. In one instance 1 cc. of the blood of an infected bird was injected into one of the veins of the forearm of a healthy man, but without any particular effect. The author then compares, in the following table, the differences between malarial infections in man and infections with the similar haematozoa in the dove : The Malarial Fevers of Baltimore. 211 In the malarious individual. Elevation of temperature occurring as paroxysms of fever. Paroxysms occurring in relation to the cycle of the parasite. Quinine and arsenic are efficacious. Local conditions are a considerable and important factor in the infection. The oft-confirmed hereditary infection. Artificial inoculation of an healthy in- dividual with malarial blood always produces the infection. In the infected dove. No elevation of temperature. No relation between the cycle of the para- site and the temperature. Quinine and arsenic have no action. Local conditions have no influence. Hereditary infection does not occur. Artificial infection by means of the blood from infected to healthy doves does not occur. From these facts he concludes that the two processes are not iden- tical ; that the parasites occurring in birds, though similar morpho- logically, differ materially from the malarial haematozoa of man. He believes, therefore, that these haematozoa of birds should not be called " malarial." In the second paper, Bastianelli and Bignami(358) present the results of some valuable studies upon malarial infection. In the first part of their paper they treat of the finer structure of the parasites of the aestivo-autumnal fevers. A review of this part of their work may be found in an earlier part of this article (vid. p. 47). Particularly interesting are their views concerning the crescentic bodies. They trace the gradual development of these forms from the small hyaline bodies; they deny the existence of a membrane. The central chromatin spot or spots, on which Mannaberg lays so much stress, are often lacking; " usually there is a lack, then, of the structure which, in these parasites, represents the nucleus." " In (p. 180) the body with central pigment, after the solution (fusione) of the central body " (chromatin granule), " the chromatin substance increases in a more or less marked manner, and from these forms segmentation occurs. On the other hand, in the bodies not destined to sporulate (semilunar phase of the parasites) the dispersion of the chromatic granule of the protoplasm takes place as in the others, but, with the ulterior development, the nuclear sub- stance does not increase. This is not an hypothesis. We have, in fact, seen that the young form of the semilunar phase has more 212 W. S. Thayer and J. Hewetson. chromatin than the adult form, indeed the adult forms are the paler the more voluminous they are. " But we already know that with all malarial parasites the chromatic substance increases with the increase in volume, especially just before division. In the forms of the semilunar phase the contrary occurs. So, then, by this fact also, as well as for the reasons to which we have given utterance elsewhere, we may arrive at the conception that the crescents are sterile forms of the aestivo-autumnal parasites." Mannaberg's idea that the crescents are conjugate forms, they be- lieve to be without foundation. With regard to the biological significance of these bodies, they assert that in several unicellular parasites belonging, especially, to the coccidia, the existence of two cycles of development has been demonstrated. One cycle is accomplished during the ordinary life of the parasite. But after the parasite has lived, as such, through a series of generations, there begins a second cycle of existence, which is represented by forms which cannot terminate their development unless in the external air or in the tissues of another animal. If these forms of the second cycle do not escape from the body of the animal in which they are formed, they remain sterile and, after a certain time, degenerate and die. So many facts of this nature have been recently discovered that it appears not improbable that this may be a general law for this class of endo-cellular parasites. It appears probable to the authors that these parasites, which develop in a closed cavity and cannot reach the external air, have a phase of life which represents a rudiment of this second cycle. Being deprived of the possibslity of completing the cycle, they have lost, also, the power to reach the complete development that belongs to the other forms of this second cycle in other closely related organisms. " The semilunar phase of the malarial parasites repre- sents an abortive phase, sterile, of that cycle of development which, in closely related parasites, is completed only in the external air (am- biente). The analogy is also found in the fact that the forms of this abortive phase make their appearance only after a greater or less number of generations which have passed through only the ordinary cycle of the parasite." They then pass on to consider certain points in connection with phagocytosis. Golgi(309) has recently advanced the hypothesis that The Malarial Fevers of Baltimore. 213 the entire cycle of development of the parasite may be passed through while it is yet contained within a phagocyte. Bastianelli and Bignami assert that, with the exception, occasionally, of spores, all included parasites are rapidly destroyed unless they be contained in red blood corpuscles. If this progressive growth of the included bodies occurs, they believe that one should find all stages of development, with equal frequency, within the phagocyte. But this is not the case. While the included parasites may be in every stage of development, certain forms are found with much greater frequency than others. The youngest forms are, for instance, rarely seen, while the older are more common; facts which, they believe, are strong evidence against Golgi's idea. The second part of their paper is devoted to a consideration of cer- tain lethal infections with but few parasites. They assert that if one takes into consideration the number of parasites in the whole system, not only in the peripheral blood, there exists, always, in pernicious fever, a considerable number of organ- isms. They have never observed a case of pernicious fever where the diagnosis was not to be made by the examination of the peripheral blood. They take up those acutely fatal cases with marked cerebral symptoms which, at autopsy, show evidences of but a slight or, indeed, of an old cured malarial infection, in association with cerebral hyper- aemia, pulmonary hypostaxis and haemorrhages, the other organs showing no grave degenerations. These cases, which occur almost invariably, at the hottest season of the year, often in individuals who work in the fields, they believe to be very possibly instances of isola- tion and not due, as some have supposed, to an unusual toxicity of the parasites. Another section of the paper treats of the period of incubation of the experimental malarial fevers, and of the nature and origin of the recrudescences and relapses. They report four new cases of experimental infection with the aestivo-autumnal parasites. In the first case the injection (how made?) consisted of 2 cc. of blood; irregular fever with the typical parasites appeared two days later. In the second case, where the parasites were few, 5 cc. were inocu-' lated with exactly the same result. In the third case, f cc. of blood produced lever in five days; the inoculated blood contained but few organisms. 214 W. S. Thayer and J. Hewetson. In the fourth case, where A cc. of blood, containing a fair number of parasites, were inoculated, the incubation period lasted four days. From a table of all observations which they have collected, they conclude that the time of incubation in the several varieties of fevers varies as follows: Maximum. Minimum. Mean. (days) (days) (days) Quartan fever 15 11 13 Tertian fever 12 6 10 Aestivo-autumnal fever 5 2 3 The cases of Antolisei and Angelini,(111) Sacharoff,(324) and Di Mat- tei/358) where the incubation period for aestivo-autumnal fever was materially longer, are not included in this list. The periods of incu- bation in these cases were respectively 9, 12, and 15 days. In the first of these cases, however, the parasites were only scanty in the inoculated blood (only crescents were seen); in the second, they had been four days in the body of a leech on ice; in the third, the blood was mixed with sterilized water. The authors conclude that " the period of incubation with one variety of parasites varies inversely with the quantity of material inoculated." The period of incubation represents " the time necessary for the inoculated parasites to reach, by multiplying, the quantity necessary to determine the fever." .... " The mean and minimum periods of incubation, under similar conditions, vary in the various groups of fevers: it is least in the aestival fevers, longer in the tertian, and still longer in the quar- tan." .... " The period of incubation in experimental malarial infection is not a constant quantity, but varies in the same group of fevers and in different groups of fevers. In the same group of fevers it depends chiefly on the quantity of the inoculated material. In different groups of fevers it varies with the rapidity of the cycle of development of the parasite and with the special capacity for reproduction of the parasitic variety." The ordinary recurrences and relapses, the authors ascribe, as they have before, to the fact that certain spores which have escaped destruc- The Malarial Fevers of Baltimore. 215 tion, continuing their development, begin again to multiply, increas- ing until the parasites have reached a number sufficient to produce fever. The length of time separating the relapse from the last attack depends on the number of organisms which have escaped destruction. Those relapses which do occasionally occur at intervals of weeks or even months from the primary attack, the authors can explain only by the hypothesis advanced first by Bignami, that certain spores which have been included by phagocytes remain a long time living. These bodies, they assert, certainly retain their form and staining properties for some time, even if they do fail to show any sign of a membrane; if they be not spores, in the proper sense of the word, yet they have some properties which seem to indicate that they possess a greater resistance. The writers state, however, that nothing appears to them " a priori contrary to the hypothesis that, of these so-called spores of malaria, some, born like all the rest without membrane, may finally acquire one." These bodies, then, might lose their staining properties and, being so small and perhaps scanty, they might escape notice. To their ultimate development, then, the relapses might be ascribed. Tn some sporozoa, for example, the Benedina octopiana, similar processes occur; the spores are born without membranes, which they afterwards acquire, losing at the same time their staining properties. Lastly, the writers report an interesting case of grave malarial infection presenting the syndroma of Dubini-the so-called "Elec- tric Chorea." The most interesting points, it appears to us, in this paper, are the views advanced concerning the crescentic bodies. Most authors have interpreted Bignami's original assertion,(179) that the crescentic bodies were " forms of a deviate and interrupted evo- lution (forme di evoluzione deviata e interrotta)," as an indication that he considered them degenerative in nature. The present theory, it is interesting to note, is similar to that recently advanced, independently, by Manson, who believes that the crescents are forms " intended to carry on the life of the species outside the human body." DESCRIPTION OF THE PLATES. The drawings* were made with the assistance of the camera lucida from specimens of fresh blood. A Winkel microscope, objective, 1/14 (oil immersion), ocular, 4, was used. Figures 4, 13, 23, 24, and 42 of Plate I were drawn from fresh blood, without the camera lucida. PLATE I. The Parasite of Tertian Fever. 1.-Normal red corpuscle. 2, 3, 4.-Young hyaline forms. In 4, a corpuscle contains three distinct parasites. 5, 21.-Beginning of pigmentation. The parasite was observed to form a true ring by the confluence of two pseudo-podia. During observation the body burst from the corpuscle which became decolorized and disappeared from view. The parasite became, almost immediately, deformed and motionless, as shown in Fig. 21. 6, 7, 8.-Partly developed pigmented forms. 9.-Full grown body. 10-14.-Segmenting bodies. 15.-Form simulating a segmenting body. The significance of these forms, several of which have been observed, is not clear to the writers who have never met with similar bodies in stained specimens so as to be able to study the structure of the indi- vidual segments. 16, 17.-Precocious segmentation. 18, 19, 20.-Large swollen and fragmenting extra-cellular bodies. 22.-Flagellate body. 23, 24.-Vacuolization. The Parasite of Quartan Fever. 25.-Normal red corpuscle. 26.-Young hyaline form. 27-34.-Gradual development of the intra-corpuscular bodies. 35.-Full-grown body. The substance of the red corpuscle is no more visible in the fresh specimen. 36-39.-Segmenting bodies. 40.-Large swollen extra-cellular form. 41.-Flagellate body. 42.-Vacuolization. * The writers desire, here, to express their gratitude to Mr. Broedel for his admir- able work. * 217 218 IF. S. Thayer and J. Hewetson. PLATE II. The Parasite of Aestivo-autumnal Fever. 1, 2.-Small refractive ring-like bodies. 3-6.-Larger disc-like and amoeboid forms. 7.-Ring like body with a few pigment granules in a brassy, shrunken corpuscle. 8, 9, 10, 12.-Similar pigmented bodies. 11.-Amoeboid body with pigment. 13.-Body with a central clump of pigment in a corpuscle, showing a retraction of the haemoglobin-containing substance about the parasite. 14-20.-Larger * bodies with central pigment clumps or blocks. 21-24.-Segmenting bodies from the spleen. Figs. 21-23 represent one body where the entire process of segmentation was observed. The segments, eighteen in number, were accurately counted before separation, as in Fig. 23. The sudden separation of the segments, occurring as though some retaining membrane were ruptured, were observed. 25-33. Crescents and ovoid bodies. Figs. 30 and 31 representone body which was seen to extrude slowly and, later, to withdraw two rounded protrusions. 34, 35.-Round bodies. 36.-" Gemmation," fragmentation. 37.-Vacuolization of a crescent. 38-40.-Flagellation. The figures represent one organism. The blood was taken from the ear at 4.15 p. m.; at 4.17 the body was as represented in Fig. 38. At 4.27 the flagella appeared; at 4.33 two of the flagella had already broken away from the mother body. 41-45.-Phagocytosis. Traced by Dr. Oppenheimer with the camera lucida. * It is unfortunate that the plate does not contain a few examples of larger forms with central pigment blocks. The writers have drawings of several as large as the segmenting body in Fig. 21. • The Johns Hopkins Hospital Reports. Vol.V. Plate I. The Parasite of Tertian Fever. The Parasite of Quartan Fever. Lith.Anst.vE.AFurike. Leipzig. The Johns Hopkins Hospital Reports. Vol.V. Plate II The Parasite of Aestivo Autumnal fever. Lith. Anst.vE. A. Funke, Leipzig TYPES OF MALARIAL FEVER OBSERVED IN BALTIMORE AND THEIR RELATIONS TO THE SEASONS OF THE YEAR. by William Sydney Thayer, M. D. Associate in Medicine in the Johns Hopkins, University; Resident Physician to the Johns Hopkins Hospital. Reprinted from the Maryland Medical Journal, June 15, 1895. Since the discovery of the malarial parasite in 1380, by Laveran, all observers who have been placed in a position to pursue satisfactory studies of the malarial fevers have been able to confirm his observations, and the dependence of the malarial fevers upon infection with a specific micro-organism may be considered a proven fact. Certain observers, however, particularly those in Italy, have greatly extended the orig- inal discoveries, separating the malarial parasite into several distinct types or varieties, each type of parasite being associated with a distinct type of fever. Some observers have denied the possibility of such further divisions of the parasites, but most clinicians, with a satisfactory raterial at their service, have recognized the existence of different types. The studies of the Italian observers have shown that, while there is a considerable similarity between the dif- ferent forms, three distinct varieties of the parasite may yet be distinguished: 1. The parasite of tertian fever. 2. The para ite of quartan fever. 3. The parasite of the more irregular fev- er, occurring chiefly in the summer and fall, the so-called "estivo-autumnal fever." It has been shown that in all these forms, the parasite, at its earliest stage, penetrates the red blood corpuscle,- within which it develops accumulating pigment at the expense of the hemo- globin of the corpuscle and finally, having de- stroyed its host and reached its complete develop- ment, the parasite undergoes sporulation, breaking up by segmentation into a number of fresh young forms - gymnospores - which, each attacking a new corpuscle, begin again their cycle of development. The parasites of the regularly intermittent, tertian and quartan fevers possess the very remarkable characteristic of being associated in the blood in large groups, all the members of which are practically at the same stage of development. Thus the millions of parasties which may constitute such a group pass through their cycle simultaneous- ly, all the parasites reaching their full devel- opment, and undergoing segmentation practically at the same time, that is, within a period of several hours; and what is most interesting is always immediately followed by the febrile paroxysm. THereare many facts which tend to show that the paroxysm depends upon some toxic substance set free in the blood at the time of the sporulation of the parasites. The parasites of tertian fever, for exam- ple, have a cycle of existence lasting about 43 hours, toward the end of the period the or- ganismf, having reached their complete develop- ment, undergo sporulation and in direct associa- tion with this segmentation of a group of parasites occurs the malarial paroxysm. It might thus be easily conjectured that infection with a single group of tertian parasites would result in a paroxysm every third day - which is the case. But in many infections with the tertian parasite we see daily paroxysms. In these instances we have to do with infections with more than one group of parasites, usually with two groups reaching maturity on alternate days, and producing, thus, daily paroxysms- "double tertian" infections. The parasite of quartan fever passes through a cycle of development lasting about 72 hours and when present as a single group produces fever every fourth day. It is easy to understand how infections with both of these groups of the quartan organism produce double or triple fever; in the one case con- sisting of chills on two successive days with an intermission on the third day, and in the other, daily chills. The third variety of parasite, the estivo- autumnal parasites, does not possess to the same degree the characteristic of being present in sharply defined groups at the same stages of development. There are often multiple groups of parasites or parasites in different stages of development present at the same time. Sporulation thus occurs frequently and at irregular intervals, resulting in a more irregular and often continuous fever. The Roman observers have noted that while the earlier cases of malarial fever, those occurring in the winter and spring consist, almost entirely,, of the regular intermittent varieties, the tertian and quartan fevers, those occurring in the summer and fall are, however, much more severe in nature, more irregular in their manifestations and are asso- ciated with the third variety of parasites - the parasite of estivo-autumnal fever. Some Italian observers have gone yet further, dividing the estivo-autumnal paras- ites into two or even three distinct varieties and associating these with different types of fever. This, however, the majority of observers have not succeeded in doing. During the last two years Dr. Hewetson and the writer have been engaged in analyzing all the oases of malarial fever occurring at the Johns Hopkins Hospital. The results have confirmed almost entirely the Italian observations. A few of our results which will appear short- ly in a volume of the hospital reports I will briefly mention. Our cases numbered 614, not including relapses of cases once included in the list. The following tables show the relation of the cases to the time of year: There occurred in- January, ... 12 July,........74 February,.. 8 August, .67 March,.....18 September,..129 April,.....28 October,....137 May, 35 November,... 45 June,....33 December,... 28 Total 614 From this table it appears that while in the winter months, December, January, February and March, malarial fever is at a minimum, the number of cases begins to increase, as a general thing, with the month of April showing a gradual steady rise until the climax, which occurs in the months of September and October. In November and December a well marked fall begins. This table, while it gives a good general idea of the distribution of the malarial infection throughout the year, is, however, a trifle misleading if taken too strictly. The cases during the latter half of the year 1889 were few, as the hospital was new and the clinics had not yet developed, while the cases from January to August of 1894 represent a much larger clinic. The proportion of cases occurring in the first seven months is thus over-represented, while the second half-year suffers, the under-representation of the cases in August being especially marked. The follow- ing table dealing with the cases during the four years from January 1, 1890, to January 1, 1894, gives a more accurate representation of the variation of malarial fever with the seasons. Table showing the dates of admission of the cases of malarial fever between January 1, 1890, and January 1, 1894; January,... 9 July, 38 February,.. 8 August, 66 March, 8 September,... 122 April,.....17 October,•••••120 May,.......21 November,.... 38 June, 18 December,.... 25 Total,...490 It may thus be seen that more than five- sixths of the oases of malaria observed by us occur in the second half-year, while nearly one- half occur in the months of September and October. We have distinguished three varieties of the malarial parasites: (1J The tertian parasite. (2) The quartan parasite. (3) The estivo- autumnal parasite. 1. The tertian parasite requires about forty-eight hours to accomplish its complete development, and is associated with relatively regular tertian paroxysms, lasting, on an average, between ten and twelve hours, associated almost always with the three classical stages- chill, fever and sweating. Frequently, infection with two groups of tertian organisms gives rise to quotidian paroxysms; rarely, infection by multiple groups of organisms gives rise to more irregular, sub-continuous fevers. 2. The quartan parasite is an organism requiring about seventy-two hours for its complete development. It is rare in this climate and is associated with a fever showing regular quartan paroxysms, similar in nature to those associated with the tertian organism. Infection by two groups of the parasite causes a double quartan fever (paroxysms on two days, intermission on the third). Infection, with three groups of the parasite, is associated with daily paroxysms. 3. The estivo-autumnal parasite passes through a cycle of development the exact length of which has not, as yet, been determined; it probably varies greatly from twenty-four hours or under, to forty- eight hours or more. But few stages of development of the parasite are found, ordinarily, in the peripheral circulation, the main seat of infection being, apparent- ly, in the spleen, bone-marrow and other internal organs. Infection with this organism is associated with fevers varying, greatly, in their manifestations. There may be quotidian or tertian intermittent fever, or, more commonly, more or less continuous fever with irregular remissions. The individual paroxysms last, on an average, about twenty hours, the irregularities in temperature depend, probably upon variations in the length of the cycle of development of the parasite, or upon infection with multiple groups of organisms. We have not been able to separate varieties of the estivo- autumnal parasite, though we feel that more investiga- tion is needed upon that sabject. The relation of the occurrence of these different types of fever to the time of the year is shown by the following tables. Thus in the first half-yesr there were: (Single 63 Tertian infection (Double 49 T1T- Quartan infection (Single 1 (Double 0 (Triple 0 I" Estivo-autumnal infection 5 Combined infections 3 Total 121 While in the second half-year there were: (Single 87 Tertian infection (Double 139 'TST' (Single 1 Quartan infection (Double 0 (Triple 3 Estivo-autumnal infection 183 Combined infections 8 Total•••••••••. 421 These tables show in an interesting manner how the severity of the type of infection increases as the summer and fall approaches; Thus in the first half-year we have more single tertian than double infections; while in the second half-year, when malarial fever assumes a more severe type, we have nearly twice as many cases of double tertian as of single tertian infection. The increasing severity of the type of malarial fever becomes more marked when we observe the course of the estivo- autumnal cases. While in the first half-year only five cases were noted, a little less than one- twenty-fourth of the total number of cases observed, in eighty-three cases, or nearly an half of all the cases which occurred. Thus it may be seen that with the earliest cases of malarial fever in the year, the mildest types of infection are met with, the single tertian type predominating. As the season advances and the months approach which are richest in malarial fever, -the single tertian cases become less frequent and the double tertian infections more common while at the height of the malarial season a majority of the cases are of the estivo- autumnal, the most severe type in this climate. It has seemed to us, however, a matter of inter- est to make another table, which appears below, showing the time at which the patient observed the first symptoms of the . "ection; this shows several interesting variations from the other table. January,.... 8 July,... 93 February,... 2 August, 103 March,......21 September156 April, 21 October,.... 69 May, 44 November,... 16 June, 23 December,... 9 Not stated, 60 Total,.. 614 We see thus that the smallest number of cases occurred in the months of December, January and February, only two cases beginning during the month of February. From xhis time on there is a fairly steady increase until the month of May, which shows the spring mad- imum; in July again an increase begins, reaching the climax in September, when 156, or more than one fourth of all the cases, appear to have shown their first symptoms; 103 cases originated apparent- ly in August, while only 69 appear to have origin- ated in October; in 50 cases the date of onset could not be obtained. Thus nearly one-half of all the cases originated in the months of August and September, and whereas 137 cases were first admitted to treatment in October, only 68 dated their symptoms from that time. Another interesting point brought out by our tables is the fact that while of all the cases observed, 21 per cent date their apparent origin to the first 3 months of the year; of the first attacks, only 15 per cent, originated during this period. Whether this means that a number of cases which were considered fresh infections were really relapses of old attacks or that the indi- vidual who has once suffered from dual fever is more subject to future infection is not yet clear. Acrcte Pancreatitis-Parapancreatic Abscess -Disseminated Fat-Necrosis. BY W. S. THAYER, M.D., ASSOCIATE IN MEDICINE IN THE JOHNS HOPKINS UNIVERSITY; FIRST ASSISTANT IN THE MEDICAL CLINIC AT THE JOHNS HOPKINS HOSPITAL. FROM THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES, October, 1895. Reprinted from The American Journal of the Medical Sciences, October, 1895. ACUTE PANCREATITIS-PARAPANCREATIC ABSCESS- DISSEMINATED FAT-NECROSIS.1 By W. S. Thayer, M.D., ASSOCIATE IN MEDICINE IN THE JOHNS HOPKINS UNIVERSITY ; FIRST ASSISTANT IN THE MEDICAL CLINIC AT THE JOHNS HOPKINS HOSPITAL. W. D., aged thirty-four years, married, piano-polisher. Family history. Father died of "old age," at seventy-eight years; mother died of " dropsy;" six brothers and four sisters living; one brother died at the age of thirty-seven of apoplexy; no history of tuber- culosis in any branch of family. Personal history. As a child had chicken-pox ; pneumonia at the age of six years ; has been married thirteen years ; has had no children. For years he has been a regular drinker of beer and whiskey ; he usually takes a drink of whiskey in the morning before breakfast; sometimes more in the day ; smokes and chews tobacco. Five years ago the patient states that he was overcome by heat. He was in bed a week, and unconscious at times during that period. Ever since this at- tack he has had, at times, peculiar " scary spells," a nervous dread of some impending disaster. For about two years he has been subject to nausea in the morning; at times he vomits a greenish, slimy substance. Frequently he vomits his breakfast on account of this feeling of nausea. For the last year and a half the patient has had several attacks of very severe cramp-like pain in the abdomen. The pains are localized in the median line, across the epigastrium and about the umbilicus. The first attack came on at night, and was very severe. The pains are relieved only by morphine, which has been administered in large doses. After the sleep following the relief given by morphine, the patient is free from pain, but with each attack he has generally remained away from work and in the house for from several days to a week. He thinks he has had fever with these attacks, which are also often associated with vom- iting. He has had, in all, three or four paroxysms of this nature. The attacks have never been associated with jaundice. On Friday, the 15th of June, 1895, the patient came home from work on account of a slight sensation of heaviness in the epigastrium and an anxious feeling which he had noticed before to precede the attacks of pain. On Friday night the pain became very severe, and was associ- ated with vomiting. The pain was intense and continuous, and a swell- ing was noticed just above the umbilicus, in the area of greatest tender- ness. There was constipation. During the next week the patient was in bed ; at times he was delirious; there was continuous fever; a diag- nosis of abscess of the liver was made by his physician. On June 25th the patient was admitted to the Johns Hopkins Hos- pital, operation having been advised. He was admitted to the surgical department of Professor Halsted, Dr. J. M. T. Finney in charge. To 1 Read before the Johns Hopkins Hospital Medical Society, Jan. 7,1895. 2 THAYER: ACUTE PANCREATITIS the courtesy of Professor Halsted and Dr. Finney I owe the oppor- tunity of examining and following this case. I saw the patient shortly after his entry, and made the following note: " On physical examination the patient is a well-formed man, quite corpulent; lips and mucous membranes of good color. The tongue is coated, the temperature elevated ; the mental condition dull; the patient is a little confused. Examination of the thorax is negative. On inspec- tion the abdomen is full, showing a rather undue prominence in the median line across the epigastrium. Hepatic flatness begins at the sixth rib in the mammillary line, while in the same line the lower border of the liver can, apparently, be felt about on a level with the umbilicus; it is not, however, very distinct, owing to the tension of the abdominal muscles. Liver-flatness is coextensive with this area. Passing toward the median line the resonance becomes tympanitic. Just below the xiphoid cartilage the resonance is loudly tympanitic, and from the sen- sation conveyed by palpation there is evidently an air-containing organ (stomach?) just below the skin. Below, between this and the umbili- cus, at the point of maximum prominence, is to be felt a deeply-seated mass, over which there is well-marked tympany. The outline of the mass is indistinct. It is not tender on ordinary palpation. To the right this mass is not to be sharply separated from what would appear to be the liver ; to the left it reaches about to the costal region. Pressure over the lower left ribs does not cause pain. In the knee-elbow position nothing further is to be made out. Splenic duluess is about normal in area, and does not pass the costo-articular line. There are no glandular THAYER: ACUTE PANCREATITIS. 3 enlargements." The appended chart, made at the time of this examina- tion, shows the position of the deep mass, of the hepatic dulness, and the epigastric tympany. The urine was free from albumin or sugar. The blood showed a leucocytosis. From the fever and general condition of the patient it was believed that there was an acute intraperitoneal inflammatory process. Though the mass was not distinctly fluctuating, it gave, on palpation, the im- pression that it contained fluid, and the diagnosis lay between an he- patic abscess, an abscess resulting from perforation of the stomach or in- testine, and an acute inflammatory process, starting, probably, from the pancreas. While no sharp separation could be made out between the deep mass and the liver, the absence of motion on deep inspiration, the sharp outline of the hepatic dulness, the loss of the lower border of the liver, which was to be made out on palpation to the right of the mass, as well as the entire absence of jaundice, made the presence of an he- patic abscess improbable. A fecal abscess was not to be definitely ruled out, though the situation was certainly unusual. There was nothing in the history of the case to suggest the existence of a perforating gastric or duodenal ulcer. Nothing pointed to implication of the gall-bladder. On the other hand, the situation of the mass, which was deep, was ex- actly that of the pancreas. The history of the case was, also, not un- like that in other cases of acute pancreatitis which have been reported. The patient was a fat man, with a somewhat alcoholic history. There had been several sharp attacks of pain, localized quite definitely in the pancreatic area, associated with fever, vomiting, and collapse. That the mass might be a pancreatic cyst, or a cyst of the lesser omentum, ap- peared improbable, owing to the suddenness of the appearance of the tumor, to the inflammatory nature of which the fever and general symp- toms strongly pointed. The diagnosis, then, of acute pancreatitis with disseminated fat-ne- crosis, and possible sequestration of the pancreas, was made, and an ex- ploratory operation advised. The operation was performed under ether, on June 27th, by Dr. Fin- ney. An incision was made in the median line above the umbilicus. On opening the peritoneal cavity the large right lobe of the liver was found on the right, much as indicated by the dulness upon the chart. In the median line, adjoining the liver and stomach, a mass of adher- ent fatty tissue was found, which was filled with numerous discrete and confluent small, opaque, yellowish-white nodules, presenting the charac- teristic appearance of disseminated fat-necrosis. This mass of tissue was adherent to the stomach and to the liver. Involved in the adhesions over the lower part of the opening passed the transverse colon. The general abdominal cavity was packed off with gauze, and an opening was left for future drainage. For the next several days the temperature remained somewhat ele- vated, but the general condition of the patient was fairly good. On July 3d, on dressing the wound, the tumor-mass was found to have diminished considerably in size. On the 5th and 6th of July the patient was restless, nauseated, and, at times, delirious. On the evening of the latter date a small coil of intestine was expelled, on coughing, from the lower end of the wound ; it was returned without subsequent trouble. 4 THAYER: ACUTE PANCREATITIS. At 10 p.m. on the 7th an examination was made by Dr. Halsted. The examining finger opened, in the upper angle of the wound, a large cavity containing thick, brownish-yellow pus and large masses and shreds of necrotic fat. The finger passed far backward at the bottom of the wound into what appeared to be a cavity in the pancreas. The main excavation represented, evidently, the lesser peritoneal cavity. A drainage-tube was placed in the wound, which continued to discharge. Several days later the wound presented an interesting appearance. Across the middle of the incision stretched the transverse colon, which presented a raw and granulating surface, while above this an opening extended into the large cavity, discharging creamy pus and large masses of necrotic fatty tissue. The cavity was drained freely, and slowly granulated and contracted, while the general condition of the patient improved greatly. The patient left the hospital on the 23d of September, feeling quite well. The wound at this time was entirely closed excepting for a small sinus, which was two inches deep and one and a half inches in diameter. The discharge from the cavity on the day after the opening was made showed pus-corpuscles, bacteria in great quantities, numerous fatty acid crystals, with large and small masses of necrotic fat. Cul- tures were, unfortunately, not made, the opening occurring unex- pectedly. No tissue which could be identified as pancreatic was found in the discharge. Some of the detritus discharged from the wound was placed in alcohol and hardened, while sections were examined under the microscope. These masses proved to consist simply of necrotic fatty tissue. Several small pieces of the fat found at the first operation were removed and sent to the pathological laboratory, to Dr. Barker, who made the following report: " The naked eye shows here and there in the tissue opaque white areas which are entirely different in appearance from the rest of the fat. They remind one of particles of tallow; they are slightly grayish and inclined to be granular. Under a low power one observes masses which tend toward a spherical shape, though they are often irregular in outline, with a peculiar yellowish tint. Some of the masses appear more or less homogeneous, showing fissures, transverse or radiating from the centre, not unlike the appearance of hyaline muscle in infectious diseases. Other masses of similar size are seen under the high-power to consist of myriads of short acicular crystals arranged usually more or less ir- regularly, sometimes radially placed. There are many single crystals and bundles of crystals, resulting evidently from the breaking up of these masses. Some of the large, apparently homogeneous bodies show within them what appear to be large radiating crystals, resembling the so-called margarine crystals. In addition to these there are numerous small masses, the substance of which, in its homogeneous appearance, resembles much that of the larger homogeneous bodies. "On application of heat, after mixing the mass with salt-solution, the homogeneous bodies become flatter, sometimes fuse, and show still more the appearance of hyaline muscle. " On heating the tissue with cold glacial acetic acid the crystals and masses are rapidly transformed into fat-droplets. Each single crystal can be watched changing into a fat-droplet. Many of them which meet one another fuse. There is a marked activity in the masses with THAYER: ACUTE PANCREATITIS. 5 an almost immediate transformation of the substance into minute fat- droplets. These remain separate for awhile, but later fuse, especially if the cover-glass be pressed. There is a rapid appearance of fat-drops at the edge, with violent streaming movements. Toward the centre the action is very slow and the acicular crystals become at first much more distinct. Both the crystals and the homogeneous substance dissolve. " On treating with hot glacial acetic acid there is a rapid transforma- tion into fat-globules. In sections the same process takes place, large, clear spaces of fat being seen in the transparent tissue. " The masses do not dissolve in absolute alcohol nor in ether. " 20 per cent, hydrochloric acid in 70 per cent, alcohol acts as does cold glacial acetic acid, though rather more rapidly. Pure hydro- chloric acid produces, also, the same changes. " 10 per cent, caustic potash, hot or cold, produces no marked change. " Oxalic acid alone has no special influence, but, after treating the nodules of fat-necrosis with glacial acetic acid, the subsequent addition of oxalic acid gives an immediate white precipitate, while later typical crystals of calcic oxalate may be made out microscopically." These observations confirm entirely the views of Langerhans,1 who demonstrated that these fat-necroses consisted of a combination of lime with fatty acids. Cultures on slant agar from the necrotic areas and from the adjacent tissues were negative. Cultures made at the operating-table from similar areas were also negative. The operation, then, revealed a deep-seated abscess occupying the lesser peritoneal cavity, arising apparently from the pancreas. This was associated with extensive disseminated fat-necrosis. Acute inflammatory affections of the pancreas have occupied con- siderable attention during the last five years, since the appearance of Dr. Fitz's Middleton-Goldsmith Lectures on Acute Pancreatitis.2 Fitz collected from his own cases and literature fifty-four examples of acute pancreatitis, where satisfactory accounts of the cases were given, as well as sixteen cases of extensive hemorrhage from the region of the pan- creas. From careful analysis of these cases he concluded that acute inflammation of the pancreas was a " well-characterized disease," one which could and should be more often recognized. He divided these cases into three main classes: (1) suppurative pancreatitis; (2) hemor- rhagic pancreatitis ; and (3) gangrenous pancreatitis. (1) In suppurative pancreatitis there exists an acute purulent inflam- mation of a smaller or larger part of the pancreas. (2) In hemorrhagic pancreatitis the process consists of an acute cellular or fibrino-cellular infiltration of the connective tissue of the organ with a more or less extensive necrosis of the lobules. This inflammatory 1 Verhandl. d. x. Internal, med. Cong., Bd. ii. abth. iii. p. 144, Berlin, 1891,8vo., and Virchow's Archiv, Bd. 122, p. 252, 1890. 2 Acute Pancreatitis, Boston, 1889, 8vo. Also Bost. Med. and Surg. Journal, v. xxi. pp. 181, 205, 227, 1889. 6 THAYER: ACUTE PANCREATITIS. process is associated with numerous diffuse hemorrhages throughout the organ ; these may sometimes be quite extensive ; these cases are not to be confused with those instances of extensive apoplectiform hemorrhage which are not so uncommon in the pancreatic region. (3) The gangrenous pancreatitis appears in many cases to be an after- result of an attack of acute hemorrhagic pancreatitis. Here the peri- toneal covering of the pancreas may be destroyed, while large or small portions of the organ may be sequestrated. Perforation into neighbor- ing organs may occur, and discharge of the necrotic pancreas by the rectum has been noted in two instances. Disseminated fat-necrosis was noted in nearly half of the cases of hemorrhagic and gangrenous pancreatitis ; it was less commonly seen in the suppurative forms. Clinically the symptoms presented by these cases formed quite a striking picture, consisting usually of1 "sudden, severe, often intense, epigastric pain, without obvious cause, in most instances followed by nausea, vomiting, sensitiveness, and tympanitic swelling of the epigas- trium. There are prostration, often extreme, frequent collapse, low fever, and a feeble pulse. Obstinate constipation for several days is the rule, but diarrhoea sometimes occurs. If the case does not end fatally in the course of a few days, recovery is possible, or a recurrence of the symp- toms in a milder form takes place, and the characteristics of subacute peritonitis are developed." The cases of hemorrhagic pancreatitis are usually very acute and often fatal within a few days. When the pro- cess is not immediately fatal it may last a little longer, going on pos- sibly to sequestration and gangrene. The cases of suppurative inflam- mation of the pancreas may, in some instances, last for weeks or months. The differential diagnosis, according to Fitz, lies " between an irritant poison, perforation of the digestive or biliary tract, and acute intestinal obstruction." Since the appearance of this paper a considerable number of cases of acute pancreatitis have been reported by Dr. Fitz2 himself and by other authors. The study of the literature shows that most of the cases would fall under Fitz's headings of hemorrhagic or gangrenous pan- creatitis, where this case also probably belongs, the extensive para- pancreatic abscess being probably a secondary process. A case which was very similar to that above reported was noted by Walsh.3 Here a similar abscess was found and successfully drained. The symp- toms had been of six months' duration, consisting of " sharp burning pains in the epigastric region and tenderness on pressure." The physical examination showed " an area of dulness extending from the ensiform 1 Loc. cit., p. 89. 2 Trans. Assoc. Amer. Phys., 1890, p. 191, and Bost. Med. and Surg. Journal, vol. cxxvii. p. 573. 8 Medical News, Phila., Dec. 1893, p. 737. THAYER: ACUTE PANCREATITIS. 7 cartilage half way to the umbilicus and reaching to the left costal area." The cause of these inflammatory processes is not by any means entirely clear. Fitz1 believes that they are due in most instances to infectious agents entering through the pancreatic duct. The presence of biliary or pancreatic calculi seems to be somewhat favorable to their develop- ment. One of the most interesting points, however, in connection with these cases of acute pancreatitis is the frequent association of the condition which was first described by Balser2 as disseminated fat-necrosis. The very common association of fat-necroses with acute pancreatitis naturally suggests that there is some close relation between the two processes, and the views as to the nature of these fat-necroses and as to their asso- ciation with acute pancreatitis it may not be uninteresting to summarize. Balser believed these areas to be due to an excessive growth of fatty tissue, which destroyed the tissue which it surrounded, the central por- tions of fat becoming necrotic from lack of nutrition. He found these areas of fat-necrosis in the interlobular fat in a number of bodies where no special symptoms had been present during life. The changes in the pancreas he believed to be secondary. Chiari3 was unable to find any evidence of this overgrowth of fatty tissue and regarded the process as degenerative, the result simply a con- dition of general marasmus. Fitz4 is inclined to believe in two varieties of fat-necrosis; first, a simple " necrobiotic " fat-necrosis, which has, he believes, no direct re- lation to severe pancreatic lesions ; and secondly, an inflammatory fat- necrosis, which he believes to be generally secondary to an acute inflam- mation of the gland. This process may be extensive and lead to seques- tration of the organ. The fat-necroses are not the cause of the hemor- rhages in hemorrhagic pancreatitis. The hemorrhages result from the infectious process, which is also the cause of the necrosis. The inflam- matory nature of these areas, Fitz believes, is suggested by the round- celled infiltration which one always finds about their periphery, and by the fact that microscopically he has, in several cases, demonstrated the presence of bacteria in or about the affected spots. Langerhans3 in two interesting communications demonstrated that the substance of these necrotic areas consisted in a combination of cer- tain lime salts with fatty acids. These observations Prof. Welch has been able to confirm in a number of instances. The observations of Dr. Barker in this case were also wholly confirmatory of these views. Trans. Assoc. American Phys., 1890. Virch. Archiv, Bd. 90, S. 520,1882. Prager med. Woch., 1893, No. 30, S. 285, and No. 31, S. 299. Acute Pancreatitis, Boston, 1889, 8vo. 6 Loc. cit. 8 THAYER: ACUTE PANCREATITIS. Later Langerhans1 makes the interesting suggestion that the process may possibly result from the action of the fat-splitting ferment from the pancreas upon the surrounding fat-tissue, the fatty acids entering after- ward into combination with lime. He asserts that in one instance he has been able to produce similar changes in the subcutaneous fat of a dog by the injection of an extract of the pancreas.2 Rolleston3 suggests that they are rather due to some trophic influence exerted by the abdominal sympathetic system, which is very probably affected in most of these instances by the extension of some morbid process from the pancreas. Balser4 in* 1892 made a preliminary communication in which he stated that in certain areas of fat-necrosis in hogs he had found num- bers of fine rod-like bodies collected often into aster-like masses. These rods were somewhat thickened at one end, resembling the " clubs " of actinomycosis. From their staining-reactions he believed that they were not crystals but bacteria. Culture-experiments, though unfinished, showed growths of a short rod-like bacterium. No further communication on the subject has, however, appeared. Prof. Welch5 in 1891 obtained the bacillus coli communis in pure culture from areas of fat-necrosis associated with acute hemorrhagic pancreatitis. There was, however, a general colon infection following extensive intestinal ulceration, and it is explicitly stated in Dr. Welch's note that he is of the opinion that the fat-necroses were not the result of a primary colon infection. It was more probable, in his opinion, that the organisms gaining entrance into the system through the intestinal ulceration reached these areas which already existed. In a number of other instances since then culture-experiments by Prof. Welch have remained entirely without result. The true cause, then, of these fat-necroses is not entirely settled. No one to-day believes in the original views of Balser with regard to the overgrowth of fatty tissue. Rolleston's idea is ingenious, but purely speculative. It is an undoubted fact, as pointed out by Balser, that fat-necroses may be found in a very considerable number of instances in the inter- lobular pancreatic fat of individuals who have shown no symptoms 1 Festschrift R. Virchow, Berlin, 1891. 2 Hildebrand recently experimented by tying the pancreatic duct in cats, and in other cases introducing pieces of pancreas into the abdominal cavities of other animals. He asserts that wherever the tissues were exposed to the action of pancreatic juice, alterations resulted which were identical to the fat-necroses observed in man. His experiments led him to believe that these changes are due to the fat-splitting ferment, not to trypsine. La Semaine M6dicale, April, 1895, p. 193. 3 Trans. Path. Soc., London, 1893. 4 Verhandl. d. xi. Cong. f. Innere Med., Wiesbaden, 1892, p. 451. 6 Medical News, 1891, v. lix. p. 669. THAYER: ACUTE PANCREATITIS. 9 pointing to the process during life. These observations have been fre- quently confirmed in the pathological institute of this university. It is also undoubtedly true that in many of these instances there is no gross evidence of pancreatic disease, while in the great majority of the cases there is nothing to suggest that the condition is purely necrobiotic or marantic. In a like manner it is difficult to account for these ne- croses by the assumption that they are of infectious origin, particularly in that cultures have so often proved entirely sterile. Especially sug- gestive is the fact that even in cases associated with marked pancreatitis of undoubted infectious nature cultures have also been sterile. The exact etiological relation of disseminated fat-necrosis to pancreatic disease is not, then, by any means settled. That the process may occur without evidence of pancreatic disease is undoubted. In these instances, however, the areas are almost always limited to the interlobular fat-tis- sue of the pancreas. On the other hand, it is very probable that the great majority of cases of acute pancreatitis are associated with this pro- cess, a proportion probably much larger than indicated by the cases originally collected by Fitz. The writer has had the good fortune to observe, in the past six years, six cases of acute pancreatitis at autopsy and one at operation. Four of these cases he has been able to follow clinically. In six of these seven instances the process was associated with disseminated fat-necrosis. The only instance in which this association was not present was a case of a small abscess in the pancreas involving an area no larger than a walnut. Here the symptoms produced were not referable to the pan- creas, but to complete biliary obstruction caused by implication of the common duct, This case was reported by Dr. Fitz in 1890.1 While, as has been said, the relation of disseminated fat-necrosis to acute pancreatitis is not definitely settled, the researches of I. angerhans are certainly very suggestive. The process seems in almost all instances to take its origin from the region of the pancreas. The affected areas are usually quite sterile. It has, apparently, been shown that exactly similar changes may be produced by the action of pancreatic juice upon fatty tissue. In the great majority of instances of acute pancreatitis these areas are present. The pancreatic affection would seem in these instances to be certainly infectious in origin, while the individual areas of fat-necrosis are sterile. In view of these facts one can but recognize the possibility that the sequence of events may be, as suggested by Langerhans, a primary lesion of the pancreas which offers the opportu- nity for the escape of the fat-splitting ferment from the organ into the surrounding tissue, and secondary disseminated fat-necrosis, which is inflammatory only in its remote origin; this, by its extension and 1 Trans. Assoc. Amer. Phys., 1890. 10 THAYER: ACUTE PANCREATITIS. progress, may lead to most serious results (sequestration, gangrene of the pancreas, parapancreatic suppuration). In this particular in- stance it is probable that the primary process, whether in the pan- creas or in the fatty tissue, was of some duration, as testified to by the several attacks from which the patient had suffered during the past two years. Clinically the case is of considerable interest in showing the possibility and importance of early diagnosis and operation in certain cases of acute pancreatitis. It is, I believe, the second case reported in literature in which a correct diagnosis of acute pancreatitis has been made-the first in which the diagnosis has been followed by a successful operation. That recovery may occur where the process has been most extensive has been shown by the cases of Trafoyer1 and Chiari,2 where large portions of the necrotic pancreas were passed by the rectum. This, however, is an outcome which we can expect in but a small proportion of the cases. The great majority, if not fatal during the first few days, would lead probably to a fatal general peritonitis. It is probable, then, that in a certain number of instances where the process is not acutely fatal, and yet is followed by extensive suppuration or sloughing, timely operation may, as in this case, save the life of the patient. [Since this article was written two very similar cases have been re- ported, in each of which an ante-mortem diagnosis was made. In the first case, reported by Korte {Semaine Medicale, April, 1895, p. 193), operation and drainage were followed by temporary relief. The patient died, however, eight days later. In the second case, reported by Atkinson, an operation was not at- tempted (Journ. of the Amer. Med. Assoc., 1895, xxiv. p. 999). Cutler {Boston Med. and Surg. Journal, 1895, cxxxii. 354) reports also two cases of acute hemorrhagic pancreatitis, in one of which an ante-mortem diagnosis was made.] 1 Wiener med. Woch., 1880, xxx. 139,164. 2 Ibid. p. 142 ^ipericai) Journal ofthe MEDICAL SCIENCES. MONTHLY, $4.00 PER ANNUM. WITH 1895 The American Journal of the Medical Sciences enters upon its seventy- sixth year, still the leader of American medical magazines. In its long career it has developed to perfection the features of usefulness in its department of literature, and presents them in unrivalled attractiveness. 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ARCHIVES / DE MEDECINE EXPERIMENTALE ET D'ANATOMIE PATII0L0G1QUE FONDEES Par J.-M. CHARCOT PUBLIEE8 PAR MM. GRANCHER, JOFFROY, LEPINE, STRAUS Secretaire de la redaction : R. WURTZ EXTRAIT Endocardite ulcereuse blennorrhagique. Seplicdmie d'origine blennorrhagique; par MM. W.-S. Thayer et G. Blumer. (Arch, de Medecine experim. et d'Anatomie pathol. N° 6 - ler Novembre 1895). PARIS G . MASSON, EDIT EUR 120, BOULEVARD SAINT-GERMAIN Les communications relatives a la redaction doivent dtre adressees a M. Ie Dr WURTZ, 67, rue des Saints-Pdres, Paris CONDITIONS DE LA PUBLICATION Les Archives de Medecine experimentale et d'Anatomie pathologique paraissent tons les deux mois et torment chaque amide un volume d'environ 700 pages avec planches noires et en couleurs. PRIX DE L'ABONNEMENT ANNUEL Paris, 24 fr. - Departements, 25 fr. - Union Postale, 26 fr. Les Abonnes aux Archives de Physiologic normale et pathologique out droit a une reduction de 2 francs sur le prix de 1'abonnement, Les Auteurs des memoires re^oivent gratuitement 50 exem- plaires a part de leurs memoires. Ils peuvent en faire tirer, a leurs frais, un nombre plus considerable, apres entente prealable avec Pimprimeur. Les tiragcs a part ne peuvent, en aucun cas, etre mis dans le commerce. II ENDOCARDITE ULCEREUSE BLENNORRHAGIQUE SEPTIC^MIE d'oRIGINE BLENNORRHAGIQUE PAR MM. William Sydney THAYER M. D. et George BLUMER M. D. Associate in medicine A I'universite John Assistant de pathologie A 1'universite John Hopkins A Baltimore. Hopkins. Chef de Clinique midicale A 1'hdpital John Hopkins. Les observations cliniques de complications cardiaques survenant an cours de la blennorrhagie ne sont point une nouveaute. D'apres la note de Brandes', un bon nombre de cas de soi-disant endopericardites blennorrhagiques ont et<S publies. Lacassagne2, apres avoir relate une observation personnelle, oil une pericardite aigue etait survenue dans le cours d'une blennorrhagie, conclut que : « 1° La blennor- rhagie pent se compliquer d'inflammation de toutes les sereuses; 2° la localisation particulibre dans chaque cas est determinde par la predisposition de l'indiv.idu; 3° les com- plications cardiaques sont tres rares; 4° le myocarde (peut- etre), parfois 1'endocarde, mais surtout le pericarde sont atteints. » Dans la majorite des cas on une association directe entre I'endo-pericardite et la blennorrhagie a ete demontree en clinique, une arthrite a exists en meme temps. Morel3, ce- pendant, affirme dans ses conclusions que l'arthrite n'est 1. Brandes, Arch. gin. de med., 1854, XC1V, 257. 2. Lacassagne, Arch. gen. de mid., 1872, CXXIX, 15. 3. Morel, Des complications cardiagues de la blennorrhagie, these Paris, 1878, n° 269. ARCH. DE MED. EXPER. TOME VIT. 46 702 W.-S. THAYER ET G. BLUMER. pas un intermediaire necessaire entre les lesions spyciliques et celles des membranes sereuses, quoique la coexistence de ces deux lesions soil ce qu'on observe ordinairement. I n cas de cette nature, particuliyrement interessant, 1'endo-pyricar- dite apparaissant le cinquidme jour apr6s le commencement de lecoulement urethral, sans qu'une arthrite coexistat, a der- nidrement yty rapporty par Pryvost*. Onsait bien que 1'endo- cardite et la pyricardite son! parfois des complications de la blcnnorrhagie, mais la veritable nature de ces complications et leur relation avec la lesion primitive sont loin d'dtre ylu- cidyes. Depuis la description du gonocoque par Neisser et sur- lout depuis la publication de mythodes de cultures satisfai- santes par Bumm en 18852 et Wertheim en 18923, les com- plications variees et les consequences de la blcnnorrhagie ont ete etudiees plus intelligemment et avec plus de soin. Hormis les complications ordinaires de la blennorrhagie; conjonctivite, cystite, salpingite, epididymite, arthrite et periarthrite, 1'existence de nombreuses autres complications a etc demon!rde dans ces dernieres annees;la peritonile (sur- tout chez la femme), la pleurdsie, la myocardite, des affec- tions cutanees variees, iritis, meningite, myelite, albuminu- ric, etc. Mais dans ces complications, comme dans le cas des affections cardiaques, la meme controverse sur la vraie nature du processus existe toujours. Wertheim4 a demontre claircment que 1'infection directe (par continuity) pent partir de ruterus. des trompesou de 1'ovaire, ou meme du peritoine de la femme. Le fait que le gonocoque pent causer la suppu- ration est aujourd'hui hors de doute. L'ophthalmie est aussi clairement une infection par trans- mission directe du virus. Mais si la penetration du gono- coque dans les trompes et les ovaires et dans les yeux, par transmission directe, a ete constatee, on ne pent pas en dire de meme de 1'iritis qui a etc observe dans une conjonctivite 1. Prevost, Arch. med. beiges, 1895, 5. 2. Bumm, Der Microorganismus der Gonorrhoischen Schleimhaiiterkrankun- gen, Wiesbaden, 1885. 3. Wertheim. Die ascendirende Gonorrhoe beim Weibe, Leipzig, 1892. 4. Loe. cit. ENDOCARDITIS ULCEREUSE BLENNORRHAGIQUE. 703 concomitante,ni de 1'arthrite si frequemment observee, ni de ces affections diverses qui ont ete observees dans le systeme nerveux. En effet, parmi les nombreuses complications men- tionndes ci-dessus il y en a relativenient pen que nous puis- sions attribuer a une extension par continuite de 1'infeclion, on. autant que nous pouvons le soupQonner, a une transmis- sion directe de 1'agent infectieux. Meme pour Fepididymite pour laquelle 1'extension par continuite etait generalement acceptee, 1'absence complete d'infection des voies urinaires, entre I'urethre et lepididyme, nous a forces de chercher une autre explication. Ces processus secondaires sont-ils vraiment d'origine blennorrhagique? Et, ce fait admis, quelle est leur relation avec la lesion primitive? Comme Finger1 le dit tres bien, il y a pour ces cas des hypotheses variees « a. La complication vraiment blennorrhagique est pro- duite par le gonocoque seulement. b. La maladie delamuqueuse ouvre la porte d'entree, par laquelle les microcoques pyogenes penetrent et causent la complication {infection mixte}. c. Le gonocoque produitla complication; les microcoques pyogenes entrent cependant plus tard en scene; les deux in- fections existent ensemble jusqu'a ce que le gonocoque soil remplace par le microcoque pyogbne {infection secondaire). d. La complication n est pas essentiellement de nature microbienne; elle est produite par les produits de ddvelop- pement du gonocoque dans I'urethre, et absorbes {compli- cation de nature toxiqueY » Que des infections secondaires puissent exister dans la blennorrhagie, cela a ete prouv6, et ce fait a induit certains observateurs a admettre que cela etait vrai pour tons les cas, que le gonocoque etait incapable par lui-mdme de produire des processus d'inflammation secondaire. Des observations posterieures faites a I'aide des methodes perfectionnees ont demontre que cette hypothese est fausse. 1. Finger, Arch. f. Derm. u. Syph., Wien u. Leipzig, 1891, XX VIII. 704 w.-s. THAYER ET G. BLUMER. Dans 1'arthrite qui est une complication si commune de la blennorrhagie, Petrone, en 18831, a trouve a 1'aide du microscope ce qu'il a cru 6tre des gonocoques dans une arti- culation malade. Cette observation fut suivie d'un grand nombre d'antres, mais aucune n'est vraiment demonstrative, 1" identification des micro-organismes trouves etant purement morphologique. Deutschmann, en 18902, avan^a la question d'un pas. Dans deux cas d'arthrite secondaire a 1'ophthalmie, il trouva les diplocoques caracteristiquesen forme de biscuit, qui etaient surtout situps dans le corps des leucocytes. Ces microcoques furent decolores par la methode de Gram, tandis que les tentatives de cultures faites sur les milieux ordinaires ne donnerent aucun resultat. Lindemann3 a aussi obtenu, d'une articulation atteinte d'arthrite cons^cutivement a une ophthalmic, le diplocoque caracteristique qui 6tait decolore par la methode de Gram. 11 avait aussi reussi a le cultiver (d'apr^s la methode <le Wertheim) quoiqu'il y cut contami- nation. Hock4 a reussi a trouver le gonocoque a 1'aide du microscope el a robtenir en culture pure, avec le liquide d'arthrite du genou d'un enfant atteint d'une ophthalmic blennorrhagique. Neisser3 en 1894, a trouve le gonocoque dans la cheville et 1'articulation du doigt d'un adulte, etentin Bordone-Uffreduzzi Gn'a pas settlement obtenu 1'organisme en culture pure avec le liquide d'une arthrite tibio-tarsienne, mais a reproduit une blennorrhagie typique par inoculation de la seconde generation de ces cultures dans lurethre d un homme sain, qui n'avait jamais jusqu'alors en de blennor- rhagie. Ces cas vont montrer que maintes fois les infections secondaires dans les articulations sont de vraies infections blennorrhagiques, les gonocoques atteignant les articulations sans doute, par la circulation generale. Un cas rapporte dernidrement par Finger7 est d un grand interet. Dans un 1. Petrone, Riv. clinica, 1883, 94. 2. Deutschmann, Graefes Archiv f. Opth., XXVI, abth. 1, 109. 3. Lindemann, Reitr. z. Augenheilk., 1892, I, t. V. 30. 4. Hock, Wien. kiln. Woch., 1893, n08 41, oct. 12, 73 6. 5. Neisser, Deutsch, med. Woch., 1894, XX. 484. 6. Bordone-Uffreduzzi, Deutsch, med. Woch., 1894, XX, 484. 7. Finger, Loc. cit. ENDOCARDITE LLCEREUSE BLENNORRHAGIQUE. 705 cas d'arthrite de 1'articulation du genou gauche precedee d une ophthalmic, il old inf le gonocoque en culture pure, le malade etant en vie. L'enfant fut ensuite atteint d'un phlegmon, etendu an cou et au mddiastin et mourut. A 1'autopsie des gonocoques furent trouves, a 1'etat de purete, dans une p^richondrite du cartilage d'une cote; des gonocoques et streptocoques dans 1'articulation du genou (oil pendant la vie des gonocoques seuls furent trouves) et dans un abc&s periarticulaire de la cuisse gauche; des strep- tocoques seuls dans 1'articulation temporo-maxillaire gauche et dans le phlegmon du cou et du mediastin; dans les foyers de pneumonic, il y avait des pneumocoques et des streptocoques. Ce cas cst particulierement interessant car il demontre la possihilite et le mode de developpement d'infec- tions secondaires mixtes. D une synovite tendineuse sup- puree pr£ced£e d'une blennorrhagie, Jacobi et Goldmann1 obtinrent dans le pus les gonocoques qui furent decolores par la methode de Gram pendant quo les cultures faites sur les milieux ordinaires rest^rent negatives. Mais Bloodgood et Plexner (observation inedite) obtinrent plus preeminent les organismes en culture pure d'une pareille tendo-vaginite. Lang et Paltauf2 obtinrent le gonocoque en culture pure d'un abces du doigt survenu pendant une blennorrhagie aigue, aucune connexion ne paraissant exister entre I abces et I'arti- culation ou lagaine du tendon. Mazza3 isola le gonocoque en culture pure d'une pleurrsie suppur^e, compliquant une blennorrhagie. Dans ce cas il existait aussi une endo-peri- card ite. Wertheim4 a dernierement, dans un cas de cystite, enleve un morceau de la muqueuse de la vessie, dans lequel il a trouve non seulement les cellules epitheliales, mais aussi le tissu conjonctif sous-epith61ial, remplis de gonocoques; les capillaires etaient remplis d'amas de gonocoques. Le malade avait en meme temps une arthrite blennorrhagique. 1. Jacobi et Goldmann, Beitr. z. klin. Chir., 1894, XII, 827. 2. Lang et Paltauf, Arch. f. Derm. u. Syph., 1893, 330. 3. Mazza, Of. Bordone-Uffreduzzi, loc. cit. 4. Wertheim, Deutsch, med. Woch., Vereins Beilag., n° 1, 1893, 1187. 706 W.-S. TH A YEH ET G. BLUMER. Kiakow1 fait mention d im cas de septicemie blennor- rhagique, compliqude d'une arthrite suppurative et d'une ophthalmic blennorrhagique et de pemphigus chez le nou- veau-nd. On trouva, dans le vagin, et aussi dans le pus des articulations, des gonocoques. Finger2 est done - parait-il - justilie dans ses conclu- sions : « 2b. Le gonocoque on entrant dans la circulation du sang et etant vehicule par celui-ci, pout etre la cause des affections articulaires et pdri-articulaires les plus varices... « et : « 26. En penetrant dans le tissu conjonctif le gonocoque pout rdussir a produire une veritable suppuration. » Gependant le fait que beaucoup de ces processus suppura- lifs secondaires sont de nature vraiment blennorrhagique, n'est pas une preuve suffisante pour justilier la supposition qu'ils sont lous de meme nature. La lievre, les symptomes generaux et raibuminurie, si frdquente, tout indique une intoxication gendrale, pendant que 1'insucces de la recherche infructueuse des gonocoques dans les Idsions du systeme nerveux nous fait soup^onner que ces lesions sont peut-etre dues a une toxine soluble. Nous devons probablement reconnaitre dans la blennorrhagie une maladie gdndrale qui, partant d'un point local, pent causer des symptomes gendraux graves, la lievre, des fris- sons, de 1'albuminurie, tandis qu'en d'autres cas de graves Idsions secondaires locales peuvents'ensuivre. Dans quelques cas de conjonctivite, d'epididymite, de salpingite, d'arthrite, de synovite, depleurcsie, de processus suppuratifslocaux, etc., il a dtd ddmontrd ddfinitivement que le gonocoque lui-meme pent etre la cause efficienle, le gonocoque atteignant les rdgions affeetdes, sans doute'par la circulation generate. En d'autres cas de nevrite, de myelite, de manifestations cuta- ndes, d'iritis, le rdsultat ndgatif des recherches microsco- piques et des cultures, fait supposer que les lesions locales peuvent dtre dues a une toxine scute. Quant a la nature des complications cardiaques de la blennorrhagie, on ne possede actuellement que pen de don- 1. Kiakow, Gaz. Lakaiska, 1894, 632. 2. Finger, /. c. ENDOCARDITE ULCEREUSE BLENNORRHAGIQUE. 707 nees positives. Martin1 a rapports un cas de blennorrhagie, avec prostatite suppuree et cystite, endocardite ulcereuse et abces dans le myocarde et dans les reins. Au niveau des valvules du coeur et dans les foyers suppures il trouva an microscope deux varietes de bacteries, dont l une ressem- blait beaucoup au gonocoque de Neisser. ^Gluzinski2 a rap- porte un cas d'endocardite ulcereuse avec des bacteries ayant la forme de gonocoques sur les valvules. His3 a trouve dans un thrombus sur une valvule, dans un cas d'endocar- dite ulcereuse mortelle, precedee d une blennorrhagie, des organismes rappelant le gonocoque; ils se decoloraient par la methode de Gram. Malheureusement hauteur dit que le coeur avait ete durci dans la liqueur de Muller, de sorte que la valeur de I'epreuve est douteuse. Councilman4, a rapports un cas de blennorrhagie avec prostatite suppurde, arthrite, pericardite, avec des foyers sup- purds dans le muscle cardiaque. 11 trouva les diplocoques caractdristiques en forme de biscuit, dans 1'urethre, 1'arti- culation du genou, le pdricarde et dans les abces du muscle cardiaque. Ces organismes etaient entidrement ddcolords par la methode de Gram. Winterberg3 a trouve des gonocoques sur les valvules dans un cas d'endocardite ulcereuse precedee d une blen- norrhagie compliquee elle-meme d'une arthrite. Ils se deco- loraient par la methode de Gram. Ces cas sont interessants, surtout les deux derniers dans lesquels 1'identification des organismes a ete plus satisfaisante. Mais 1'absence des essais de culture rend les resultats pen concluants. Le cas de Ley- den6 fait avancer la question d'un pas. 11 s'agissait d une endocardite ulcereuse precedee d'une blennorrhagie, d'epidi- dymite et d'arthrite. Des cultures faites sur les milieux ordi- naires et recueillies du sang d'une veine pendant la vie et du 1. Martin, Rev. med. de la Suisse Romande, 1882, 2, 308. 2. Gluzinski, Of. Councilman, Tr. Assoc. Amer. Phys., 1893, VIII, 165. 3. His, Deutsch, med. Woch. XXIX, 1892, 993. 4. Councilman, Tr. Assoc. Amer. Phys., 1898, VIII, 165. 5. Winterberg, Festsch. z. 25 Jllhr. Jub d. Verein Deutsch, Aertzt. zu San Francisco, 1894, 8°, 40. 6. Leyden, Deutsch, med. Woch., 1893. 708 W.-S. TUAYER ET G. BLUMER. venlricule gauche apres la mort, furent negatives. Par 1'exa- men microscopique apr^s lamort, cependant, des gonocoques typiquesfurent trouv^s dansle thrombus surla valvule. Ceux- ci montrerent les formes caract^ristiques et les 'reactions histo-chimiques des gonocoques. 1° II y avail dos diplocoques caracteristiques en forme de biscuit, jamais disposes en grappes comme les slaphylo- coques. 2° Bon nombre de diplocoques se trouvaient a 1'intdrieur des cellules. 3° Ils perdaient leur couleur apres traitement par la me- thode de Gram. 4° Ils dtaient facilement ddcolores par 1'alcool et 1'essence de lavande. 11 parait hors de doute quo les organismes observes dans ce cas ne fussent des gonocoques el 1'absence de ddveloppe- ment dans les tubes de cultures, sur les milieux ordinaires, du sang pendant la vie et du venlricule gauche apres la mort, font bien penser quo les gonocoques existaient en culture pure. Cependant la preuve definitive de F existence d'une septi- cdmie blennorrhagique aussi bien que d'une endocardite suppur6e, due an gonocoque seul, a ete fournie, nous le croyons, par le cas suivant que nous allons relater. Observation. - L. S..., veuve, agee de 34 ans, est entree a I'hdpital John Hopkins, le 25 avril 1895, se plaignant de faiblesse, de toux et de douleurs generales. Antecedents hireditaires. - Le pere est mort d'un coup de soleil, la mere est en vie et bien portante; elle est enfant unique. Son mari est mort de phtisie pulmonaire. Antecedents personnels. - Bit qu'elle n'a pas eu de maladie d'en- fance. Ni chorGe, ni pneumonic, ni paludisme, ni fievre typhoide. Les regies out commence a 1'age de 14 ans, ont toujours et6 r^gulieres; la malade a ete mariee a 24 ans, a eu cinq enfants, deux fausses couches, a souffert de rhumatisme il y a trois mois. Les douleurs se montraient surtout aux doigts, aux poignets, aux genoux, et aux epaules. Elles n'ont pas ete aigues, disparaissant en un endroit pour se reproduire dans un autre. La malade affirme que les articulations n'ont point ete enllees. A ete alitee pendant dix jours, avec un pen de dyspnee; pas d'oedeme aux pieds ou aux jambes. ENDOCABDITE ULCEREUSE BLENNORRHAGIQUE. 709 Etat actuel. - La malade date sa maladie actuelle du commence- ment de son rhumatisme, il y a trois mois. Depuis ce temps elle n'a jamais ete forte. Il ya trois jours elle se trouvait tres faible et fatiguee. A ce moment elle apercut sur la levre inferieure quelques vesicules d'herpes, elle eprouva des douleurs vagues dans le dos et dans les membres, pas de diarrhee; pas d'epistaxis; elle a cesse de travailler il y a deux jours; des frissons se sont declares hier matin. Le 25 avril i son entree, la malade est amaigrie, teint colore, levres, membranes muqueuses, un peu cyanotiques. Pouls 132, petit, regu- lier, respirations 30, temperature 10 R. 2 F. Poumons, rien; le coeur bat dans les 4e et 5e espaces intercostaux. Les bruits sont le mieux, per^us dans le 4e espace en dedans du mamelon. Le premier bruit est clair, precede d'un souffle presystolique et suivi d'un souffle systolique transmis dans l'aisselle. La matitd du foie sur la ligne mamelonnaire commence a la 6e cote. Le bord infdrieur du foie est palpable environ a 3 centimetres au-dessous des cartilages costaux. La rate n'est pas pal- pable. L'examende I'abdomen est negatif; il n'yapas de taches lenticulaires. L'examen du sang au point de vue des parasites de la malaria fut negatif; il y avait de la leucocytose, 12 000 leucocytes par centim. cube. 26 avril 1895. Urine. - Couleur ambrSe, rougeatre, acide, 1 015; des traces d'albumine, pas de sucre; depot blanc, ties abondant, avec quan- tity de pus, des cellules epitheliales, pas de cvlindres, pas de reaction d'Ehrlich. # A la visite du matin la note suivante a ete prise par le Dr Thayer : « La malade a passd une bonne unit; la ildvre a diminue ce matin. Le thorax est. symetrique, l'angle costal petit, 1'expansion des deux cotes est dgale. L'auscultation et la percussion sont claires partout. « Coeur. - Le point d'impulsion maxima du coeur est visible dans le 5e espace, a peu pres dans la ligne du mamelon a 9 centimetres et demi de la ligne mediane, Fimpulsion est forte et precddee par un leger fr6missement. La matite relative commence a la 3e cdte, ne va pas au dela du bord gauche du sternum. Le premier bruit est accentu6 et precede d'un leger souffle presystolique qui disparait au-dessus de la 4° cdte; il est suivi d'un souffle systolique qui se perd dans l'aisselle et n'est que faiblemenl entendu a la base du coeur; le second bruit pul- monaire est accentue. Le pharynx, la luette et le voile du palais sont injectes de sang. La rale est palpable, sa matite commence a la 8e cote. » 27 avril 1895. - L'urine est 4 peu pres la m^me qu'au premier examen. Reaction d'Ehrlich. 29 avril 1895. - La malade a eu des exacerbations de temperature journalidres, se declarant a intervalles irreguliers. Hier il y en a eu deux; 1'une etait accompagnee d'un frisson assez intense. Aujour- d'hui la peau est humide, les pupilles sont dilatees, le pouls rapide. Les 710 W.-S. THAYER ET G. BLUMER. battements du coeur sont irreguliers; un fremissement presystolique se fait sentir an point oil 1'impulsion est la plus intense. Le souffle systo- lique est peut-Atre un pen plus intense qu'au premier examen. Les deux reins sont faciles b palper. 30 avril 1895. - L'urine^ apres catheterisme, est ambree, rougeatre, acide, 1014, trace d'albumine; depot blanc; pas de cylindres, pas de reaction d'Ehrlich. 3 mai 1895. - Ce matin la peau est chaude, le pouls 104, regulier. Le point d'impulsion maxima du coeur se trouve toujours dans le 5e espace, tres accentue et precede d'un fremissement. Le souffle pr£- systolique n'est pas si intense, mais le premier bruit est plus intense et suivi toujours par un 16ger souffle systolique. Le second bruit pulmo- naire est accentuS. 4 mai 1895. - La rate est tres hypertrophiee, s'etendant a plus de 6 centim. au-dessous du bord des cdtes. Le coeur est tresrapide; les bruits toujours les memes. L'examen vaginal est negatif. 7 mai 1895. - Ce matin la malade est caline, la peau est froide et humide, la chemise de nuit tremp^e; pouls regulier, 116, de petit vo- lume. Il y a une pulsation visible dans les 4* et 5e espaces, tout pr&s du mamelon. La pointe du coeur bat dans le 5° espace 11 centim. en dehors de la ligne mediane. 11 y a un leger fremissement presystolique. La matite relative du coeur commence a la troisieme cote et ne d^passe pas le bord gauche du sternum. Au point d'impulsion maxima on en- tend toujours un leger murmure presystolique et un souffle systolique ires fort qui se fait entendre dans 1'aisselle. Le premier bruit est tres fort. Le souffle presystolique est entendu seulement au point d'impul- sion maxima; il disparait au fur et a mesure qu'on s'approche de la base. Le deuxieme bruit pulmonaire est tres accentue tandis que Ie deuxieme bruit aortique est tres faible. A la base du coeur le souffle systolique n'est pas entendu, mais au niveau de la 4e cote il y a un leger frottement apres le premier bruit qui fait penser un pen a une pericardite. Ceci est le mieux entendu au 3e espace gauche pr^s du sternum. 8 mai 1895. - A l'examen du sang, il n'y avail pas de parasites du paludisme; leucocytes, 17 500 par centimetre. 9 mai 1895. - Urine ambree, acide, I 008, trace d'albumine, l'examen microscopique montre du pus et des cellules epitheliales. 11 mai 1895. - La malade a beaucoup maigri; elle est tres pale, la langue est blanch4tre. La temperature etait plus basse hier qu'elle n'a ete depuis plusieurs jours; une fois seulement elle a atteint 102° F. La peau ce matin est tres chaude et tres seche. Poumons; 1'auscultation en avant et aux aisselles est normale, en arriere a la base on pent en- tendre quelques rales humides, Coeur. - La pointe se trouve 13 centim. en dehors de la ligne mediane. La matite relative s'etend jusqu'au bord droit du sternum. Le premier ENDOCARDITE ULCEREUSE BLENNORRHAGIQUE. 711 bruit est tres accentue. Le souffle systolique est court et a peine en- tendu dans 1'aisselle, tandis que le murmure presystolique est bien marque; mais il disparait en dedans du mamelon et au-dessus de la quatri^me cote. Le deuxieme bruit pulmonaire est tres accentue. Le premier bruit parait 6tre dedouble au niveau de la partie mediane du sternum. L'action du cceur est tres rapide. Le 7 du mois la malade a commence a souffrir d'une diarrhee qui devint de plus en plus noire; les garde-robes etaient tres liquides, verdcltres. Au microscope on n'y a trouv6 qu'un debris granuleux, des cristaux de phosphates, un grand nombre de bacteries. La fitrvre et la diarrhee continuaient et la malade s'affaiblit de plus en plus. 14 mai 1895. - I.a malade est tres amaigrie, sans forces. Le pouls aujourd'hui, au moment de la visite, est faible, tension tres basse. Les bruits du cceur toujours les memes. 15 mai 1895. - Aujourd'hui on a compte le sang : Globules rouges I 840 000 Globules blancs 14 000 Hemoglobine 22 p. 100 Les lamelies sech^es, colorees d'apres la methode d'Ehrlich, mon- trent une poikilocytose moder6e, une difference marquee en grandeur des globules rouges individuels, tr^s peu de globules rouges a noyaux (un seulement a ete vu), une leucocytose marquee. Une numeration differentielle de 500 leucocytes a montre : Leucocytes mononucleaires petits 2,8 p. 100 - - grands 2,4 - -inoyens 0,4 - - polynucleaires 94,2 - - eosinophiles 0,2 - 100 p. 100 L'urine (par catheterisme) est claire, de couleur normale, acide. Au microscope, un nombre assez grand de cellules de pus; quel- ques cylindres avec des cellules : pas de bacilles de Koch, traces d'al- buminurie, un d&pdt blanc tres abondant. (Legere reaction d'Ehrlich.) 16 mai 1895. - Ce matin la malade est tres faible. La diarrhee de- vient de plus en plus forte. Sur le corps et les extremitSs on pent voir quelques pelites taches hemorrhagiques. Le pouls aujourd'hui est de- double. Cceur : La pointe bat dans le 4e espace a 15 cc. de la ligne mediane. La matite relative commence au deuxieme espace ef depasse de quelques centimetres le bord droit dusternum; a gauche elle s'etend obliquement en basket en dehors jusqu'au point d'impulsion maxima. Les battements du cceur qui 6taient d'abord reguli^rement dedoubles deviennent pendant Lexamen tres rapides et irreguliers. A la pointe le premier bruit est fort et dur; il est suivi d'un mur- mure systolique qu'on peut entendre dans 1'aisselle. Dans les 4e et 712 W.-S. THAYER ET G. BLUMER. 5e espaces, juste en dedans de la ligne mamelonnaire, tin fremisse- ment se fait sentir et un murmure presystoliques se fail entendre. Le 2e ton pulmonaire est accentue; le 2° aortique est faible. A 1'ausculta- tion en avant on peut entendre de nombreux rilles humides au cote droit, en arriere la respiration est norinale. L'urine,par cath^terisme est de couleur fonc6e,acide, 1011 ;une trac- marqu^e d'albumine, pas de reaction d'Ehrlich; a l'aide du micros- cope, beaucoup de pus, pas de cylindres, quelques globules rouges. La malade perdit rapidement ses forces el mourut environ une heure et demie apr^sla derni^re note, a 11 h. 20 du matin. L'autopsie tut fait par M. le Dr Flexner deux heures et demie apres le dec&s. Diagnostic anatomique. - Endocardite ukereuse aigue blennorrha- gique ; infection generale due au gonocoque; tumeur subaigue de la rate; infarctus de la rate; infarctus des poumons; gommes aux pou- mons; nephrite subaigue; congestion des visceres; gonocoques dans le vagin et 1'uterus. Longueur du corps 163 centimetres; bien nourri; encore chaud; pas de rigidite cadaverique ; legere decoloration des extremit6s;petites taches hdmorrhagiques de la peau du corps et des cuisses. La graisse existe en petite quantile; les muscles de couleur rouge foncee. P^ri- toine: pas d'exc^s de liquide ; les deux feuillets sont normaux. Pericarde: Dans la cavity il y avait environ 300 cc. de liquide, de couleur citrine; les deux feuillets polis a 1'exception de deux endroits fibreux au-dessus de I'oreillette droite. Coeur. - Toutes les cavites du coeur mais surtout I'oreillette droite sont distendues el contiennent du sang liquide. L'endocarde du coeur droit est poli; la valvule tricuspide est un peu epaissie le long de son bord libre, mais elle n'est pas raccourcie. Les valvules sigmoides apparaissent normales. Sur la valvule mitrale, surtout sur le segment aortique, existent des thrombus. Sur la face supcrieure de cette valvule - la face inferieure etant toute lisse - se trouvent des granulations rouges, et surle segment aortique une masse pediculee; cette masse fait hernie dans Lorei 1 lette; sa grandeur est de 3 centimetres. Les vegeta- tions sont pour la pluparl faciles a enlever; quelques-unes sont cepen- dant plus resistantes. La oil elles furent enlevees la surface de la val- vule apparait com me rongee. La perte actuelle de substance etait assez grande pour causer une depression distincte. Le thrombus _sl de couleur rose et grise et est d'une consistance differente par endroits. Quoique assez mou 4 1'interieur, il n'a pas subi un ramollissement puriforme. La surface est granuleuse. 11 etait solidement attache a la valvule qui au point d'attache parut plus epaisse. Le muscle cardiaque est piile, plus mou qu'a 1'etal normal et un peu marbrg. Les arteres coronaires sont friables. Le coeur pese 350 grammes. Dimensions: longueur du ven- tricule gauche, 8 centimetres; longueur du ventricule droit, 8 centi- ENDOCARDITE ULCEREUSE BLENNORRUAGIQUE. 713 metres; epaisseur du ventricule gauche, 13 millimetres; du ventricule droit, 4 millimetres. L'aorte au-dessus des valvules est de 6C",5. Le foramen ovale admet le bout du petit doigt. Poumons. - Il y a de vieilles adh&rences au-dessus du sommel. A la coupe les poumons out une couleur un peu ros6e ; la consistance est assez ferme. Au lobe gauche inferieurily a un infarctus hemorrhagique qui mesure 15 centimetres de diametre. Plusieurs foyers broncho-pneu- moniques s'y trouvent egalement. Dans la partie inferieure du lobe se trouve aussi une masse grisatre homogene et assez ferme, de lcm,5 en diametre, bien circonscrite et enfoncee dans le tissu pulmonaire. Rate. - Poids 780 grammes; dimensions 22 x 13x8 centimetres ; la surface, a 1'exception de quelques flocons fibrineux a 1'extremite supe- rieure, est polie. A la face externe se trouve un infarctus de 2om,5 de diametre surlaquelle on remarque de la fibrine. La rate est assez con- sistante; la pulpe abondante; les corps de Malpighi Saillants. Reins. - Poids des deux reins, 380 grammes; la capsule un peu adh6rente ; la surface un peu congestionnee, on y voit des taches ecchy- moliques. La substance corticale est pale. Les glomerules sont diffi- ciles a voir. Quelques hSmorrhagies se trouvent dans la muqueuse du bassinet. Foie. - Poids 2030 grammes; un peu hypertrophie. L'estomac, intestins, vessie, rectum, pancreas, capsules surrdnales ne montrent rien de particulier. Le cerveau n'a pas ete examine. L'uterus n'est pas augmente de volume; la membrane muqueuse est polie et couverte d'un leger exsudat opaque. Le vagin est convert d'un exsudat opaque leger. Coupes apres congelation.- Le muscle cardiaque montre une degene- ration graisseuse assez etendue. Reins: Gonllement marque de 1'epithe- lium des tubuli contorti; les glom6rules contiennent de la graisse en petites goultes; pas de graisse dans 1'ephithelium des tubuli. 11 y a de petits foyers de cellules rondes dans I'dcorce au voisinage des glome- rules. Foie : Une congestion moderee. L'examen microscopigue des preparations apres durcissement donne les resultats [suivants : aux valvules on constate une endocardite subaigue. Le processus consiste en 1'inflltration de la substance valvulaire par des cellules differentes les unes des autres. Ges foyers sont plus aigus a la surface des valvules et le deviennent moins au fur et a mesure qu'on penfetre dans le parenchyme valvulaire. A la surface, la oil le processus est le plus aigu, les lissus sont inliitres de leucocytes polynucleaires et de quelques petites cellules rondes. Ges leucocytes sont generalement en petits groupes, leurs noyaux sont souvent entiers, mais quelquefois fort fragmentes; ces fragments de noyaux ne sont pas faciles a colorer, et le tissu qu'on voit entre eux est d'un caractere granuleux et sem- blable a de la flbrine. La base de ces foyers aigus, les leucocytes deviennent de moins en moins nombreux et sont remplaces par des 714 W.-S. THAYER ET G. BLUMER. cellules rondes et en fuseau, et plus profonde'ment par des cellules en fuseau settlement, de sorte qu'a la base de la valvule il y a un tissu con- ionctif bien form6, maiscellulaire. Au niveau des foyers inflammatoires, on pent voir de grandes cellules reniplies de petites granulations qui se coIorent vivement. Au premier abord on pourrait les considerer comme des cellules contenant des bacteries, mais ce sont evidemment des Mastzellen. La surface de la valvule est recouverte d'un caillot san- guin dans lequel on trouve encore des globules rouges; il y a evidem- ment une augmentation du nombre des e!6ments nucleaires polymorphes dans le sang qui forme ce caillot. Coiflant ce caillot, dans maints endroits se trouve une couche de substance finement granuleuse qui rappelait 1'apparence des hematoblastes qu'on voit parfois dans les thrombus. Ce tissu se colore bien avec 1'eosine et aussi par les couleurs d'aniline employees pour la coloration des bacteries. Dans toutes Ies coupes de tissu inflammatoire on trouve des diplocoques en petit nombre, en moindre quantity qu'on ne pourrait le penser apr6s 1'appa- rence des preparations faites sur lamelies de verre; leur petit nombre est evidemment du a ce qu'ils se decolorent si facilement. Ges diplo- coques sont parfois ovales et paraissent disposes bout a bout, quoiqu'on les voie souvent cdte a cdte, en forme de biscuit. Les diplocoques exis- tent surtout au niveau des foyers les plus aigus et oil les noyaux sont fragmentes. Parfois les organismes sont en dehors des cellules; parfois en dedans des leucocytes polynucleaires. On a constate un tres petit nombre de diplocoques dans le caillot qui se trouvait a la surface des valvules; ces diplocoques paraissaient libres dans le sang et non inclus dans les leucocytes. Poumons. - Les poumons montrent une pneumonic chronique interstitielle. La pleyre est epaissie et dans quelques endroits on voit des bandes de tissu eonjonctif qui s'etendent de la plevre jusque dans la profondeur des poumons. Les alveoles sont partout epaissis soit par congestion, soit par une neoformation de tissu conjonctif dans leurs pa- tois. Quelques alveoles sont dilates et vides; quelques-uns contiennent un exsudat compost d'une substance granuleuse, des cellules epitheliales pavimenteuses, des leucocytes polymorphes nucleaires et quelques grandes cellules contiennent un pigment tres fonce (Staubzellen). Les vaisseaux sanguins des poumons contiennent une quantite assez consi- derable de sang, et il existe un thrombus non obliterant dans une des grosses branches de I'artdre pulmonaire. Ga et la dans le parenchyme pulmonaire on constate une neoformation epitheliale atypique. Les branches paraissent normales; il n'y a pas d'exsudat. Le nodule qu'on a trouve au lobule inferieur du poumon droit se compose de trois couches; la premiere en dehors formee de tissu libreux formant une espece de capsule; une seconde contenant des cellules epithelioides longues et quelques cellules rondes; une troisieme couche centrale qui est ndcrosde et qui contient les fragments de plusieurs noyaux; dans la ENDOCARDITE ULCEREUSE BLENN0RRHAG1QUE. 715 zone exlerieure de cette couche on trouve des cellules geantes aussi bien que dans la zone adjacente qui rappelle la premiere en tons points. Ces foyers sont, sans doute, des gommes. Rate. - La rate contient beaucoup plus de sang que d'ordinaire, les globules etant bien conserves, et c'est au sang, d'une part, qu'on pent attribuer l'augmentation du volume de la rate. Les leucocytes poly- nucleaires sont beaucoup plus nombreux dans le sang que d'ordinaire, et il y a aussi une augmentation du nombre des petites cellules rondes de la pulpe. Les corpuscules de Malpighi sont les plus alteres; ils sont augments de volume a cause de [l'augmentation du nombre des pelites cellules rondes qui les composent. Une lesion moins bien deflnie (dans une coupe (»n en a trouve au moins six) est constitute par un petit amas de cellules dans le tissu mtme du corpuscule de Malpighi. Ces cellules dif- ferent de celles de la rate normale en ce qu'elles sont plus grandes et qu'elles ont une forme plus tpithtiioide. Elles composent la plus grande partie de ces foyers; elles sont plusieurs fois plus grandes que les cel- lules lymphoides. Elles contiennent un noyau vesiculaire et generale- ment ovale. Elles sont pourvues d'une grande quantity de protoplasma. On y trouve aussi un grand nombre de leucocytes et quelques fragments de noyaux. Au point de vue de leur grandeur, mais non [de leur struc- ture, ces lesions rappellent des tubercules miliaires. Au point de vue de leur structure elles rappellent les Itsions diphteriques decrites par Oer- tel. Dans ces foyers se trouvent quelques cellules assez grandes contenant beaucoup de protoplasma et de grands noyaux bourgeonnants rappe- lant les noyaux des cellules de la moelle osseuse. Le foyer en forme d un cone, qu'on a vu microscopiquement dans la rate, presente deux couches : une externe qui est composee presque entierement de glo- bules rouges; et une interne oil, en outre des globules, existe une quantile considerable de tissu necrotique Les arteres dans le voisi- nage de cet infarctus paraissent etre normales, cependant deux ou trois des acini contiennent des thrombus de formation rtcente. Dans un endroit silue tout pres de cet infarctus se trouve un foyer constitue par du tissu splenique en etat de necrose et contenant quelques noyaux fragmentes et quelques leucocytes polynucleaires. Reins. - Les reins montrent une nephrite chronique interstitielle et des signes d'inflammation recente au niveau des glomerules. La sub- stance corticale est diminute d'epaisseur et dans quelques endroits manque entierement, de sorte qu'ici les glomerules se trouvent imme- diatementau-dessous de lasurface. Onyvoitcaet la du tissu conjonctif, ayant parfois une forme pyramidale, la base se dirigeant vers la sur- face et le sommet plongeant dans le tissu meme du rein. Le tissu con- jonctif se trouve surtout autour des glomerules, empittant sur la cap- sule de Bowman et les tissus adjacents. Ce tissu conjonctif est surtout fibreux, mais dans les parties les plus profondes de la substance corti- 716 W.-S. THAYER ET G. BLUMER. cate, etn'ayant rien a faire avec les glomerules, on remarque des cellules rondesdu type lymphoide. En outre, on voitque le tissu conjonctif intra- tubulaire est augments de volume. Les glomerules paraissent contenir plus de cellules qu'a 1'etat normal; il y a des amas de cellules dans les capillaires, donl quelques-uns sont entierement remplis de cel- lules. Ces cellules sont de deux variates : a) cellules ovales d'un type epithelioide contenant des grands noyaux v6siculaires et une quantite assez considerable de protoplasma; b) des leucocytes polynucleaires. Dans quelques endroits les leucocytes polynucleaires sont sorlis des capillaires et sont visibles pres de la capsule et dans les tubuli meme assez eloignes des glomerules. L'epithelium des tubes est ici et la gontle et d'un aspect granuleux, les bords libres des cellules denteles, tandis que la lumiere des tubuli contient une assez grande quantite d'une substance finement granuleuse. Quelques cylindres hyalins existent dans la substance mcdullaire. On n'a pas pu constater de gonocoques dans aucun de ces organes. Examen bacteriolog ique. - L'examen des lamelies faites des vegetations de la valvule mitrale amontre un nombre con- siderable de leucocytes polymorphonucleaires et quelques-uns grands et petits, mononucieaires, aussi bien qu'une quantite d une substance finement granuleuse. Entre les elements cel- lulaires, il y a un grand nombre de bacteries, composees de petits diplocoques ovales, se trouvant cote a cdte, ayant souvent la forme de biscuit, les cdtes opposes etant concaves. Parfois il existe des pseudo-chainettes de troisou quatre ele- ments et rarement ces organismes sont groupes par quatre. Les leucocytes polynucleaires, presque sans exception, con- liennent des diplocoques. 11 se pent qu'on netrouve que deux ou trois diplocoques dans le protoplasma, on la cellule tout entiere peut etre remplied'une masse de cesdiplocoques. Dans un bon nombre de cas on a observe que non settlement le protoplasma, mais le noyau est envahi par ces diplocoques et Lon pent voir plusieurs paires de microcoques dans le noyau entoures d'une couche de protoplasma non coloree. II n'y avail pas de bacteries dans les leucocytes mononucieaires grandson petits. Gesmicrocoques avaient lescaracteres mor- phologiques des gonocoques. Les lamelies colorees de violet de gentiane (qui colorait facilement les microcoques) puis traitees par la solution de Lugol et 1'alcool (methode de Gram) se sont d<5colorees com- ENDOCARDITE ULCEREUSE BLENNORRHAGIQUE. 717 pletement; pas un micro-organisme n'a retenu la couleur. L'examen de lamelies enduites de mucus vaginal etuterin montrerent les memes diplocoques, qui se decolorent quand ils sent traites par la methode de Gram. Les lamelles faites avec Linfarctus de la rate ne donnerent aucun resultat. Cultures. Pendant la vie, 4 mai 1895. - Les cultures prises du sang furent faites d'apres la methode de Sitzmann. Le sang fut pris de la veine mediane basilique avec une seringue qu'on avait fait bouillir pendant vingt minutes. Le bras avait 6t6 bien lavd auparavant a 1'eau et au savon et enveloppe d une compresse au sublime a I p. 1000. Environ 2 centimetres cubes de sang furent meles avec de 1'agar- agar. 11 n'y eut aucun developpement. 7 mai 1895. - D'autres tentatives de culture furent faites de la meme maniere ; le melange sur les plaques contenait au moins un tiers de sang. Apr^s 48 heures a 1'etuve, on pouvait voir des petites colonies blanches de la grosseur d'une pointe d'epingle. L'exa- men de ces colonies montra de petits diplocoques ovales, parfois couches cote a cote, en forme de biscuit. On reense- mence sur agar-agar, gelatine, pommes de terre, bouillon et tournesol, lait. Aucun developpement. 12 mai 1895. - Descultures furent faites d'apres la meme methode avec lememe resultat. On obtint une culture pure du meme microcoque. Des colonies pareilles furenttrouv6es sur les plaques avec les memes r^sultats negatifs daus les ten- tatives de reensemencement. A rautopsie. - Des cultures sur 1'agar-agar et le s^rum de sang de boeuf faites avec le sang du cceur, les valvules, le foie, la rate, les poumons, les reins, furent entibrement negatives; une Ires petite quantile de sang du coeur fut en- semencee. Le laboratoire etait a cette epoque depourvu des milieux necessaires au developpement du gonocoque. La ressemblance extraordinaire des organismes, trouves dans les vegetations sur la valvule mitrale, avec le gono- coque, et sa reaction caracterislique avec les matieres colo- rantes corrobore les resultats negatifs obtenus en essayant de transplanter les colonies obtenues pendant la vie. En exa- ARCH. DE MED. EXPER. - TOME VII. 718 W.-S. THAYER ET G. BLUMER. minant encore ces cultures les colonies furent trouvees composes d'organismes ressemblant tout a fait a ceux trou- ves dans le thrombus sur la valvule. Ils montrerent les memes reactions colorantes, se decolorant immediatement par la me- thode de Gram. Si 1'on consid^re la quantity considerable de sang employe, on peut facilement se dire que le milieu n'etait pas essentiellement different de celui recommande par Wer- theim. Les developpements sur ce milieu furent abondants, tandis que des transplantations sur des milieux ordinal res demeurerent sans rdsullats. Le 17 mai les transplantations furent rep6tees sur du s6rum et de I'urine de 1'homme, sur du serum de boeuf, sur 1'agar-agar et I'urine, 1'extrait de fad us (Flexner) et agar- agar, mais les organismes ne se developperent pas. Ges mi- lieux ensemenc6s avec des gonocoques avaient rdussi. La conclusion est que le sixidme jour les organismes etaient morts. Experiences sur les animaux. -Une souris fut inoculee a la base de la queue avec un morceau de thrombus de la gran- deur d un grain de chenevis; le resultat fut negatif. Ges rdsultats justifient, nous le croyons, 1'hypoth^se que 1'organisme isole en culture pure dans le courant sanguin et sur les valvules affectees6tait bien le gonocoque de Neisser. a. Sa forme et sa disposition etaient caracteristiques. I). Quoique parfois libres, les microbes furent souvenl trouves accumuMs dans le protoplasma des leucocytes du thrombus sur la valvule. c. Ge micro-organisme ne put se developpersurles milieux ordinaires. d. 11 se developpa facilement sur un melange de sang humain et d'agar-agar (un tiers de sang). e. 11 se decolorait par le Gram. Nous n'avons point dedonn^es sur la porte d'entree du virus. Mais, 1'examen microscopique du vagin el de linterieur de l ut^nis ayanl montrd des diplocoques pareils, se decolo- rant par la methode de Gram, il y a peu de doute que 1'infection n'ait eu lieu par les voies ordinaires. Baltimore, aout 1895. Librairie G. MASSON, 120, boulevard Saint-Germain Anatomie du cerveau de I'homme, inorphologie des hemispheres cerebraux ou cerveau proprement dit, texte et figures, par E. Brissaud, agrege de la Faculty de medecine de Paris, medecin de 1'hdpital Saint-Antoine. Get ouvrage comprend un atlas grand in-4°, de 43 planches gravees sur cuivre, repr6- sentant 270 prriparations grandeur naturelie, avec explication en regard de chacune, et un volume in-8° de 580 pages, avec plus de 200 figures schema- tiques dans le texte. L'atlas et le texte sont relies en toile anglaise. Prix des deux volumes 80 fr. Atlas d'Embryologie, par M. 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Grancher, professeur a la Faculte de medecine de Paris. 1 vol. in-8°. 4 fr. Traite elementaire de clinique therapeutique, par ieDr Gaston Lyon, ancien chef de clinique m6dicale ci la Faculte de medecine de Paris. 1 vol. grand in-8° 15 fr. Recherches sur les centres nerveux. Alcoolisme, Folie des hereditaires dege- neres, Paralysie generate, Medecine legale, par le Dr V. Magnan, medecin de 1'Asile clinique (Sainte-Anne), membre de l'Academie de medecine. Deuxiemc serie, avec 6 planches hors texte, un graphique en chromolithographic, et 27 figures dans le texte. 1 volume in-8°. Broche 12 fr. Precis d'Embryologie adapts aux sciences medicales, par Paul Gilis, profes- seur agrege a la Faculte de medecine de Montpellier, avec preface par M. le professeur Mathias Duval. 1 vol. in-18 diamant avec 175 figures. Cart, toile, tranches rouges 6 fr. Du sang et de ses alterations anatomiques, par g. Hayem, professeur a la Faculte de medecine de Paris, medecin des hdpitaux, membre de 1'Acaddmie de medecine. 1 vol. in-8° avec nombreuses figures noires et en couleur dans le texte. Relie toile a biseaux , 32 fr. Precis de Microbie. Technique et Microbes pathogenes, par le Dr L.-H. Thoinot, auditeur au Comite consultalif d'hygi^ne de France, et E.-J. Masselin, mede- cin-vdterinaire. Ouvrage couronne par la Faculte de medecine (Prix Jeunesse). Deuxieme edition, revue et augmentee avec 89 figures dont 21 en couleurs. 1 vol. in-16 diamant. cartonne 7 fr. A LA MEME LIBRAIRIE TRAITE DiFmEDECINE Public sous la direction de MM. CHARCOT, BOUCHARD, BRISSAUD PAR MM. BABINSKI - BALLET - BLOCQ BOIX - BRAULT - CHANTEMESSE CHARRIN - CHAUFFARD - COURTOIS-SUFFIT - DUTIL - GILBERT - GEORGES GUINON - L. GUINON HALLION - LAMY - LE GENDRE - MARFAN - MARIE - MATHIEU - NETTER OETTINGER - ANDRt PETIT - RICHARDIltRE - ROGER - RUAULT - SOUQUES - THIBIERGE THOINOT. - F. WIDAL. G vol. grand in-8° avec fig. en noir et en couleurs 125 fr. Tome I. - Pathologic gendrale infectieuse. - Troubles et maladies de la nutrition. - Maladies infectieuscs communes a 1'homme et aux animaux. - Fievre typhoide. - Maladies infectieuscs 22 fr. Tome II. - Typhus exanthematique. - Fievres eruptives. - Maladies venerienncs et cutanecs.- Pathologic du sang. - Intoxications 18 Ir. Tome III. - Maladies de la bouche ct du pharynx. - Estomac. - Pancreas. - Maladies de 1'intestin. - Maladies du pdritoine. - Maladies du foie et des voies biliaires. 20 fr. Tome IV. - Maladies des fosses nasales, maladies du pharynx. - Asthme. - Coquc- luche. - Maladies des bronches , maladies chroniqucs du poumon, Maladies du mediastin. - Maladies aigues du poumon, Maladies de la plevre 22 fr. Tome V. - Maladies du coeur. - Maladies des vaisseaux sanguins. - Maladies des vais- seaux pdripheriques. -Rhumatisme articulaire aigu. - Maladies du rein et des cap- sules surrenales, avec 45 figures 20 fr. 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I vol. avec nombreuses figures etune carte des eaux mineraleset stations climaUriques. 12 fr. Paris. - Typ. Chamerot et Renouard, 19, rue des Saints-P^res. - 32540. Reprinted from the New York Medical Journal, for January 11, 1896. HYPERTROPHIC PULMONARY OSTEO-ARTHROPATHY AND ACROMEGALY. A CLINICAL LECTURE, WITH THE HISTORIES AND PHOTOGRAPHS OF FOUR CASES. By WILLIAM SYDNEY THAYER, M. D., ASSOCIATE IN MEDICINE AT THE JOHNS HOPKINS UNIVERSITY ; FIRST ASSISTANT IN THE MEDICAL CLINIC AT THE JOHNS HOPKINS HOSPITAL. In 1889 Bamberger demonstrated before the Wiener medicinische Gesellschaft two cases of bronchiectasis with clubbed fingers and painful- enlargements of the ends of certain long bones. He noted that this condition was not extremely rare, and suggested its dependence upon the ab- sorption of certain substances from the putrefying bronchial secretion. In 1891 * he added five more cases of bronchiectasis with similar changes, as well as four cases of cardiac dis- ease with more or less similar disturbances. In the cardiac cases, however, the changes in the long bones were scarcely as marked. In five of these instances the autopsy showed well-marked periostitis ossificans in the affected parts of the long bones. In discussing the cause of these changes, he mentions the fact that Wagner produced similar pro- cesses in hens by feeding them with phosphorus. He ex- perimented with rectal injections of putrefying bronchial secretion in rabbits, but was unable to obtain any positive results. He speaks guardedly as to the cause of these changes, noting the frequency with which one (clubbed fingers) may exist without the other (periostitis of the * Zeitschr. fur klin. Med., xviii, 193. Copyright, 1896, by D. Appleton and Company. 2 OSTEO-ARTDROPATHY AND ACROMEGALY. ends of the long bones), and suggests that possibly several causes may be at work. In the mean time, in 1890, Marie,* quite ignorant of Bamberger's observations, reported a similar case and, re- viewing the literature of acromegaly, became convinced that a certain number of cases had been included in this list which did not properly belong there. The majority of these cases presented features closely similar to those re- ported by Bamberger. Only in those instances where the changes had reached an excessive degree had the condition been confounded with acromegaly. These advanced cases showed, first, in contradistinction to the condition of things in acromegaly, very few changes in the face; the nose, skin of the face, lips, orbital ridges, and lower jaw were practi- cally unaffected. In some instances a certain degree of thickening of the alveolar border of the upper jaw had been described. Secondly, the almost constant cervical kyphosis of acro- megaly was wanting. When present in these cases it was more usually seen in the lower dorsal or lumbar regions. Thirdly, the hands and feet in this condition may be enormous, but the affection differs in many ways from that occurring in acromegaly. The hand in acromegaly is un- usually large, short, and plump. There is great thickening of the skin and soft parts, and deepening of the furrows of the palm. In this other condition the hand may also be enormous, but it is distinctly deformed. The most strik- ing point is, perhaps, the enlargement of the terminal phalanges, which are usually characteristically club-shaped, like drumsticks. The carpal and metacarpal regions, on the other hand, are but little affected, while at the wrist the bones are again unusually large. Fourthly, the nails in acromegaly appear small owing to the general broadening and thickening of the fingers. In this other condition they are usually large, and show a marked incurvation, sometimes resembling a parrot's beak. They also show the characteristic pinkish coloration ; they are typical " Hippocratic" fingers. Fifthly, the long bones of the forearm and of the leg in * Bull, med., 1889; Revue de med., Paris, 1890, x. 1. OSTEO-ARTHROPATHY AND ACROMEGALY. 3 acromegaly are but little changed, or more or less sym- metrically thickened, while in these other instances there is a most striking increase in the size of the bones toward the epiphyses, more particularly at the distal extremities. Tn considering eight cases of this affection which he had gathered together, it was noted that in two there existed a purulent pleurisy, in two a pulmonary neoplasm, in three bronchitis. Marie considered the process to be purely secondary- secondary probably to the pulmonary affection-and to be sharply distinguished from acromegaly, which forms a well- marked disease by itself. He thus summarizes his theories concerning the cause of these changes: " A lesion of the respiratory apparatus permitting probably, under the influ- ence of micro-organisms, of the production at this spot, of putrid or fermenting substances (bronchitis, purulent pleu- risy, with or without the operation for empyema); secondly, the absorption and passage into the general circulation of these substances produced in the respiratory apparatus ; thirdly, the elective action of these substances on certain parts of the bones and of the articulations, determining the lesions of hypertrophic osteo-arthropathy. This last possi- bility presents certainly nothing unreasonable, if one only recalls the precision with which, by a wholly analogous process (nonparasitic), gout, thanks to the presence of uric acid in the blood, attacks always, or almost always, the same points in the osteo-fibrous system." Since this time a considerable number of cases similar to those originally collected by Bamberger and Marie have been reported. A majority have been associated with pul- monary lesions of one sort or another, though fairly char- acteristic cases have been reported in other conditions- cardiac diseases, syphilis, in two instances of which no pul- monary or cardiac lesion was found. In several instances autopsies have been made, revealing the dependence of the thickening of the long bones upon a periostitis ossificans, resulting sometimes in a more or less symmetrical thicken- ing and condensation of the bone, and again in the forma- tion of osteophytes. In one instance an increase of the synovial fluid with erosion of the cartilages was noted in several joints. 4 OSTEO-ARTHROPATHY AND ACROMEGALY. Thorburn * reported three cases, all of which were asso- ciated with pulmonary tuberculosis, and suggests, from a consideration of the cases which have come to autopsy, that the process is actually of a tuberculous nature, but " of a benign type, having no tendency to break down and caseate." lie suggests the name "tubercular polyarthri- tis" as a fitting one for the process. Two cases of this condition have been reported in this country, those of Packard f and of Davis. J A considera- tion of the cases which have been reported can leave but little doubt in the mind of the observer that Marie was justi- fied in drawing a sharp line between this process and acro- megaly. It appears to be essentially a secondary process, occurring in most instances after chronic pulmonary dis- orders. Tn the simplest cases it is represented by marked clubbing of the finger tips, associated with subjective symp- toms of slight tenderness about the epiphyses of the long bones, particularly the distal extremities of the bones of the forearm and of the leg, while at autopsy a slight peri- ostitis is to be made out in these regions. In the more ad- vanced cases the enlargement of the lower ends of the bones of the forearm and of the leg may be extreme, as well as the increase in size of the terminal phalanges, and indeed of the fingers as a whole. It is only in this condition that the process is to be compared in any way with acromegaly, and even at this time the relatively slight affection of the soft paits, the entire absence of many of the common subjective symptoms of acromegaly-head- ache, nervous symptoms, evidences of tumor of the hy- pophysis-leave but little chance for error in diagnosis. The autopsy in these instances has never shown tumor of the hypophysis, which is so common in acrome- galy. The true cause of the process is really a matter of great doubt. While almost invariably secondary to some other condition-usually pulmonary or cardiac dis- ease-there are cases which show evidences of a very early development of the symptoms. The evidence is certainly * British Med. Journal, 1893, i, 1155 f Am. Journal of the Med. Sciences, June, 1892, ciii, 65*7. | Journal of the Am. Med. Assoc., June, 1895, xxiv, 845 (with literature). OSTEO-ARTHROPATHY AND ACROMEGALY. 5 quite insufficient to justify Thorburn's suggestion that the process is always of a tuberculous origin. The term pro- posed by Marie-hypertrophic pulmonary osteo-arthropathy -has been quite generally accepted, though it would prob- ably be safer were it possible to adopt the more conserva- tive suggestion of Arnold-secondary hyperplastic osteitis. The course of the process appears to be extremely slow, having of itself little influence upon the progress of the primary disease. In several instances partial or complete recovery has been reported ; in one instance under syphi- litic treatment, in another after draining of an empyema, in another after drainage of a tuberculous cavity. The rela- tion of this group of symptoms to ordinary Hippocratic fingers is interesting. Clubbed fingers exist in almost all of these instances, but they may also be present in their most characteristic form in a very considerable number of pulmonary and cardiac affections where no involvement of the long bones is to be made out. Whether the same cause is at work in both instances, the one condition being simply a more advanced grade of the other, can not be definitely stated. It is certainly true that the most ex- quisite Hippocratic fingers may exist entirely alone, while again, in some cases of well marked hypertrophic pulmonary osteo-arthropathy, the clubbing of the terminal phalanges may be by no means as characteristic. I wish to show you to-day a well-marked case of hypertrophic pulmonary osteo arthropathy, with the photographs, casts, and histo- ries of two other cases, and to cbmpare them with this other patient, the case of acromegaly which you have al- ready seen. If you will compare now the photographs of the woman (Case I) and those of Case HI with the patient whom we have here (Case II), you will be struck by the similarity between the large hands, the long fingers, the clubbed fin- ger tips, the large nails, and particularly with the similarity between the condition of the ends of the long bones at the wrists and ankles. In each instance you will see the strik- ing expansion of the lower ends of the tibia and fibula. You will also note that the face is practically unaffected. If you take the skin of the face or of the most affected parts of the hands or feet of this man between your fin- 6 OSTEO-ARTLIROPATIIY AND ACROMEGALY. gers, you will find that it is as delicate and as easily mov- able as your own. If you examine the palms of his hands, you will find that they are smooth, and that there is no deepening of the furrows. In Case II you will also find a marked thickening of the distal extremities of the meta- carpal and metatarsal bones. On examining the casts of the hands and the photo- graphs of Case III you will be struck by the great en- largement of the ends of the long bones, particularly at the wrists and ankles. But you will notice here that not only is the same enlargement marked at the distal extremities of the metacarpal and metatarsal bones, a point on which no stress has been laid by other authors, but also about the ar- ticulations between the first and second phalanges, as well as at the knee joint. The same clubbing of the finger tips with incurvation of the large nails is to be made out. The marked lengthening of the fingers is not noticeable in this case, and on a superficial glance at the palm the hand pre- sents a more spadelike appearance than is usually seen in this condition. If you examine the cast you may readily see that there is no thickening of the skin and no deepen- ing of the normal furrows. There is, as you will see from the photograph, no change in the bones or soft parts of the head or face. Comparing these three cases with this woman with acromegaly, the difference in the whole picture can not but strike you. The great increase in the size of the nose and lips, the thick hanging folds of the face, the broad, flat, spadelike hands, with the deep furrows in the palms, the extreme thickening of the skin in all the affected parts, the entire absence of any deformity of the long bones, form a striking contrast to Cases I, II, and III, and this contrast becomes much more evident vs hen one considers the clinical history of the case. In Cases I, II, and III the changes in the hands and feet have come on apparently secondarily to a pulmonary affection. Thus, in one case they followed apparently a general bronchitis with pleurisy with effusion, while in the two others a chronic pleurisy (empyema) occurred. In one of these instances there was bronchiectasis with foetid expectoration. The discomfort suffered by these patients has been disproportionately small OSTEO-ARTHROPATHY AND ACROMEGALY. 7 in comparison to the visible changes; it was in the first patient almost wanting; in the two other cases it was present only as a moderate tenderness at times over the ends of the long bones, with transient effusion into the knee joints. In Case IV the condition began in a perfectly healthy woman without any apparent cause. From the onset it has been associated with the most distressing and excru- ciating headaches, aching, " tearing " pains in the extremi- ties, in the jaw, and in the tongue, with grave vaso-motor disturbances, profuse sweating, frequent vomiting, and great thirst. In the first three instances the process is undoubtedly a purely secondary affair-the hypertrophic pulmonary osteo-arthropathy of Marie; the secondary hyperplastic osteitis of Arnold. The third case is a primary progressive disease-the acromegaly of Marie. Therapeutically, little can be done beyond treatment di- rected toward the alleviation of the primary process-the em- pyema, bronchiectasis, cardiac disease. The only instances in which much hope may be held out are apparently those associated with syphilis. It may, however, be said that the process may exist for years with relatively little dis- comfort to the patient. In acromegaly also we are equally, indeed more, helpless ; and after two years of palliative treat- ment we have been compelled in the case of patient No. 4 to resort finally to injections of morphine to relieve the continuous and excruciating pains. Even with this the patient is but little relieved. Owing to the existence of the goitre in this case, treatment with extract of the thy- reoid gland was carried on for about two months without beneficial effect. Case I.-Stella M., married, twenty-eight years of age, native of Poland, was admitted to the Johns Hopkins Hos- pital on the 12th of July, 1892. She complained of cough, pain in the region of the heart, and swelling of the legs. Her father died at fifty of unknown cause; patient re- members that his legs were swollen; mother is alive and healthy at seventy; no brothers; two sisters living and nealthy, one thirty-six and the other forty years old. There is no history of tuberculosis or of cancer in the family. The patient speaks only Polish, so that a very satisfactory 8 OSTEO-ARTHROPATHY AND ACROMEGALY. history was not obtained. She says, however, that at the age of ten, while carrying wood, she " strained herself," and was sick in bed with abdominal pains for eight weeks; other- wise she had always been strong and well, and while in Poland she had worked in the fields. She came to this coun- try two years before admission. She said that she had fever on board the ship. She had been in this city ever since her arrival in the country. The catamenia appeared at the age of nineteen ; had four children; no miscarriages. Last child was born four years ago. Iler last catamenia occurred fourteen weeks ago. Patient says that about fifteen weeks ago she " caught cold," and ever since then has had consid- erable cough and expectoration. Has never had any haemop- tysis. Some shortness of breath; no palpitation. The appe- tite is fair; the bowels are regular. She says that her legs have always been fat, but about six weeks ago she noticed for the first time that her ankles were getting thicker, and this has progressed, she thinks, ever since then. There is some pain in the legs on walking. She is said to have lost sixty or seventy pounds in weight. She has had night sweats and does not sleep well on account of the cough; no headaches. On the 13th of July the note was as follows: In bed on herback; rather sparely nourished; skin of a muddy color ; peculiarly expressionless countenance; bridge of the nose rather broad; lines of the face not sharp; eyes rather heavy. The ends of the fingers, particularly on the right side, are clubbed and a trifle expanded. There is some in- curvation of the nails. Thorax.-The right side of the chest seems to move more than the left on inspiration. There is marked dullness in the lower left front, becoming flat at the fifth rib in the recumbent posture and at the fourth rib in the erect posture about mid- way between the mammary and anterior axillary lines. At the apex the resonance is more tympanitic and higher pitched than on the right side. The right side of the back moves materially more than the left; resonance throughout the right back is good. On the left side flatness begins at the spine, at about the origin of the ninth rib, extending upward to slightly above the angle of the scapula. In the right front the respiration is clear. On the left side respiration is enfeebled and of a somewhat tubular modification at the apex, accompanied by medium, fine, and coarse moist rales. Passing downward in the second and third spaces the rales become more numerous and somewhat coarser. On passing into the flat area the respiratory sounds become feeble and distant; vocal fremitus absent; voice sounds far away. In the back, respiration is OSTEO-ARTHROPATHY AND ACROMEGALY. 9 clear throughout the right side. Above the spine of the left scapula respiration is enfeebled; fine, moist rales are heard at the end of inspiration, while below in the flat area vocal fremitus is absent; vocal resonance and respiration feeble and distant. Heart.-Cardiac dullness is continuous with that of the eflfusion. There is well-marked heaving over the fifth, sixth, and seventh costal cartilages, but the exact point of maximum impulse is hard to determine. Dullness extends fully two fin- ger-breadths to the right of the sternum in the fourth inter- space. Sounds are heard loudest in the fifth interspace about two finger-breadths from the margin of the sternum; they are clear and of normal relative intensity. Hepatic flatness begins at the sixth interspace in the mammary line; the bor- der can be felt three finger-breadths below the costal mar- gin. Splenic flatness is continuous with that of the effusion. A sharp border is to be felt low down in the splenic region, possibly muscular, but resembling more the spleen. The abdomen is very flaccid, bulging markedly between the separated recti; negative on palpation. Nothing re- markable about the hands or arms beyond the clubbing of the finger tips and the incurving of the nails. The feet and legs are, however, much enlarged; the tibiae at the upper end are about normal in size. As one reaches the lower third on each side there is a great expansion, particularly on the right side. At the level of the malleoli both tibiae are very thick and heavy. The feet themselves are not so remarkably large considering the development of the patient. There is no oedema of the extremities and there are no marked glandu- lar enlargements. Patient has a distressing cough with con- siderable thick, greenish muco-purulent expectoration. No tubercle bacilli were found in the sputum on repeated exam- inations. The urine was normal in color, cloudy, 1'017, acid in reaction, trace of albumin, no sugar, no diazo reaction ; microscopically, epithelium and leucocytes; no casts seen. On the 21st of the month, nine days after entry, the lungs were almost entirely clear. A slight dullness at the left base with enfeebled respiration was still present. The adventi- tious sounds had wholly cleared up, and the patient was dis- charged at her own request. Since this time it has, unfortu- nately, been impossible to follow the further history of the case. Case II.-H. H., aged twenty years, presented himself at the out-patient department of the Johns Hopkins Hospital on the 13th of March, 1893, complaining of pain in the right chest and of cough. 10 OSTEO-ARTHROPATHY AND ACROMEGALY. Family History.-Father and mother living and healthy ; three brothersand one sister living and well; one brother died from the effects of some throat trouble, having been ill for two years previous to his death. No other distinct his- tory of tuberculosis in the family. Personal History.-As a child he had measles and chicken- pox; since then has always been quite healthy. There is no history of typhoid fever, rheumatism, pneumonia, pleurisy, or malarial fever. He smokes and drinks moderately; denies venereal disease. Present Illness.-Seven weeks ago, after exposure to in- clement weather, the patient was seized with a chill, which was followed by fever and a severe cough. He was in bed three weeks, the doctor telling him that he had pneumonia. Since that time, off and on, he has had intermittent chills, fever, and sweating, with occasional pain in the right chest. The appetite is fair; bowels regular; no nausea or head- ache. Physical Examination.-The patient is thin, pale, and looks ill; lips and mucous membranes are pale ; tongue clean ; pulse full, soft, thirty to the quarter; temperature, lOO'S0 F. Examination showed evidence of a pleural effusion upon the right side, which, from the symptoms, was believed to be purulent, and the patient was advised to enter the hospital. He did not, however, appear, and was next seen two years later, on the 18th of March, 1895, when he applied for admis- sion to the hospital, complaining of cough, spitting of blood, and pain in the right side. The patient states that after the consultation at the dis- pensary in 1893 the cough had steadily persisted. Often, however, for several days in succession it would be quite slight, while upon the third or fourth day he would have a sudden spell of coughing, and in five minutes would expecto- rate as much as a pint of thick, yellow sputum. This condi- tion has existed throughout the last year or more. On Wednesday, March 13tb, the patient had an attack of haemop- tysis, and on the 14th expectorated about " three pints " of bright red blood. This has continued daily since, the quanti- ties, however, greatly diminishing. He has been in the habit of leaning toward his right side and pressing the hand against the right side of his chest to get relief from pain. Nine months ago he first noticed that his spine was becoming "crooked." For two weeks the patient has had pain be- low the right scapula. He sweats a good deal at night; says he does not think he has lost iu weight. For two months the patient has complained of not being able to grasp OSTEO-ARTHROPATHY AND ACROMEGALY. 11 small objects firmly, owing to his inability to close the hand tightly. He has never suffered any pains in his hands or feet. For four months he has had occasional pain in his knees when he attempted to kneel down ; it gives him the sensation of pins sticking into him. He states, on questioning, that his mother has told him that his hands were enlarged ever since he was a child, but that he had never had difficulty in getting stockings or shoes to fit him. Within the last six months however, he has noticed that it was impossible to lace his boots, and he has noted the increase in the size of the wrists and ankles. On the next day I saw the patient and made the following note: The patient is in bed on his back. He is tall-six feet anti two inches in height. The frame is otherwise not re- markably large. The lips and mucous membranes are dis- tinctly pale ; tongue clean. The face is symmetrically formed; no thickening of the lips, no prognathus, no marked thicken- ing of the upper or lower jaw, no apparent enlargement of the nose or supraorbital ridges. As the patient lies in bed there is a very marked contraction of the upper part of the right chest, the right shoulder being considerably lower than the left. Slight scoliosis in the upper dorsal region with con- vexity toward the left. One is immediately impressed with the remarkable size of the hands as compared with the rest of the frame. The muscular development of the arms is rather slight, but the hands are extremely large. On further examination it is to be noted that the lower extremities of the long bones of the arm, especially on the left side, are quite markedly enlarged, the expansion just above the wrist on the left side being considerable. The hands, particularly the left, show interesting changes. The carpal region does not appear to be particularly changed. The metacarpal bones, however, are universally thickened, especially at their distal extremities. The first metacarpal bone on the left side is extremely large at the distal extremity, though this characteristic is apparent upon both sides. The fingers are long and massive; the phalanges feel large, but show by no means a proportionate enlargement to that of the meta- carpal bones on the left side. The ends of the last phalanges are markedly enlarged. They are somewhat club-shaped and are held in a position of super-extension. The finger nails are large, well formed, and smooth, but show a quite marked incurvation similar to that seen in the clubbed fingers of tuberculosis. The appearance of the hands as a whole is quite characteristic of the cases classified by Marie as hyper- trophic pulmonary osteo-arthropathy. 12 OSTEO-ARTHROPATHY AND ACROMEGALY. The clavicles appear natural; nothing remarkable about the humerus on either side. The legs present a remarkable appearance. The feet are- rather large and heavy, but what is particularly striking is the great thickening of the lower third of the tibia and fibula. The tibiae on either side at their upper extremities are of nor- mal size in proportion to the general development of the in- dividual. Below the junction of the lower and middle thirds they become remarkably large, and at their lower extremities, just about the ankle joints, the thickening is extraordinary. The feet do not seem to be particularly enlarged in the tarsal region. The metatarsal bones are not as much enlarged relatively as the metacarpals. The metatarsal bone for the little toe on the right side feels, however, considerably thick- ened. The toes are somewhat massive and slightly clubbed. The lower end of either femur seems also to be dispropor- tionately thickened. Thorax.-Marked flattening in the upper right chest; ex- pansion nearly absent on the right side. Resonance through- out the left front is good. On the right there is a dull tympany at the apex; flatness beginning in the recumbent posture in the third space; no movable dullness. The point of maximum cardiac impulse is in the fifth space, about three centimetres outside the mamillary line. Vocal fremitus in the lower right chest is very slight, but yet to be felt; at the apex it is increased. Respiration clear throughout the left front and axilla. In the resonant area at the right apex the respiration is clear, though it is enfeebled, while the ex- piration is somewhat prolonged. Passing downward into the dull area, the respiratory sounds are almost absent and the voice sounds a trifle nasal. In the right back there is flatness up to a point about five centimetres above the angle of the scapula; vocal fremitus almost absent. Throughout the left back the resonance is clear and also the respiration. In the upper right back the respiration is feeble and distant; in the flat area it is almost absent; a few distant, dry, crackling sounds only are to be heard. In the interscapular region, at the upper border of dullness, there is a suggestive creaking sound rather like a friction rub, as well as a few moist rales. The right breast is rather prominent and tender, and the gland is very distinctly felt. Heart.-Point of maximum cardiac impulse three centi- metres outside of the mamillary line; relative dullness in the third space, extends obliquely outward to the point of maximal impulse. The first sound is dull and thudding, fol- lowed by a soft systolic murmur, which is lost in the raid- OSTEO-ARTHROPATIIY AND ACROMEGALY. 13 axilla. The murmur grows much louder at the base, and is ■of particular intensity in the aortic area and over the manu- brium, also in the carotids. The second pulmonic is some- what accentuated. The pulse is of rather small volume, but of fairly good tension. Abdomen.-Border of the liver not palpable, possibly ow- ing to the tenseness of the abdominal wall. On percussion, dullness extends four centimetres below the costal margin in the mamillary line; in the median line, six to seven centime- tres. The spleen is not palpable; flatness begins apparently at the eighth rib, extends about to the tenth; it does not pass the costo-articular line. The abdomen is otherwise negative ; no marked glandular enlargement. The left epitrochlear and one or two cervical glands may be felt. An exploratory aspiration was made in the eighth space in the right back, and only one drop of clear fluid removed. The needle passed through an almost cartilage-like pleura. Urine normal, clear, yellow; specific gravity, T020; faint trace of albumin, no sugar, diazo reaction absent, a slight white flocculent precipitate. Microscopically, a few hyaline and granular casts; occasional leucocytes and epithelial cells; crystals of oxalate of calcium. Sputum thick and tenacious, purulent, containing a con- siderable quantity of blood in streaks and mixed with some small nummular masses; no special odor. Microscopical ex- amination showed red blood and pus cells, a fair number of alveolar cells, a few diplococci, no tubercle bacilli. Blood.-Red corpuscles, 5,464,000; white, 3,000 ; haamo- globin, forty-eight per cent. The patient showed no fever, and rapidly improved in his general condition. There was, however, considerable cough, which wa^ more marked in the morning, and accompanied by a profuse muco-purulent expectoration, the blood rapidly dis- appearing. On the 9th of April the patient complained of pain in the right chest. Examination showed a well-marked friction rub. The chest was strapped, with great relief to the patient. Re- peated examinations of the thick, muco-purulent greenish expectoration showed no tubercle bacilli. The sputum was measured daily, ranging between five and one hundred and thirty cubic centimetres in the twenty-four hours, the amount upon the whole diminishing. On the 16th of May the following note was made : Patient has gained altogether three pounds in weight. The color has improved and he feels better. There is no pain in the left side. Physical examination almost exactly as on the former 14 OSTEO-ARTHROPATHY AND ACROMEGALY entry. The median cephalic vein in the right arm is thick- ened ; it is quite distinctly to be felt and can be rolled under the finger; occasionally a vein in both forearms can be felt. At his own request the patient is discharged. He returned to the hospital on the 10th of June, complain- ing of severe pain on the right side, following a sharp chill several days before. On examination the patient was found to be more emaciated than on last entry, paler, tongue red and clean. The right side of the chest showed almost exactly the same signs as on the last entry, flatness beginning at the upper border of the fourth rib and not changing with change of position. The sternal ends of the clavicles appear rather large as compared with the other parts of the bone. No tubercle bacilli are found in the sputa, which is closely similar to that at the last entry. ' The patient remained in the hospital a little over a month, the temperature showing at first a slight elevation, but falling after four or five days to normal. The sputa were at first very abundant and at times of a very foul odor. On the 14th, 15th, and 18th of June there were four hundred cubic centi- metres. The amount, however, rapidly diminished, and was under thirty cubic centimetres at the time of his discharge. The patient weighed a hundred and forty-six pounds on entry, and remained at the same weight at the time of his discharge on the 29th of July. He returned again on the 5th of August, complaining of the same symptoms, the temperature being slightly elevated. Under rest and iodide of potassium he improved, however, rapidly. The quantity of sputum diminished steadily. August 20th. - Temperature has been normal now for several days; expectoration muco-purulent, fairly abun- dant. Appearance of chest much as on last note. There is marked flattening of the right front, which expands but little on inspiration. Auscultation and percussion just as on last entry. Point of maximum impulse thirteen centimetres from median line. At the right base behind there is a slight scratching sound with inspiration, suggesting a friction rub. During the months of September and October the patient has complained of considerable tenderness over the ends of the long bones of the legs and arms, and for about a week during October there was a marked increase of fluid in both knee joints. This was associated with little tenderness and disappeared on bandaging and rest in bed for several days. There appears, as measurements show, to be a slight steady increase in the size of the hands and feet, as well as of the lower ends of the long bones of the arms and legs. OSTEO-ARTHROPATHY AND ACROMEGALY. 15 Careful measurements were made on July 28th and on November 5th with the following results: Height, 183 centi- metres; November 5th, 183'5 centimetres. In standing erect with hands close to the side, the tips of the fingers of right hand extend to a point nine centimetres above the level of the upper margin of the patella; the fingers of left hand to a point 12'3 centimetres above the level of the upper margin of the patella; a difference probably accounted for by depression of the right shoulder. On November Sth the left hand was 12'5 centimetres above the upper margin of the patella. JULY. SEPTEMBER. Right. Left. Right. Left. Ctm. Ctm. Ctm. Ctm. Upper Extremity. Tip of acromion to tip of middle finger 85'1 86-3 86'0 86-5 Tip of olecranon to tip of styloid process of ulna 29-0 29'0 310 30-5 Circumference of lower end of the forearm 1 ctm. above tip of stvloid process 18'0 18-0 18-75 18'75 Circumference of mid-carpal region 17-5 17-0 19-0 19-75 Length of metacarpal bones: First metacarpal 5-0 5-5 6-0 5-75 Second " 7'5 7'5 8-5 8-25 Third " 7'5 7'2 8-5 8-25 Fourth 7-2 6-5 7-5 7-5 Fifth " 6-3 5'5 6-3 6-0 Circumference at broadest part of metacarpus 26-5 26 ' 5 Length of fingers from base of first phalanx to tip: Thumb 6'5 7'0 7'5 7-0 Index finger 11-0 10-6 11-0 10-5 Middle " 12-0 11-5 12-0 11-5 Ring " 11'3 11-5 11-5 11-6 Little " 8-5 8-9 9'0 9-0 Circumference of fingers at base of second phalanx: Thumb 7'0 7-1 7-75 7-75 Index finger 7'0 7-0 7-5 7-5 Middle " 7-3 7-0 8-0 8-0 Ring " 7'2 6-8 7-75 7-5 Little " 6-2 6-0 7-0 6'75 Lower Extremity. Distance from tip of greater tro- chanter to level of sole of foot 102'5 103-5 103-75 104 5 Circumference of knee at the mid- die of the patella 36-5 35-0 36-5 36-0 Length of tibia from articulation at knee to tip of internal malleolus 45-0 45 ■ 0 46-0 45-0 Circumference of leg 7 ctm. below lower margin of patella 29-5 29-5 30-5 30-0 16 OSTEO-ARTHROPATHY AND ACROMEGALY. •hilt. NOVEMBER. Right. Left. Right. Left. Circumference of calf, widest part, 18 ctm. below patella Circumference of leg 8 ctm. above Ctm. Ctm. Ctm. Ctm. 83 0 33-0 34'0 33 • 75 tip of external malleolus Circumference at level of external malleolus; foot at right angle 26-0 25*8 27'0 26-0 to leg Circumference at instep, tape pass- 31-0 81-5 32-75 32 • 25 ing over the tip of heel....... 35 • 5 36'0 36 • 25 36-0 Length of foot Length of femur from tip of great trochanter to articulation be- 28-5 28-5 28-5 29-5 tween femur and tibia Length of toes from metatarso- phalangeal joints to tips of toes: 47-0 47-0 Big toe .... 7-0 7'0 Second toe 6-0 6'0 Third " .... 5-5 5-25 Fourth " 5-0 5-0 lifth " Circumference of terminal phalanx of the great toe at its thickest 4-5 4-5 point 10'5 10-5 Case III.-L. A. K., aged thirty-one years, farmer, was admitted to the Johns Hopkins Hospital on September 27, 1895, complaining of cough, weakness, pain in the right side of the chest, and enlargement and soreness of the bones of , the wrists, hands, ankles, and feet. Family History.-Father died of paralysis at fifty-three. Mother died in childbirth. One brother died of influenza and one in infancy. Three brothers and one sister living and healthy. No history of pulmonary tuberculosis in any branch of the family. No history of any nervous trouble or of any condition similar to that from which he now suffers. Personal History.-Measles, mumps, and w'hooping-cough when a child. No history of chorea, scarlet fever, or rheu- matism. As a child had a "low fever," keeping him in bed six or eight weeks (typhoid ?). Has never had malarial fever. Denies venereal infection. Has led a very regular life, never drinking to excess. Present Illness.-Up to January, 1890, the patient w-as in good health. At this time he was confined to his bed for four or five weeks with pneumonia. A few days after leaving his bed he had a severe attack of left-sided pleurisy, which again confined him to bed for about two weeks. By this time the acute pain in the side had diminished, but the patient states that he suffered intensely with a general soreness throughout the chest. Three weeks later, in a paroxysm of coughing, he OSTEO-ARTIIROPATHY AND ACROMEGALY. 17 suddenly felt as though he " had a rotten egg in the mouth," and expectorated a considerable quantity of pus, which he was told came from an abscess which had developed in the left lung. For about three days the cough was continuous day and night, fully a quart and a half of pus being raised." The cough then ceased quite suddenly, and for the next two years the patient considered himself in good health and free from cough. In October, 1892, the patient began to complain of weakness and lassitude and took to bed. Three days later he again had a sudden attack of coughing, the sensation of a rotten egg in his throat, and the expectoration of a consider- able quantity of pus. In a day and a half he thinks he coughed up a pint of pus. For the next two months, though the cough was not very severe, he was unable to do any work. Soon after beginning work in January, 1893-shipping oranges from his grove in Florida-the cough returned, and in the latter part of March he was compelled to take to his bed again for two or three weeks. There was severe cough with profuse expectoration. The patient states that at this time he was much prostrated. In May he went to the Lithia Springs in Georgia. From March, 1894, to April, 1995, the patient was in Tucson, Arizona. Since May of this year he has been under the care of Dr. Trudeau, at Saranac Lake, N. Y. To the kindness of Dr. Trudeau we owe the opportunity of observing the case. During the summer of 1894 the patient noticed from time to time a stiffness in his knees and a peculiar chilly feeling in the calves of his legs. Tn October or November, 1894, he first began to notice that his insteps were getting longer and he had to change his shoes for a larger size. In December, 1894, he began to notice an enlargement of the ends of his fingers, and in January, 1895, of his wrists. The enlargement of the wrists was associated with considerable pain of a dull char- acter, which was aggravated by movement. This pain ceased entirely after two months. At the same time the patient began to notice a painless increase in the size of the ankles. In June, 1895, the knuckles were first noticed to be swelling, and the metacarpo-phalangeal joints also began to enlarge. Since then the patient has had no pain, excepting in the knees, which are very much enlarged. He has lost much power in his hands and complains of lassitude after slight exertion. In six months he has lost sixteen pounds (143 to 127). There is a dry, hacking cough during the day; at night there is a certain amount of expec- toration. Over a year ago the patient says he had a discharge of pus from the bowels; this was preceded by pain in the left 18 OSTEO-ARTHROPATHY AND ACROMEGALY. sacral region. Since then these discharges have been fre- quently repeated, always associated with pain more or less severe in the same region. Dr. Trudeau failed to find tuber- cle bacilli in this pus. The appetite is good. The bowels are regular-daily movements. Physical Examination.-The following note was made by Professor Osler on the 27th of September. The patient looks thin. The chest is well shaped1; the clavi- cles are a little prominent-the right more so than the left. Suprasternal notch marked. Sterno-mastoid muscles promi- nent. The intercostal spaces are more marked on the right side than on the left. On quiet breathing expansion is good; on deep breathing the left side moves slightly less than the right. The point of maximal cardiac impulse is in the fifth space just below the nipple. From behind the left shoulder is a little lower than the right, while the dorsal spine is a little curved to the left. Expansion, on deep breathing, is more marked on the right side than on the left, though it is fairly good on the left side. The right scapula is a little winged. Percussion.-The lungs are clear in front on percussion. Behind, on the right side, the percussion note is good to the angle of the scapula; resonance defective in the outer axil- lary region. On the left side there is dullness in the lower half of the back, extending into the axillary region, where it begins at the lower border of the sixth rib. becoming fiat at the eighth. Auscultation.-Breath sounds are clear on both sides in the infraclavicular and mamillary regions. In the left axilla, below the fifth rib, the respiration becomes feeble and a few dry, somewhat crackling rales are heard on deep respiration. Behind, at the left base, the respiration is feeble and distant, not tubular. Crackling rales are to be heard. The abdomen was negative. The following note was made by Dr. E. P. Carter : As the patient lies in bed on his back both knees are prominent and enlarged. The lower end of the femur on both sides is considerably increased in size, while, at the same time, the upper ends of the tibiae seem to be enlarged. There appears to be a little excess of fluid in the right knee joint. The enlargement of the knees contrasts strongly with the development of the thighs. Both ankles are enlarged, the lower end of the tibia and also, to a slighter extent, of the fibula being involved, to- gether, apparently, with an increase in the size of the bones forming the instep, while the toes on both feet are elongated and markedly clubbed at their ends. This is especially marked 0STE0--ARTHR0PATHY AND ACROMEGALY. 19 in the second and third toes on both feet. The clubbing of the great toes is not so distinctly marked, but they are greatly increased in width. There is slight impairment in the move- ment of the knees. Left Hand.-The lower ends of the radius and ulna are markedly enlarged and thickened, though there is no impair- ment of motion at the wrist joint. The clubbing of the fin- ger tips is very marked, particularly in the index and middle fingers, while the first interphalangeal articulations are also considerably enlarged. The appearance of the hand from the palmar surface is rather spadelike. The nails are large and show a marked incurvation. Right Hand.-The same enlargement of the lower ends of the radius and ulna is to be noted as on the left side. The same clubbing of the fingers is present, though this is even more marked, particularly in the index, middle, and ring fin- gers. There is the same enlargement of the first interpha- langeal articulation and the same well-marked incurvation of the nails. Measurements. Right. Left. Height, 173'8 centimetres. Ctm. Ctm. Upper Extremity. Tip of acromion to tip of middle finger 75-0 74-0 Tip of olecranon to tip of styloid process of ulna.. 57'5 56'6 Standing erect, with hands at side, distance of tin- ger tips from upper margin of the patella... . 17-8 16'3 Circumference of the lower end of forearm, 1 ctm. above the tip of the styloid process of the ulna 19-0 18'5 Circumference of midearpal region 19-6 19-6 Length of metacarpal bones: First metacarpal 5'4 5 • 6 Second " 7'7 7'8 Third " 8-0 8-0 Fourth " 7-4 7-5 Fifth " 5-8 Circumference at broadest point of metacarpus ... 22-0 21-9 Length of fingers from base of first phalanx to tip: Thumb 6-8 6-4 Index finger 9-2 9-8 Middle " 10-0 10-3 Ring " 9'5 9-5 Little '' 80 7'8 Circumference of finger at base of second phalanx : Thumb 7'4 7'6 Index finger 7-5 7'5 Middle " 7'8 7-6 Ring " 7-5 7'3 Little " 6'8 6'6 Lower Extremity. Distance from greater trochanter to level of sole of foot 90-5 91-0 20 OSTEO-ARTHROPATHY AND ACROMEGALY Kight. Left. Ctm. Ctm. Circumference of knee at the middle of the patella 36 2 35'8 Length of tibiae from articulation at knee to tip of internal malleolus 37-0 37'2 Circumference of leg 7 ctm. below lower margin of patella 30'3 30'0 Circumference of calf, widest part 30'6 30-0 Circumference of leg 8 ctm. above tip of external malleolus 22-0 22-0 Circumference at level of external malleoli (foot at 90° with leg) 27'5 27'0 Circumference at instep, the tape passing over the tip of the heel 36-0 35-0 Length of foot 26-3 26-3 Length of femur from tip of trochanter to articu- lation between femur and tibia 43-5 44-0 Length of toes from metatarso-phalangeal joints to tips: Big toe 6-0 6-0 Second toe 5'6 5-5 Third " 5-0 5-0 Fourth " 4-5 4'6 Fifth " 4'0 4-4 Circumference of terminal phalanx of great toe at thickest point 9-6 9-5 Case IV. Acromegaly.-P. S., single, forty-one years of age, was admitted to the Jolins Hopkins Hospital on the 30th of March, 1893, complaining of a pain in her head, in the back of her neck, and of dyspnoea. She is a German by birth ; a domestic by occupation. Family History.-Father died of "asthma"; mother died of "heart disease"; two brothers and two sisters living and healthy; two brothers were killed in the war. No history of hereditary disease in the family. The patient thinks she had the usual children's diseases, and among them diphtheria. About eighteen months ago she was in a hospital in Germany suffering with acute in- flammatory rheumatism. Present Illness.-About ten years ago the patient noticed that the throat was somewhat swollen in front, and that she was somewhat shorter of breath than she used to be. She thinks that the swelling almost disappeared at one time, but for how long she can not remember. The swelling is not painful, but gives her a feeling of oppression at times. Cata- menia had always been perfectly regular and painless untL two years ago, when they ceased. The patient of her own accord stated that this, the cessation of her menses, was the beginning of her trouble. She began at that time to have OSTEO-ARTHROPATHY AND ACROMEGALY. 21 pains in her shoulders and the back of the neck shooting up into her head. At first she felt these only occasionally, but for the last few weeks she has had them continuously every evening. She also complains of dull, continuous pains in the back of the neck and in the back of her head. At times, with the sharp attacks of pain, she says there is vomiting. She says that her memory has been getting weaker and that she has been at times very irritable. Since the beginning she has noticed that her hands have been swelling, and her sister has noticed that her face looks " bloated." The appetite is good; she says that she occasionally has attacks of vomiting after the sharp headache. Bowels are constipated. She com- plains of considerable " innerliche Durst." Since the begin- ning of her illness she has complained much of sweating, particularly of the feet. Physical Examination.-Patient is of rather small stat- ure, but well nourished. The features are remarkably large and coarse. The nose is broad and large, the alee and sseptum being extremely thick and firm. The skin of the face everywhere is thick, heavy, and leathery, with marked folds about the corners of the mouth and on the forehead. On taking the skin between the hands it is found to be ex- traordinarily thick and firm. The jaw is massive, but there is no very marked prognathus. The lower teeth project, how- ever, a little beyond the upper. The orbital ridges are rather prominent, as are the malar bones. The ears are not remark-, able. The thyreoid gland is markedly enlarged, particularly to the right. On the left the enlargement is not particularly marked. It is soft and almost fluctuating in places. The pa- tient has a very rough, coarse, harsh voice. Thorax.-Symmetrical; expansion equal. The respiration is rather wheezing in character; expiration somewhat pro- longed. Percussion is clear throughout. On auscultation the same wheezing rales are heard which can be heard with- out the stethoscope externally. Heart.-Point of maximal impulse in fourth space in about the normal position; sounds are clear, of normal relative intensity. Abdomen.-Natural; hepatic flatness begins at the seventh rib and extends to the costal margin in the mamillary line. The border is not palpable. The right kidney is just to be felt; spleen not palpable. The skin of the hands and forearms is thick and heavy. The hands show a remarkable appearance. They are ex- tremely broad and heavy, and spadelike. The fingers are 22 OSTEO-ARTIIROPATHY AND ACROMEGALY. much expanded, the nails appearing rather small in compari- son, and showing a well-marked longitudinal striation. The skin over the fingers, and particularly in the palms of the hands, is greatly thickened. The folds in the palms of the hands are remarkably deep and firm (these folds may be seen in the photograph). The enlargement of the handsappears to be general and symmetrical. The long bones of the arms appear quite unaffected, pre- serving their relative proportions. The feet appear rather large; the skin over them is thick and firm, as in the case of the hands, but the increase in size is not as striking. There is nothing remarkable about the bones of the legs. While the examination of the face and hands when the patient was in bed suggested a woman with very large frame, further examination reveals a woman below the medium size. The urine is normal, barring a faint trace of albumin, which disappeared shortly after entry. The blood shows nothing remarkable. The patient has been under observation steadily since this time. She has complained almost continually of very severe headaches, more particularly occipital, but felt in all parts of the head. At times also there have been what the patient calls "tearing" pains in the hands and arms and tongue. There has been always a tendency to very profuse sweating, and the patient has almost always complained of marked thirst. Repeated examinations of the fundus oculi and of the fields of vision have been negative. The patient has left the hospital for short periods at various times, but since her last admission, July 1, 1895, she has suffered more than ever before, complaining continually of the most intense pain in the head, and having had since this time almost daily attacks of nausea and vomiting. At times the vomiting has been continuous and excessive. The pain has been so great that morphine, which at first was avoided, is now administered in doses of 0-13 (two grains), p. r. n. The general appearance dur- ing this time has changed but little. There has been, per- haps, a slight increase in the prognathus, while the patient herself has noticed an increase in the spaces between the teeth of the lower jaw. The patient is becoming emaciated and is losing ground rapidly. Measurements made in May, 1893, and on September 9, 1895, are as follows: OSTEO-ART11ROPATHY AND ACROMEGALY. 23 Measurements of P. S. SEPTEMBER, 1893. SEPT. 9, 1895. Kight. Left. Bight. Left. Ctm. Ctm. Ctm. Ctm. Weight 1444 lbs. 135 lbs. Height 15fi • 5 ctm. Distance from margin of hair to tip of chin 19-5 ctm. 20-0 44 Extreme width of face 15-5 a 14-0 From meatus of ear to edge of right nasal orifice From meatus of ear to the central 13-7 13.7 13'5 13-5 point between the eyes Breadth of nasal bones between 15'2 152 13'5 13*5 canthi 2-3 ctm. 2'5 ctm. Breadth of nose over bridge 5-0 U ' 3-7 ) u Greatest width of alie nasi 4-7 44 4-7 5 u Extreme width of mouth 5-3 44 6-0 44 Breadth of face over nose.*. 18'5 44 " " " " (measure- ment by tape from antitragus to antitragus) 33-0 44 Length of inferior maxilla over sym- physis (by tape) 23-3 44 24-0 44 Thickness of tongue at edge of lip. 1-0 44 1-0 44 Length of ears 6-5 6-5 6'5 6-75 Circumference of neck at hyoid bone 31-2 ctm. 36'5 44 Trunk. Circumference of thorax over nipple 47-4 | 47-1 47-0 45 • 5 94'5 92 •5 Length of each clavicle 15-2 15-3 15'5 14-5 Breadth of clavicles near sternum . . 2-6 3-0 3-0 3-3 Length of each arm from internal 23-4 24-7 25-0 25-0 condyle to styloid process Circumference at middle of biceps. . 26*7 27-2 26-0 27-0 Length of each radius 22-5 22-6 23-5 22'5 Greatest circumference of forearm.. Circumference of wrist just below 26'5 26-0 25-5 25'5 extremity of radius and ulna Length of hand from carpo-metacar- 18-8 19-0 18-0 18-5 pal articulation to end of middle finger 17-8 17-2 17'3 16-5 Circumference of metacarpus over right thumb 23-7 23'9 23-0 23-0 Circumference of the hand without the thumb at the head of the metacarpal bones 22-8 23-0 22-0 22'5 Length of middle finger, dorsal aspect 10-8 10'8 10*0 10-0 Length of ring finger 10'4 10-2 9-5 9-8 Circumference of thumb, first pha- lanx 7'9 8'0 7-5 8-5 Circumference of index finger 8-4 8-5 8-0 8-0 Greatest thickness of hand 4-0 4-0 3-75 3'75 Length of nail, middle finger 1 • 5 1-4 1-75 1-5 Breadth " " 'r 1-9 1-9 1-75 1-75 Length of nail of thumb 1-5 1-6 1-75 1-75 Breadth " " 2-1 2-2 2-0 2-3 24 OSTEO-AKTHROPATHY AX'D ACROMEGALY. SEPTEMBER, 1893. SEPT. Right. , 1895. Left. Right. Left. Lower Extremities. Ctm. Ctm. Ctm. Ctm. Length of thigh 44-0 44-0 42-0 42-0 Circumference of thigh 46-8 47-5 54'0 51-0 Vertical diameter of patella 6-5 6'5 6-0 6-0 Transverse diameter of patella 5-6 5'4 6-5 6-5 Length of leg 38'0 38-0 35-0 36-5 Circumference over knee 37-4 38'8 36-5 36-0 " of middle of calf.... Circumference just above internal 33'5 33-0 310 30-5 malleolus Greatest circumference of foot (in- 22-8 22-2 22-5 21-5 step) 25-5 25 • 6 25-5 24-0 Greatest width of foot 10'5 10-25 10-0 9-5 Length of plantar surface of foot... 23'5 24-0 23'25 23'0 " " great toe, dorsal aspect. . 6'6 6-7 6-5 6-5 " " second toe, " " 6'2 6 • 2 5-75 5-25 " " nail of great toe 1-5 1-6 1-5 1-4 Breadth of nail of " " 2-5 24 2-2 2-2 Certain slight differences in these two measurements may be due to their having been made by different men. The diminution in measurements noticeable in many in- stances in the soft parts is doubtless due to the emaciation, the patient having lost about ten pounds in weight. It may be noted, however, that the length of the lower jaw has increased 0'7 centimetre. REMARKS ON DR. BARKER'S PAPER ON MALARIA. There is as yet no absolute proof that the malarial parasite produces a toxine, and yet there are observations which are rather suggestive, par- ticularly those by Brousse and by Roque and Lemoine, who have shown an increased toxicity of the urine just following the attack; and by Queirolo, who has shown that the sweat during the sweating stage is much more toxic than that obtained under other circumstan- ces. It much be said, however, that Botazzi and Pensuti have shown that much, if not all of this increased urinary toxicity may be accounted for by the increased excretion of certain potassium salts and urobilin, as well as by the presence of peptone. Taking into consideration, however, the various symptoms of malarial fever, there is, by analogy to the other similar conditions, every reason to believe in the existence of some soluble toxic substance. Particularly suggestive are the focal necroses of which Dr. Barker has spoken. Another evidence of some grave alteration in the blood serum is shown in the haemoglobinuria which occurs in some of the graver malarial infections. With reference to the occasional paucity of parasites in the peripheral circulation, I have seen several very severe cases where, at certain times, but very few parasites could be found. I have never, however, seen a severe case where they could not be found on careful search. The fact that in certain severe oases they were present in such small numbers in the peripheral circulation led Baocelli to think that in some instances a small number of parasites might produce the gravest symptoms owing to their excessive virulence. In their recent ad- mirable article Bastianelli and Bignami rather dispute this and say that in no case of pernicious fever in which they have studied the tissues postmortem have they failed to find a total very large number of par- asites; very few perhaps in the peripheral circulation, but numerous in the spleen, brain, liver, or gastro- intestinal tract. With regard to the localization of the parasites in the pernicious bases:- In a case of com&tose per- nicious malaria which recovered, there existed while the patient was entirely comatose a clonic spasm of the lower facial muscles on the left side, which disappeared entirely with the cessation of the par- oxysm. We have had within the Last six months one case of algid pernicious malaria. This man gave the history of having had quite an active diarrhoea for three or four days, slight attacks of fever and an occasional chill. Dr. Smith noticed the man as he was led into the dispensary one morning at about 11 o'clock, and was impressed by the cyanosis and apparent prostration of the man; upon examination he found him cold and pulseless. He was put to bed and was dead within two hours and a half. His mind was perfectly clear; he was excessively weak; voice husky; skin cold and clammy; cyanosis very marked; quite the picture of a man in the algid stage of Asiatic cholera. At the autopsy there was very marked injection of the mucous membrane of certain parts of the intestinal tract, particu- larly in the upper part of the large intestine, while on examination of fresh specimens the capillaries were seen to contain much pigment. The brain showed little or no melanosis. The specimens have not been thoroughly worked up as yet. It is a very interesting fact with regard to phagocytosis that while, in fresh malarial blood, a large number of the phygocytes that one sees are mononuclear, yet I have never seen any active phagocytosis by mononuclear leucocy- tes. Occasionally one sees in the fresh specimen a fairly well preserved parasite in polymorphon- uclear leucocyte. Occasionally, also, we may see pigment and some of the remains of the parasite ly- ing within a vacuole-like space within the leucocyte. Within a few days I have seen a fragment of par- asite taxen up, the mass of pigment becoming sur- rounded by an apparent vacuole and presenting an app arance which might well have suggested that the whole structure represented a complete en- gulfed parasite. Bignami makes the suggestion that some of the so-called ''latent" cases and some of the relapses may be due to the preservation of certain forms of the parasite within leucocytes. In his last article he suggests that perhaps the best explan- ation that one can offer is the supposition that there is some encysted form of the parasite which has as yet escaped our observation. Johns Hopkins Hospital Bulletin, 1896, viii, 78. ULCERATIVE ENDOCARDITIS DUE TO THE GONOCOCCUS; GONORRHEAL SEPTIC/EMIA. By William Sydney Thayer, M. D., Associate in Medicine in the Johns Hopkins University; Resident Physician to the Johns Hopkins Hospital, and George Blumer, M. D., Assistant in Pathology in the Johns Hopkins University. [From The Johns Hopkins Hospital Bulletin, No. 61, April, 1896.] [From The Johns Hopkins Hospital Bulletin, No. 61, April, 1896.] ULCERATIVE ENDOCARDITIS DUE TO THE GONOCOCCUS; GONORRHEAL SEPTIC/EMIA* By William Sydney Thayer, M. D., Associate in Medicine in the Johns Hopkins University; Resident Physician to the Johns Hopkins Hospital, and George Blumer, M. D., Assistant in Pathology in the Johns Hopkins University. Clinical observations of cardiac complications of gonorrhoea are not new. Since the note of Brandes (Arch. Gen. de Med., Par., 1854, XCIV, 257), a considerable number of cases of so-called " gonorrhoeal " endo- and pericarditis have been reported. Lacassagne (Arch. Gen. de Med., 1872, CXXIX, 15), after discussing the literature and reporting a case of his own where an acute pericarditis occurred in the course of a gonor- rhoea, concludes that: 1. Gonorrhoea may be complicated by inflammation of any serous membrane; 2. the particular localization of the process, in such cases, is determined by the predisposition of the individual; 3. the cardiac complications are very rare; 4. the myocardium, perhaps, the endocardium, sometimes, but particularly the pericardium, are attacked. In the majority of the cases in literature where the direct association of endo- or pericarditis with gonorrhoea has been made out clinically, an arthritis has also existed. Morel (Des complications cardiaques de la blennorrhagie, Thdse, Par., 1878, No. 269), however, in his conclusions, asserts that "rheumatism is not a necessary intermediary between the specific lesions and those of the serous membranes, though the coexistence of these two lesions is the usual condition." A particularly interesting case of this nature, endo- and pericar- ditis appearing on the fifth day after the beginning of the * Vid. Arch, de Med. Exp^r., Paris, Nov., 1895. 2 urethral discharge, without coexisting arthritis, has recently been reported by Prevost (Arch. M6d. Beiges, 1895, 5). With the recognition, however, of the fact that endo- and pericarditis are occasional complications of gonorrhoea, the true nature of these processes and their relation to the primary lesion is far from being settled. Since Neisser's description of the gonococcus, and more par- ticularly since the demonstration of satisfactory methods of culture by Bumm, in 1885 (Der Micro-organismus der Gon- orrhoischen Schleimhauterkrankungen (Gonococcus Neisser), Wiesbaden, 1885), and Wertheim, in 1892 (Die Ascendirende Gonorrhoe beim Weibe, Leipzig, 1892), the various complica- tions and sequelae of gonorrhoea have been studied more intel- ligently and with greater care. To the more common complications of gonorrhoea, con- junctivitis, cystitis, metritis, salpingitis, epididymitis, arthri- tis and periarthritis, the occurrence of numerous other complications has of recent years been recorded-peritonitis (particularly in the female), pleurisy, local foci of suppura- tion, myocarditis, indeed general pyaemia, various cutaneous affections, iritis, neuritis, meningitis, meningo-myelitis, albu- minuria, etc. But in these complications, as in the cases of the cardiac affections, the same question has existed with regard to the nature of the process. Wertheim (I. c.) showed clearly that in the female direct infection (per continuum} of the uterus, tube, ovary and peri- toneum might occur. The power of the gonococcus to cause suppuration is now undoubted. The ophthalmia is also clearly an infection by direct transmission of the virus. But if the entrance of the gonococci into the tubes and ovaries can be traced per continuum, and into the eyes by direct transmission, the same cannot be said of the iritis, which has been observed without a coincident conjunctivitis, nor of the commonly observed arthritis, nor of the various processes which have been observed in the nervous system. Indeed there are rela- tively few of the numerous complications above-mentioned which we can clearly trace to an extension per continuum, or, however much we may suspect it, to a direct transmission of the infective agent. Even in epididymitis, where until recently the extension per continuum has been generally 3 accepted, the entire freedom from disease of the tracts con- necting the urethra and epididymis has compelled us to seek another explanation. Are these secondary processes truly gonorrhoeal ? If so, what is their relation to the primary lesion ? As Finger (Arch. f. Derm. u. Syph., Wien u. Leipzig, 1894, XXVIII) well says, there are various possibilities in this con- nection : " (a) The complication is produced by the gonococcus alone -purely gonorrhoeal. (5) The disease of the mucosa furnishes the opening through which the pyogenic cocci enter and give rise to the complica- tion-mixed infection. (c) The gonococcus produces the complication into which, however, the pus cocci enter later; both exist together until the gonococcus, dying, is succeeded by the pyogenic coccus- secondary infection. (d) The complication is essentiallv not of a microbic nature; it is produced by the absorption of the products of the growth of the gonococcus in the urethra-of toxic nature." That secondary infections may exist in gonorrhoea has been clearly proven, and this fact has led certain observers to the extreme view that this was true in all instances-that the gono- coccus was unable of itself to produce these secondary inflam- matory processes. Later observations with improved methods have shown that this idea is erroneous. In the arthritis, which is so common a complication of gonorrhoea, Petrone, in 1883 (Riv. Clinica, 1883, 94), found microscopically what he believed to be gonococci in an affected joint. This observation was followed by a number of others. The evidence, however, was suggestive, not positive, the identification depending only on the form of the bacteria. Deutschman, in 1890 (Graefe's Archiv f. Ophth., XXXVI, Abth. I, 109), went a step farther. In two cases of arthritis secondary to ophthalmia neonatorum he found, microscopi- cally, the characteristic biscuit-shaped diplococci, which lay chiefly in the bodies of pus cells. These cocci became decolor- ized when heated according to Gram's method, while cultures taken on the ordinary media proved negative. 4 Lindemann (Beitriige z. Augenheilkunde, 1892, I, H. V, 30) obtained, likewise, from a joint involved after ophthalmia neonatorum the characteristic diplococci, becoming decol- orized on staining by Gram's method. He also believes that he succeeded in cultivating them (after Wertheim), though there were contaminations. Hock (Wien. Klin. Woch. 1893, No. 41, 12th Oct., 736) finally succeeded in obtaining the gonococcus microscopically and in pure culture from a knee-joint in an infant with gonorrhceal ophthalmia. Neisser, in 1894 (Deutsch. Med. Woch. 1894, XX, 484) obtained gonococci microscopically and in pure culture from the ankle-joint and a finger-joint in an adult. And finally Bordone-Uffreduzzi (Proc. XI Internat. Med. Congr. and Deutsch. Med. Woch. 1894, XX, 484) not only obtained the organism in pure culture from an affected ankle-joint, but reproduced a typical gonorrhoea by inocula- tion from the second generation of these cultures, into the urethra of a healthy man who had never before suffered from urethritis. These cases go to show that in many instances the secondary processes in the joints are pure gonorrhoeal infections, the gonococci reaching the joints, doubtless, through the circulation. A case recently reported by Finger (Z. c.) is of much interest. From an arthritis of the left knee-joint following on ophthal- mia neonatorum he obtained gonococci microscopically and in pure culture during life. The child developed extensive phlegmon in the neck and mediastinum and died. At autopsy gonococci alone were found in an area of perichondritis about the cartilage of a rib; gonococci and streptococci in the knee- joint {where, during life, gonococci alone were found}, and in the periarticular abscess of the left thigh; streptococci alone in the articulation of the left jaw and in the phlegmons of the neck and mediastinum. In patches of pneumonia pneumo- cocci and streptococci were found. This case is particularly interesting in showing the possibility and manner of develop- ment of secondary mixed infections. From a suppurative tendo-vaginitis {m. tibialis anticus} secondary to a gonorrhoea, Jacobi and Goldmann (Beitrag z. Klin. Chirurgie, 1894, XII, 827) obtained, in microscopical specimens of the pus, characteristic gonococci, decolorizing by 5 Gram's method, while cultures on ordinary media proved negative; while more recently Bloodgood and Flexner obtained the organism in pure culture from a similar tendo-vaginitis (unpublished observation). Lang and Paltauf (Arch. f. Derm. u. Syph. 1893, 330) obtained the gonococcus in pure culture from an abscess on the finger coming on during an acute gonorrhoea. No connection could be made out between the abscess and the joint or the tendon sheath. Mazza (cf. Bordone-Uffreduzzi, I. c.) obtained the organism in pure cul- ture from a suppurative pleurisy complicating a gonorrhoea. In this case there existed also an endo- and pericarditis. Wertheim (Deutsch. Med. Woch., Vereins Beil. No. 17, 1895, p. 118) has recently, in a case of cystitis, excised a piece of the mucous membrane of the bladder, where he found not only all the epithelial cells filled with gonococci, but also the subepi- thelial connective tissue, where capillaries entirely filled with masses of gonococci were to be found. The patient had, at the same time, gonorrhoeal joint affections. Krakow (Gaz. Lekarska, 1894, p. 632) reports a case of puerperal sepsis complicated with joint suppuration, and gonorrhoeal ophthal- mia and pemphigus bullosus in the new-born. Both in the vagina and in the pus from the joints gonococci were found. Finger (Z. c.) is then apparently justified in his conclusions: "25. By entrance into the blood current, distributed by this, the gonococcus may be the cause of the most varied articular, periarticular, perichondritic metastases ..." and " 26. Enter- ing into the connective tissue, the gonococci may succeed in causing a genuine suppuration." The proof, however, that many of these secondary suppura- tive processes are genuine gonorrhoeal metastases is not enough to justify the assumption that all are of the same nature. The fever and constitutional symptoms, the albu- minuria so commonly present, all point to a general intoxi- cation, while the unsuccessful efforts to demonstrate bacteria in the lesions of the nervous system suggest strongly that these changes may be due to a soluble toxine. We must, probably, recognize in gonorrhcea a general disease, one which from a local starting point may cause severe general symptoms, fever, chills, albuminuria, while in other instances grave secondary local lesions may follow. In some instances, 6 conjunctivitis, epididymitis, metritis, salpingitis, arthritis, synovitis, pleurisy, local suppurative processes, it has been definitely shown that the gonococcus itself may be the exciting cause, the coccus reaching the affected areas doubt- less through the blood current; in other instances, neuritis, myelitis, cutaneous manifestations, iritis, the negative results of microscopical and cultural researches suggest that the local lesion may be due to a toxine alone. As to the nature of the cardiac complications of gonorrhcea, little that is in any way positive has been contributed until a recent date. Martin (Rev. Med. de la Suisse Romnade, 1872, 2, 308) reported a case of gonorrhoea, suppurative prostatitis, cystitis, ulcerative endocarditis, myocardial abscesses and metastatic abscesses in the kidneys. In the thrombi on the valves and in the suppurative foci he found, microscopically, two varieties of bacteria, one of which resembled, strongly, Neisser's gonococcus. Gluzinski reported a case of ulcerative endocarditis with what morphologically resembled gonococci on the valves. His (Deutsch. Med. Woch. XXIX, 1892, 993) found in the thrombi on a valve in a fatal case of ulcerative endocarditis following gonorrhoea, organisms resembling gonococci which decolorized when treated by Gram's method. Unfortunately, the heart had been hardened in Muller's fluid, so that the value of this test is doubtful. Councilman (Tr. Assoc. Amer. Phys. 1893, VIII, 165) reported a case of gonorrhoea, suppurative prostatitis, arthritis, pericarditis with suppurative foci in the heart-muscle. He found the characteristic biscuit-shaped diplococci in the urethra, knee-joints, pericardium, and in the abscesses in the heart-muscle. These organisms decolorized entirely when treated according to Gram's method. Winterberg (Festschr. z. 25 Jahr. Jub. d. Vereins Deutsch. Aerzte zu San Francisco, 1894, 8°, 40) found gonococci on the valves in a case of ulcerative endocarditis following gonorrhoea complicated with arthritis; they decolorized on treatment according to Gram. These cases are certainly suggestive, especially the latter two, where the identification of the organism was more satis- factory. But the absence of culture experiments renders the results inconclusive. 7 Leyden's (Zeitschr. fur Klin. Med., 1893) case goes a step farther. The case was one of ulcerative endocarditis follow- ing gonorrhoea, epididymitis, arthritis. Cultures on ordinary media, taken from a vein during life and from the left ventricle after death, were negative. On microscopical examination, however, after death, typical gonococci were found in the thrombus on the valve. These showed all the morphological and tinctorial characteristics of gonococci: 1. They were biscuit-shaped diplococci, never arranged in masses like sta- phylococci ; 2. A good number of the diplococci lay in the characteristic manner within cells; 3. They lost their color when treated by Gram's method; 4. They were easily decolor- ized when treated with alcohol and oil of lavender. The evidence here that the organisms present were gono- cocci is strong, and the absence of growths on culture experi- ments on ordinary media, from the blood during life and the left ventricle after death, forms certainly suggestive evidence that the gonococci were present in pure culture. The definite proof, however, of the existence of a gonorrhoeal septicsemia as well as of an ulcerative endocarditis due to the gonococcus alone is, we believe, furnished in the following case: Case. L. 8., widow, 34 years of age, entered the Johns Hopkins Hospital on April 25, 1895, complaining of weakness, cough and vague general pains. Family History.-Father died of sunstroke. Mother is living and well. Is an only child. Her husband died of pulmonary tuber- culosis. Personal History.-Says that she had none of the ordinary diseases of childhood. No history of chorea, pneumonia, malarial or typhoid fever. Catamenia began at the age of 14 ; have always been regular. Was married at 24; has had five children ; two miscarriages. Three months ago suffered from "rheumatism"; the pains were chiefly in the fingers, wrists, knees and shoulders; they were apparently not severe ; would last only a few hours in one place, disappearing to return in another joint. She asserts that the joints were not swollen at the time ; was in bed ten days. Has been short of breath on exertion for three or four years. No history of oedema of the feet or legs. Present Illness.-The patient dates her present illness to the time of the rheumatism, three months ago. Since this time she has never been strong. Three days ago she became worse, feeling very weak and tired ; at this time she noticed a patch of herpes upon 8 her lower lip. Since this time she has felt weak and exhausted ; vague pains in the back and limbs, drowsiness, thirst, anorexia; no epistaxis or diarrhoea. Gave up her work two days ago. Yester- day morning had a distinct chill. On entrance, April 25th, the patient was a rather sparely nour- ished woman ; face flushed ; lips and mucous membranes a trifle cyanotic ; pulse 132, of small volume, regular in force and rhythm ; respiration 30; temperature 102.2°. Lungs: clear throughout. Heart: the point of maximum impulse in the fourth and fifth spaces; sounds best heard just inside the nipple line in the fourth space. The first sound was loud and rough, preceded by a pre- systolic murmur and followed by a blowing systolic murmur which was transmitted into the axilla. Hepatic dulness at fifth rib in the mammillary line; border palpable about 3 cm. below the costal margin. Spleen, not distinctly palpable. Abdomen, negative ; no rose spots. The blood showed no malarial parasites, but a slight leucocytosis, 12,000 leucocytes per cu. mm. 26, 4, 95. Urine.-Reddish amber, acid, 1015, distinct trace of albumen, no sugar, abundant white flocculent sediment; micro- scopically, numerous pus and large epithelial cells; no casts seen. Distinct diazo-reaction. At the morning visit the following note (Dr. Thayer) was made : "The patient passed a good night; the fever has diminished this morning. The thorax is symmetrical; costal angle narrow ; expan- sion of the two sides equal. Auscultation and percussion clear throughout. Heart: point of maximum impulse is in the fifth space about in the mammillary line, 9} cm. from the median line ; impulse strong and preceded apparently by a slight thrill. Relative dulness begins at the third rib, does not pass the left sternal border ; passes obliquely out to the point of maximum impulse. The first sound is flapping and valvular and is preceded by a short vibratory mur- mur, presystolic in time, which disappears above the fourth rib ; it is followed by a loud blowing systolic murmur which is lost as one reaches the mid-axilla, and is but feebly heard at the base. The second pulmonicsound is accentuated. Alongtheleft sternal border the sounds have a peculiar sticky quality. The pharynx, uvula and fauces are injected. The spleen is easily palpable ; dulness above begins at the fifth rib." 27, 4, 95. Urine.-Practically the same as on last note. Diazo- reaction present. 29, 4, 95. " The patient has had daily exacerbations of tempera- ture, coming on at irregular intervals ; yesterday there were two, one associated with a sharp chill. To-day the skin is moist; pupils dilated ; pulse rapid. The heart's action is tumultuous. There is a distinct presystolic thrill to be felt at the point of maximum 9 impulse. The systolic murmur is perhaps a little louder than on the first note. The right kidney is easily palpable, as is also the left, 'which can be easily felt below the spleen." 30, 4, 95. Urine.-Catheterized specimen ; deep reddish amber, acid, 1014, trace of albumen, sediment white and flocculent; epithelial cells, no pus cells, no casts seen, no diazo. 30, 5, 95. This morning the skin is hot and dry ; pulse twenty-six to the quarter, regular. The point of maximum impulse is in the fifth space, very sharply defined and preceded by a thrill. The presystolic murmur is not as intense as it has been, but the valvular flapping first sound is very intense and is followed by a slight but well-marked systolic whiff. The second pulmonic is accentuated." Urine.-Same as on former notes. Diazo-reaction present. 4, 5, 95. " The spleen is very large, reaching more than six cen- timeters below the costal margin. Heart's action rapid, sounds much the same. Vaginal examination negative." 7, 5,95. "This morning the patient is quiet; skin cold and moist; night-gown wet. Pulse regular, 29 to the quarter, volume small, tension rather low. There is visible pulsation in the fourth and fifth spaces just about the nipple. The point of maximum impulse is in the fifth space, eleven cm. from the median line. There is a slight presystolic thrill. Relative dulness begins at the third rib, does not pass the left sternal margin. At the point of maximum impulse is heard a short slight presystolic murmur, followed by a snapping valvular first sound and a loud blowing systolic murmur which is heard throughout the axilla. The presystolic murmur is heard only just about the point of maximum impulse ; it is lost as one passes toward the base. The second pulmonic sound is sharply accentuated, while the second aortic is feeble. At the base the systolic murmur is not to be heard, but above the fourth rib there is a slight, sticky, grating sound heard after the first sound, very suggestive of a pericardial rub. This is particularly marked in the third left space close to the sternum. There is apparently a faint diastolic murmur heard along the left border of the sternum." 8, 5, 95. Examination of the blood negative for malarial organ- isms. Leucocytes 17,500 per cu. mm 9, 5, 95. Urine.-Normal, acid, 1008, trace of albumen, abundant sediment of pus and vaginal epithelium. 11, 5, 95. " The patient is much emaciated and very sallow. Tongue quite anaemic. The temperature yesterday was lower than it has been for several days, reaching only once 102°. The skin this morning is very hot and dry. Lungs: clear in fronts and axillae; backs clear, excepting for a few fine moist rales at the bases. Heart: point of maximum impulse 13 cm. from the median line. Relative cardiac dulness reaches to the right sternal margin, beginning above at the third rib. The first sound at the 10 point of maximum impulse is intensely sharp and valvular. The systolic murmur is short and scarcely to be heard in the mid-axilla, while the presystolic rolling murmur is well marked and echoing; it disappears, however, inside of the mammillary line and above the fourth rib. The second pulmonic sound is intensely accentuated. The first sound is reduplicated over the mid-sternum. The heart's action is very rapid, and the soft diastolic murmur, of which there was a suspicion at the last note, 7s not to be heard." The patient began on the 7th to suffer from a slight diar- rhoea, which increased steadily in severity ; on the 11th there were eight movements. These consisted of a greenish watery fluid with small curds of milk : microscopically, granular debris, triple phos- phate crystals, great numbers of bacteria. The fever and diarrhoea continued and the patient grew rapidly worse. 14, 5, 95. ''The patient is much emaciated, dull, apathetic. The pulse at the time of the visit is slow, but of small volume and very low tension. The anaemia has become very marked. Heart sounds same as on last note." Blood Count.-Red corpuscles, 1,840,000, Colorless " 14,000, Haemoglobin, 22 per cent. Dried specimens stained with the Ehrlich triple stain show a mod- erate poikilocytosis ; considerable difference in the size of the corpuscles ; very few nucleated red corpuscles ; marked leucocytosis. A differential count of 500 leucocytes showed : Small mononuclear, 2.8 per cent. Large mononuclear, 2.4 " Transition forms, 0.4 " Polynuclear leucocytes, 94.2 " Eosinophils, 0.2 " Urine.-Specimen obtained by catheter ; clear, normal, 1009, acid, trace of albumen; sediment abundant, white; considerable numbers of pus cells, occasional casts with pus adherent ; no tubercle bacilli; faint diazo-reaction. 16, 5, 95. " This morning the patient is very dull, feeble and apathetic. The diarrhoea grows steadily worse. Over the trunk and arms, and to a less extent over the thighs and legs, are a number of small pin-head petechial spots. The pulse, which has heretofore been regular at the time of the visit, is to-day bigeminal, the first of the two beats being the stronger ; it is of small volume, very soft. Heart: point of maximum impulse is in the sixth space 15 cm. from the median line. Relative dulness begins at the second space and extends several cm. to the right of the sternum. To the left it passes obliquely outward to the point of maximum impulse. The heart's action, which was at first regularly bigeminal, becomes rapid and irregular after slight exertion, returning to the bigeminal 11 rhythm again on rest. At the point of outermost impulse the first sound is snapping and resonant; it is followed by a systolic blowing murmur, which is heard throughout the axilla, and is preceded at the point of maximum impulse by a slight echoing sound which hardly deserves to be called a presystolic murmur. In the fourth and fifth spaces, however, just inside the mammillary line a thrill is to be felt and a presystolic murmur is well heard. A slight pre- systolic tremble may sometimes be heard in the mid-axilla. The second pulmonic is accentuated ; the second aortic is feeble. Along the left border of the sternum there is a slight soft diastolic mur- mur. In the lower right chest, in front and behind, are numerous fine moist rales ; elsewhere the respiration is clear." Urine.-Specimen obtained by catheter ; slightly smoky, acid, 1011, marked trace of albumen; sediment considerable ; much pus ; no casts seen ; red blood corpuscles ; diazo-reaction absent. The patient failed rapidly and died about an hour and a half after the last note was made, at 11.20 a. m. Autopsy, by Dr. Flexner, two hours after death. (Abstract.) Anatomical diagnosis : Acute ulcerative endocarditis caused by the gonococcus. General infection with gonococci. Sub- acute tumor of the spleen; infarction of the spleen. Infarction of lungs. Gumma of lung. Subacute nephritis. Chronic passive congestion of the viscera. Gonococci in the vagina and uterus. Externally.-Body 163 cm. long ; well nourished ; still warm ; no rigor mortis. Slight livor mortis of the dependent parts. Small petechise in the skin of the trunk and thighs. Internally.-Subcutaneous fat moderate in amount. Muscles dark red in color. Peritoneum: no excess of fluid ; both layers smooth. Pericardium : in the pericardial cavity, about 30 cc. of clear straw- colored fluid. Both layers of the pericardium smooth, with the exception of a few old fibrous patches over the right auricle. Heart.-All the cavities of the heart, but especially the right auricle, are distended and contain fluid blood. The endocardium of the right side of the heart is smooth. The tricuspid valve is a little thickened along its free border, but it is not retracted. The pulmonary and aortic valves appear normal. To the mitral valve, affecting especially the aortic segment, thrombus masses are attached. Springing from the auricular surface of the valve, the ventricular surface being comparatively smooth, there are red granulations, and to the aortic segment a pedunculated mass is attached. This mass measures 3x2 centimeters and projects into the auricle. The vegetations are for the most part easily removed ; some are, however, more resistant. Where they were removed the surface of the valve was found eroded, the actual loss of substance being great enough to leave a distinct depression. The large thrombus is variegated, pink and grey in color, and is of different 12 consistency in different parts. While quite soft in its interior it had not undergone puriform softening. Its surface is granular. It is firmly attached to the heart valve, which at the point of attachment appears to be thickened. The cardiac muscle is pale, softer than normal, and a little mottled. Coronary arteries deli- cate. The heart weighs 350 grams. Dimensions: length of left ventricle 8 cm.; length of right ventricle 8 cm.; thickness of left ventricle 13 mm.; of right ventricle 4 mm. Aorta above valves measures 6.5 cm. Foramen ovale admits the tip of the little finger. Lungs.-Old adhesions over right apex. On section, the lung has a salmon color; its consistency is quite firm. In the lower left lobe is an hemorraghic infarction measuring 1.5 cm. in diameter at the pleura. Several broncho-pneumonic areas are also present. In the lower portion of this lobe there is a grey, homogeneous and quite firm mass 1.5 cm. in diameter, sharply circumscribed and embedded in the lung substance. Spleen.-Weight 780 grams. Dimensions 22x13x8 cm. The surface, excepting for a few flakes of fibrin at its upper end, is smooth. On the outer surface there is an infarction 2.5 cm. in diameter, over which the fibrin is present. The spleen is moder- ately firm in consistency; pulp abundant; malpighian bodies prominent. Kidneys.-Combined weight 380 grams. Capsule slightly adhe- rent, surface somewhat mottled by congestion and small ecchymoses. Cortex swollen and pale, striae indistinct. Glomeruli difficult to see. A few hemorrhages into the mucous membrane of the pelvis. Liver.-Weight 2030 grams ; cloudy swelling. Stomach, intestines, bladder, rectum, pancreas, adrenal show nothing remarkable. Brain.-Not examined. Uterus.-Not enlarged ; mucous membrane smooth; covered by a thin opaque exudate. Vagina covered by a thin opaque exudate. Frozen sections.-Heart's muscle shows extensive fatty degener- ation. Kidney: much swelling of the epithelium of the convoluted tubules. The glomeruli contain fat in small droplets. No fat on the tubular epithelium. There are small accumulations of round cells in the cortex between the tubules and in the neighborhood of the glomeruli. Liver: moderate chronic passive congestion. Microscopical examination of hardened specimens. -The cardiac valves show a condition of subacute endocarditis. The process consists in the infiltration of the valve substance with cells of various character and arrangement. The process is most acute at the surface of the valves and gradually becomes less acute as the 13 depths are reached. On the surface, where the more acute process exists, the tissues are infiltrated with large numbers of polymor- phonuclear leucocytes and a few small round cells. These leuco- cytes occur as a rule in masses, the nuclei being in places intact, in other places very extensively fragmented, the remnants of the nuclei staining poorly and the tissue between them consisting of a granular, fibrinous-looking material. From the base of this acute process there is a gradual shading off into a subacute one, the leucocytes decreasing in number and their place being taken at first by small round and spindle cells, deeper down by spindle cells only, so that at the base of the valve there is a well-formed but cellular connective tissue. In places scattered through the areas of inflammation there are seen large cells filled with fine darkly staining granules. These at first sight might be taken for cells containing bacteria, but they are evidently " mastzellen." The surface of the valve is covered by a blood clot in which the corpuscular elements are still very distinct; there is evidently an increase of the polymorphonuclear elements in the blood forming this clot. Capping the clot in many places is a layer of fine granular material presenting the appearance, offered at times in thrombi, of blood platelets. This material stains well in the eosin used as a counter-stain for the haematoxylin, and also retains at times the aniline colors used for demonstrating the bac- teria. Diplococci are found scattered through the sections in small numbers, much smaller than would be expected from the appear- ances shown by the cover-slip from the valve. Their small number is evidently due to the facility with which they are decolorized, but a small portion of those present probably taking the stain. These diplococci are usually oval and appear often to lie end to end, though in places pairs are seen with a well-marked biscuit arrangement. The diplococci are found in greatest number in the more acute areas, more especially in those areas where the frag- mentation of the nuclei is most marked. A.t times the organisms lie outside of the cells, but at times they may be distinctly made out to be within polymorphonuclear leucocytes. One or two diplo- cocci were seen in the blood clot, lying on the surface of the valves; they seemed to be free in the blood and not in leucocytes. The lung shows a condition of chronic interstitial pneumonia. The pleura is moderately thickened, and in places markedly so, large bands of connective tissue running from the surface into the depths of the lung substance. All through the lung the walls of the alveoli are much thickened, partly from engorgement of the vessels, but more particularly by an extensive formation of new connective tissue in the alveolar walls. Many of the alveoli are somewhat dilated and empty ; many con- tain a slight exudate of granular material, flat epithelial cells, a 14 few polymorphonuclear leucocytes, and a few large cells containing dark-brown pigment("staubzellen "). The blood-vessels of the lung contain much blood, and there is a non-occluding thrombus in one of the larger branches of the pulmonary artery. Here and there through the lung substance an atypical growth of epithelium is seen. The bronchi appear normal; they are free from exudate. The nodule which was situated in the lower lobe of the right lung con- sists of three zones : an outer zone composed of dense fibrous tissue, forming a capsule for the mass; a peripheral zone immediately beneath this, containing long epithelioid cells and a few round cells ; and a central zone consisting of tissue which has undergone coagu- lation necrosis, containing fragments of many nuclei. A few large giant cells are seen in the peripheral zone of this area, as well as in that of a second much smaller area which is adjacent and which resembles the first in every respect. These areas are evidently gummata. The spleen pulp contains much more blood than normal, the indi- vidual corpuscles being usually well preserved, causing partly, no doubt, the increased size of the organ. The polymorphonuclear leucocytes in the blood are evidently much increased in number, and there is also an increase in the small round cells of the pulp. The malpighian bodies show the greatest changes ; they are uni- formly enlarged, this enlargement being due to an increase in the number of the small round cells normally composing them. A lesion which is less uniform, but which is commonly found-in one section at least six were present-consists of small accumulations of cells in the substance of the malpighian bodies. These cells differ from the normal spleen elements in their larger size and more distinctly epithelioid form ; they compose the larger part of these areas, which are distinctly focal in character ; they are several times as large as the lymphoid cells, contain distinctly vesicular and usually oval nuclei, and are supplied with a relatively large amount of protoplasm. As well as these cells there are present in the foci a relatively increased number of polymorphonuclear leuco- cytes and a few nuclear fragments. In size, but not in structure, they resemble miliary tubercles. In the latter respect they are very like the focal lesions of diphtheria described by Oertel, etc. In these areas a few very large cells with a good deal of proto- plasm and very large vesicular budding nuclei, similar to the nuclei of bone-marrow cells, are seen. The wedge-shaped area observed in the spleen macroscopically is seen to consist of two zones: an outer one consisting almost entirely of blood corpuscles, and an inner in which besides these elements a certain amount of necrotic spleen tissue is also to be seen. The arteries in the neighborhood of this infarction seem clear. One or two of the veins in the neighborhood, however, are 15 seen to contain fairly fresh thrombi. In one place, in the imme- diate neighborhood of the infarction, a small area of necrosed spleen substance containing fragmented nuclei and a few polymor- phonuclear leucocytes was observed. The kidney shows a chronic interstitial nephritis of moderate grade, and evidences of a fresh process in the glomeruli. The capsule is not present in the sections. The subcortical layer is decreased and in places absent, the glomeruli here lying immedi- ately beneath the surface. There is a moderate amount of connec- tive tissue scattered through the kidney substance, more particu- larly in the cortex. There, at times, it assumes the form of a wedge-shaped mass of connective tissue, the base outwards, dipping down into the kidney substance. The greater increase in connec- tive tissue is around the glomeruli, affecting the capsule of Bow- man and adjacent tissues. The connective tissue just described is of the fibrous variety, but besides this there are a number of collec- tions of small round cells of the lymphoid type, occurring mostly in the deeper layers of the cortex and usually having no connection with the glomeruli. Besides these changes there is a diffuse increase in the intertubular connective tissue. The glomeruli appear much more cellular than normal, and this is seen to be due to collections of cells within the capillaries, many of which on cross-section are entirely filled with cells. These cells are of two varieties : (1) oval cells of an epithelioid type with large vesicular nuclei and a moderate amount of protoplasm, and (2) polymorpho- nuclear leucocytes. In places the polymorphonuclear leucocytes have escaped from the capillaries and are seen in the capsular space and in the tubes themselves at quite a distance from the glomeruli. The tubular epithelium is in places swollen and gran- ular, the free edges of the cells ragged, while the lumina of the tubules contain much finely granular material. One or two hyaline casts were seen in the medulla. Gonococci could not be demonstrated in any of the organs. Bacteriological Examination.-In the cover-slip from the vegeta- tions on the mitral valve there are numerous polymorphonuclear and a few large and small mononuclear leucocytes, besides a quan- tity of finely granular material. Between the cellular elements there are a very large number of bacteria, consisting of small oval cocci, occurring in pairs, side by side, and very often having a distinct biscuit shape, the opposing sides being concave. At times pseudo-chains of three or four elements are seen, and in a few instances the organisms have a tetrad arrangement. The polymor- phonuclear leucocytes, almost without exception, contain diplo- cocci; there may be only one or two pairs in the protoplasm, or the whole cell body may be replaced by a mass of diplococci. In quite a number of cases not only the protoplasm but also the nucleus has 16 been invaded, and several pairs of cocci may be seen lying in the nucleus surrounded by a clear non-staining zone. No bacteria were seen in either the large or small mononuclear leucocytes. These cocci presented the morphological features of gonococci. Cover-glass specimens stained with gentian violet, which readily stained the cocci, and then treated with Lugol's solution and alco- hol (Gram's method), become completely decolorized ; not an organ- ism retains the stain. Cover-glass specimens from the vagina and uterus show similar diplococci, decolorizing when treated by Gram's method. Cover-slips from the infarction in the spleen are negative. Cultures.-(1) During life : 4,5,95. Cultures from the blood were made by Sittman's method. The blood was drawn from the median basilic vein by a syringe which had been boiled for twenty minutes. The arm had been previously thoroughly scrubbed with soap and water and wrapped with a towel wet with a solution of bichloride of mercury, T^. About 2 cc. of blood was thoroughly mixed with a tube of agar- agar and plated. No growth resulted. 7, 5, 95. Cultures were taken again in the same manner. The mixture in the plates was at least one-third blood. After forty- eight hours in the thermostat the plates were crowded with white pin-point colonies. Cover-slips from these colonies showed a small oval diplococcus, at times biscuit-shaped, the elements lying side by side. Transplantations were made into agar-agar, gelatine, potato, litmus milk and bouillon. No growths resulted. 12, 5, 95. Cultures were again taken by the same method with the same result-an apparently pure culture of the same coccus. Similar colonies were found in the plates, and the same negative results were noted on attempts at transplantation. (2) At the autopsy : Cultures on agar-agar and bullock's blood serum from all sources -heart's blood, valves, liver, spleen, lungs, kidney-were wholly negative. But little of the heart's blood was transplanted. The laboratory was at this time out of the media necessary to grow the gonococcus. The extraordinary resemblance of the organisms found in the vegetations on the mitral valve to the gonococcus and its charac- teristic reactions to staining reagents recalled immediately the negative results obtained on attempts to transplant the growths obtained during life. On re-examining these plates the colonies were found to consist of organisms exactly resembling those found in the thrombi on the valves. They showed the same staining reactions, decolorizing immediately when treated by Gram's method. Considering the large quantity of blood used, it may readily be seen that the medium was not materially different from 17 that advised by Wertheim. The growths on this medium were abun- dant, while transplantations on to ordinary media were without result. Transplantations were again made, May 17th, on human serum and urine, bullock's serum, agar-agar and urine, foetus extract (Flexner) and agar, but the organism refused to grow. These media tested with living gonococci proved suitable. The conclusion is that by the sixth day the organism had died out. Animal Experiment.-A mouse was inoculated into the root of the tail with a piece of the large thrombus the size of a hemp-seed. The result was negative. These results, we believe, justify us in assuming that the organism present in pure culture in the circulating blood and on the affected valves was the gonococcus of Neisser. (a) Its form and arrangement were characteristic. (J) While present free, the cocci were frequently found crowded in the protoplasm of leucocytes in the thrombus on the valve. (c) It refused to grow upon the ordinary media. {d} It grew readily upon a mixture of human blood and agar-agar (one-third blood). (e) It decolorized when heated by Gram's method. The question of the point of entry arises, of course, imme- diately. Nothing definite was known of the manner of life of the patient before entry. The fact that cover-slips from the vagina and the interior of the uterus showed similar diplo- cocci, decolorizing on treatment according to the method of Gram, leaves little doubt that the infection took place through the ordinary channels. Note.-Since the writing of the above, two publications have appeared treating of cases of the same nature. In the first instance (Dauber und Borst, Deutsch. Arch, fur klin. Med., Bd. 56, H. V and VI, 1896), cultures were obtained from the affected valve on blood serum agar, while transplanta- tions and attempts to grow the organisms on the ordinary culture media failed. Though the morphology of the organ- isms was characteristic, while they decolorized when treated by Gram's method, yet owing to certain irregularities in the gross appearance of the colonies, the authors hesitate to assume that they were gonococci. 18 This conclusion is (properly, we believe) disputed by Michaelis (Zeitsch. fur klin. Med. XXIX, H. V and VI, 1896, p. 556), who reports a characteristic case. The diplococci on the affected valves showed all morphological and tinctorial characteristics of gonococci, while cultures taken upon the ordinary media were negative. One of the authors with Dr. Lazear has had occasion to observe, within the last month, a second typical case of ulcerative endocarditis associated with gonorrhoea where the gonococci were obtained from the circulating blood three times in pure culture, while at the autopsy (Dr. Flexner) growths were obtained upon human blood serum agar from the affected valves, from the heart's blood aud from the pericardium (pericarditis). The case will be reported in full shortly. Postscript.-The attention of the authors has just been called to a review (by C. Fraenkel in the Hygienische Rund- schau, 1896, No. 6) of a previous report of this case. The reviewer states that "because during life, a gonor- rhoeal affection was not discovered in the patient despite careful examination, (while) moreover, cultures of the micro- organism which was found were not made on human blood serum or Wertheim's serum agar, the case cannot be considered as an entirely unassailable (einwandsfreie) observation." We confess that we cannot see the justice of these objections. It is a well known fact among all gynaecologists that gonor- rhoeal affections in the female may easily exist without being recognized by ordinary methods of examination during life. Examination of the vaginal secretion was not made in our case during life, but after death, in both vagina and uterus, characteristic organisms were found, diplococci of character- istic biscuit shape existing frequently within leucocytes, decolorizing when treated according to Gram's method. Furthermore, it would appear that the reviewer bad failed to take into account the constitution of the medium upon which successful cultures were twice obtained during life. This medium consisted, as is stated above, of an intimate mixture of the blood drawn immediately from the median basilic vein with about a double quantity of melted agar, the mixture 19 being immediately plated. Upon such a medium, practically that of Wertheim, the organisms were successfully cultivated. In the second case which has been mentioned above and will be reported later, cultures of the organism were obtained in the same manner during life, and, after death, upon human blood serum agar, while attempts to cultivate the organism upon all other media were without result. It may be added that the second case, which occurred in a man, was coincident with a gonorrhoea recognized during life. W. S. T. AND G. B. EXHIBITION OF A CASE OF HEMIPLEGIA WITH MOTOR APHASIA, OCCURRING IN A PATIENT CONVAL- ESCING FROM TYPHOID FEVER. (From the Proceedings of the Johns Hopkins Hospital Medical Society.) By George Blumer, M. D., and Wm. S. Thayer, M. D. [From The Johns Hopkins Hospital Bulletin, No. 61, April, 1896.J [From The Johns Bopkins Hospital Bulletin, No. 61, April, 1896.] EXHIBITION OF A CASE OF HEMIPLEGIA WITH MOTOR APHASIA, OCCURRING IN A PATIENT CONVAL- ESCING FROM TYPHOID FEVER. (From the Proceedings of the Johns Hopkins Hospital Medical Society.) By George Blumer, M. D., and Wm. S. Thayer, M. D. The case which I exhibit to-night illustrates one of the rare complications of typhoid fever, viz., hemiplegia with motor aphasia. The little girl was brought to the dispensary because of a paralysis of one side. The family history is negative and there is nothing of importance in her personal history. We saw her for the first time on the 23d of last August. Seven- teen weeks before that she had an attack of typhoid fever, typical and somewhat prolonged. The attack began with malaise and a feeling of weakness; then there was a con- tinuous fever for ten weeks, with constant headache, diarrhoea, pain in the abdomen, and mental dullness. Her brother had an attack at the same time. About one week after she had begun to eat solid food she was suddenly seized with violent convul- sions. This attack occurred about eight o'clock in the morn- ing while she was at breakfast. She was immediately put to bed. The convulsions were confined almost entirely to the right side as far as the extremities were concerned. The movements were also quite marked in the head, but I have been unable to find out definitely from her mother whether they were confined to the right side of the face or not. These movements were violent from eight o'clock in the morning till four o'clock in the afternoon. At four o'clock the movements of the head and face almost ceased, but the movements in the arm and leg continued with greater or less intensity for two days. During that time the child seemed unable to speak and did not seem to understand anything. About five weeks after the onset of these convulsions she began to recover the 2 use of both limbs on the right side, which up to then had been paralyzed, and some power of speech. At first she did not recognize any of her family, or, rather, probably recog- nized them but miscalled them, calling her father " mother," and so on. At the time she was brought to the dispensary she was able to walk, although she dragged the right foot a little. The arm had not recovered like the foot. There was no evidence of facial paralysis at that time and no hemianopsia. She apparently at that time had a pure motor aphasia. She understood perfectly all that was said to her, would do any- thing she was asked to do, but when an object was held up to her, while apparently recognizing it, would often call it by the wrong name. Some few things she would name correctly. Since she has been in the Hospital she has been improving steadily as far as speech is concerned and now names most objects correctly. There has also been some slight improve- ment in the walking. In the arm there has been no apparent improvement. The arm is generally held at right angles, as you observe it; it is a rigid paralysis. She is unable to move her elbow and can hardly move her fingers. She shows no signs of facial paralysis; the tongue is protruded straight, and there is apparently no abnormality about the muscles around the angles of the mouth. We have here a complete right-sided hemiplegia originally with motor aphasia. The question is, what was the lesion which produced it? The lesion evidently implicated the motor areas in the cortex and also the area presiding over motor speech, that is to say it implicated the ascending frontal and ascending parietal convolutions, and also the posterior portion of the third left frontal convolution. Was the lesion a hemorrhage, was it a thrombus or an embolus ? The age of the child is rather against the lesion being a hemorrhage, as is also the fact that the irritative lesion lasted such a long time. In case of a hemorrhage of such an extent, in all probability destruction of the tissue would have taken place at a much earlier period and the irritative lesions would have ceased. As for an embolus, there never was any source of origin for an embolus, there being no heart lesion at all. Of course the child had gone through a very long period of illness, and in such illnesses there is always a chance for the formation 3 of thrombi in the auricular appendages, and the dislodgment of these thrombi with subsequent emboli and softening. It is impossible, of course, to make an absolute diagnosis between thrombosis and embolism in this case. We have been led to make the diagnosis of thrombosis by the similarity of this case to another case which occurred in this hospital earlier in the year. In that case the patient was seized with convulsions, which were not, however, one-sided as in the child's case, but which terminated fatally in a short time. At the autopsy, extensive thrombosis of the greater number of the branches of the middle cerebral artery was found. In the present case the first three branches of the middle cerebral-the inferior frontal, the ascending frontal and the ascending parietal- were probably involved. We have two arterial trunks to be con- sidered. Sometimes the inferior frontal and ascending frontal branches arise from a single trunk; sometimes the ascending frontal and ascending parietal branches arise from a single trunk; and it is possible that all three might arise from a single trunk. In the latter event we would have to take into consideration only a single thrombus in the common trunk. We can, however, assume that there was a partial thrombosis of the middle cerebral, the thrombus covering the origin of these three branches and cutting off the blood supply. The fact that the signs of irritation existed so long before the actual paralysis would rather point to softening than to pri- mary destruction by hemorrhage. These cases are apparently pretty rare. I have been able to find but six or seven cases in the literature at my command, some with convulsions and some without. There was one case reported by Doctor Gee in 1878 which was almost identical with this. He was inclined to think it was due to embolus, although there was no heart lesion to account for it. He thought it might have originated in one of the auricular appendages. Dr. Thayer.-I had the good fortune to observe two quite similar cases while interne in the Massachusetts General Hos- pital, in the service of Dr. G. G. Tarbell, with whose kind permission these notes are communicated: Case 1.-J. McD., aged 21, single, a currier, was admitted to the Massachusetts General Hospital on the 6th of October, 4 1888. His family history was good; previous history nega- tive. He had complained for two weeks of headache and " sore bones." Four days before entry he gave up work and went to bed. Physical examination showed a large, well-formed man; well nourished; face flushed; conjunctivae injected; lipsand mucous membranes of good color; tongue moist, thick yellow coat. The abdomen was rather depressed; moderate tympa- nitic gurgling in the ilio-caecal region; slight tenderness in the epigastrium; a few rose spots on abdomen and back. The area of splenic dullness was enlarged; spleen easily felt. Urine normal; acid; 1020; albumen, trace; sediment slight; hyaline and fluely granular casts. 7, 10, 88.-"Stupid and apathetic ; numerous rose spots." 9, 10, 88.-No change. 11, 10, 88.-" To-day has been particularly stupid, puts tongue out only when spoken to sharply. Swallows milk when it is poured into his mouth, but cannot be made to suck it through a tube. Pulse rather small, somewhat dicrotic." 12, 10, 88 (10th day).-"At about 1 A. M. the ward tender noticed that the patient was unable to move the right leg and arm. At 12.15 A. M. the patient was seen in bed, on his back, face flushed, eyes half closed, pupils rolled upwards, equal, respond to light. Conjunctivae injected; wrinkles on the left side of the mouth slightly more marked than on the right. Patient is very stupid, will not protrude the tongue when asked to. When asked questions, several times made a noise as if trying to answer, but seemed unable to speak. Unable to move right hand, arm, or leg. The arm or leg can be placed in any posi- tion without movement. When asked sharply to move the arm he pulls it with the left hand. Cutaneous reflexes pres- ent on the left side, absent on the right. Marked ankle- clonus on the right side; bicipital reflex increased on the right. Patellar and tricipital reflexes not markedly increased on the right. Pulse 80, regular, of moderately good strength." 13, 10, 88.-" This morning the condition of the patient is about the same. In the sputa-cup is about an ounce of a viscid, finely aerated mucous and blood-stained expectoration; a purulent matter. Some of the blood in streaks, some rather intimately mixed and dark in color." 14, 10, 88.-" Yester- day afternoon and to-day the patient seems to be brighter; smiles when spoken to; tried to speak, but is unable to articu- 5 late words." 18, 10, 88.-On this date the temperature, which had been gradually falling, reached the normal point, and the following note was made: " The patient is decidedly brighter; when spoken to he seems to understand what is said, but shakes his head, indicating that he cannot speak. Cannot protrude tongue, but opens his mouth better; the drawing of the mouth to the left side has grown much more marked. On more careful examination it seems much more doubtful whether he understands the remarks made to him. He looks brighter, but on a more careful examination he appears to shake and nod his head, usually nodding without regard to the question asked." (It may be said that the nurses who were constantly about him were convinced that he understood per- fectly what was said.) 20, 10, 88.-"Temperature normal. From the 25th to the 7th of November patient had slight rises of temperature and cough with the blood-stained expec- toration and evidences of a consolidation at the left base. On the 30th of October he was able to protrude his tongue." 13, 11, 88.-" Improving; bright and cheerful; cannot talk ; makes a meaningless noise to attract one's attention; cannot copy any noise or word." 27, 11, 88.-" There is still moder- ate dulness through the left side, with somewhat modified respiration and medium and coarse rales on inspiration." 3, 12, 88.-" Can turn over in bed." 6, 1, 89.-" Can pull him- self up in bed and stand alone." 10, 12, 89.-" Can say a few words indistinctly; can write his name with his left hand." 11,1,89.-"He desires to go home; can walk fairly well, though cannot go up and down stairs. Can understand what is said to him apparently perfectly well; reads the paper, can say but a few words. As far as can be seen, understands the use of articles shown him but cannot name them. Can move right arm from the shoulder, but can move muscles of fore- arm but little; is bright and cheerful, but sometimes cries when he fails to do something which he attempts." Case 2.-J. D., 10 years of age, school girl, was admitted to the Massachusetts General Hospital on the 21st of Novem- ber, 1888, with characteristic symptoms of typhoid fever of five days duration. The urine was free from albumen. Rose spots were noted for the first time on the 25th of November. On the 9th of December, the twenty-third day of the disease, 6 it was noted that the patient was " dull, in a typhoidal condi- tion ; defecation and micturition involuntary." 10, 12, 88.- "Yesterday afternoon the nurse noticed that the child did not answer questions and lay persistently on the right side. This morning cannot speak; apparently understands ques- tions; tongue protruded straight when asked; no facial paralysis; motion and sensation in legs good; right arm and hand are moved slowly and with difficulty; grasp of right hand decidedly weaker than left; reflexes apparently not exaggerated." 13,12, 88.-" To-day made a few sounds; nurse thought she said 'milk.'" 16, 12, 88.-"Has said several words this morning; calls 'nurse'; cries out; smiles when spoken to, evidently understands what is said; uses right hand and arm almost as well as left." 20, 12, 88.-"Talks a good deal; says, 'yes, yes,' and 'no, no' to herself." 27, 12, 88.-" Talks more and expresses herself fairly well." 4, 1, 89.-" The temperature was normal to-day for the first time." 18, 1, 89.-The patient had been up and about, but while she talked and understood what was said, she appeared decidedly weak-minded and irritable; very dull; it is noted that she "still seems stupid and weak-minded." 23, 1, 89.-"Has been doing perfectly well; walking about; hungry all the time; mentally still stupid and below par. Two days ago insisted that one of the patients had stolen her clothes and that she had been sent for to come home. Mother came for child to-day and she was discharged." Thus, in each of these instances, during the height of an uncomplicated typhoid fever (10th and 24th days), in young and robust individuals, there appeared suddenly a right-sided hemiplegia with complete motor aphasia. In neither case were there convulsions. I had not seen another instance of this nature until the case" of my unfortunate colleague, to which Dr. Blumer has re- ferred. The lesion in each of the Boston cases was probably a thrombosis; there were none of the ordinary sources for an embolus; the heart was in good condition in each case. Arterial thromboses, though rare, do occur in other regions, while venous thromboses are, of course, common. REMARKS ON DR. NORTON'S PAPER: "IS MALaPIA A WATER-BORNE DISEASE?" Certainly all experimental evidence points di- rectly against the idea that malarial fever can be conveyed by drinking water, and more than that against the idea of an infection through the alimentary tract. Grassi and Feletti fed patients upon the dew collected from malarious districts, and further upon fresh blood taken from patients suffering from malarial fever, blood which, as is well known, if introduced hypodermically or intra- venously, always results in a transference of the infection, without any positive result. Despite the fact that the patients on whom these exper- iments were made were ofien debilitated individuals suffering from chronic nervous diseases, etc., yet as they were well fed and well cared for, it would be impossible to entirely refute the critic who might suggest that it was the good surroundings which saved the patients from a progressive infection which otherwise would have occurred. Such a critic might suggest that had these individuals been suffering from distinct gastro-intestinal lesions, infection would readily have occurred. In connection with this possibility it is interesting that out of 46 cases of amoebic dysentery which we have had in the Johns Hopkins Hospital, 5, or nearly 11 per cent, have suffered at the same time from malarial infection. May it be possible that the amoebic ulcers were in these instances the portals of entry for the malarial parasite? It must of course be said, upon the other hand, that most of these instances of amoebic dysentery occurred during the malarial season and came from districts where the malarial parasite is doubt- less endemic. Dr. Norton's quotation from the author who thought he had found a large number of endoglobular, hyaline.parasites in infant's blood is interesting, inasmuch as any observer who is familiar with exam- inations of fresh blood will immediately see how the author quoted has deceived himself# The vacuolic-like figures found particularly in the blood of children or infants who are anaemic or suffering from fever of any sort, simulate often very closely the malarial parasite, and always deceive the uninitiated; to the skilled observer, however, they are readily recognizable. J. H. H. Bulletin, 1397, viii, 43. REMARKS ON THE PAPERS OF DRS. OPIE AND MacCALLUM ON THE PARASITES OF THE BLOOD OF BIRDS. Let me also congratulate Mr. Opie and Mr. MacCallum unon their careful piece of work. The importance of such studies was impress- ed upon me several years ago by M. Laveran who expressed his conviction that a careful study of the haematozoa of lower animals, and especi- ally of those of birds, which so closely resemble the parasites of human beings, was perhaps more likely to throw light upon some of the dark points in connection with the etiology of malaria than any other branch of research which is at present open to us. Recent observations appear to show that the parasites of birds and human beings are not iden- tical; they are, however, so similar that it is not improbable that the form in which they exist outside of the body and their method of entrance to the body are likewise not unlike the corres- ponding phases in the life history of the parasite of human beings. There are, of course, many more points to be studied with regard to the morphological and biological characteristics of these avian hae- matozoa. In these present observations, for in- stance, no idea has been formed with regard to the length of the cycle of existence of the par- asites. Danilevsky believes that he has been able to distinguish an acute and a chronic form, while Celli divided the parasites of birds into three forms with cycles of existence correspond- ing to the quartan, tertian, and aestivo-autumnal parasites. Here, however, there has as yet been nothing to point out the exact length of the cycle of existence of each generation of parasites. Further, it would be advisable to make care- ful measurements and observations of the tempera- ture in infected birds, observations which, to be sure, have been made by other authors, but with regard to which there is as yet a lack of agreement. It is also, I think, very important that the intimate structure of the parasites of birds 1 blood should be carefully followed out; this can be done with much greater facility than in the human being, inasmuch as specimens of tissues can be instantly obtained at any time desired. But really the most important point, it seems to me, as Bignami has emphasized in a recent paper, is to determine, if possible, the manner in which the parastie exists outside of the body, or more particularly its manner and portal of entry. It may well be possible that careful and continued observations of this sort may bring us nearer the solution of the greatest questions in connection with malarial infection. With regard to the remark of Prof. Osler concerning the possibility that a human being may harbor the malarial parasites in an active condition fPr a considerable time without showing distinct clinical symptoms, I must say that the more of the disease one sees, the more reason- able seems the possibility that this condition may exist with relative frequency. In many cases of tertian fever after insufficient doses of quinine, or during attempts at spontaneous re- covery, a few parasites may be found in the blood for very considerable periods of time without actual clinical symptoms.resuiting. Dr. Gamble tells me that in private practice he has found the parasite in a number of instances in the blood of patients complaining of vague symptoms who had not as yet any actual paroxysm. In these instances it is in every way probable that the parasites had not as yet accumulated in sufficient number ot produce a chill. If now in a certain number of instances a single tertian paroxysm may be followed, without treatment, by so extensive a destruction of the organisms that fever does not recur for a week or ten days (not very infrequent occurrence), theoretically there would seem to be no reason why in certain instances a similar destruction might not occur in groups which have not as yet reached a size sufficient to produce actual manifestations; thus there would result an in- definite prolongation of what one might call the incubation period of the infection. That such conditions exist is, I believe, not only possible, but probable, though definite proof has yet to be advanced. POST-DIPHTHERITIC PARALYSIS. A CLINICAL LECTURE DELIVERED AT THE JOHNS HOPKINS HOSPITAL, OCTOBER 15, 1896. By Wm. Sydney Thayer, M. D., Associate Professor in Medicine in the Johns Hopkins University. Reprinted from the Maryland Medical Journal, January 9, 1897. The two patients which I shall bring before you today are a mother and her child who were admited to the hospital together on the 15th of last month suffer- ing with diphtheria. The boy is two years of age ; he has always been a healthy child, having had as yet none of the ordinary dis- eases of childhood. His mother states that four days previous to his ad- mission he had several convulsions, after which he seemed ill ; he was not inclined to eat and complained of a sore throat. There was a profuse nasal dis- charge and a swelling at the angles of his jaws. The day before his entrance to the hospital he was brought to the out-p-itient department and a diagnosis of diphtheria having been made he was givin 500 antitoxine units (Mulford's antitoxine). This was repeated upon the following day just before admission to the hospital. At the time of entrance the child showed a well-marked enlargement of the tonsils, while both tonsils and a part of the pharynx were covered with a thick greyish-yellow membrane. The membrane extended also on to the velum and posterior surface of the uvula. On the tip of the tongue there was an area the size of a pea covered with a firmly adherent greyish membrane. There was a profuse foul nasal dis- charge ; the temperature on admission was to2°; the pulse 126. The child was hoarse ; there was well marked in- spiratory dyspnea and it was feared that tracheotomy might have to be per- formed. It was not known that he had had antitoxine outside and he was given a fresh dose of Behring's number 3 (1500 antitine units). The boy did per- fectly well ; the throat cleared up rapidly; the temperature was quite nor- mal by the 19th of October. On the 21st the patient began to suffer from an in- teresting sequel which has been ob- served in a considerable number of cases after the antitoxine treatment. The temperature rose and the child be- came cross and irritable, while at the same time there developed a well- marked general urticarial eruption. This lasted for a week and was associ- ated with considerable fever; but at the end of the week the urticaria disap- peared and the temperature cleared up. At about the same time that the urti- caria appeared, that is within a week after entrance, the mother noticed that the child had difficulty in swallowing ; when drinking water or milk he would choke and cough, while often a part of the fluid which he was drinking would flow out through his nose. She also noticed that the voice, which had previ- ously been quite clear, began to have a peculiar nasal quality, while articula- tion of certain letters became difficult and the child's speech was extremely hard to understand. A little later dur- ing convalescence it was noticed that the child manifested no desire to stand; when placed upon his feet, immediately collapsed upon the floor. Of late he has begun to walk, but, as you will notice shortly, in a peculiar manner. 2 As you listen now to the child's voice you will note that it it is impos- sible to understand without very care- ful attention what he is trying to say. All letters requiring the closure of the posterior nares cannot be pronounced by him. I ask him to say P or B; as you notice they sound really more like M. The voice has a very characteristic nasal twang ; it is much like the voice in a case of congenital cleft palate. You have observed as he drank the water which was handed to him a minute ago how frequently he choked and coughed. This morning the milk could be observed coming through his nose drop by drop as he swallowed. The child is unable to walk alone, and when I take his hand you will notice how unsteady and ataxic is his gait. If you examine the child's throat you will observse that the velum and uvula hang in a motionless, flabby manner. When he attempts to speak there is scarcely any motion nor is there any active reflex when the uvula is tickled. The knee-jerks are absent. He is too young to allow us to study carefully the loss of power in his legs, but it is easy to appreciate that the legs are weak and flabby. As far as can be made out there is no reaction of degeneration. The mother is 24 years old and entered at the same time with the child. Her illness began 24 hours before entrance. At this time she began to complain of bachache, headache and sore throat. The temperature on entrance was 104.8°, the pulse 104. There was a well-marked grey diphtheritic membrane on the up- per part of either tonsil, extending up- wards a little way on to the velum. On the day of entrance she was given a bottle of No. 1 Behring's antitoxine, that is 500 units ; on the following morning she was given 1500 units. During the first 24 hours the membrane extended to the uvula ; then gradually disappeared. The temperature was nor- mal in three days. About a week after entry the mother began also to notice that on attempting to swallow fluids she choked, while there was regurgitation at times through the nose. This condition has existed during the past two or three weeks but has improved during the last week until now there is but little trouble in the swallowing. If you examine the moth- er's throat you will see that the velum on the left side hangs much lower and more flabbily than that upon the right; while the uvula is drawn distinctly toward the right. On attempting to speak or on tickling the palate you see how marked a reflex there is upon the right side, how the uvula is drawn in that direction. In other words, the mother has an unilateral paralysis of the soft palate. For the last two or three weeks the mother has had the same trouble with regurgitation but it was due to an unilateral lesion. The knee-jerks are almost absent. Thus in these two cases we are deal- ing with conditions generally included under the term post-diphtheritic paral- ysis. In the first case there is complete paralysis of the muscles associated with the velum and uvula as well as a partial loss of power in the lower extremities with well-marked ataxic symptoms. In the second case we have to do with an unilateral paralysis of the velum and uvula. You are probably familiar with the frequency of post-diphtheritic paralyses. They are, as you know, the commonest and at times the most serious sequels of diphtheria. Statistics, as will be men- tioned later, show that they occur prob- ably in over io per cent, of all cases. As a rule, they appear within the first three weeks. By far the commonest form is that which we have here in the mother and in the child, namely, paralysis of the soft palate, resulting in the regurgita- tion of fluids and in the peculiar charac- teristic nasal voice. An unilateral par- alysis such as is observed in the mother is not an infrequent occurrence. At times there may occur further paralyses of the pharyngeal muscles resulting in serious dysphagia. But there are many other forms of paralysis which follow this disease ; thus, various ocular paralyses are per- haps next in order of frequency to those of the palate. Disturbance of accommo- 3 dation from paralysis of the tensor chorioidea is particularly frequent. Next perhaps in frequency comes the ataxia and loss of power in the lower extremities. In young children we see also at times paralysis of the muscles of the back of the neck, so that the head hangs flac- cidly forward ; paralysis of the abdomi- nal muscles sometimes occurs. At times there may be total paralysis of the extremities or of single cerebral nerves, oculo-motor, facial, abducens. Henoch has twice seen paralytic apho- nia, while paralyses of the respiratory muscles may occur. Disturbances of sensibility are most unusual. The sphincters are affected only in the later stages of fatal cases. In almost every case, however, where symptoms of post-diphtheritic paralysis are manifest there is a loss of the knee-jerk ; this is true in many instances where no other signs of post- diphtheritic nervous disturbance are present. The great majority, if not all, of these disturbances, are now generally recognized to be due to a toxic neuritis of the peripheral neurone. Other changes, however, may follow in the nervous system after diphtheria, hemorrhages or degenerative changes in the brain or spinal cord. Schoenfeld has noted two cases of multiple sclerosis following diphtheria. Again, a number of instances of hem- iplegia have been reported. Thomas of Boston has collected 30. These have doubtless been due to different causes; embolism, thrombosis or hemorrhage. They are probably similar in nature to those which are observed after many other infectious diseases, in particular in typhoid fever. Many observers have described ca- pillary hemorrhages in the brain and in the cord as well as in the heart mus- cle and in other organs. Among the post-diphthetric paralyses are often included those instances of sudden cardiac failure which may, as is well-known, occur late as an apparently normal convalesence. It is a question whether these cases of cardiac paralysis depends chiefly upon changes in the heart nerves, or upon the affection of the heart muscle itself. The frequency with which post-diph- theritic paralyses occur is difficult to de- termine. Different epidemics show the greatest variations in the frequency of post - diphtheritic nervous manifesta- tions. Thus, Unterholzer in Vienna asserts that after some epidemics he has seen the percentage of post-diphtheritic paralyses as low as 4 per cent, and in oth- ers as high as 17 per cent. Hoppe-Seyler in Kiel found post-diph- theritic paralyses in 27 per cent, of his cases, while Johannes, in Norway, esti- mated the average occurrence of post- diphtheritic paralyses at 12.5 per cent., although in severe epidemicshe has seen the percentage as high as 50. Duck- worth estimates the percentage at from 10 to 20 per cent. Lennox Browne out of 1000 cases found post-diphtheritic paralyses in 14 per cent., while Sann6 out of 2448 cases found 11 per cent, of post-diphtheritic paralyses. Combin- ing Brown's and Sanne's statistics we find that out of 3448 cases, post-diphthe- ritic paralyses occurred in 11.8 percent. What influence does treatment by an- titoxine have upon the frequency of these manifestations? In the recent discussions which have taken place upon thewalue of the anti- toxine treatment, numerous statements are to be found with regard to this point. A priori, one might expect to find a reduction in the number of cases of pos.t-diphtheritic paralyses in those treated early by antitoxine. For cer- tainly the shorter the time during which the circulating poison is allowed to act upon the tissues of the body, the less severe might we expect the result to be. As a matter of fact a number of ob- servers, while not offering any definite statistics, state their impression that the frequency of post-diphtheritic paralyses is somewhat greater after use of anti- toxine. Thus, Baginsky in his large clinic has seen, he believes, more post- diphtheritic paralyses since he began the use of the antitoxine, while he quotes Hirschberg as saying that he has seen more ocular paralysis than ever before. 4 Von Noorden noted 21 instances of post - diphtheritic paralyses out of 81 cases, an enormous percentage, while Kohts and Steegenberg report that they have met with no great change in the frequency of this manifestation. On the other hand, many of the other sta- tistics show a surprisingly small number of cases of post-diphtheritic palsy. The most valuable report which is available is probably that of the Ameri- can Pediatric Society, where out of 3384 carefully observed cases, there occurred 328 instances of post-diphtheritic par- alysis, or 9.7 per cent. These figures, as will be seen, are a little below the estimates of the frequency of these man- ifestations based upon the combined statistics of Brown and Sanne of ca.^es untreated by antitoxine. If we add to these cases the statisticsofSeitz, Hubler, v. Noorden, Sonnenberg, Steegenberg, Gerloczy, Havas and Weber, we have in 3982 cases, 382 instancesof post-diphthe- ritic paralyses, or 9.5 per cent. The evi- dence, then, based upon a very consid- erable number of cases is rather in favor of a slight diminution in the frequency of post-diphtheritic paralyses in cases where the antitoxine has been used. The significance of these figures becomes rather more striking when we remember the fact that from 5 to 20 per cent, more patients survive under this treatment. It is easy to conceive that many of the instances of diphtheria which result fa- tally might, if the life were saved, de- velop nervous disturbances afterwards. The more intense, indeed, the poison, the more frequently might we reasonably expect to meet with grave results. Granting that in any one given case the administration of antitoxine, by cutting short the period during which the tis- sues are exposed to a circulating toxic substance may diminish the likelihood of peripheral neuritis, yet the addition of 10 to 20 cases in every hundred to the number which would have survived without the administration ofantitoxine -cases which during a certain length of time have been exposed to a most in- tense poisoning-might well result in an equal or even greater number of post- diphtheritic paralyses than were ob- served in the cases treated according to the old method. If in spite of this fact the number of cases of post-diphtheritic paralysis in every hundred is no greater, or indeed really less than previously, as seems to be the case, then we may well assume that the early administration of anti- toxine has exerted a distinctly favor- able influence in protecting the nervous system. A striking feature, however, of the antitoxine report of the American Pedi- atric Society is the large number of late sudden deaths from cardiac paraly- sis ; thus, 32, or nearly 10 per cent., of the cases of post-diphtheritic paralyses were instances of sudden death. Only three of these occurred, however, in in- stances where the inoculations were made in the first two days. Two-thirds of the cases occurred in patients where the injection had been made after the third day. As is stated in the report, many of these instances would probably have proven fatal earlier in their course had the serum treatment been omitted. The antitoxine cannot be reasonably expected to overcome the damage done by toxines before it was injected. The prognosis in these cases of post- diphtheritic paralysis is usually good if we leave out those distressing instances of sudden death due to cardiac paralyses. It may well be that more of these in- stances than we suspect are really de- pendent rather upon changes in the heart muscle itself. The simple par- alyses of the soft palate are usually rel- atively innocuous, and convalescence is to be looked forward to without treat- ment. In some instances, however, particularly if there be associated par- alysis of the pharyngeal mucles, there is a certain danger of pneumonia from the inhalation of foreign particles, while strangulation from the lodging of large particles in the gullet or the larynx has occurred. The paralyses of the muscles of the trunk and extremities are often of annoyingly long duration, but almost invariably end in recovery. With regard to treatment different observers give different advice. Thus, some are urgent in their recommenda- 5 tion of electrical treatment,while others, and among these Henoch, are inclined to rely more upon general tonic treat- ment with thorough massage and pas- sive motion. November 1, 1896.-You will, I think, all recognize the child I bring before you today as the same which you saw two weeks ago. At that time, if you re- member, he was suffering from a post- diphtheritic paralysis of the velum and uvula as well as from a paresis of both legs with well-marked ataxia. The mother brought the child back to the hospital two days ago, complaining that it had grown much weaker, that it had not only continued to regurgitate fluids through the nose but had had great diffi culty in swallowing solids, any solid particles sticking apparently in the gul- let and causing attacks of strangulation which greatly alarmed her. She also says the child has become "cross-eyed." You will observe as you look at the boy now, the manner in which his head falls first to one side, then to the other ; now forwards, and, if he suddenly lifts his head up, it often topples over back- wards. There is then apparently a great weakness of the muscles of the neck as a whole. You will notice also that the child has a well-marked convergent strabismus. On as careful examination as is possible with so small a child this appears to be due to a bilateral paresis of the external rectus ; it is somewhat more marked on the right than on the left. You still notice the markedly nasal voice and as the . boy walks you will see that he is still very unsteady and ataxic. There is, however, one feature which was not evident two weeks ago; the child stands with an extremely marked lordosis ; the abdomen is prom- inent, the back is arched forward in the lumbar region, while the shoulders are thrown back in order to keep the equili- brium. The attitude of the child is just that of a patient with a progressive hy- opathy. When the child is placed upon the floor he is, as you see, quite unable to get up again. You perhaps observed a few minutes ago as he entered the room how when he walked across to the black- board and raised up his hands to seize the shelf upon which the chalk lies, his back suddenly gave way, leaving him hanging by his hands, his abdomen hav- ing as it weie " caved in " against the wall. This case, then, is an instance of rather remarkably generalized post- diphtheritic paralysis. The child has had, first, paralysis of the velum and the uvula ; second, probably slight pharyn- geal paralysis; third, double paralysis of the external recti; and fourth, a general weakness of the muscles of the 'trunk and of the legs with well-marked ataxia. The heart remains in apparently good condition. The child is to reenter the hospital to- day, where it will be kept quiet, placed upon a full diet and cod liver oil and given regular daily massage with pas- sive motions. December 23.-The child is still in the hospital, but has improved in every way. He no longer regurgitates fluids and has no trouble in swallowing. The ataxia, though still present, is much di- minished ; the power of the muscles of tl'.e trunk and legs has greatly improved and the strabismus has nearly gone. MALARIA. By WILLIAM H. WELCH, M. D., and WILLIAM S. THAYER, M. D. DEFINITION, SYNONYMS, HISTORY, AND PARASITOLOGY. By WILLIAM H. WELCH, M. D. Definition. Malaria comprises the diseases caused by the specific protozoan parasite called Hcematozoon malaria. The name " malaria," derived from the Italian moT aria and signi- fying " bad air," was applied originally to the miasm or poison which was supposed to produce the disease. It is now used to designate the disease itself, and is the most convenient term for this purpose. The most characteristic malarial manifestations are intermittent or remittent fever, certain forms of the disease described as " pernicious," and a chronic cachexia with enlarged spleen and anaemia. The parasite discovered by Laveran is invariably present in malaria and produces from the haemoglobin of the red blood-corpuscles the brown or black pigment granules which are characteristic of the disease. Synonyms. Malarial fever; Intermittent fever ; Chills and Fever; Fever and Ague; Paludism or Paludal fever; Swamp or Marsh fever; Miasmatic fever; Periodical fever ; Autumnal fever. Names derived from localities where the disease has prevailed with especial intensity have sometimes been used; as, Walcheren fever, Batavia fever, Hungarian fever, African fever, Panama fever, Chagres fever. Special names have been applied to certain types or manifestations of malaria; as, remittent fever, bilious remittent fever, hemorrhagic remittent fever, congestive fever, dumb ague, black-water fever, black jaundice. History. There are few diseases which can be traced so surely and continuously as malaria in medical writings from ancient times to the present. Various types of malarial fever are described by Hippocrates, Celsus, Galen, and other ancient writers,.although it is often impossible to determine the precise characters of many of the fevers described by these authors. Vol. I.-2 17 18 MA LARIA. Celsus and Galen divide intermittent fevers into quotidian, tertian, quartan, semi-tertian, and irregular. They recognized intermittent fevers with long intervals. The nature of their semi-tertian fever (hemitritaeus) has given rise to much discussion. Certain forms of intermittent fever were believed by Galen to have their seat in the spleen, others in the liver. The influence of marsh effluvia and of seasons of the year in the causation of certain of these fevers was recog- nized. Various symptoms were discriminated as to their prognostic significance, often with much acuteness of observation. A passage in Celsus clearly alludes to the type of malarial fever now called aestivo- autumnal fever. The Arabian physician Rhazes described the so-called subintrant malarial fevers. No important advance beyond the knowledge of Celsus and of Galen concerning malarial fevers was made until toward the end of the sixteenth century, when Mercatus in his work on malignant fevers described various forms of pernicious paroxysms in association with intermittent fever, particularly with the tertian type. The introduction of cinchona bark from Peru into Europe by the Countess del Chinchon and her body-physician, Juan del Vego, in 1640, gave great impetus to the study of malarial fevers, and, indeed, in its revolutionizing influence upon medical doctrines this event marks an epoch in the history of medicine. In the latter half of the seventeenth and the beginning of the eigh- teenth century there appeared a voluminous literature regarding mala- rial fevers. The most notable of the works upon this subject of this period are those of Sydenham, Richard Morton, Torti, Ramazzini, and Lancisi. These works remain to this day the great classics upon malaria. They contain the fundamental clinical and therapeutical facts and many etiological data relating to this disease. Morton and Lancisi demon- strated clearly the relation of malaria to marsh miasm. Sydenham pointed out the differences between vernal and autumnal intermittent fevers. Especially complete and keen in analysis is the nosography of Torti,1 whose classification of the malarial fevers, particularly of the pernicious and mixed forms, has been followed by most subsequent authors. The diagnostic as well as the therapeutic value of the prepara- tions of Peruvian bark was recognized, and assisted materially in the discrimination of the malarial fevers from the other so-called essential fevers. It is interesting to note the relative accuracy of diagnosis and of description of the group of malarial fevers from the latter half of the seventeenth century onward, in contrast to the confusion which existed regarding the other essential fevers until the discrimination of the latter by the pathological-anatomical studies of the present century. The military and colonial enterprises of England in the eighteenth century served to extend the knowledge of the geographical distribution of malaria, particularly in tropical climates, the works of Pringle and of Lind containing especially noteworthy observations on this point. But the great mass of the very extensive literature on the epidemi- ography of malarial diseases which has been so industriously collected and ably analyzed by Hirsch2 belongs to the present century. 1 Torti: Therapeutice specialis ad febres quasdam perniciosas, etc., Mutinse, 1712. 2 Hirsch: Handbuch der historisch-geographischen Pathologic, Stuttgart, 1881. HISTORY. 19 The significance, as regards malaria, of the active studies in morbid anatomy of the first half of the present century relates to the clear dif- ferentiation of typhoid fever from malarial and other fevers rather than to the actual contributions to the pathology of malaria, although these were not lacking. The occurrence of enlarged spleens, so-called fever- cakes or ague-cakes, and even the dark color of the organs in association with malarial fevers, had been occasionally observed by the older writers, notably by Lancisi, but the intimate relation of these altera- tions to malaria was not established until during the first half of the present century. Audouard (1808, 1812, 1818) emphasized congestion and enlarge- ment of the spleen as the essential anatomical lesion of malarial fever. Bailly (1825) noted in a series of autopsies on cases of pernicious mala- rial fever observed in Rome in 1822 the dark color of the cortical gray matter of the brain and the congestion of the cerebral meninges and substance. He laid especial emphasis upon evidences of supposed inflammation of the central nervous system and of the stomach and intestine. These anatomical observations, together with those of Nepple (1828, 1835), and, to a less extent, of Maillot (1835), were interpreted in favor of Broussaisism, which at this period exerted such a pernicious influence upon medical practice. Valuable contributions to the pathological anatomy of malarial fevers, especially of the remittent type, were made in the United States during the fourth decade of this century by Stewardson in Philadelphia, Swett in New York, and Anderson and Frick in Baltimore. Steward- son demonstrated the bronzed color of the liver in remittent fevers, and regarded this as the characteristic anatomical criterion of the disease. His observations were confirmed and extended by the other writers named. Alonzo Clark in 1855 demonstrated that the bronzed color of these livers is due to the presence of granules of yellow, brown, and black pigment, which he regarded as derived from the coloring matter of red blood-corpuscles. The monumental work of Daniel Drake on The Principal Diseases of the Interior Valley of North America (1850, 1854) contains a large amount of valuable information, based upon personal observation and research, as to the distribution and characters of the malarial fevers in the then Western States of this country. In the light of recent discoveries it is interesting to note the ingeni- ous arguments advanced by John K. Mitchell in his work On the Cryp- togamous Origin of Malarious and Epidemic Fevers, published in 1849, in favor of the doctrine of contagium animatum. This book deserves to rank with the more frequently quoted work of Henle relating to the same line of argument. At about the same period Bassi and Rasori in Italy also advocated the parasitic theory of malaria. The discoverer of the malarial pigment is Heinrich Meckel, who found and described the pigment in 1848 in the blood and organs of the dead body of an insane patient. He was, however, ignorant of the relation of this pigment to malaria. The next report concerning the pigment was in 1849 by Virchow, who observed it in the body of a man who had suffered from chronic malaria. There soon followed the obser- vations of Heschl, Planer, A. Clark, Tigri, Frerichs, and others, fully establishing the relation of the pigment to malaria. The source of the 20 MALARIA. pigment was regarded by Meckel and Virchow as in the spleen, and this doctrine was elaborated by Frerichs. Planer (1854) was the first who saw the pigment in the fresh blood of living patients, and he sug- gested that the pigment may be formed in the circulating blood-a view which was more fully presented and advocated by Arnstein (1874) and by Kelsch (1875). There is no doubt that some of the pigmented bodies which are now recognized as parasitic organisms had been seen by earlier observers without knowledge of their true nature. Thus Meckel noted the presence of pigment granules in colorless, hyaline bodies devoid of definite nuclei. He, and more particularly Virchow and Frerichs, observed pigment in fusiform and curved bodies in the blood, which, although interpreted as endothelial cells of splenic origin, in all proba- bility were, at least in part, the crescentic forms of the parasite. Some of the larger pigmented spherical organisms must have been seen and mistaken for pigmented leucocytes. In November, 1880, Laveran discovered the parasitic nature of these and previously unrecognized forms in the blood of malarial patients, and thereby introduced a new era into our knowledge of the malarial diseases. The discovery of the malarial parasite has furnished an unfailing means of diagnosis of malarial diseases, has materially advanced our knowledge of their pathology, has led to a better understanding of their clinical phenomena and various types, has furnished important data for prognosis, and has led to improvements in methods of treatment.1 Parasitology. Historical. Tn 1879, A. Laveran, a French military surgeon, stationed at the time in the province of Constantine, Algeria, began to study the path- ological anatomy of malaria, and at once directed his attention to the much discussed question of the origin of the pigment. He observed in the blood of malarial patients certain pigmented bodies different from the melaniferous leucocytes, but he was uncertain as to their nature until, on November 6,1880, he discovered that some of these pigmented bodies threw out long flagella endowed with such active lashing move- ments as to convince him, as they have convinced every one who has since then seen them, that they are living parasites. Laveran published his observations in a note to the Academic de M^decine in Paris, pre- sented November 23, 1880. This was followed by the publication of several notes in 1880 and 1881, and in the latter year appeared a small monograph by Laveran on the parasitic nature of malaria.2 1 The so-called bacillus malariae described in 1879 by Klebs and Tommasi-Crudeli, which for a short period had a certain vogue, chiefly with Italian writers, never rested upon satisfactory observations which indicated that it bore any relation to malaria, and it deserves no more consideration than the palmella of Salisbury and the other alleged malarial organisms described before Laveran's discovery. 2 Only occasional references to the voluminous literature on the parasitology of malaria are given in this article. A. full table of references to the works treating of malarial fever since the recognition of its parasitic origin up to and partly including the year 1895 will be found in "The Malarial Fevers of Baltimore," by William Sydney Thayer, M. D., and John Hewetson, M. D. (The Johns Hopkins Hospital Reports, vol. v., 1895). PARASITOLOGY. 21 In these various early publications Laveran describes (1) pigmented crescentic and ovoid bodies ; (2) spherical, transparent bodies, sometimes free, sometimes applied to the surface of red blood-corpuscles, the smallest about one-sixth of the diameter of a red blood-corpuscle and containing only one or two fine pigment granules, these representing an early stage of development of (3) larger, pigmented, spherical bodies averaging 6 [t in diameter, but sometimes larger than a red blood-cor- puscle, and containing numerous, often moving, pigment granules; (4) bodies similar to the last mentioned, but beset with actively motile flagella; (5) free motile flagella; and (6) swollen spherical or deformed bodies, 8-10 in diameter, containing pigment, and regarded as cadaveric forms of the spherical parasites. Laveran noted amoeboid movements of the spherical forms, grouping of the small spherical bodies together, and the occurrence of small, colorless, motile bodies, without specific characters, which he suggested may perhaps represent the first phase of development of the parasitic elements. He regarded all of the forms as different stages of development of the same species of organism, and considered the free flagella, which he believed were formed within the spherical bodies and escaped by rupture of the enveloping membrane, as the most characteristic and perfect stage of development of the parasite. Laveran communicated his results to his colleague Richard, stationed in Philippeville, Algiers, who in February, 1882, published a commu- nication confirming Laveran's observations and adding certain points of importance. He describes the development of the parasite from small, perfectly transparent bodies contained in otherwise normal red blood- corpuscles. This clear body grows larger, forms pigment out of the haemoglobin of the enveloping red corpuscle, which thereby becomes gradually decolorized and reduced to a mere colorless shell-like rim, which finally ruptures and sets free the parasite. This now generally accepted view as to the intracorpuscular development of the parasite, which was first announced by Richard, was, however, in the following year abandoned by him in favor of Laveran's view that the parasites develop either free in the plasma or in close attachment to the surface of red corpuscles or in depressed spots on the surface. Richard observed amoeboid movements of the parasites, and noted spherical bodies with a central block of black pigment from which delicate lines radiated so as to produce rosette forms. Laveran continued to publish brief communications in 1882 and 1883, and in 1884 he published a larger work 1 presenting his observationsand views in detail. In this work he tiescribes more fully the forms already mentioned, and he notes the occurrence of segmenting forms, which, however, he interpreted as forms of degeneration, not of reproduction. The observations of Laveran and of Richard were made by micro- scopical examination of the fresh blood. In 1883 and 1884, Marchia- fava and Celli published in a number of articles the results of their studies of stained specimens of dried malarial blood. With the excep- tion of small, spherical stained bodies in the red blood-corpuscles, which they thought might be micrococci, they interpreted the various other stained and usually pigmented bodies found in the red corpuscles of malarial patients as probably degenerative changes. As a matter of 1 Laveran : Traits des Figures palustres, Paris, 1884. 22 MALARIA. fact, the coccus-like dots were probably in part Ehrlich's degenerations, whereas their drawings show that the supposed degenerative forms were in reality the actual parasites, which in many of their phases were accurately depicted, although not recognized as such. In 1885, Councilman and Abbott in the organs from two cases of pernicious comatose fever found and described small pigmented hyaline bodies in and outside of red corpuscles, most abundantly in capillaries of the brain. In 1885, Marchiafava and Celli, as the result of the examination of fresh malarial blood, came to a correct interpretation of these bodies and described them fully and accurately. They emphasized especially the amoeboid, unpigmented, transparent intracorpuscular bodies, to which they gave the inaccurate name of plasmodia, which has been widely adopted. They described clearly the intracorpuscular develop- ment of the parasite, the formation of pigment out of the blood coloring matter, the consequent changes in the blood-corpuscles, and they pointed out the probable reproductive nature of the segmenting bodies, which they described more fully and accurately than had been done by Laveran and Richard.1 The publications of Marchiafava and Celli attracted wider attention than had those of Laveran, and from the year 1885 up to the present time there has been a steadily flowing stream of literature upon the various questions connected with the parasitology of malaria. Immediately following the confirmation of Laveran's discoveries by Italian observers came similar confirmation from Sternberg, Council- man, and Osler (1886-87), and somewhat later by James (1888) and Dock (1890), in this country, and within a few years numerous reports from various parts of Europe, America, Asia, and Africa demonstrated the invariable association of Laveran's parasites with all cases of mala- rial fever. There are no observers of any prominence who, with suffi- cient opportunity and training for such examinations, have failed to recognize the parasites in cases of malaria, nor is there now any authori- tative voice of dissent from the acceptance of the parasite as the specific cause of this disease. Since the fundamental researches of Laveran, Richard, and Marchia- fava and Celli (1880-85) other observers have greatly extended our knowledge as to many details concerning the structure and life-history of the parasite and its relation to various types, phenomena, and lesions of malaria, although not a few important questions still remain unsettled. The most important of these later discoveries are due to the demonstra- tion by Golgi (1885-86) of a definite relation between the cycle of development of the parasite and the different stages of malarial fever, and to the recognition by Golgi (1885-86) of the two varieties of the parasite belonging respectively to quartan and to tertian, fever, and by Marchiafava and Celli and Canalis (1889) of the variety or varieties belonging to sesti vo-autumnal fever. These observations have led to 1 Marchiafava and Celli claim for themselves the discovery of the intracorpuscular amceboid forms with and without pigment, and of the segmenting forms, but, as is appar- ent from the review of Laveran's and Richard's preceding publications, this claim cannot be admitted. Marchiafava and Celli, however, described and interpreted these phases of the parasite far better than Laveran, and to them belongs the credit of demonstrating the intracorpuscular development of the parasite. PARASITOLOGY. 23 two schools of doctrine-the one, headed by Laveran, holding to the unity of a pleomorphic malarial parasite, the other, headed by Golgi and other Italian writers, upholding the plurality of malarial parasites. The latter doctrine has the larger number of supporters. Dock (1890-92) was the first to differentiate the three principal varieties of the malarial parasite in the United States, and recently Thayer and Hewetson 1 have published a thorough study of the malarial fevers of Baltimore with careful descriptions of these varieties. Investigations concerning the intimate structure of the malarial parasites have been made especially by Celli and Guarnieri, Grassi and Feletti, Romanowsky, Sacharoff, Mannaberg, Antolisei, Bastianelli and Bignami, and others. The results of these later studies concerning the malarial parasites will be considered in various parts of this article. They are fully and systematically presented in the recent monograph of Thayer and Hewet- son, already cited. Nomenclature. Various names have been suggested for the malarial parasite. Among these may be mentioned Oscillaria malariae (Laveran), Plasmodium malariae (Marchiafava and Celli), Haematomonas malariae (Osler), Haema- tophyllum malariae (Metchnikoff), Haemamoeba malariae (Grassi and Feletti), Haemococcidium malariae (L. Pfeiffer), Haemosporidium mala- riae (Danilewsky), Haematozoon or Haemocytozoon malariae (Osler and various authors). Of these names, Plasmodium malariae has gained wide currency, but it is on zoological grounds singularly inappropriate, and there is no reason why it should be perpetuated. The name Haemosporidium malariae has much to recommend it, but it has not been generally adopted. Upon the whole, the name Haema- tozobn malariae, which expresses nothing as to the zoological classification of the parasite, and which has been adopted by many writers, may be provisionally accepted until more precise knowledge is reached concern- ing the zoological position of the parasite. Haemocytozoon is more precise, but the other term has the advantage of greater brevity. Zoological Position of the Malarial Parasite. The malarial parasite belongs to the class of Protozoa, under which name are grouped the unicellular organisms with the physiological cha- racters of animals. Biitschli divides the Protozoa into the orders- Sarcodina, Mastigophora, Sporozoa, and Infusoria. Grassi and Feletti classify the malarial parasite among the Sarcodina, subdivision Rhiz- opoda, and adopt the name Haemamoeba malariae. Antolisei considers that the parasite belongs to the Gymnomyxa, or, more precisely, the Proteomyxa of Ray Lankester. The great majority of authors classify the malarial parasite among the Sporozoa, which are divided by Balbiani into the groups Gregarinida, Sarcosporidia, Myxosporidia, and Micro- sporidia. Under the Gregarinidae are included the Coccidia, with which 1 Op. cit. 24 MALARIA. some writers group the malarial parasite. Kruse makes under the Gregarinidae a speeial family which he designates as Haemogregarinidae, and to whieh he refers the malarial parasite and similar haemocytozoa in lower animals. Danilewsky suggests forming a new group under the Sporozoa to be called Haemosporidia, in which he places the malarial and similar haematozoa, and Labbe calls the group Gymnosporidia. As we know nothing of the malarial parasite in the outer world, it is evident that our knowledge of its life-history is incomplete, so that any attempt at a zoological classification must be regarded as only provisional. Such information as we possess favors classifying the parasite among the Sporozoa, but it possesses characters which do not enable us to fit it exactly into any of the existing subdivisions of the Sporozoa, so that the suggestions of Kruse and of Danilewsky of establishing a new sub- division of the Sporozoa or of the Gregarinidae to include the malarial parasite and similar organisms in birds seems to be a good one, and the name Haemosporidia for this new subdivision appears to be appropriate. According to this classification, the malarial parasite may be called the Haemosporidium malariae. Methods of Investigation. The methods for demonstrating and studying the malarial parasite will be described under the heading Diagnosis. It may here be stated that generally the most useful procedure is the examination of thin layers of fresh blood with an oil-immersion objective. The description of the parasite which is to follow is based mainly upon this method. This procedure may be advantageously combined with the examination of stained specimens. For the study of the finer details of structure this latter method is indispensable. General Morphology and Biology. The malarial parasite is a unicellular, protozoan organism which develops within the red blood-corpuscles, and therefore belongs to the group of Haemocytozoa. As will be described subsequently, organisms closely resembling the malarial parasite have been found in the blood of birds. The numerous attempts to cultivate artificially the malarial parasite have hitherto been unsuccessful, nor has this organism been recognized in the outer world. Our entire knowledge of it is derived from its study in human beings. Three varieties of the parasite have been differentiated. These varieties are that of quartan fever, that of tertian fever, and that of aestivo-autumnal fever. This last variety it is proposed by the writer to call the Haematozobn malaria? falciparum. Before considering the justification of this division and the speeial characters of each of these varieties it is desirable to describe the more important characters com- mon to all varieties of the malarial parasite. The cycle of development of the malarial parasite embraces a vege- tative and a reproductive phase. Its duration varies from twenty-four to seventy-two hours, according to the variety of parasite. The vegetative phase begins in the form of small, colorless, amoeboid, PARASITOLOGY. 25 hyaline bodies, 1-2 // in diameter, within the red blood-corpuscles.1 These amoeboid bodies increase in size, and, with the occasional exception of the sestivo-autumnal variety, they develop within them a variable number of dark pigment-granules, situated, as a rule, near the margin of the parasite. The pigment increases in amount and in the coarseness of the granules as the organisms continue to develop. It occurs in the form of irregular grains and of fine rods, which may be in active motion within the parasite. Having attained a certain stage of development, which differs as regards the size of the organism in the different varieties, the parasite gradually ceases its amoeboid movements, assumes a spherical or oval shape, and becomes somewhat sharper in contour. In this condition it may continue for a while to grow. When it has reached its full size it may completely fill the red blood-corpuscle or may occupy only a small part of it, these differences depending mainly upon the variety of para- site. The parasite now may be called the full-grown or adult form. Coincidently with these stages of development the enveloping red blood-corpuscle may undergo various changes, which are of significance in distinguishing the varieties of parasite from each other. The cor- puscle may become swollen and pale, or shrunken, or brassy-green in color, or otherwise deformed, or it may appear unaltered, as will be described in considering the varieties of the parasite. The subsequent stages in this cycle of development belong to the reproductive phase, which is shorter in duration than the vegetative. The first evidence of this reproductive phase is the collection of the pigment into a mass of granules or a solid block situated usually at or near the centre, but sometimes near the periphery, of the organism. These bodies with clumps of pigment may be designated, in accordance with Thayer and Hewetson's suggestion, as the presegmenting forms (corpi con blocchetto of the Italian writers). Coincidently with or following this gathering of the pigment into a clump, sometimes without a definite collection of the pigment, the pro- cess of segmentation begins. In its most typical form segmentation is ushered in by the appearance of delicate lines radiating from the per- iphery toward the centre. Eventually the substance of the spherical organism is divided into a variable number of round or oval bodies called spores. The enveloping red corpuscle, which now may be 1 As has already been mentioned, Laveran believes that the forms of the parasite which have, since the publications of Marchiafava and Celli, usually been regarded as within the red corpuscles, are attached or applied (accoles) to the outer surface of the corpuscles. Mannaberg (1893) has again raised this question by his statement that many of the amoeboid forms, particularly in their younger stages of development, are attached to the corpuscles, often in little niches or indentations on the surface. There is no doubt that the organism may be situated as described by Mannaberg. Marchiafava and Celli, who had previously noted this appearance, interpreted it as indicating the extrusion of the parasite from the red blood-corpuscle. It is, in fact, often very difficult to determine with precision whether the organism is on the surface of or within the corpuscle, but the evidence is that the majority of the younger forms are intracorpuscular. Marchiafava and Bignami (1894) describe in the following words their conception of the manner of penetration of the youngest forms into the corpuscle: " The youngest amoebae, the offspring of sporulation, by virtue of the viscidity of their protoplasm adhere to the surface of, and by their movements bury themselves in, the contour of the red corpuscle. In this posi- tion the parasite attacks the external strata of the corpuscle as a means of nourishment, and after altering these layers is able to penetrate within, and thus becomes entirely endo- globular.' ' 26 MALARIA. reduced to a narrow pale rim, bursts and the spores are set free, or the corpuscle may have disappeared before the process of segmentation is completed. The pigment remains behind, and is quickly engulfed by phagocytes. Sometimes in the aestivo-autumnal variety segmentation occurs in organisms entirely devoid of pigment. These segmenting bodies are called also sporulating forms. The free spores speedily invade fresh red blood-corpuscles, where, as the small, colorless, amoeboid, hyaline bodies already mentioned, they begin again the cycle of development. The direct transformation of the motionless1 round spores into the small, hyaline, amoeboid bodies has been very rarely observed, but there is no reason to suppose that there exists any stage intervening between these two forms. In the complete sporulating cycle of development which has been described we can distinguish, therefore, the following forms of the para- site : (1) unpigmented, amoeboid, hyaline bodies; (2) pigmented, amoe- boid, hyaline bodies ; (3) full-grown or adult bodies ; (4) presegmenting bodies; (5) segmenting or sporulating bodies; and (6) spores. All of these various bodies are depicted in Plates I. and II. As already mentioned, in the aestivo-autumnal variety this cycle may be completed without the appearance of pigment. These bodies are to be thought of, not as separate and distinct forms, but simply as successive stages of development with all transitions from the youngest to the most advanced. Especially can no sharp distinction be drawn between bodies (1) and (2) and between bodies (3) and (4). The recog- nition, as a distinct form, of the body designated as presegmenting is of less practical importance for the quartan and tertian varieties than for the aestivo-autumnal. The name " plasmodium " was applied by Marchiafava and Celli originally to the unpigmented, amoeboid forms. It is frequently em- ployed to designate both the pigmented and the unpigmented amoeboid bodies, as well as the parasite in all of its forms. These amoeboid bodies may be called, in general, hyaline forms or amoebae. As will be explained subsequently, it is only the quartan variety which is found in all its forms with equal frequency in the peripheral circulation and in the blood of internal organs; whereas segmenting tertian parasites are more abundant in the spleen and bone marrow than in the peripheral vessels, and the aestivo-autumnal parasite develops mainly in the internal organs, its segmenting forms being extremely rare in the peripheral circulation. Each of the forms of the parasite which have been described as developing within the red blood corpuscles may also be found free in the plasma. They probably escape by rupture of the enveloping cor- puscle, a process which one can often witness when examining the fresh blood microscopically. Extracorpuscular mature forms may possibly segment in the usual way, but there is no evidence that forms in the earlier stages may complete their cycle of development free in the plasma. The important discovery was made by Golgi that all of one genera- tion of the parasite form a group, the members of which develop 1 Plehn claims to have observed that the spores are actively motile and flagellated, but this statement is opposed to the observations of all others. PARASITOLOGY. 27 approximately at the same time, and that a definite relation exists between the phases of development of the parasite and the stages of malarial fever. The onset of a paroxysm corresponds to the ripening of one generation of the parasite. A few hours or shortly before the paroxysm segmenting forms appear, and enable the observer to predict the approaching paroxysm. The spores which are set free by the act of sporulation invade the red blood-corpuscles and start a fresh generation, which pursues during the paroxysm and the subsequent apyrexia so regular a development that in typical cases the experienced observer can tell approximately by examination of the blood the stage of the disease-that is, the time which has elapsed since the last paroxysm and the time when the next paroxysm may be expected. It is not, however, always the case that the parasite develops with the regularity expressed by Golgi's law, and especially in the aestivo- autumnal fevers irregularities are very common. The simultaneous occurrence of two or more generations in different stages of develop- ment may render difficult the interpretation of the phases observed, although even here careful observation will enable the observer to draw correct conclusions in tertian and quartan fevers. It has not been satisfactorily demonstrated that there occurs any other cycle of development of the malarial parasite in human beings than that which has been described, although the possibility of such an occurrence is by no means disproven. Canalis (1889) believes that he has found evidence that a second, slower cycle of development of the aestivo-autumnal parasite occurs, which is represented in certain of its phases by bodies of the crescentic group, to be described subsequently ; and this view, with certain modifications, has been accepted by Golgi, Antolisei and Angelini, Grassi and Feletti, and Sacharoff. This doctrine is, however, opposed by many observers, and it does not at present rest upon sufficient evidence. It seems necessary to suppose, on the basis of clinical evidence, that the malarial parasite may remain for months in a latent condition in the human body, and then begin to develop again, causing a relapse of the fever. As such relapses may occur in forms of malaria in which cres- cents do not appear, there must be in these cases some resistant organism other than bodies belonging to the group of crescents. We know noth- ing as to the nature of these resistant bodies. The hypothesis is advanced by Bignami that they may be spores which are enclosed within leucocytes and other cells, and which have become surrounded by a resistant mem- brane and have lost their usual staining properties. Besides the forms which have already been described as representing phases of the regular sporulating cycle of development of the malarial parasite, there occur other forms which cannot at present be referred to any cycle of development. These other forms are-(1) crescentic bodies and fusiform, oval, and round bodies belonging to the same group ; (2) flagellate bodies and free flagella; and (3) degenerative forms. The crescentic and flagellate bodies, from their size and remarkable appearance, are the most striking forms of the parasite, and from the beginning have attracted much attention. Their significance, although there are many hypotheses concerning it, is not understood. (1) The crescents develop only from the aestivo-autumnal parasites, 28 MALARIA. and will therefore be described in connection with these. They are never formed from quartan and tertian parasites. (2) Flagellate bodies, on the other hand, may form from each variety of the parasite, tertian, quartan, or aestivo-autumnal. The weight of evidence is that they do not exist in the circulating blood, but develop after the blood has been withdrawn from the body, usually within ten to twenty minutes, sometimes earlier. Some observers have found them frequently, others only rarely. They are frequently found if the blood is examined at the right stage of the disease and time is allowed for their development. Councilman showed that they are more commonly found in blood aspirated by a hypodermic needle from the spleen than in the peripheral blood. They develop in tertian and quar- tan fevers from the mature, full-grown extracorpuscular forms-in tertian especially from swollen forms larger than the red blood-corpus- cles. They are therefore found most frequently a short while before and during the paroxysm. In infections with the sestivo-autumnal parasite the flagellate bodies develop from round bodies belonging to the group of crescents, and do not occur in definite relation to the stage of the fever. Rarely intracorpuscular bodies may develop flagella. The spherical bodies which become transformed into the flagellate bodies are always or nearly always pigmented. Marchiafava and Celli state that they once saw an unpigmented flagellate body. These bodies may be somewhat smaller or larger than the red blood-corpuscles, the size varying to some extent with the different varieties of the parasite, as will be explained later. The process of development of the flagella may be studied under the microscope. The pigment granules, which at first (aestivo-autumnal variety) may have been in repose, usually begin to dance about within the organism, often in a lively way. In the aestivo- autumnal variety they usually gather in the central part, but in the others they may be near the periphery or irregularly distributed. The spherical body may acquire an oscillatory or jerking movement. Pro- jections may be formed and retracted at the periphery, and the whole edge may acquire a vigorous undulating movement. These changes are attributed to the movements of the flagella within the body or in its peripheral layers, and have been graphically compared by Richard to the struggles of an animal to get free. Suddenly the flagella shoot out from the periphery, and with their active lashing movements produce a violent commotion among the red blood-corpuscles and other small particles which may be in their neighborhood (Plate I. Figs. 22 and 41 ; Plate II. Figs. 43, 44). The flagella are pale and thin, and present often at their extremities and along their course small olive-shaped swellings which may change their position. Here and there a pigment granule is occasionally seen in a flagellum. The flagella vary in size, number, and position. Their length may be three or four times the diameter of a red blood-corpuscle or not more than half that size. One to six may be attached to the spherical body. They may project from one side or from any part of the circumference of the body. Their movements may be somewhat rhythmical; they may become slow or even cease, and again start up. Flagella may become detached and move about freely among the red blood-corpuscles. On account of their pallor such free flagella would PARASITOLOGY. 29 usually be overlooked were it not for the commotion which they produce among the red blood-corpuscles. The motion of the flagella may be observed on the slide for half an hour, sometimes longer. These flagellate bodies are the most startling forms of the malarial organism, and no one who sees them doubts for a moment that he is looking at a living parasite. It is not surprising that they attracted in an especial manner the attention of Laveran, who, as already mentioned, regarded the flagella as the most characteristic and perfect form of development of the parasite. Subsequent studies have not, however, tended to confirm the conception of Laveran as to their significance. As has already been made clear, the flagellated bodies do not belong to the regular sporulating cycle of development of the malarial parasite in the human blood. The most prominent theories as to their significance are the following: (a) They are forms of degeneration or appearances belonging to the death-agony of the parasite. In support of this view it is urged that the flagellate bodies do not belong to any known cycle of development; that they are developed only outside of the human body; that they are developed from mature forms which are known frequently to undergo undoubted degeneration, such as hydropic swelling, vacuolation, and fragmentation, and which may already show beginning evidences of degeneration ; that nuclear substance is absent from the flagella; and that similar appearances of extrusion of motile filaments in other uni- cellular organisms are known to zoologists and are interpreted as degen- erative. (6) Sacharoff, from the study of their structure on stained specimens, believes that the flagella are extruded chromatin filaments derived from perverted karyokinetic nuclear division. He regards the process as degenerative. (c) Dock suggests that the flagellate bodies " represent resting states of the organism, capable of existing independently, perhaps even of reproducing themselves, but also able, under favorable circumstances, of reproducing the typical growth of the parasite." (d) Mannaberg's opinion is that the flagellate bodies may represent a state belonging to fhe saprophytic existence upon which the mature forms of the parasite enter soon after the blood is withdrawn from the body. On account of unsuitable conditions of environment they are unable to continue this existence in the blood outside of the body and soon perish. A similar view is advanced by Manson, who suggests that the flagellate bodies represent the first stage, and the detached flagella, in search of their appropriate host, represent the second stage of life of the parasite outside of the body. Manson 1 conjectures that the mosquito is the extracorporeal host of the malarial parasite, and he reports observations of Ross showing the development of flagellate forms in the stomach of mosquitos fed on malarial blood. There are arguments for and against each of these theories. Reluc- tant as one may be to consider such striking forms as the flagellate 1 Manson: "The Goulstonian Lectures on the Life History of the Malaria Germ Outside the Human Body" {The British Medical Journal, 1896, March 14, 21, 28). Man- son lays much emphasis upon supposed analogies between the malarial germ and the filaria sanguinis. Only future investigations can determine the correctness of Manson's hypothesis. 30 MALARIA. bodies as phases of degeneration, the existing evidence seems upon the whole to be more in favor of this hypothesis than of any other which has been advanced. Still, if Sacharoff's observation as to the presence of nuclear material in the flagella be correct, the objection of Grassi and Feletti, that the flagella are incapable of reproductive development because the nucleus of the parasite does not divide and enter them, would be overthrown and the hypothesis of Mannaberg and Manson would become more probable. It is evident from the description of these bodies that the use of the word " flagella " to designate the motile filaments is of doubtful propriety, but it is the term commonly employed. (3) There are- various bodies, often seen in the examination of mala- rial blood, which are undoubtedly degenerative forms of the parasite, and others which are probably degenerative, although opinions con- cerning the latter are divided. The more common signs of degeneration of the parasite are vacuolation, pseudo-gemmation, fragmentation, deformities of shape, particularly swelling, granular condition of the protoplasm, certain alterations in the arrangement and appearance of the pigment, disappearance of nuclear material, defects and irregulari- ties in staining, and changes in the refraction of the organism. These various degenerative changes produce forms too numerous to describe in detail. They have often been misinterpreted and described as special forms of the parasite, some of them, particularly certain vacuolated and budding forms, as special modes of reproduction. Degenerations may occur in any form of the parasite, but they are particularly common in the extracorpuscular forms. Mannaberg de- scribes the disintegration of young intracorpuscular forms, with dis- appearance of their nuclei. Fragmentation of forms extruded from the blood-corpuscles can sometimes be watched while examining fresh blood under the microscope (Plate I. Fig. 21). As a rule, only a certain number of the mature forms actually enter into reproductive segmenta- tion, and many of the spores or segments perish. If all segmented and the offspring survived, the number of the parasites after a few paroxysms would become enormous. As a matter of fact, degenerations of full- grown parasites are often observed. An interesting form of such degen- eration, found most frequently in the mature forms of the tertian variety, is the appearance of swollen, pigmented, so-called hydropic bodies, often much larger than red blood-corpuscles (Plate I. Figs. 18, 40), and sometimes containing vacuoles (Plate I. Figs. 18, 19, 23, 24, 40, and 42). Round bodies simulating spores are sometimes seen in these vacuoles, but on properly stained specimens they are devoid of the nuclear mate- rial of genuine spores. Pseudo-gemmation, or the appearance of sarcodic buds on the surface of the organisms, is doubtless a form of degenera- tion. Such buds may become separated, in the form of hyaline balls, from the parent organism (Plate I. Figs. 19, 20). These evidences of degeneration may appear also in crescents and bodies belonging to this group (Plate II. Figs. 40, 41) and in flagellate bodies. From the latter small hyaline balls with a flagellum attached may break off and move around actively. Such bodies might be mistaken for flagellated spores. There is no good evidence that the malarial parasite ever multiplies PARASITOLOGY. 31 by budding1 or by simple cell-division. The only form of multiplica- tion which has been demonstrated is that of sporulation, also called seg- mentation, already described, although it cannot be denied that other forms of reproduction may exist. Various interesting degenerative changes are produced by the in- fluence of quinine. These will be fully described under Treatment, Action of Quinine on Malarial Parasites, page 146. As the malarial parasite passes its vegetative life mostly within the red blood-corpuscles, it is evident that it finds its food in this situation. This food may be appropriated both by intussusception and by diffusion. Evidence of intussusception is found in the occasional presence of frag- ments of the corpuscular substance within the body of the amoeboid forms. Doubtless diffusion is the more important mode of nutrition of the parasite. The question has been raised whether the parasite may develop in other cells of the body than the red blood-corpuscles. Nearly all forms of the parasite have been found enclosed in cells, chiefly leucocytes, splenic or medullary cells, and endothelial cells. As such included parasites often present evidences of degeneration, these appearances have been generally interpreted as referable to phagocytic destruction of the parasites, and such they unquestionably usually are. Golgi and Monti have, however, recently published observations intended to show that the aestivo-autumnal parasite may develop within endothelial and other cells, as will be explained in considering this variety of parasite. The malarial parasite in the condition in which it exists in the human body is very susceptible to injurious agencies. It is quickly killed by the addition of distilled water and of dilute acids and alkalies. Under ordinary conditions it does not long survive in blood withdrawn from . the body. Under certain special circumstances it has been kept appa- rently alive for two to four days, possibly for a week. Sacharoff observed amoeboid movements in aestivo-autumnal hyaline bodies which had been for a week in the intestinal canal of leeches kept on ice, and he obtained a positive result by inoculating himself with malarial blood preserved in this way for four days in leeches. The tertian and quartan parasites were found to be less resistant than the aestivo-autumnal. Ripe bodies may segment in blood outside of the body, but no further development or multiplication of the parasites has been positively observed in the various attempts made to preserve or cultivate them. The parasite does not continue to develop and multiply in the human body after death. Of course no inferences can be drawn from these observations as to the resistance of the parasite in its natural condition in the outer world. As to what this natural condition is we can only speculate. Grassi and Calandruccio have thought that certain species of amoebae which they have observed in malarial districts might be the extra parasitic form. The failure of artificial cultivations and certain analogies drawn from the zoological characters of the parasite have led to the prevalent theory 1 Celli and Guarnieri for a time believed that spherical bodies of the crescentic phase may multiply by the formation of buds (gemmation), but they subsequently abandoned this view and adopted the now generally accepted opinion that these budding forms are degenerative. The "buds" are devoid of the structure of genuine spores. 32 MALARIA. that the malarial parasite passes at least a part of its existence as a parasite in animal or vegetable organisms. Mention has already been made of Manson's hypothesis that the mosquito may be a host for the malarial parasite. That the germ is capable of entering upon some resistant phase of development seems highly probable in view of the evidence that malaria can be contracted from the air, There is no evi- dence that the malarial parasite is eliminated from the human body in a condition capable of infecting another individual or the locality. The disease, however, can be transmitted by inoculating into healthy indi- viduals, either subcutaneously or intravenously, blood from a malarial patient. Unity or Plurality of the Malarial Parasite. As has already been mentioned, there are two schools of doctrine as to the malarial parasite-the one led by Laveran holding that the mala- rial parasite is a single species with pleomorphic characters, the other believing that there are three or more species, or at least varieties, of malarial parasites. The observations upon which the latter doctrine is based originated with the Italians, and have been supported by investi- gations in this country and elsewhere. Golgi in 1885 and 1886 first differentiated the parasite of quartan fever from that of tertian fever, and Marchiafava and Celli and Canalis in 1889 and 1890 differentiated the variety of parasite characteristic of sestivo-autumnal fever.1 There is much difference of opinion as to the number of sestivo-autumnal parasites. All adherents of the doctrine of plurality agree that there are at least three varieties of malarial parasite -namely, the quartan, the tertian, and the sestivo-autumnal-distin- guished from each other by morphological and biological characters to be subsequently described. The discovery by Golgi of the definite cycle of development of the malarial parasite and the recognition of several distinct varieties have done much to bring order out of the earlier chaotic condition when a multitude of parasitic bodies were described without knowledge of their significance or relations to each other. There remain, however, many unsolved problems which it may be expected that further investigations will clear up. 1 Marchiafava and Celli on the one hand, and Canalis on the other hand, have con- ducted a polemic as to which of them belongs the credit of first distinguishing the aestivo- autumnal parasite. The differentiation of this parasite was not made all at once, and with the same precision in all details, as in the case of Golgi's sharp separation of the quartan and tertian parasites. Golgi from the beginning of his researches (1885-86) suggested that the crescentic bodies belong to a special cycle of existence different from that of the tertian and quartan organisms, and noted their occurrence in irregular mala- rial fevers. Councilman in 1887 emphasized the association of crescents with remittent fevers and malarial cachexia. Golgi in February, 1889, definitely expressed the opinion that in addition to the malarial fevers caused by the quartan and the tertian parasites we must recognize another type of fever associated with unpigmented amoeboid forms and crescents. On September 13, 1889, appeared a preliminary communication of Marchia- fava and Celli, which must be regarded as furnishing the first clear and sharp description of the essential differential characters of the aestivo-autumnal parasite, with especial em- phasis on the occurrence of unpigmented organisms. On October 10, 1889, appeared the preliminary communication of Canalis, in which likewise the essential characters of this parasite were described, and a greater emphasis was laid upon its relation to the crescents than had been done by Marchiafava and Celli. The full publication of Canalis antici- pated by a short time the complete article of Marchiafava and Celli on the aestivo- autumnal parasite. PARASITOLOGY. 33 In opposition to the doctrine of plurality it is urged by Laveran that all of the so-called varieties of the parasite may be explained simply as phases of a single pleomorphic organism influenced by various conditions of environment, such as locality, season, individual predispo- sition, and various unknown circumstances. He contends that the characters upon which a division into separate varieties is based are insufficient for such a purpose and inconstant; that one so-called variety under certain conditions may be transformed into another; and that there is no definite, necessary relation between the types of fever, such as quartan, tertian, quotidian, irregular, continued, and the form of parasite present. The variations of the malarial parasite can be ex- plained, he thinks, in large part by the varying rapidity of development. He emphasises the view that malaria with all its diverse manifestations is nevertheless clinically and anatomically one disease, and has always been so regarded. He argues that the experimental production of malaria by inoculation does not support the doctrine of plurality. In considering the force of these objections it must be admitted that so long as we are unable to cultivate the malarial parasite artificially, and are ignorant of its life-history and the conditions of its existence outside of the human body, the possibility must be admitted that under certain conditions, at present unknown, one variety may be transformed into another. But, on the other hand, the existing evidence-and it is already considerable-goes to show that under the conditions which we can at present control and study each of the three principal varieties of the parasite preserves its identity and is not transformed into another variety; that is to say, there is no evidence that a quartan parasite ever becomes metamorphosed into a tertian, or either of these into an sestivo- autumnal parasite. The principal arguments in support of this doctrine of plurality may be summarized as follows : (1) Each well-established variety of parasite presents morphological and biological characters which suffice for its identification. (2) Each variety of parasite corresponds to definite types of fever. Genuine quartan fever can be produced only by the quartan parasite. As will be explained in the clinical part of this article, other types of fever may be caused by more than one variety of parasite, and much complexity may result from multiple and mixed infections and various irregularities; but all of this does not prevent the recognition of certain fundamental types of fever especially characteristic of each variety of the parasite. (3) Cases of pure infection with one variety of parasite have been carefully studied for weeks and months without any indication of the transformation of one variety into another (Calandruccio, Grassi and Feletti). Opportunities for such study are exceptional. The appear- ance of a second variety of parasite in localities where there is oppor- tunity for renewed infection cannot of course be interpreted in favor of the metamorphosis of one variety into another. (4) In certain localities only one or two of the varieties of the para- site are met with. In a few places only the quartan, or more frequently only the tertian, parasite is observed; in most places where malaria is mild and infrequent only tertian, and occasionally quartan, parasites, Vol. I.-3 34 MALARIA. with entire absence of sestivo-autumnal parasites, are found. Instances of this localized distribution of the parasites, which manifestly is a strong argument in favor of the doctrine of plurality, will be subse- quently mentioned (page 99). (.5) Strong arguments in favor of the constancy of the varieties of the malarial parasite are furnished by the experimental production of malaria. Gerhardt in 1882 and 1883 (reported in 1884) was the first to produce malaria experimentally by the subcutaneous injection of blood obtained from malarial patients. At this time the malarial organism was not generally recognized. Since these first experiments similar ones have been repeated, usually in the manner of intravenous injections of malarial blood, with positive result in over thirty cases. The experiments before 1889 were made without determination of the exact variety of parasite injected and found in the experimental case. In 1889, Gualdi and Antolisei, without full knowledge of the critical nature of the experiment, injected two patients intravenously with 3 c.cm. of blood from a patient suffering with quartan fever and possessing quar- tan parasites. In each of the inoculated individuals irregular fever with sestivo-autumnal parasites developed. These two cases are constantly adduced as a main support of the doctrine of mutability of the varieties of the parasite, but unjustly so, for it was subsequently determined that the patient from whom the blood was obtained had previously suffered from irregular fever, and he subsequently developed characteristic sestivo-autumnal organisms, so that the experimenters themselves later expressed the opinion that at the time of the inoculation the patient furnishing the blood had combined quartan and sestivo-autumnal organ- isms, the latter being overlooked. In view of the uniform results yielded by the numerous subsequent experiments in support of the doctrine of immutability of the varieties of the parasite there can be little doubt that this later opinion of Gualdi and Antolisei is correct. It has been found regularly since these experiments that if blood containing only the tertian or the quartan or the sestivo-autumnal parasite be injected intravenously into a person unaffected with malaria, the variety of para- site injected, and only that variety, appears in the blood of the experi- mental case. When two varieties of parasite are injected, or when the malarial blood is injected into a patient already affected with a malarial organism other than that injected, then it usually happens that one variety supplants the other, most frequently the one injected supplanting that already existing in the inoculated individual. For such displace- ment of one organism by another we have numerous examples in bacte- rial infections. The bearing of the inoculation experiments upon the determination of the periods of incubation of malaria will be considered in the clinical part of this article (pages 97, 98). These already numerous inoculation experiments, showing the iden- tity of the parasite in the experimental case with that in the blood used for injection, furnish the strongest existing arguments in favor of the plurality of the malarial parasites.1 Whether, accepting this doctrine, we shall designate the different 1 Di Mattei: ' ' Contribute allo Studio della Infezione Malarica Sperimentale nell' Uomo e negli Animali," Arch, per le Scienze Mediche, vol. xix. N. 4, 1895. PARASITOLOGY. 35 types of the malarial organism as separate species or separate varieties is with our present knowledge a matter of secondary importance and of individual judgment. If it be admitted that under no existing circum- stances one type is transformed into another, then we are justified in speaking of separate species of malarial parasites. As at present we can study only a small part of the conditions which surround the entire life- history of the parasite, it seems to the writer preferable to designate the different types as varieties rather than species. Classification. We have already had occasion repeatedly to mention the division of the malarial parasites into three principal varieties-the quartan, the tertian, and the aestivo-autumnal. No further subdivision of the quar- tan variety has ever been suggested. Nor has any attempt been made to subdivide the tertian parasite originally described by Golgi; but, as it has since been found that the aestivo-autumnal parasite-or, according to some observers, one form of this parasite-may likewise produce tertian fever, the latter form of the aestivo-autumnal organism is designated by Marchiafava and Bignami as malignant tertian or aestivo-autumnal (sum- mer-autumn) tertian, and the former is called mild or vernal (spring) or genuine tertian or Golgi's tertian parasite. This so-called aestivo-autum- nal or malignant tertian is, however, in no sense a subdivision of the tertian parasite originally described by Golgi, which remains a well- differentiated, separate variety. When the name " tertian organism" is used without any epithet, it is always this variety which is meant. The name "parasite of aestivo-autumnal fever," introduced by March- iafava and Celli and already adopted by many writers, leaves much to be desired. It is intended to indicate that this form of the parasite is the cause of the malarial fevers prevailing in summer and autumn. This application, however, is correct only for certain localities, chiefly those warmer regions where severe as well as mild types of malaria occur. In localities where the prevailing type of the disease is mild at all seasons the summer and autumn malarial fevers are caused generally or exclu- sively by tertian or quartan parasites. Even in the warmer situations where the aestivo-autumnal parasite is common, not all of the summer- autumn fevers are caused by this parasite, but often a large proportion are caused by the ordinary tertian parasites. In subtropical and tropical regions the aestivo-autumnal parasites may occur in winter and spring fevers. It is evident that the epithet "aestivo-autumnal," as applied to a special variety of malarial parasite, is sufficiently designative for many localities, as, for example, the southern parts of the United States and Central and Southern Italy, but it is not so for all. The term " parasite of aestivo-autumnal fever " does not at once sug- gest the relation of the parasite to a definite type of malarial fever, and is therefore out of harmony with the designations " parasite of quartan fever" and " parasite of tertian fever." But it is characteristic of a large pro- portion of the fevers caused by aestivo-autumnal organisms that they do not correspond to any definite type, but are notably irregular. Hence these organisms were designated by Golgi and by Sacharotf as the " para- site of irregular malarial fevers." But the objection to this latter name is 36 MALARIA. that aestivo-autumnal organisms may cause typical quotidian and tertian fevers. Indeed, this is the only form of malarial parasite which, it is believed, may complete its cycle of development in twenty-four hours, and thus when present in only a single group or generation may cause quotidian fever. As leading characters of the aestivo-autumnal organisms are their small size, their slight formation of pigment, and the ring-like shape of the amoeboid forms, they are sometimes spoken of as the small malarial organisms (forme piccole), or the unpigmented, colorless, or slightly pig- mented organisms, or the ring-like, annular organisms. They are also called the organisms of grave or pernicious malaria, although they may likewise cause mild types of the disease. As it is to the group of aestivo-autumnal parasites that the crescents exclusively belong, these parasites have been described as the semi- lunar variety. They may be designated as crescent-producing. Haematozoon falciparum is suggested by the writer as a suitable techni- cal name for this variety of parasite.1 The three varieties of the malarial parasite may therefore be tech- nically designated-(1) Haematozoon febris quartanoe ; (2) IIcematozobn febris tertiance ; (3) Hamatozobn malanoe falciparum. The name aestivo-autumnal parasite, as the more commonly used and generally understood designation, will, however, continue to be used, as well as the term "Haematozoon falciparum," in this article for the last-named variety. There is no difference of opinion, except among the unicists, that the aestivo-autumnal organisms form a variety or group which is to be differ- entiated from both the quartan and the tertian organisms even more sharply than the tertian and the quartan are differentiated from each other. But the question as to the unity or the plurality of the aestivo-autumnal organisms is still an open one, and is the most important unsolved problem relating to the divisions of malarial parasites. Its solution is attended with unusual difficulties, but we may reasonably expect that they will be surmounted by future investigations. In distinction from the quartan and the tertian organisms the aestivo- autumnal are often irregular and atypical in their cycle of development. Some, it is believed, may complete their cycle in twenty-four hours, others in forty-eight or a longer period : their tendency to develop simultaneously in well-defined generations is far less marked than is the case with tertian and quartan organisms, so that several or all phases of development of aestivo-autumnal forms may be observed in the inter- nal organs at the same time. The occurrence of multiple groups of the parasite is common. Forms appear which pass through their amoeboid, mature, and segmenting phases without any formation of pigment within the parasite. The development takes place largely in the internal organs. The development of crescents occurs at a variable period after 1 The name Haematozoon falciforme suggested by Antolisei and Angelini is objection- able, as it implies that the shape is always falciform, and is applicable only to the cres- centic forms. The adjective "falciparum" (falx, "sickle," parire, "to bring forth," "to produce"), on the other hand, indicates that the property of forming crescents is a distinctive character of the organism, and it is therefore applicable to the variety of the parasite which possesses exclusively this property. PARASITOLOGY. 37 the onset of the disease, but rarely in less than a week. Corresponding to these variations and irregularities the types of fever with which aestivo-autumnal organisms are associated are various and irregular. The attempt has been made to deduce certain laws controlling these variations and apparent irregularities, and to subdivide the aestivo- autumnal organisms into certain varieties or subvarieties, but there is little agreement of opinion as to this subdivision. The following are the principal divisions of the malarial parasite which have been proposed, the essential differences in these various divisions relating, of course, to the different views held concerning the aestivo-autumnal organisms: I. Marchiafava and Celli (1889) recognized a short cycle of develop- ment of the aestivo-autumnal parasite, unaccompanied by development of pigment, and a longer cycle with formation of a few pigment granules. Marchiafava and Bignami (1891) make two varieties of this parasite- viz. the amoeba of aestivo-autumnal quotidian, with a twenty-four-hour cycle, and the amoeba of aestivo-autumnal tertian, with a forty-eight- hour cycle-Amoeba febris quotidiance and Amoeba febris tertiance cestivo- autumnalis. The latter variety is the malignant tertian organism of these authors. The main differences between these varieties, according to Marchiafava and Bignami, relate to the length of the cycle of development, but there are claimed to be also minor morphological and biological differences to be mentioned subsequently (page 51). These authors, therefore, make four different varieties of the malarial parasite. They divide the malarial fevers into two main groups : 1. Mild malarial fevers which prevail in winter and spring. These are- (a) Quartan fever (with its varieties of double and triple quartan). This is caused by the Amoeba febris quartance (Golgi), which completes its life cycle in seventy-two hours. (6) Tertian fever (with double tertian and rarely certain subcontinued fevers). This is caused by the Amoeba febris tertiance (Golgi), which completes its life cycle in forty-eight hours. 2. Severe or aestivo-autumnal fevers, including the pernicious and most of the subcontinued fevers. This group comprises- (a) 2Estivo-autumnal quotidian fever (to be distinguished from quo- tidians of tertian and of quartan origin), caused by the Amoeba febris quotidiance, which completes its cycle in twenty-four hours. This is the only variety of malarial parasite which can complete its life cycle in so short a period as twenty-four hours. (6) 2Estivo-autumnal or malignant tertian fever, caused by the Amoeba febris tertiance cestivo-autumnalis, which completes its cycle in forty-eight hours. Most of the pernicious cases belong to this variety, the remainder to the aestivo-autumnal quotidian variety. II. Canalis (1889) does not subdivide into varieties the aestivo- autumnal parasite, which he calls the " semilunar variety," but he con- siders that it has two cycles of development: (a) a rapid cycle with the usual phases of amoeboid, mature, segmenting forms and spores, and (6) a slower cycle associated with the development of crescentic bodies, which he considers to be reproductive and to represent one phase in this second cycle. A similar view is held by Antolisei and Angelini. 38 MALARIA. III. Grassi and Feletti (1890) regard the crescent-producing forms as an entirely separate species, which they call Laverania malarice, and which they distinguish both from the directly spore-forming unpig- mented sestivo-autumnal forms, which they call Hcemamoeba immaculata, and from similar rapidly developing, but pigmented, aestivo-autumnal parasites, without crescents, which they call Hcemamoeba proecox. Their classification of the malarial parasite is as follows: (a) Hcemamoeba, malarice, identical with the quartan parasite; (6) Hcemamoeba vivax, which is identical with the tertian parasite of Golgi; (c) Hcemamoeba proecox,u form of the aestivo-autumnal parasite, giving rise to quotidian fever; (d) Hcemamoeba immaculata, similar to the preceding, but without development of pigment; (e) Laverania malarice, the crescent-producing variety, giving rise to irregular fevers. Sacharoff formerly regarded the crescents as belonging to a separate species of malarial parasite, and adopted the following classification : (a) Hcemamoeba febris quartanoe (Golgi), (6) Hcemamoeba febris tertianoe (Golgi), (c) Hcemamoeba proecox (Grassi), (d) Laverania (Grassi). Re- cently (1896) he holds that all variations of the aestivo-autumnal para- site are modifications of a single variety due, mainly, to the development of the parasite within nucleated red blood-corpuscles. IV. Mannaberg (1893) accepts Marchiafava and Bignami's division of aestivo-autumnal parasites into quotidian and tertian, and also adopts Grassi and Feletti's division into pigmented and unpigmented quotidian parasites. He does not, however, consider the crescents as belonging to a species or variety distinct from these, but considers them as developing from each of these three divisions of aestivo-autumnal parasites. He has a peculiar view as to the origin of the crescents from conjugation of cells, and regards them, therefore, as forms of syzygia. He divides the malarial parasites into two groups-the first group, with sporulation and without syzygia, comprising (o) the quartan and (6) the tertian parasites of Golgi; the second group, with sporulation and with syzygia, com- prising (a) the pigmented quotidian parasite, (6) the unpigmented quo- tidian parasite, and (c) the malignant tertian parasite. V. Golgi (1893), an admirable and successful investigator of the malarial parasites, does not consider the semilunar forms as belonging to a species or variety distinct from the ordinary sporulating aestivo- autumnal parasite. He attempts no subdivision of the aestivo-autumnal parasite. His conception of the mode of development of this parasite (lifters in essential points from that of Marchiafava and Bignami and of most other investigators, as will be explained in considering the special characters of the aestivo-autumnal parasite. The following statement of Golgi's classification of the malarial fevers is quoted from Thayer and Hewetson's work on The Malarial Fevers of Baltimore, already cited.1 Golgi divides the malarial fevers into two groups: (1) Fevers the pathogenesis of which is connected with parasites which have their principal habitat in the circulating blood, where, by preference, they accomplish the phases of their cycle of existence. (2) Fevers the pathogenesis of which is connected with parasites 1 The writer wishes to acknowledge his indebtedness to this excellent monograph for much valuable assistance in the preparation of this article. PARASITOLOGY. 39 which have their chief seats in the internal organs, particularly the bone marrow and the spleen, where, by preference, they accomplish their cycle of existence in conditions of relative stability. (1) The fevers of the first group are unquestionably associated with different species or varieties of the parasite-viz. (ci) the quartan para- site ; (6) the tertian parasite. (2) "To the second group belong the fevers which appear clinically under multiform types, very often irregular, of which for the present it is impossible to make a grouping based upon an ascertained biology or cycle of development of the parasite We are dealing in these cases with generations of parasites which, occurring in the parenchyma of organs in different stages of development, give origin, at periods of a certain regularity or in a more or less continuous succession, to colonies of young forms which, in large or small numbers or in insignificant quantity, may escape into the blood current, permitting one to discover by microscopical examination of the blood the presence of the small endoglobular amoebae." Golgi refers to the crescents as " forms the biol- ogy of which has not yet been well determined." VI. Thayer and Hewetson (1895) were likewise unable to confirm Marchiafava and Bignami's subdivision of the aestivo-autumnal parasite into a quotidian and a tertian variety. They say: " We have been unable to trace a constant length of the cycle of development, and we have been unable further to separate two or more types of the [aestivo- autumnal] parasite depending either upon the length of the cycle of development or upon any other morphological or biological differences. We believe that the length of the cycle varies greatly in different cases, lasting usually from twenty-four hours, or even a little less, to forty- eight hours or more. After the infection is five days or a week old certain of the organisms, instead of segmenting, pursue a further growth, developing into the hyaline, refractive, ovoid, and crescentic bodies." They do not feel justified in making any positive statement as to the significance or capacity of reproductive development of the crescentic bodies. The question has been raised whether in tropical regions, where per- nicious types of malaria are common, any form of malarial parasite different from those already mentioned occurs. The observations of Van Dyke Carter, Dock, van der Scheer, Plehn, and others show that the same parasites are found in India, Panama, Java, and other tropical countries as elsewhere. The negative reports which have been published are referable doubtless to insufficient training in such examinations on the part of the observers. The fact that a large part of the tropical malarial fevers are caused by aestivo-autumnal organisms which appear in the red blood-corpuscles as small, pale, feebly-staining, delicate, diaphanous, often unpigmented amoeboid rings of hyaline protoplasm, difficult to detect in many cases, and sometimes scanty or at times even absent, will account for many of these negative observations. The singular distribution of the haemoglobinuric type of pernicious malarial fevers in certain definite localities suggests the possibility that this may be caused by a special type of organism. The sporadic cases of malarial haemoglobinuria examined in Italy have shown, however, 40 MALARIA. ordinary sestivo-autumnal organisms. Plehn 1 found in cases of black- water fever occurring on the West Coast of Africa small, annular amoe- boid forms, staining with great difficulty and never pigmented, in the red blood-corpuscles. u Out of the amoeba there develops by thickening of the peripheral zone an oval or egg-shaped body, with well-staining double contour. In course of time this divides into five or six small oval forms, staining at one pole, which, when they are set free, move about with great rapidity in the blood. These probably develop into the amoeboid forms." The organism never attained a size larger than one quarter of the red blood-corpuscle. Crescents were occasionally found. Plehn seems to regard this organism as allied to, but not iden- tical with, the sestivo-autumnal parasite described by Italian writers. Although his description presents certain peculiarities of the parasite which he observed in the pernicious malarial haemoglobinuria and other pernicious fevers of the West Coast of Africa, especially the constant absence of pigment, the extremely small size, the sporulation in the blood, and the apparently motile spores,2 nevertheless it is not suffici- ently complete and satisfactory to justify the inference that the organ- ism differs from forms of the ordinary sestivo-autumnal parasite as previously observed. From the preceding review of the various investigations and opinions concerning the divisions or varieties of the malarial parasite, especially of the sestivo-autumnal form, we may draw the conclusion that whereas the separation into quartan, tertian, and sestivo-autumnal varieties rests upon a sound basis of fact, the various attempts to further subdivide the aestivo- autumnal group have not as yet been sufficiently successful to jus- tify our acceptance at the present time of any of these subdivisions. There is, however, some reason to believe that this last group, as at present constituted, may comprise varieties which will hereafter be satisfactorily differentiated from each other. We will now consider the special characters of each of the three varieties of the malarial parasite. I. The Parasite of Quartan Fever (HtEmatozoon Febris Quartans) (Plate I. Figs. 25-42). In most malarial regions this is the rarest form of the malarial parasite, but there are certain places (none of these have been recog- nized in this country) where it is the prevailing variety. Being par- ticularly common in the neighborhood of Pavia in Italy, the quartan parasite was the first to be differentiated and described by Golgi (1885- 86), to whose masterly description nothing of essential importance has been added by subsequent investigators, with the exception of certain details of intimate structure. The quartan parasite completes its cycle of development in seventy- two hours and entirely within the circulating blood. The youngest forms of the parasite are small, amoeboid, when at rest discoidal, hyaline bodies, 1 Plehn : " Ueber das Schwarzwasserfieber an der afrikanischen Westkiiste," Deutsche, med. Wochenschrift, 1895, Nos. 25, 26, 27. 2 It may here be mentioned that Plehn considers that the spores of all varieties of the malarial parasite are flagellated-a view which has not been confirmed by other observers. PARASITOLOGY. 41 within the red blood-corpuscles. They are about one-fifth to one-fourth the size of the red blood-corpuscle (Plate I. Fig. 26). The central part of the body may appear paler than the peripheral. These unpigmented, youngest forms are found during and for several hours after the paroxysm ; they may begin to appear two hours before the paroxysm. The very ear- liest forms are not to be distinguished from the youngest tertian parasites, but as they begin to develop they present a sharper outline and somewhat more refractive appearance, and their amoeboid movements are more slug- gish and restricted than those of the corresponding stages of the tertian organism. These movements become more active on the warm stage of the microscope. The presence of more than one parasite in a red blood- corpuscle is sometimes observed. Shortly, or within twelve to eighteen hours, after the paroxysm pig- ment granules appear within these hyaline bodies, which continue to increase slowly in size, and for a while to exhibit lazy amoeboid move- ments (Plate I. Figs. 27, 28, 29). The pigment appears in the form of brownish or black rods and grains, which are coarser and darker than those seen in tertian parasites. The rod form of pigment is less common than in the tertian organism. These pigment granules are arranged generally in the peripheral part of the parasite, and they present only a sluggish movement in comparison with the active motion of the pigment in the tertian parasite. With the gradual increase in size of the hyaline bodies and in the amount of contained pigment the red blood-corpuscles enclosing them may appear unchanged, or often they become a little smaller, more refractive, and deeper in color, which may be somewhat greenish or coppery in tint (Plate I. Figs. 28, 29). There is not that tendency to decolorization and swelling of the infected red blood-cor- puscles which is noticed in the case of the tertian parasite, although in the more advanced stages of development there is usually some loss of color in red corpuscles containing quartan organisms. In the process of development the amoeboid movements cease, and the parasite appears as a quiescent, pigmented, spherical, or ovoid body occupying perhaps one-half to two-thirds of the red corpuscle (Plate I. Figs. 30, 31). Such bodies are usually seen within forty-eight hours after the paroxysm. These bodies continue to grow, and when they have reached their full development in sixty to seventy hours after the parox- ysm they are somewhat smaller than the normal red blood-corpuscles. These full-grown forms are spherical or ovoid, refractive, hyaline bodies, with nearly or quite motionless dark pigment granules of variable size, but coarser than in the tertian parasite, and with a tendency to periph- eral arrangement, but at times irregularly distributed. Around these bodies a thin layer of the colored, refractive substance of the red blood- corpuscle can usually still be seen (Plate I. Figs. 32, 33, 34), or the haemoglobin may be entirely removed, so that only a delicate, thin, color- less rim or line surrounding the parasite is all that is left of the original red blood-corpuscle. In unstained specimens these latter forms often appear to be free in the plasma (Plate I. Fig..35), and are sometimes spoken of as free bodies, which may also occur. In six or eight to ten hours before the febrile paroxysm the first phases of reproduction begin to appear. These are ushered in by the gradual withdrawal of the pigment from the periphery toward the centre 42 MALARIA. of the body. The pigment in this process is often arranged in definite radial striae (Plate I. Fig. 36). Such regular stellate arrangements of the pigment as are seen in this stage of the quartan parasite are rarely, if ever, observed in the tertian (Thayer and Hewetson). Finally the pigment is concentrated into a central mass of granules or a solid block of coalesced pigment, less frequently into two or more collections, and the organisms assume a somewhat more refractive and slightly granular appearance. At the same time or soon afterward radial divisional striae begin to appear in the periphery (Plate I. Fig. 37), and quickly extend to the central part of the parasite, whereby the substance of the spherical organism becomes divided into six to twelve ovoid or pear-shaped seg- ments arranged with characteristic and exquisite regularity around the central mass of pigment like the petals of a daisy (rosettes of Golgi) (Plate I. Fig. 38). In each of the segments can be seen a small round glistening body which represents the nucleus or nuclear material. The pyriform segments assume rapidly a round or oval shape, and become separated from the central mass and from each other. The delicate enveloping membrane, which may not be recognized on unstained speci- mens, derived from the red blood-corpuscle ruptures, or it may previ- ously have disappeared, and the small round or oval bodies, each pro- vided with a bright nucleiform dot, are set free in the plasma (Plate I. Fig. 39). These bodies are the so-called spores. Simultaneously with this process of sporulation young amoeboid hyaline bodies, formed di- rectly from the spores, make their appearance in the red blood-corpus- cles, and the cycle of development is completed and another cycle is begun. Segmenting or sporulating forms of the parasite may appear six or eight hours before the paroxysm, and are most abundant shortly before and during the onset of the paroxysm. It is of course not to be under- stood that all of the parasites of one group pass through their develop- mental phases and mature at exactly the same moment. One parasite of the group may be several hours in advance of another, but this does not interfere with the recognition of distinct groups or generations, each standing in definite relation to a paroxysm, or with the establishment of Golgi's law that the onset of each paroxysm corresponds to the matura- tion of one group of organisms. The cycle of development of the quartan parasite is attended with fewer irregularities than that of any other variety of the malarial para- site. Nevertheless, certain irregularities may occur. As pointed out by Antolisei, segmentation may occur exceptionally in pigmented bodies considerably smaller than the usual full-grown forms, containing less pigment and filling only a part of the red blood-corpuscle. Here the segments do not usually exceed four to six or eight. The accumulation of pigment in the segmenting forms may be peripheral, or distributed between the spores, or otherwise irregular. As the quartan parasite completes its development entirely within the circulating blood, there is no appreciable difference at any stage between the splenic and the peripheral blood as regards the number and variety of the parasitic forms observed. Moreover, segmenting forms of the quartan parasite are often seen in small number in the blood at a PARASITOLOGY. 43 period before the total number of organisms is sufficiently large to pro- duce by their ripening a paroxysm, whereas segmenting tertian parasites are very rarely seen in the peripheral blood without the occurrence of a paroxysm in relation to the segmenting forms. Not all of the mature forms proceed to sporulation. Some, especially those which may have escaped from the red corpuscles, swell up, become transparent and larger than a red blood-corpuscle, and present irregu- larly distributed and actively moving pigment granules (Plate I. Fig. 40). These swollen, hydropic forms are probably sterile. It can often be seen in examining these bodies in fresh blood that the pigment becomes quiescent, the outlines of the body become irregular ami indistinct, and evidently cadaveric forms result. Or these bodies may break up into a number of fragments which become misshapen and indistinct, or the whole body may become vacuolated, as is represented in Plate I. Fig. 42. Bodies more or less resembling spores, but without the nuclear structure of spores, may appear in these vacuoles. As may occur with any variety of the malarial parasite, the mature forms of the quartan parasite, instead of sporulating, may develop into flagellate bodies in the manner already described. These bodies are smaller and contain coarser pigment than the flagellate forms of the tertian parasite. (Compare Plate I. Fig. 41 and Plate I. Fig. 22.) De- generated and flagellate forms are less common in quartan than in tertian infections. Not only may mature forms degenerate in the ways described, but forms in earlier stages of development may be liberated from the red corpuscles and likewise degenerate. The phenomena of phagocytosis are observed with regularity during and for some hours after the paroxysm in quartan as well as in other malarial infections. The pigment set free by the process of sporulation is taken up by phagocytes. Extracorpuscular organisms, particularly the various degenerated forms, are engulfed by phagocytes. The assault on the flagellate bodies by leucocytes can be watched with interest on the slide of fresh blood. The leucocytes can also be seen to take up segmenting bodies and spores when the specimen of blood is kept for a while. The details ami the significance of these phagocytic phenomena will be considered subsequently (page 65). The intimate structure of the quartan and other malarial parasites, as revealed by methods of staining, will also be described subsequently. Two or more groups of quartan parasites are often present in the blood at the same time, causing double and triple quartan infections. On account of the regularity in the development of the quartan para- site, anticipating, retarding, and irregular fevers are less common in quartan than in the other malarial infections. Careful examination of the blood enables the observer to recognize the presence of two or more groups of the parasite by noting the simultaneous occurrence of bodies in noticeably different stages of development; as, for example, during the paroxysm the association of segmenting and young hyaline bodies with half-grown pigmented bodies. 44 MALARIA. II. The Parasite of Tertian Fever (H^ematozoon Febris Tertians) (Plate I. Figs. 1-24). This variety of the malarial parasite is common in most malarial regions. Where only mild types of malaria occur it is, as a rule, the prevailing, and sometimes the sole, variety observed. The tertian and the quartan parasites cause most, or in some places all, of the winter and spring intermittents, but they, and especially the tertian parasite, may cause in districts of even severe malaria not a few of the malarial fevers of summer and autumn, although the more severe and irregular of these latter fevers are caused chiefly by the aestivo-autumnal parasite. The tertian parasite may, however, produce severe, as well as mild, types of malaria. The tertian parasite was differentiated from the quartan and described in its essential characters by Golgi in 1886 and 1889. Other observers, particularly Antolisei (1889-90) and Bastianelli and Bignami (1890), have added to, and in some points corrected, Golgi's first description. The chief points to be emphasized in this description of the tertian parasite are those which distinguish it from the quartan parasite. Unlike the quartan parasite, certain stages of development of the tertian- namely, those concerned with sporulation-take place by preference in the spleen and the bone marrow, although segmenting forms are seen also in the peripheral blood. The cycle of development is completed in forty-eight hours. During the paroxysm or shortly after it small, unpigmented, hyaline, amoeboid bodies are found within the red blood-corpuscles, of which they are about one-fifth to one-fourth the size (Plate I. Figs. 2 and 3). Usually one hyaline body is found, but not very infrequently two or more are present, in a single blood-corpuscle. The tertian amoebae, especially in their pigmented stage, change their shape and position within the corpuscles much more actively than the quartan amoebae, these movements being vigorous at ordinary room temperature. Several branching pseudopodia are sent out, often reaching nearly or quite the periphery of the corpuscle, and are retracted. All sorts of shapes may thus be assumed by the parasite, which with its long branching processes may seem to pervade nearly the whole corpuscle. By the union of two pseudopodia the shape may be that of a ring enclosing a bit of the corpuscular substance (Plate I. Fig. 5). The tertian amoebae are paler, less sharply outlined, than the quartan (compare the two varieties in Plate I.). In a short time tine reddish-brown or yellowish- brown rods and granules of pigment, varying somewhat in size, appear in the margins of the amoebae (Plate I. Fig. 5). Pigment granules often collect in the bulbous ends of pseudopodia (Plate I. Figs. 6 and 7), and the intervening parts of the pseudopodia may be so thin and delicate as to be readily overlooked, so that the appearance may be that of several distinct bodies within one red blood-corpuscle. Careful examination will, however, detect the fine connecting processes or the retraction of the apparently separate bodies into the substance of one parasite. Two or more parasites may, however, be present occasionally within one red corpuscle (Plate I. Fig. 4). The pigment is in finer grains and rods, and of a lighter, somewhat different, tint in the tertian, than in the PARASITOLOGY. 45 quartan parasite. (See Plate I.) It is also in much more active move- ment in the tertian amcebse. This movement is not altogether like the Brunonian or molecular motion, and is probably due to intrinsic proto- plasmic movements or currents. With the continued growth and increased pigmentation of the amoebae the infected corpuscles as a rule become distinctly swollen and paler than normal-a change which may be already indicated even with quite small pigmented forms, and which is one of the most distinctive cha- racters of the tertian parasite (Plate I. Figs. 4-9). Occasionally the enveloping corpuscle is not noticeably swollen or altered, and exception- ally it may even shrink and acquire something of the brassy appearance commonly seen with red corpuscles infected with the aestivo-autumnal parasite. On the day of apyrexia the parasite, now with somewhat sharper contour and more richly pigmented, may attain a size equalling one-half to two-thirds that of the infected blood-corpuscle. The amoeboid move- ments have become more sluggish, but they persist in stages of develop- ment corresponding to which forms of the quartan parasite have become quiescent. The pigment continues in active motion. The fully developed parasite is about the size of a normal red cor- puscle, sometimes a little smaller, sometimes somewhat larger, and it is therefore smaller than the swollen corpuscle in which it is contained. It is nearly or quite spherical in shape, and without amoebic movements. The pigment for a while preserves its marginal arrangement or less fre- quently is irregularly distributed (Plate I. Fig. 9). The expanded red blood-corpuscle enveloping the parasite becomes still paler. These fully grown forms change into the presegmenting bodies by the collection of the pigment, which has already become quiescent, into a mass of granules or into a solid block situated usually in or near the centre or sometimes near or at the margin. As with the other varie- ties of the malarial parasite, the pigment with the development of the parasite becomes coarser, and the delicate rod-like forms of pigment become relatively less numerous. These spherical bodies with central pigment chimps are more refractive than is the parasite in preceding stages of development. Stained specimens show that in these preseg- menting bodies there appear multiple, deeply staining chromatin gran- ules, which represent nuclear substance, and which are the first indica- tion of the inception of sporulation. This phase of segmentation presents more variation than is observed in the quartan parasite. Sometimes it begins with the appearance of radial striation extending from the periphery to the centre, and proceeds by a division of the substance of the parasite into twelve to twenty or even more segments arranged in a rosette form around the central clump of pigment. A little later the pigment clump is surrounded by a group of small round bodies, which are the spores. More commonly, without the formation of such regular figures, the protoplasm breaks up into a mass of fourteen to twenty or more spores. Sometimes one sees an outer and an inner ring of spores concentrically arranged around the central mass of pigment. The larger number of segments or spores formed by the tertian as contrasted with the quartan parasite is an important dif- ferential characteristic. 46 MALARIA. The modes of segmentation described (Plate I. Figs. 10-14) corre- spond in the main to Golgi's second type of segmentation. His first mode of segmentation of the tertian parasite has not been noted by other observers. It is as follows : After the collection of the pigment in the centre the organism is differentiated into a peripheral zone sharply sepa- rated from a central body containing the pigment. The peripheral ring becomes radially striated, and then divides into fifteen to twenty small hyaline segments. The central pigmented body does not segment, but remains behind after the separation of the spores. Golgi's third variety of segmentation is now generally recognized as a process of degenerative vacuolation. Sometimes the segmenting bodies show, instead of one central accu- mulation of pigment, two or more clumps excentrically placed, or the pigment may be concentrated in the periphery or distributed between the spores or otherwise irregularly arranged. The spores are set free by rupture of the enveloping membrane derived from the red corpuscle, or this membrane may have disappeared before the segmentation is completed. The individual spores are some- what smaller than those of the quartan parasite. They usually show a refractive nucleiform dot, which is, as a rule, less distinct than in the quartan spores. Coincidently with sporulation the young, colorless amoebae, formed from the spores, make their appearance in the red blood-corpuscles and start on a fresh cycle of development. The segmenting bodies may make their appearance several hours before the paroxysm. They are most numerous shortly before and dur- ing the onset of the paroxysm. They may be scanty in the peripheral blood, for the process of sporulation takes place largely in the internal organs. The red corpuscles containing mature and presegmenting bodies accumulate especially in the spleen and the bone marrow, and there the organisms complete their reproductive development. During most of the period of apyrexia no noticeable difference is observed in the num- ber and kinds of parasites between the peripheral blood and that with- drawn by hypodermic syringe from the spleen. But shortly before and during the paroxysm far more ripe and sporulating forms are found in the splenic than in the peripheral blood. Precocious segmentation into five to ten spores may occur in bodies, sometimes containing only a grain or two of pigment, which have not attained a size exceeding one-half to two-thirds that of the red blood- corpuscles (Plate I. Figs. 16, 17), the usual size of a segmenting body being about that of a red corpuscle, but sometimes considerably larger. Such immature forms of segmentation are associated by Bastianelli and Bignami with anticipating fevers, but Mannaberg and Thayer and Hew- etson, although not inclined to discredit this interpretation, were unable to convince themselves of this relation. Partly developed and mature tertian parasites are often seen free in the plasma. Swollen, transparent, extracorpuscular forms, which may attain the size of large leucocytes, and which contain scattered dancing pigment granules, are generally considered to be degenerative or inca- pable of reproductive development (Plate I. Fig. 18). These so-called hydropic forms are considerably larger and paler and more common than PARASITOLOGY. 47 the similar forms of the quartan parasite. These swollen, richly pig- mented forms are very common in tertian infections. In general, the various forms of degeneration which have already been described, such as fragmentation, vacuolation, pseudo-gemmation (Plate I. Figs. 19, 20, 21, 23, 24), are more common with the tertian than the quartan parasite. Flagellate bodies are likewise more common. They are, as a rule, larger and contain finer pigment than the quartan flagellates (Plate I. Fig. 22). They develop chiefly from the round, swollen, extracorpuscular forms with scattered pigment, although flagella have been observed to develop from forms still surrounded with a distinct layer of hsemoglobin-con- taining substance of the red blood-corpuscle. Flagellate bodies are most abundant in blood withdrawn from the spleen shortly before and during the paroxysm. Phagocytosis occurs with the same regularity and with similar phenomena in tertian as in quartan infections. Infection with two groups of tertian parasites (double tertian), as described for quartan infection, is more common than with a single group, especially in the later period of the malarial season in the spring and in summer and autumn. The resulting type of fever is quotidian. In some cases there seem to be several irregularly distributed genera- tions causing remittent or subcontinued fevers. It is not necessary to attribute the presence of two or more groups of the same variety of parasite to corresponding multiple infections from without. There is evidence that certain members of a group may, in their development, lag behind or advance beyond others of the same group, and in course of time by further multiplication may constitute a separate group capable of causing its own paroxysms of fever. It is remarkable, however, that the second group should be separated in its cycle of development by such definite intervals from the first as we usually observe in quotidian fevers of tertian origin. Genuine mixed infections with malarial parasites, the most frequent combination being that of the tertian and of the aestivo- autumnal parasites, are not very uncommon. The length of the cycle of development of the tertian parasite may occasionally be noticeably shorter than forty-eight hours, perhaps only forty hours or less, or, on the other hand, it may be longer than the normal period. This may explain the anticipating and the postponing fevers. III. The Parasite of ^Estivo-autumnal Fever (H^ematozoon Falciparum) (Plate II.). This was first clearly differentiated from other varieties of the mala- rial parasite by Marchiafava and Celli (1889), and was subsequently more fully described by the same authors and by Canalis (1889-90). (See foot- note, page 32.) The extensive literature concerning the parasitology of malaria during the last six years has been concerned to a large extent with this variety, but we are still far from possessing so full and accurate knowledge regarding the characters and development of the Hsematozobn falciparum as regarding those of the quartan and tertian parasites. Such knowledge is much to be desired in view of the fre- quency of the aestivo-autumnal parasite in regions, such as the southern part of the United States, where the more severe types of malaria occur, 48 MALARIA. and of the almost exclusive association of this parasite with pernicious malarial fevers. Chief reasons for the difficulty in investigating the entire life historv of the Hsematozoon falciparum are that it develops mainly within the internal organs and often in multiple groups, and that the later repro- ductive phases of development are met with in the circulating blood only very exceptionally. Under the Classification of the malarial para- sites we have already presented the more important opinions which have been advanced concerning possible subdivisions of the aestivo-autumnal variety (page 35 et seqfi The youngest forms of this parasite are small hyaline bodies, about one-sixth the diameter of a red blood-corpuscle, which make their appearance in the blood-corpuscles during or shortly after the paroxysm. It is not uncommon to find two or more hyaline bodies in a single cor- puscle. These sestivo-autumnal hyaline bodies are in general the smallest forms of the malarial parasite which are observed in the red blood-corpuscle (Plate II. Figs. 1 and 2). The youngest forms may be (pliescent, but as they develop they manifest amoeboid movements resembling in their activity those of the tertian amoebae. The young aestivo-autumnal amoebae may not be readily distinguish- able from the similar forms of the quartan and tertian parasites. Par- ticularly characteristic, however, of the young hyaline forms of the Haematozoon falciparum when in repose and in stained specimens is the ring shape. The appearance in fresh specimens is that of a somewhat refractive, clear, hyaline ring, usually thicker on one side, surrounding a small round central, or oftener excentric, shaded part, or sometimes two or three such parts, through which the color of the red corpuscle shows. In stained specimens the ring appears thinner than in fresh specimens, and the central or excentric part is unstained, while a minute deeply stained granule is situated in the outer ring. The study of the further development of these forms, especially on stained specimens, has demonstrated that these apparently annular bodies are not actual rings, as some have supposed, enclosing a bit of the red corpuscle, but that the clear area which does not stain is a trans- parent part of the organism, which, as will be subsequently explained, some regard as the nucleus. Actual rings, however, as has already been mentioned, may be formed by the junction of pseudopodia, which thereby enclose some of the corpuscular substance, but such is not the explanation of the typical annular appearance of the sestivo-autumnal hyaline bodies. It is not uncommon to Hud free hyaline bodies in the blood plasma. These hyaline bodies may, while under observation, become some- what expanded and paler and lose their annular appearance, and again resume the ring shape. While the very smallest intracorpuscular hyaline bodies may present no amoeboid movements, as they grow larger these movements become active. Hyaline bodies are occasionally observed to change their position within the corpuscle without change in their shape. Manifold shapes are assumed during the amoeboid movements (Plate II. Figs. 4-6). Usually in the course of development a few very fine dark reddish- brown or black pigment granules appear in the outer layer of the PARASITOLOGY. 49 hyaline bodies (Plate II. Figs. 8-12). They may be situated near the periphery or on the inner margin of the ring near the clear part. Sometimes the pigment does not appear until shortly before a paroxysm. The presence of many bodies containing a considerable number of grains of pigment is generally indicative of an impending paroxysm. The pigment granules are at first very minute and few, and may be readily overlooked. The granules of pigment increase in number and size, but it is one of the characteristics of the sestivo-autumnal amoebre that the formation of pigment is, as a rule, scanty and in fine grains. Often only one or two very fine pigment granules are seen in the periphery or on the inner edge of the refractive border of the hyaline bodies. Usually about six or seven granules of pigment are developed in the hyaline bodies. The pigment generally shows but little motion in con- trast with that in the tertian amoebae. The aestivo-autumnal amoeboid forms do not generally grow larger than one-quarter to one-third the diameter of the red blood-corpuscle, and they may remain smaller. The infected red corpuscles may appear otherwise normal. They do not become swollen and decolorized in this stage, as is the case in the tertian infections. On the other hand, they often become shrunken, creased, or otherwise deformed, and present a deep brassy color (globuli rossi ottonati of the Italian writers) (Plate II. Figs. 7, 16). Sometimes the haemoglobin separates from a part or the whole of the outer part of the stroma of the corpuscle and collects around the enclosed hyaline body (Plate II. Fig. 13). These changes in the red corpuscles, which are particularly characteristic of the aestivo- autumnal variety, although not absolutely limited to it, are to be regarded as degenerative or necrobiotic. Marchiafava and Celli and some others have thought that the parasite within these profoundly altered corpuscles is also dead or incapable of further development. Bastianelli states that sporulation forms are not observed in the brassy corpuscles, but this statement is opposed to observations of Marchiafava and Bignami and others. The view that parasites within profoundly altered corpuscles are incapable of further development is by no means proven, and is opposed to the natural interpretation of many observations. As the time for the onset of a paroxysm approaches, the hyaline bodies gradually cease their amoeboid movements, assume a spherical or ovoid shape, become somewhat more refractive and homogeneous, and present a small collection of quiescent or but slightly moving pigment granules at about the centre or often near the periphery (Plate II. Figs. 13, 16, 17, 18). This pigment usually fuses into a single small, black, round or irregular mass or block (Plate II. Figs. 14, 15, 19-24), or there may be two such blocks. These round, refractive bodies with pigment blocks or collections of pigment granules (corpi con blocchetto) are the presegmenting bodies, and when they are present the onset of a paroxysm, within at most a few hours, may generally be safely predicted. These bodies are much smaller than the corresponding forms of the quartan and tertian parasites. They do not generally exceed one-quarter or one-third of the size of the corpuscle, although they may be considerably larger. They are sur- rounded with luemoglobin-containing substance of the corpuscle, which is often of a brassy color. Vol. I.-4 50 MA LA UTA. The next phase of development is that of sporulation, but the seg- menting forms are found in the peripheral blood only most exception- ally, save in some pernicious cases, in which they may in rare instances be even abundant. Sacharoff observed in the Transcaucasus sporulating forms in the blood, and on this account, but apparently without suffi- cient reason, he regards this form as a special variety. For a few hours before and during the early stage of the paroxysm very few parasitic forms of any kind are to be found in the circulating blood, and at this period they may be entirely absent, in marked contrast to quartan infec- tion. During this period the presence of pigmented leucocytes in the blood may aid in the diagnosis. In tertian infections an analogous con- dition is found, but not in the same degree. The disappearance of the parasites from the blood is believed by most authorities to be due to their deposition in internal organs, especially the spleen and the bone marrow, and is attributed to the profound changes in the red blood- corpuscles containing them, these changes rendering the corpuscles vir- tually foreign bodies which, like other foreign particles, are caught and retained especially in the spleen and the bone marrow. Blood withdrawn by puncture of the spleen at this time will, with rare exceptions, show abundant intracorpuscular and free round bodies with central or peripheral pigment, and also segmenting forms. In certain cases segmenting forms are few in the spleen, but abundant in certain other internal organs, as has been shown by post-mortem exam- inations. These sporulating bodies are smaller than those of the quartan and tertian parasites, and occupy, as a rule, only a relatively small part of the corpuscle, which is always altered in appearance, being shrunken and brassy-colored or more frequently decolorized. They may appear to be free or may be actually free. In pernicious cases they are present in large, often enormous, numbers in the internal organs, especially in the spleen and bone marrow, and in some types of pernicious fever in the capillaries of the brain and in those of the intestinal mucosa. This varied distribution of the parasites in internal organs is in relation with the types of pernicious fever. The stage of sporulation occupies a rather long period and takes place in successive groups. This circumstance is believed to explain the long duration of the paroxysm in sestivo- autumnal fevers. In pernicious cases sporulation seems to be going on continually in the vascular areas of certain internal organs. In sestivo-autumnal infections the process of sporulation is in general similar to that of the tertian parasite, but it is more irregular and vari- able and the spores are much smaller (Plate II. Figs. 25-28). The number of spores formed by a segmenting aestivo-autumnal organism is extremely variable. There may be not more than six to ten spores, or even fewer; often there are ten to twenty, and the number may exceed thirty. Some segmenting forms are much larger than others. Golgi has observed exceptionally very large ones containing as many as forty to fifty spores. There are slight differences often to be observed in the finer structure between the sestivo-autumnal spores and those of the quartan and tertian parasites, as will be described when we consider the intimate structure of the malarial parasites. The young hyaline bodies of the new generation may be found in the blood in the early part of the paroxysm, but often they do not make PARASITOLOGY. 51 their appearance until several hours after the beginning of the paroxysm or during its decline. Not all of the aestivo-autumnal amoebae develop pigment. Sporula- tion may occur in bodies, usually of small size, entirely devoid of pig- ment. As a rule in these cases both pigmented and unpigmented forms occur, but cases of aestivo-autumnal malaria have been observed, especially in tropical climates, in which only unpigmented bodies could be found at any stage of the fever before the appearance at a later period of crescentic bodies which always contain pigment. As has already been mentioned (page 38) Grassi and Feletti regard the parasites which do not develop pigment as belonging to a distinct variety (^Hcemamoeba immaeulata), but it is difficult to reconcile this view with the frequent association of pigmented and unpigmented forms, the frequent transitions from one to the other as regards the quantity of pigment developed, and the absence of any points of distinction other than the presence or absence of a variable, but generally small, amount of pigment. Still further researches, especially of the grave tropical malarias, may perhaps demonstrate the existence of a distinct unpig- mented variety of the parasite. There is considerable uncertainty as to the length of the cycle of development of the Haematozobn falciparum. This uncertainty is due to the manner of development of the parasite, usually in multiple groups, in the internal organs, the most characteristic reproductive phases being absent from the circulating blood. So far as one can judge from the study of these phases in connection with the different types of fever with which they may be associated, the length of the cycle of develop- ment may vary from twenty-four hours or less to forty-eight hours or more. The Haematozoon falciparum may be associated with typical quotidian fever or with tertian fever, and in some of these cases the blood shows apparently only one group of organisms. Ag already mentioned, Marchiafava and Bignami believe that there are two distinct varieties or subvarieties of the aestivo-autumnal parasite, the one a true quotidian organism, with a cycle of twenty-four hours' duration, and the other their so-called malignant or summer-autumn tertian variety, with a cycle of forty-eight hours' duration ; and this division has been accepted by some other authors. This distinction is based mainly upon the apparent duration of the cycle of development-in the quotidian about twenty- four hours, and in the malignant tertian forty-eight hours, more or less -but there are claimed to be other differences of a minor character relating to the pigmentation, the size, and the amoeboid movements of the organisms.1 The differential diagnosis is said to be possible only 1 The following are the biological and morphological differences between the aestivo- autumnal quotidian and malignant tertian parasites, according to Marchiafava and Big- nami {On Summer- Autumn Malarial Fevers, translation, p. 83, The New Sydenham Society, London, 1894): Duration of cycle of development in the quotidian, about twenty-four hours, in the summer tertian, forty-eight hours, more or less ; in the quotidian sporula- tion on rare occasions is completed before the amceba? have become pigmented-this is not observed in the summer tertian; the fine granules of pigment in the periphery of the summer tertian are sometimes endowed with oscillatory movements-this is not noticed in the quotidian ; in the same relative stage of development the tertian amoeba is usually larger than the quotidian, the adult pigmented tertian forms may be one-third of the size of the red blood-corpuscles, and the forms of segmentation may be one-half or two thirds of it; 52 MALARIA. with the adult forms. The differential characters claimed to exist between the quotidian and the tertian varieties of the aestivo-autumnal parasite are, for the most part, only such as one would expect with a malarial parasite developing more rapidly in some cases than in others, and they, at least so far as at present formulated, scarcely suffice for a distinction into two well-defined varieties. Thayer and Hewetson, while confirming Marchiafava and Bignami's recognition of quotidian and tertian fevers caused by the sestivo-autumnal parasite, emphasize the occurrence of intermediate types of fever, and in general the essential irregularity of the fevers caused by this organ- ism. They were unable to distinguish any morphological or biological differences between the parasites associated with these various types of fever. Although unwilling to commit themselves to a positive conclu- sion, they are "inclined to believe that the irregularity of the febrile manifestations is due chiefly to the tendency on the part of the parasite to irregularities in the length of its cycle of development (this variability being dependent, perhaps, upon the malignity of the organism or upon the resistance of the individual affected); to the fact that the period of time required for the sporulation of one group of organisms is materially greater than in the regular infections, owing to the fact that the arrange- ment of the parasites in definite sharp groups, sporulating nearly at the same time, is much less distinct than in the tertian and quartan inter- mittents ; to the fact that, frequently, organisms in all stages of develop- ment are present at one time, segmentation occurring almost contin- uously." 1 Golgi also considers that Marchiafava and Bignami's division into quotidian and tertian aestivo-autumnal organisms is based upon insuf- ficient evidence, and that the duration of the cycle of development of the sestivo-autumnal parasite is indeterminate, or at least has not as yet been accurately ascertained. This cycle is probably, he thinks, longer than is supposed by Marchiafava and Bignami. This form of parasite, accord- ing to Golgi, is characterized by the fact that it develops entirely in the internal organs, and that the forms, chiefly of the earlier stages of development, which appear in the circulation, although they are found there at certain periods of the disease in practically all cases, are, in a sense, accidentally present in this situation, being washed into the circu- lation from their foci of development, as nucleated red blood-corpuscles may be conveyed from the bone marrow into the blood current in certain ansemias. Golgi at first thought that the forms present in the circula- tion degenerate, but he does not now deny that they may lodge in internal organs and there develop into segmenting organisms. Marchia- fava and Bignami with much reason vigorously contest Golgi's concep- tion of the " accidental " nature of the presence of sestivo-autumnal organisms in the circulating blood, although they also believe that a large part of the parasites develop wholly in the internal organs, and in the tertian the amoeboid movements are maintained longer, even in the adult pigmented forms, and the motion is more lively than in the quotidian during the pigmented phase ; the duration of the non-pigmen ted amoeboid phase in the tertian is relatively long and may exceed twenty-four hours ; the young forms of the new generation in the tertian usually appear in the blood several hours after the beginning of the paroxysm, which is much later than in the quotidian. 1 Op. dt., pp. 151, 153. PARASITOLOGY. 53 that sporulation occurs only most exceptionally in the circulating blood. The two most important and original points in Golgi's doctrine con- cerning the aestivo-autumnal parasite are that groups of the parasitic organisms are variously distributed in vascular areas in the internal organs, and there develop more or less independently of each other, " with relative stability," and that a large number of the organisms develop within leucocytes, endothelial cells, and other tissue-cells. All phases of development, according to Golgi, are found within these cells. The spleen and the bone marrow are situations preferred by the parasite, but the capillaries of the liver, of the brain, of the lungs, of the intes- tinal mucosa, may also contain them enclosed within cells. A. Monti1 has recently described these intracellular forms in perni- cious malaria, and he confirms the observation of many others that cells containing parasites frequently degenerate and die. He finds apparently intact parasites not infrequently within cells, particularly endothelial cells. It is contended by Marchiafava, Bignami, and Bastianelli that the intracellular inclusions of the parasite, upon which Golgi bases his doc- trine, are simply the well-known phagocytic phenomena, and that such enclosed parasites belong chiefly to the later stages of development (presegmenting and segmenting bodies and spores), and that, instead of developing, they degenerate within the cells. The young amoeboid bodies, which, according to Golgi's doctrine, should be frequently found within cells, they found only with comparative infrequency within pha- gocytes, and then almost always within their corpuscular hosts, which had been swallowed by cells. They admit the possibility of some development of intracorpuscular parasites which have been taken up by phagocytes, but not of free parasites within cells. As with the other varieties of the malarial parasite, the aestivo- autumnal do not all mature and segment. Extracorpuscular forms are common, and it is more particularly these forms, deprived of the pro- tective covering of the red blood-corpuscles, which degenerate. Adult and presegmenting bodies and bodies of the crescentic phase frequently become swollen and pale or vacuolated or fragmented, or throw off buds, or present other degenerative changes which have been described. Phagocytism in the sestivo-autumnal, as in all malarial infections, is a phenomenon of much importance, as will be subsequently explained. The frequency with which two or more groups of parasites in differ- ent stages of development are found in aestivo-autumnal infections has already been repeatedly emphasized. Marchiafava and Bignami believe that even in the pernicious fevers there are not generally present more than two groups of the sestivo-autumnal parasite, and that the short cycle of development and the prolonged period of sporulation suffice to explain the simultaneous presence of parasites in notably different stages of development. Combined infections with the sestivo-autumnal para- site and one of the other varieties occasionally occur. It is important to bear in mind the discrepancy which characterizes sestivo-autumnal malaria between the number of parasites in the blood and the number in the internal organs. In the majority of cases the 1 A. Monti: Bollettino della Society medico-chirurgwa di Pavia, 1895. 54 MALARIA. more severe the infection the greater the number of parasites found in the circulating blood, but there are so many exceptions to this that the number of parasites in the blood cannot be considered a trustworthy index of the number within the body. Pernicious cases have been repeatedly observed where the splenic blood examined during life or the internal organs examined after death contained enormous numbers of testivo-autumnal parasites, although the blood of the finger showed very few. The organisms may be few even in the spleen when they are abundant in the cerebral capillaries or in some other situation. As will be explained subsequently, the varying symptoms and types of perni- cious malaria can be explained in large part by the varying distribution of the parasites in internal organs. It is evident from the description which has been given of the aestivo- autumnal parasite that this variety is characterized especially by its great activity in multiplication, and it will appear from the considera- tion of the clinical features of the infections caused by this parasite that other most important characteristics are its virulence, greater than that of other varieties, and its greater resistance to quinine. There is a group of bodies of crescentic, fusiform, oval, or round shape, presenting certain common and peculiar characters, which develop only from the Haematozoon falciparum. The crescents are the most typical of these bodies, which may be designated, therefore, as bodies of the crescentic (or semilunar) phase or group. They merit special con- sideration. Bodies of the Crescentic Group.-When a malarial fever caused by the Haematozoon falciparum has lasted a week or more bodies of the crescentic or semilunar phase are likely to appear in the blood. They are very rarely found in the blood in the latter part of the first week. If the fever is treated with sufficient doses of quinine during the early part of the first week, crescents do not appear, but the administration of quinine after the fever has lasted much longer than a week does not prevent their appearance. They may persist in the blood two weeks or more after all other forms of the parasite have disappeared. In such cases they are often unassociated with any febrile manifestations or any symptoms which can be definitely referred to their presence. If a relapse of the fever occurs, then the young hyaline bodies already described are always present. The crescents themselves are very resist- ant to the action of quinine. Councilman in 1887 called attention to the occurrence of crescentic bodies as characteristic of the irregular and remittent forms of malarial fever and malarial cachexia. There was for a time much doubt as to the origin of the crescents, but Marchiafava and Celli's demonstration in 1886 of their intracor- puscular development has been abundantly confirmed by the later studies of Canalis, Bastianelli and Bignami, and others. The early intracorpuscu- lar stages of development of the bodies of the crescentic group are rarely seen in the circulating blood, except in certain pernicious cases, but they can often be found in the splenic blood. Bastianelli and Bignami have found these early phases so abundantly in the bone marrow that they consider that they develop by preference in this situation. Certain of the intracorpuscular spherical forms of the Haematozoon falciparum with collected pigment granules, instead of continuing their PARASITOLOGY. 55 regular cycle of development into segmenting forms, are transformed into the young bodies of the semilunar phase. This transformation takes place only after a number of febrile paroxysms; that is to say, only after the parasite has repeatedly passed through its regular sporu- lating cycle of development. The young bodies of the crescentic group occupy perhaps one-quarter of the red corpuscle. Their shape is round, oval, or fusiform. They present a characteristic homogeneous, refractive appearance, being more refractive than the presegmenting bodies with central blocks of pigment. They contain dark pigment, usually in the shape of fine rods, sometimes collected in a mass, but oftener irregularly distributed. In the fusiform bodies the pigment is often arranged along the longitudinal axis of the spindle. The haemoglobin is frequently retracted into a denser stratum around the bodies. These bodies increase in size without a correspond- ingly large increase in the amount of pigment, and, as will be explained later, without a corresponding increase in their chromatic or staining substance-a point which distinguishes the direction of crescentic devel- opment from that of the regular sporulating development. It is some time after these young semilunar bodies have begun to form in the bone marrow and spleen before the adult crescents appear in the circulating blood. These completely developed typical crescents are on the average 8-10 p long, and in the middle 2-3 p broad (Plate II. Figs. 31, 32, 33). They do not often exceed in length one and a quarter or one and a half times the diameter of a red corpuscle. They present a characteristic, homogeneous, refractive appearance. An outer double-contoured border can sometimes be seen, especially after treatment with certain reagents, and this is interpreted by Lave ran, Mannaberg, and many authors as evidence of a distinct enveloping membrane; but the weight of evidence is opposed to the view that the crescents, any more than any other form of the malarial parasite, possess a membrane other than that which pertains to the enveloping red cor- puscle. The outer refractive margin of the crescents, as pointed out by Antolisei and Angelini-who interpret it as a cuticular envelope derived from the red blood-corpuscle-may be slightly colored by haemoglobin, and it may show evidence of this presence of blood coloring matter by the staining with eosin. On the typical crescent-shaped forms a fine line can often be seen stretching like a bow across the concavity, its attachment at each end being within the extremities of the horns. This line is derived from the red blood-corpuscle within which the crescent has developed, and represents the outer contour of the partly or com- pletely decolorized corpuscle. This contour of the corpuscle can some- times be detected also on the convexity of the crescent, and parts of the corpuscle still containing haemoglobin may occasionally be seen on the margin of the crescent, or the whole crescent may be surrounded with haemoglobin-containing corpuscular substance (Plate II. Fig. 29). Sim- ilar evidences of the partly or completely decolorized enveloping blood- corpuscle can frequently be seen on the margin of the round and oval bodies (Plate II. Figs. 34, 35, 36, 38, 39). Bodies of the crescentic group are always pigmented. The pigment is very dark in color, often black, and mostly in fine rods. In the typ- ical crescents the pigment, which is without movement and in fine rods 56 MALARIA. and grains, is usually collected in the middle, sometimes in a single clump or in two clumps, often in a coronal shape. Mannaberg emphasizes the frequency with which the pigment is arranged in two adjacent clumps near the centre, presenting a figure-of-8 shape. In the immature cres- cents the pigment is often scattered, or is arranged longitudinally, as it often is in the fusiform bodies. The amount of pigment varies; it is often considerable. In certain pernicious fevers young crescents with scattered pigment maybe abundant in the blood. In the oval and round bodies the pigment is usually concentrated in the centre, often in the form of a circle, but it may be distributed throughout the body. Ovoid, round, and fusiform bodies may be changed into typical crescents, and, on the other hand, crescents may change into fusiform, oval, and round bodies. The appearance of a fusiform or ovoid body may be presented when a crescent is seen from the convex side. From the round bodies flagellate forms may develop in the manner already described (Plate II. Figs. 42, 43, 44). The sestivo-autumnal flagellate bodies develop only from round bodies of the crescentic group. They are smaller than the tertian flagellates, resembling rather the quartan. The process of transformation of crescentic bodies into oval and round forms, and the development of flagella from the latter, can sometimes be observed in studying the fresh blood microscopically. Councilman once observed a rapid undulatory movement of a body presenting the general appearance of a crescent. Crescents and the other bodies belonging to the same phase not infre- quently become vacuolated or contain or throw off from the margin little hyaline balls (pseudo-gemmation), or disintegrate or present other degenerative changes (Plate II. Figs. 34, 41, 40). Danilewsky has observed crescents of unusually large size, as much as 20-22 // long and 4-6 n broad. The biological significance of the crescents is unknown. These bodies do not belong to the regular sporulating cycle of development of the parasite, and there is no positive proof of their capacity for further development. Dr. Thayer in a personal communication to the writer reports a valuable experiment made by himself which demonstrates the incapacity of crescents when inoculated into the blood of healthy individuals to develop or to cause any symptoms. The blood was taken from a patient who had had acute sestivo-autumnal fever, which was arrested by administration of quinine. Crescents persisted in the blood. For seven days the blood was examined without finding hyaline bodies or any form of the malarial parasite other than crescents. Seven days after the disappearance of the hyaline bodies a hypodermic syringeful of blood containing crescents in considerable number was withdrawn from the median basilic vein of the patient and immediately injected into the corresponding vein of a healthy man. No elevation of temperature or other symptoms followed the injection, nor did crescents or any parasitic forms make their appearance in the blood, which was examined daily for two weeks and at intervals for over a month. In the inoculation experi- ments of Gualdi and Antolisei and others in which it is stated that the blood contained only crescents and infection with the Hsematozobn fal- ciparum followed in the inoculated individual, it is probable that hyaline PARASITOLOGY. 57 bodies were present in the blood used for the inoculation in such small number that they escaped detection. The following are the principal views which have been advanced regarding the interpretation of the crescents : 1. Laveran regards the crescentic bodies as encysted forms from which the flagella develop. There is no proof that these bodies are encysted. 2. Canalis and Antolisei and Angelini believe that they have found evidences of sporulation in the crescents and the ovoid and round bodies belonging to the crescentic phase. Grassi and Feletti and Sacharoff likewise believe that these bodies may sporulate. Golgi considers them capable of reproductive development in long cycles, and brings them into special relation with relapses and with fevers of long intervals. Most observers have been unable to find genuine sporulation or other evidences of reproduction in these bodies. 3. Grassi and Feletti consider that the crescents belong to a separate species which they call Laverania, and of which they represent a regular phase of development. The sporulating hyaline bodies with which the crescents are usually associated constitute, according to these writers, different species. This view is not generally accepted, and is opposed to the observed facts. 4. Mannaberg regards the crescents as encysted syzygies formed by conjugation of two sestivo-autumnal parasites and capable of reproduc- tion by segmentation. His view is unconfirmed by any other observer, and is improbable. It fails to explain the ovoid and round bodies which belong to the same phase of development, and it cannot be reconciled with the appearances noted in the steps of development of the cres- cents, as has been shown by Bastianelli and Bignami. 5. Councilman suggests that the crescents may be of the nature of spores. Several authors have called attention to a resemblance between these bodies and the falciform spores of coccidia, but there are such essential differences between the two that the apparent resemblance is only of the most superficial character. 6. Bastianelli and Bignami have described the crescents as deviate and sterile forms. This has been interpreted to mean that they regard the crescents as degenerative forms-a view held by Kruse and some others-but in their latest publication 1 they suggest that these bodies are a rudimentary phase of a second developmental cycle which cannot be completed within the human body, but requires for its continuation some new environment in the outer world. They call attention to the occurrence of two cycles of development in several unicellular parasites, especially the coccidia, which, after passing through several generations in their ordinary parasitic life, enter upon forms belonging to a second cycle. The forms of this second cycle remain sterile, degenerate, and die, unless the parasite can escape from its host and find its appropriate new conditions of life. Manson independently also has advanced the hypothesis that the crescents are intended for the continuance of the life of the species in the external world. It has already been mentioned that a similar view has been suggested also regarding the significance 1 Bastianelli and Bignami: "Studi sulla Infezione Malarica," Bullettino della R. Accademia Medica di Roma, Anno XX., 1893-94. 58 MALARIA. of the flagellate bodies, and that Manson believes that the mosquito may serve as the host for this second cycle of development. Differential Diagnosis of the Varieties of the Malarial Parasite. An inexperienced observer may possibly mistake for the unpigmented intracorpuscular hyaline forms of the malarial parasite the vacuoles which occasionally are present within red blood-corpuscles or the clear spots which may result from certain deformities in the shape of the corpuscles. These vacuoles and clear spots may be distinguished in the fresh specimen by their sharp outlines, the absence of amoeboid changes of shape, and a difference in refraction often suggestive of an empty space or hole, and which can be described less readily than it can be appreciated by actual observation. The absence of definite staining readily distinguishes these vacuoles from the hyaline bodies of the para- site in stained specimens. There are occasionally seen in red corpuscles in stained specimens of the blood, especially in anaemic conditions, small stained dots which do not bear much resemblance to forms of the malarial parasite, but which should be known to the observer in order to avoid the possibility of mistake. They are believed by some to be the result of degenerative changes in the corpuscles, and by others to be remnants of nuclear chromatin derived from the originally nucleated condition of the red corpuscle. Blood-plates can be mistaken only for free spores or very small extracorpuscular hyaline bodies. In general no attention should be paid as regards diagnosis to bodies free in the plasma which resemble blood-plates. Tn fresh specimens it is practically impossible to diagnose free spores with any certainty. Clumps of blood-plates have been mis- taken for sporulating bodies, but they can be readily distinguished from the latter by the absence of pigment. For the sake of convenience the principal characters which enable us to distinguish each of the three varieties of the malarial parasite, and which have already been described in detail, will here be summarized. For modifications and amplification of these general statements the reader must consult the detailed descriptions already given. 1. Duration of the Cycle of Development.-In the quartan parasite, seventy-two hours; in the tertian, forty-eight hours; in the sestivo-autumnal, irregular, varying from twenty-four hours to forty- eight hours. 2. Amoeboid Hyaline Bodies. - In their earliest stages often indis- tinguishable from each other. Later, those of the quartan parasite, sharply outlined, somewhat refractive, sluggishly amoeboid, with develop- ment of dark brown or black, relatively coarse pigment granules, which have but little motion. Amoeboid movements cease in a relatively early stage of development of the pigmented hyaline body. Those of the tertian parasite, pale and indistinct, actively amoeboid, with development of reddish-brown, actively motile, relatively fine pig- ment granules, which tend to accumulate in the bulbous swellings at the extremities of the delicate branching pseudopodia. Amoeboid move- PARASITOLOGY. 59 meats continue in late stages of development of the pigmented amoebse. Those of the testivo-rwtminal parasite, small, somewhat refractive, in repose ring-shaped, ac'tiviy amoeboid, with development of a few very fine dark reddish-brown or black, only slightly motile, pigment granules, or sometimes without pigment throughout all phases of the sporulating cycle of development. 3. Fully Developed Hyaline Bodies.-Those of the quartan parasite are somewhat smaller in size than the normal red blood-corpuscle, and are usually surrounded by a border of the colored refractive sub- stance of the enveloping red blood-corpuscle. Those of the tertian parasite attain the full size of a normal red blood-corpuscle and lie in swollen decolorized red blood-corpuscles. Swollen, extracorpuscular, transparent bodies with dancing pigment granules are common. Those of the sestivo-autumnal parasite do not generally exceed one- quarter to one-third the size of the red blood-corpuscle. The enveloping corpuscle is often shrunken and brassy. They contain much less pig- ment than the quartan and tertian forms, and sometimes none at all. 4. Presegmenting Bodies.-In the process of collection of the pig- ment into a mass or block in the centre or excentrically the pigment granules often assume a more regidar stellate arrangement in the quartan than in the tertian forms. The differential points between the three varieties in this stage relate to the same differences in size, in the amount of pigment, and in the condition of the infected corpuscle as have been mentioned under the preceding heading. The presence in the blood of quartan and tertian presegmenting bodies is associated with that of sporulating forms, whereas with the eestivo-autumnal presegmenting bodies sporulating forms are almost always missed in the circulating blood. 5. Sporulating Bodies.-Those of the quartan parasite in equal proportion in the peripheral and the splenic blood. They are some- what smaller than the red corpuscles, and present typical rosette forms with a division into six to twelve ovoid or pyriform segments, each segment becoming an oval or round spore containing a bright nucleiform dot. Those of the tertian parasite are more numerous in the splenic than in the peripheral blood. They are as large as the red blood-corpuscle, and present less regularity in segmentation than the quartan parasite. They segment usually into from fourteen to twenty spores, which are a little smaller and with less distinct nucleiform dot than those of the quartan organism. Those of the sestivo-autumnal parasite are found only most excep- tionally in the circulating blood in ordinary cases. They are abundant in certain internal organs, including, as a rule, the spleen. They do not generally exceed one-third to one-half the size of the red blood-cor- puscle. They segment irregularly, the number of spores being some- times six to ten, sometimes ten to twenty or even more. The spores are smaller than those of the quartan and the tertian parasites. The stage of sporulation is a prolonged one. 6. Behavior of the Infected Corpuscles.-These often become 60 MALARIA. somewhat shrunken and deeper in color in the quartan infections; swollen and decolorized in the tertian ; aui ashrunken and brassy, some- times with retraction of haemoglobin fron outer part of the cor- puscle, in the aestivo-autumnal. 7. Crescentic Bodies.-Crescents and bodies of the crescentic phase appear only in infections with the aestivo-autumnal parasite. 8. Pigmented Leucocytes.-Most abundant during and shortly after the paroxysm, they usually disappear during the period of apyrexia in quartan and tertian infections, whereas it is not uncommon to find them in all periods of aestivo-autumnal infections. The Intimate Structure of the Malarial Parasite. The first systematic study of the finer structure of the malarial parasite was made by Celli and Guarnieri (1888-89). This was followed by similar investigations by Grassi and Feletti, Romanowsky, Sacharoff, Mannaberg, Antolisei, and Bastianelli and Bignami. The small size and the but slightly differentiated appearance of most forms of the parasite, and the difficulty of obtaining clear differential stain- ings, obscure the insight into their intimate structure. Little detail of structure can be made out in unstained specimens. The substance of the parasite presents in general a homogeneous, color- less, hyaline appearance. In the amoeboid hyaline bodies of the quartan anol tertian parasites, particularly in the larger forms, an area of variable size in the centre, or more frequently excentrically placed, may sometimes be differentiated by its clear, pale appearance from the more refractive outer zone. This area corresponds to the unstained structure interpreted by many observers as the nucleus in stained specimens. Occasionally two or more such clear spaces can be seen. Sometimes in the larger amoeboid and the mature forms a finely granular appear- ance of the protoplasm can be detected. It is particularly characteris- tic of the aestivo-autumnal parasite that the young intracorpuscular hyaline bodies show, when at rest, a clear space surrounded by a ring of protoplasm, usually thin and delicate on one side and thicker on the other. This clear space appears unstained on stained specimens. The mature forms in which the pigment has collected into one or more clumps appear uniform in structure in fresh specimens, or may perhaps present a slightly granular appearance. Within the spores, especially distinctly in those of the quartan parasite, a bright body can often be distinguished, which represents the nucleus or a nucleiform material. The methods for staining the parasites will be described under Diagnosis, page 139. These methods are useful, not only for the study of the finer structure, but also for the ready detection of the unpig- mented young hyaline forms, particularly of the aestivo-autumnal parasites, which may, without very careful observation, escape recogni- tion on fresh specimens, whereas the presence of pigment at once attracts attention in the fresh specimens to the other parasitic forms. On suitably stained specimens the intracorpuscular young hyaline bodies show a stained outer part, an unstained, usually excentrically placed, internal part, and one or more deeply stained round or elon- gated particles situated, as a rule, near the border of the stained and PARASITOLOGY. 61 unstained parts. The constant unstained part is not to be confounded with vacuoles which may occasionally be present. There have been various interpretations of the structures thus differentiated. Celli and Guarnieri designated the stained part as ectoplasm and the unstained part as endoplasm. The deeply staining particles they interpreted as the beginning differentiation of a nucleus, which they thought they could recognize in larger forms as a definite, stained or pale body with- in the endoplasm. Grassi and Feletti do not recognize a division of the protoplasm into ectoplasm and endoplasm, and in this they are followed by most observers. The clear unstained part they interpret as a relatively large, vesicular nucleus, and the deeply staining particles as nucleoli from which may proceed a delicate reticulum of chromatin connecting them with the nuclear membrane which they assume to exist. The rest of the bladder-like nucleus is filled with clear nuclear juice. Although not all of these details in the structure of the nucleus, such as the membrane and the reticulum, have been observed by sub- sequent investigators, Grassi and Feletti's interpretation of the un- stained part as a nucleus and of the deeply staining particle as a nu- cleolus or a concentration of nuclear chromatin has been adopted by Celli and Sanfelice, Romanowsky, Sacharoff, and Mannaberg, and has been widely accepted. Bastianelli and Bignami, while not denying that this interpretation is applicable to the quartan and tertian amoebfe, adopt a different view as to the structure of the sestivo-autumnal amoebae, which they have studied with great care. They differentiate in the latter an outer colored, chromatic cytoplasm in the form of a stained ring, usually thicker on one side, and an inner uncolored, achromatic cytoplasm, which is all of the clear part enclosed by the ring. The deeply staining chromatic particle they find in the chromatic and not in the achromatic cytoplasm. Often there are two particles, each at opposite points in the ring. This particle is the only representative of nuclear material in the parasite, and they interpret it as fulfilling the functions of a nucleus. They consider that the rapidity of development and multiplication of these sestivo-autumnal parasites prevents the formation of a definite nucleus in a resting stage, such as is described for the quartan and tertian forms. According to Grassi and Feletti and Romanowsky, the nucleus and nucleolus can be found in all stages of the regular cycle of development of the parasite. The nucleus divides directly-or, according to Roman- owsky, by karyokinesis-to form multiple nuclei just before sporula- tion, each nucleus then entering into the structure of a spore. The evidence, however, is in favor of the view that at a certain stage of development the nucleus and the nucleolus disappear as differentiated structures, the latter to reappear in multiple form shortly before sporu- lation. Mannaberg was the first to demonstrate this clearly in his studies of the structure of the tertian parasite. He observed that as the amoeboid bodies approach their mature form, and then become the pre- segmenting bodies, the deeply staining particle (nucleolus) disappears, and later the clear, previously unstained part (nucleus) stains diffusely, so that there is in this stage no definite differentiation of structure in the parasite, although the outer part, as a rule, stains more deeply than the 62 MALARIA. central part. He, however, speaks of the outer part, which contains pigment granules, as the " plasma part," and the inner part, into which the pigment does not penetrate, as the " nuclear part." He attributes the deeper and more diffused staining of the parasite in this stage to the solution of nuclear chromatin into the protoplasm. The first evidence of sporulation on stained specimens is furnished by the appearance of numerous small, deeply staining granules of chromatin in the periphery of the protoplasm. These are the forming nucleoli, which increase in size, and around each the general protoplasmic substance, during the process of segmentation, divides, so that each segment or spore is a cell composed of a nucleiform, deeply staining body surrounded by its pro- toplasmic envelope. In the quartan and tertian spores a clear unstained part later is usually differentiated around the chromatin granule, and the nucleus now resembles that seen in the young amoeboid hyaline bodies within the red corpuscle. Bastianelli and Bignami likewise demonstrated the disappearance of the deeply staining nucleiform body in the forms of the sestivo-autumnal parasite containing collected pigment (presegmenting bodies), and soon afterward the appearance of diffuse staining in the previously achro- matic cytoplasm, so that in this stage no sharp differentiation of struc- ture can be made out within the parasite, which is richer in chromatic material than before* the disappearance of the nucleiform body. The first sign of sporulation is the formation of multiple nucleiform chro- matin granules in the periphery and the development of spores proceeds in the manner already described, save that the aestivo-autumnal spores are composed only of the deeply staining nucleiform body immediately surrounded by cytoplasm. The presence of the small, clear, unstained part, which with the chromatin particle is interpreted as the nucleus, often seen in the tertian and quartan spores, is rarely observed in the aestivo-autumnal spores. It is evident from this description that the spores of the malarial parasite possess a definite structure, a most important feature being the presence of a deeply staining body which serves the function of a nucleus. The recognition of this structure renders it possible to dis- tinguish from genuine spores the various pseudospores which have been at times erroneously interpreted as phases of reproduction of the para- site, and which belong to the category of degenerative forms. Although Antolisei has described a double contour, which he interprets as a mem- brane, about the spores, this observation has not been confirmed, and the spores are to be regarded as naked, thus belonging to the class of gymnospores. Some have objected to the designation of these segments as spores, but this nomenclature is in accordance with that employed by zoologists for similar bodies formed in a like manner in certain other unicellular organisms. It is evident from the preceding description that investigators are not wholly agreed as to what structure in the malarial parasite shall be called the nucleus, some applying this name to an unstained part con- taining the deeply staining chromatin particle, others regarding the chromatin granule itself as the only representative of the nucleus. There is, however, general agreement that this deeply staining particle or body is an essential constituent of the nucleus, and that the PARASITOLOGY. 63 presence of a nucleus or of a nueleiform body in the parasite has been demonstrated. This demonstration fulfils the important biological con- dition that something performing the functions of a nucleus belongs to every cell capable of reproduction, and it has served to remove any lin- gering doubt which may have been entertained as to the recognition of these bodies as parasitic organisms. It is interesting to note that during the regular cycle of develop- ment there is a continual increase in the amount of staining or chro- matic substance from the small hyaline body to the sporulating bodies, and that the cell becomes multinucleated just before segmentation occurs. As the chromatic substance is to be regarded as endowed with especial functional activity, these changes are highly significant. The mature crescents, as a rule, stain feebly and diffusely, or often only at the poles, and perhaps also along the margin. Near the middle one or two deeply stained granules, often covered up by the pigment, may be present, but they are not constant. Mannaberg finds often a narrow stained band in which are two or more deeply stained granules, stretching across the middle of the crescent. Bastianelli and Bignami find that the young developing bodies of the crescentic phase stain diffusely and less intensely than the bodies with a central block of pigment which develop into segmenting forms. Whereas in the forms of the parasite which develop into sporulating bodies there is a continual increase in the chromatic substance as the bodies continue to develop, in the develop- ment of the semilunar bodies there is no correspondingly large increase of staining substance. With rare exceptions these observers found no chromatin granules in these developing crescentic bodies, nor did they ever find in any body of this group those changes of structure, such as the appearance of several chromatin granules, which indicate sporu- lation. Laveran, Celli and Guarnieri, and, with especial emphasis, Manna- berg, consider that the crescents are enveloped in a double contoured membrane. A number of other observers have also adopted this view. We do not consider that any definite membrane, which can be regarded as a part of the parasite itself, has been satisfactorily demonstrated around the crescents or around any form of the malarial parasite. A double contour can sometimes, but not regularly, be seen in the periph- ery of the crescents, but this alone cannot be considered as proof of the existence of a membrane. The manner in which .little hyaline pieces (pseudo-gemmation) can sometimes be seen to form at the margin of the crescentic bodies speaks against the presence of an actual membrane. The Malarial Pigment. The question as to the origin of the malarial pigment, which was so long discussed without conclusive result before the discovery of the malarial parasite, has been definitely settled by this discovery. The pigment is formed by the parasite out of the luemoglobin of the blood- corpuscles by what may be regarded as a process of digestion. The pigment occurs in the form of little granules, which may be fine or coarse, and of distinct rods and spicules, which may be as much as 1 ft long. Such rods often present a certain superficial resemblance to 64 MALARIA. deeply stained bacilli. The pigment may occur in the form of extremely fine dust-like particles not easy to detect. It may be fused into black blocks. The color varies from a yellowish-brown or rusty, reddish- brown to black. Laveran speaks of fire-red and even light-blue pig- ment, and Rosenbach observed a greenish hue of the pigment. The malarial pigment is somewhat loosely ranked by pathologists among the melanin pigments. The differences in the characters of the pigment belonging to the different varieties of the malarial parasite have already been sufficiently described. The deposition of the pigment in the various organs will be described under the Pathological Anatomy. Since the examinations of malarial pigment by Meckel and by Frerichs it has been known that concentrated sulphuric acid and hydrochloric acid do not alter it, and that it disappears upon the addition of strong alkalies and of chloride of lime. Kiener observed that the pigment is dissolved by ammonium sulphide. The demonstration of the origin of the malarial pigment from the blood coloring matter at once raised the question whether, like many pigments of haematogenous origin, it contains iron demonstrable by our micro-chemical tests. A statement by Peris as long ago as 1867, that pigments in the spleen of intermittent fever respond to the test for iron, has given rise to much confusion. It is not wholly clear that Peris examined the malarial pigment, but, if he did, there can be no doubt that he mistook for the true malarial pigment other pigments which are abundantly present in certain organs of those dead of malaria, and which respond to the chemical tests for iron (haemosiderin). It has been shown by Neumann, Bignami, Stieda, Dock, and others that the pigment formed directly by the malarial parasite does not contain iron in a combination which will respond to our ordinary micro-chemical tests for this element. This, of course, does not prove that it may not contain iron in some combination, such as that in haemoglobin, which cannot be demonstrated by our micro-chemical reactions. As has been pointed out by the writers named, the organs of those dead of malaria, particularly the spleen, the liver, and the bone marrow, contain a large amount of haemosiderin, the presence of which is doubtless to be ex- plained by the extensive destruction of red blood-corpuscles in malaria. There is no evidence that haemosiderin is formed directly by the malarial parasite. Marchiafava (1889), however, has advanced the hypothesis that the black pigment may be formed not only within the malarial parasites, but also within the leucocytes out of red corpuscles altered by the action of the parasite. He thus explains the intense melanosis of the spleen, liver, and bone marrow in certain aestivo-autumnal per- nicious infections where the parasites appear only slightly pigmented. Bignami1 comes also to the conclusion, from his extensive examinations of melanotic organs in malaria, that the black pigment without micro- chemical iron reaction may have this double origin, being formed either within the malarial parasite without an intermediate haemosiderin stage or within cells out of haemosiderin derived from destroyed red corpus- cles. The objection to this conclusion of Bignami is that haemosiderin is found in the liver, spleen, and bone marrow very commonly in anaemias, but that the black pigment, without micro-chemical iron 1 Bullettino della Reale Accademia Medica di Roma, Anno xix. fasc. ii. p 230, 1893. PARASITOLOGY. 65 reaction, which characterizes malarial infections, does not appear under these conditions. It is possible that the malarial parasite may produce some chemical change in the substance of the red blood-corpuscle which permits the transformation of the specifically altered haemoglobin into black malarial pigment within certain cells of the body. This, how- ever, is a pure hypothesis. Phagocytism. The presence of malarial pigment in leucocytes and other cells has long been known. Since the observation of phagocytic phenom- ena in malaria by Laveran, Marchiafava and Celli, and Metehnikoff, important studies of this subject have been made, especially by Guarnieri, Golgi, Bastianelli, and Marchiafava and Bignami.1 These investigations have shown that phagocytosis is a common and import- ant phenomenon in malaria, although there is much difference of opinion as to the interpretation of some of the observed facts. Some assign to the phagocytes no higher role than that of scavengers charged with the collection and removal of the pigment and debris resulting from the activities of the malarial parasites and from the death and disintegration of the parasites themselves. The amount of slag which is produced in severe cases of malaria in the form of pigment, dead and disintegrating red blood-corpuscles, and degenerated and broken-up parasites is so large that even this office of scavengers becomes an important one. But Metehnikoff, Golgi, and some others believe that the phagocytes devour large numbers of intact, healthy parasites in certain phases of their development, and that in this contest between cell and parasite is to be found the most important agency for the de- fence of the body. The arguments for and against this latter concep- tion are essentially similar to those which are adduced as to the phago- cytic theory in bacterial infections, the main difficulty being to deter- mine to what extent fully active and virulent parasites are taken up and destroyed by phagocytes, and, even admitting the occurrence of this mode of disposal of the parasites, whether or not it is the most essential and the predominant factor in their destruction. That malarial para- sites, as well as bacteria, may perish in the blood plasma without incor- poration within cells cannot be doubted, as we have direct observations demonstrating this. The cells which assume the functions of phagocytes in malaria are the leucocytes, the endothelial cells of the walls of the bloodvessels, and large cells, found especially in the spleen, the bone marrow, and the liver, and called by Metehnikoff " macrophages." Of the leuco- cytes the large mononuclear, the polymorphonuclear, and the transitional forms act as phagocytes. The small lymphocytes and the eosinophils have never been observed to contain pigment or debris in malaria. Of the leucocytes it is the large mononuclear forms which are the most active and important phagocytes within the body in malaria, but, as has been pointed out by Thayer and Hewetson, the polymorphonuclear leu- 1 Especially valuable are the articles of Golgi, " Il fagocitismo nell' infezione malarica," Riforma Medica, 1888, and of Bastianelli, "I leucociti nell' infezione malarica," Bull. della R. Accademia Medica di Roma, 1892. Vol. I.-5 66 MALARIA. oocytes are the ones which can be observed to be active in the fresh blood during examination under the microscope. It is the latter which pick up the pigment and the extracorpuscular and degenerated parasites, and which attack the flagellated bodies in the fresh blood withdrawn from the body, so that there may be a notable difference between the blood examined immediataly after its withdrawal from the body and that examined at a later period as regards the number of polymorpho- nuclear leucocytes containing foreign elements. Endothelial cells con- taining pigment, parasites, or fragments of parasites or of red corpuscles are rarely seen in the circulating blood withdrawn for microscopical examination; but the study of microscopical sections of organs of those dead of malarial infections shows that the endothelial cells lining the capillaries and small bloodvessels, especially those of the spleen, bone marrow, and liver, in certain cases also of the brain, intestine, and other parts, manifest extensive phagocytic activities. So too the macrophages, although they have repeatedly been found in the circulating blood, are met with chiefly in the splenic blood and in the microscopical examina- tion of organs of those dead of malaria. These macrophages, which may attain an enormous size and are frequently destitute of nuclei, and therefore necrotic, are mononuclear cells derived probably in part from mononuclear leucocytes and certain fixed cells of the pulp of the spleen and bone marrow. Their contents may be varied, consisting sometimes within one cell of pigment, intact or degenerated parasites, and red blood-corpuscles and entire smaller phagocytes. Dock has counted as many as twenty parasites within one phagocyte in the spleen. Under Pathological Anatomy will be described the appearances of these various phagocytes as seen in sections of the different organs of the body. The foreign elements which are found within these phagocytes in malaria are-(1) malarial pigment; (2) yellowish or reddish-yellow pig- ment derived directly from disintegrated red corpuscles (haemosiderin) ; (3) red corpuscles, sometimes intact, but usually more or less altered and fragmented; (4) malarial parasites, either free or enclosed within red corpuscles, which are usually altered, such parasites appearing some- times intact, often degenerated and fragmented; (5) particles which are probably often derived from the disintegration of parasites, but which do not present appearances sufficiently characteristic to enable one to determine their origin. It has already been mentioned that a phagocyte may be enclosed by a macrophage. Leucocytes either with or without pigment may be thus enclosed. As phagocytes and other cells often degenerate and become necrotic and disintegrated in malaria, it is evident that from this source may be derived material for inclusion within living cells. First in order of frequency are phagocytes containing malarial pig- ment. Tn the examination of malarial blood obtained from the periph- eral circulation the only form of phagocyte which is to be seen with any frequency in the perfectly fresh specimen is the melaniferous leucocyte. Leucocytes containing clearly recognizable parasites are rarely, if ever, seen in the freshly drawn specimen of peripheral blood. Macrophages containing definite parasitic forms may occasionally be found in this situation. Both mononuclear and polymorphonuclear leucocytes may contain the pigment, but in the perfectly fresh specimen the former PARASITOLOGY. 67 preponderate. The pigment is found most frequently in the form of blocks and coarse granules, corresponding to that set free by the process of sporulation, but sometimes the pigment within the leucocytes is in fine rods and grains, such as belong to the earlier stages of develop- ment of the parasite. The inference is a probable one that in the latter case the leucocyte may have enclosed the parasite. As has already been stated, in the fresh blood removed from the body and examined for a while under the microscope the polymorpho- nuclear leucocytes can be seen to engulf pigment and certain parasitic forms-viz. extracorpuscular forms, especially degenerated and frag- mented forms, segmenting forms and spores, and altered red corpuscles -and especially do they attack the flagellate bodies, as has been demonstrated by Thayer and Hewetson (Plate II. Figs. 45-49). Such enclosed parasitic forms, with the exception of the spores, can be seen rapidly to become indistinct and unrecognizable within the leucocytes. From the examination of the fresh circulating blood alone one obtains a very inadequate conception of the extent and nature of the phagocytic processes in malaria. A fuller idea of these processes can be derived from the study of blood withdrawn by puncture of the spleen, where phagocytic phenomena are far more active than in the circulating blood ; but it is especially in the microscopical examination of the organs of those who have succumbed to a malarial attack that the best oppor- tunity is afforded to learn the extent of phagocytosis in malaria. Here one finds abundantly leucocytes, endothelial cells, and macrophages con- taining pigment, parasitic forms, and altered red blood-corpuscles. Parasites in their later stages of development, especially when they are free, are frequently taken up by phagocytes-in their early stages rarely, unless they have become extracorpuscular or the corpuscle con- taining them is degenerated. Sporulating forms, and somewhat less frequently forms with collected pigm'ent (presegmenting bodies), are the ones most commonly found in a recognizable condition within the phago- cytes. It is stated by Bastianelli and Bignami that the bodies with pig- ment blocks (presegmenting) are found most frequently within macro- phages, and sporulating forms within polymorphonuclear leucocytes. Pigmented amoebse they found rarely, and red blood-corpuscles contain- ing unpigmented amoebae very rarely, within phagocytes. Bastianelli gives the following as the order of frequency in which the various para- sitic elements are found within phagocytes: (1) pigment; (2) sporulat- ing forms and spores; (3) red corpuscles, normal or decolorized, con- taining sporulating forms or bodies with central pigment blocks; (4) brassy and decolorized red corpuscles containing plasmodia (hyaline bodies in the amoeboid stage); (5) free bodies with central pigment olumps ; (6) more rarely free amoebae or red corpuscles of normal appear- ance containing parasites in the amoeboid stage. According to the obser- vations of the writer, free bodies with central pigment clumps occupy a higher place in this scale than that assigned to them by Bastianelli. Crescents enclosed in phagocytes may be found even in the circulating blood. The various bodies within phagocytes often lie in an area sur- rounded by a clear zone like a vacuole. Golgi (1887-88) discovered that phagocytosis occurs in quartan and tertian infections with a definite periodicity which stands in relation to 68 MALARIA. certain phases in the cyclical development of the parasite, and therefore to certain periods of malarial fever. This is readily understood when one considers that it is especially the free pigment and the mature and segmenting parasites and the degenerative forms which are taken up by phagocytes. The pigment is liberated by the process of sporulation which, as has already been explained, occurs shortly before and during the early stages of the paroxysm. Corresponding with this, Golgi found that pigmented leucocytes are present in the circulation during the paroxysm and for a short time afterward, and that they disappear from the circulation during the apyrexia. This periodicity in the appearance of melaniferous leucocytes and of other phagocytes can be observed regularly in quartan and tertian infections. There are frequently indi- cations of it also in sestivo-autumnal infections, but on account of the irregularities in the cyclical development of the Haematozoon falciparum, of the prolonged period of sporulation, of the frequent occurrence of multiple groups of parasites, and of the presence at all periods of degenerated red corpuscles, this periodicity in the occurrence of phago- cytosis is often obscured or is not manifest at all. Pigmented leucocytes may be found in many cases of sestivo-autumnal infection during all periods of the disease, although they are more numerous during the paroxysm and shortly afterward. In the severe prolonged cases they are generally abundant, and they may persist in the circulation for sev- eral days after cure is effected. As long as crescents are present pig- mented leucocytes may be found. Parasites which, to all appearances, are normal are found within phagocytic cells. What is the fate of such enclosed parasites? That many degenerate and die cannot be questioned, for these degenerative alterations can be directly observed in progress under the microscope in examining fresh blood, and in studying malarial blood and tissues one frequently encounters evidences of this fate of the parasites. It is claimed, however, by Marchiafava, Bignami and Bastianelli that enclosed spores, although prevented from further development, may survive for a long time within leucocytes and other cells, and that such latent spores may after an indefinite period be set free and cause by their development a relapse of the fever. Attention has already been called to Golgi's belief that the aestivo- autumnal parasite may, and to a considerable extent does, develop within the leucocytes and endothelial cells of internal organs, in ordinary cases chiefly of the spleen and bone marrow. He adduces a number of considerations in support of this view, but the objective evidence he and his pupil, A. Monti, find in the detection of the frequent presence of this parasite, apparently intact and in all stages of development, within these cells. In opposition to Golgi, however, it is claimed by Marchia- fava, Bignami and Bastianelli that early phases of development of the parasite are rarely seen within the cells, and that, therefore, the much more commonly enclosed late phases cannot have developed within the cells from young parasites. Golgi also brings to his support the obser- vation, made by all who have studied the subject, that many of the cells containing parasites degenerate and die, as is made evident especi- ally by the loss of their nuclei. He interprets this as meaning that in the conflict between cell and parasite the latter often comes off the PARASITOLOGY. 69 victor. Further investigations are needed to determine to what extent Golgi's doctrine as to the intercellular residence and development of the Hsematozobn falciparum is correct. Certainly the greatly prepon- derating number of intact eestivo-autumnal parasites observed in exam- ining the organs of those dead of pernicious malaria are found within free red blood-corpuscles in the vessels of internal organs. The theory of Metchnikoff that the essential factor in the resistance of the body to the malarial parasite resides in the activities of phago- cytes is opposed by many considerations. The most important factors in determining the gravity and the course of a malarial infection are the degree and quality of virulence possessed by the parasite, on the one hand, and the resistance of the individual receiving the parasite, on the other hand. There is no evidence that phagocytic functions are in abeyance in severe and pernicious cases of malaria. On the contrary, we find here often enormous numbers of parasitic enclosures within phagocytes. There is no proof that spontaneous recoveries from malaria are associated with an increase of phagocytic activity. Inasmuch as phagocytes regularly attack degenerated and fragmented parasites, and as we know that such degenerations occur frequently, within parasites free in the plasma, it is permissible to suppose that many of the para- sitic forms found within phagocytes were already impaired in their vitality before they were engulfed by cells. After the administration of quinine, which directly injures the malarial parasite, a distinct increase in the number of phagocytes has been often observed. Certainly qui- nine does not stimulate the leucocytes to swallow the parasites. Here the increase in the phagocytes must be attributed to the increase in the number of damaged parasites. There is evidence that the blood-plasma may exert a parasiticidal effect upon the malarial organism, as well as upon other protozoa (Fag- gioli), when the parasite has escaped from the protective covering of the red blood-corpuscle. The period when the largest number of malarial parasites are destroyed is that of sporulation and of free spores, and it is during this phase of the life-history of the parasite that quinine acts most effectively. We may, at least provisionally, adopt a theory to explain natural resistance to the malarial parasite similar to that which many accept regarding resistance to bacteria-viz. that the parasites are destroyed by parasiticidal substances contained both in the plasma and within leucocytes and other phagocytic cells. The substances injurious to the parasite are in the last analysis furnished to the plasma by the cells, and are in a more concentrated or potent form within the cells than in the fluids. This theory assigns to the phagocytes a higher role than that of mere scavengers. They are endowed in especial degree with the power of destroying the parasite, but this power is shared by the plasma. Pathogenesis. The discovery of the malarial parasite has placed within our reach the means of solving many problems concerning malaria which we could not formerly even attack with any hope of success. Already we have attained a satisfactory understanding of not a few previously unexplained manifestations of malaria, and other formerly obscure malarial phenom- 70 MALARIA. ena have been brought at least within the range of our comprehension. Much still remains to be elucidated, but we cannot doubt that further studies will continue to throw fresh light upon what remains obscure. In the description of the symptoms and lesions of malaria attention will frequently be called to their relations to the parasite, and in this connection only certain salient points, relating more particularly to pathogenic properties of the parasite, require consideration. The mere presence of the malarial parasite in the body is not suf- ficient to cause symptoms. The organisms must have multiplied to a certain point before their presence is manifested by recognizable symp- toms. The bearing of this fact upon certain malarial phenomena, more particularly upon the varying periods of incubation as determined by experimental inoculations of malarial blood and upon fevers with long intervals, will be considered in the clinical part of this article. It may be stated as a general rule, which was first formulated by Golgi, that the larger the number of organisms present in the body the more severe are the manifestations of the disease; but the number of the organisms is by no means the only factor which determines the gravity of the disease. The variety of parasite which is concerned in the infection is a factor of fundamental importance. The quartan variety produces the mildest attacks, the tertian is more virulent than the quartan, and the sestivo-autumnal variety is the most virulent of all, and is the one which is almost exclusively associated with the pernicious attacks. These variations in virulence are best explained upon the assumption that the malarial organism produces toxic substances of varying virulence according to the variety of parasite. There is also clinical evidence that one and the same variety may vary in virulence, so that, for example, some sestivo-autumnal parasites are more virulent than others. In seeking an explanation of the varying clinical characters of mala- rial infections we have to reckon not only with the number, the varie- ties, and the virulence of the parasites, but also with several other factors, such as predisposing conditions on the part of the individual infected, the occurrence of multiple groups of the parasite, the distri- bution of the organisms in internal parts, the circulatory and other ana- tomical disturbances induced by the parasites. Periodicity is the most striking clinical characteristic of malarial fevers, and the explanation of this phenomenon has exercised the minds of pyretologists from ancient times. It is true that intermittence is not limited to fevers of malarial origin, but regularity of rhythm in the occurrence of the paroxysms is especially characteristic of malaria. One of the most interesting additions to our knowledge resulting from the discovery of the malarial parasite is the demonstration by Golgi, which has been abundantly confirmed, that this rhythm in the malarial paroxysms corresponds to a rhythm in the development of successive generations of the parasite. The onset of each paroxysm corresponds to the ripening and sporu- lation of a generation of parasites and the setting free of a new brood.1 1 The old idea that the periodicity of malarial fevers depends upon the periodical production in the blood of a materia peccant is thus confirmed. It is interesting in this connection to note the line of argument presented by Griesinger in his admirable and sug- PARASITOLOGY. 71 Exactly what the connection is between this act of sporulation, with the liberation of a fresh brood of young parasites, and the cause of the febrile paroxysm, is not definitely known. It was at first suggested by Golgi (1887) that the paroxysm is due to the invasion of the red blood- corpuscles by the new group of parasites, but it was shown by Antolisei (1890) that the paroxysm depends rather upon the act of segmentation than upon the invasion of the blood-corpuscles by a new generation of organisms, for quinine, administered before a paroxysm in sufficient quantity, may, by destroying the fresh brood, completely prevent the invasion of the red corpuscles, but it cannot prevent the segmentation and the impending paroxysm. The view is now widely held, and seems plausible, that in the act of sporulation and of liberation of the spores chemical poisons are set free, and that these poisons, by their action on the nervous centres concerned in the production of fever, cause the febrile paroxysms. This toxic theory of malaria has been elaborated especially by Baccelli. The fact that the malarial parasite resides in, feeds upon, and de- stroys the red blood-corpuscles furnishes an entirely satisfactory explan- ation of two of the most characteristic and important manifestations of malaria-the melansemia and the anaemia. The malarial pigment, for which we formerly had no adequate explanation, is formed as an un- digested residue within the body of the parasite by metabolic processes directly out of the haemoglobin of the infected red blood-corpuscle. Various stages of the formation of the pigment within the parasite can be seen. The liberation of this pigment, its inclusion by phagocytes, its deposition in various internal organs, have all been described, and will be further considered under the Pathological Anatomy. The relations of the biological characters of the parasite to malarial anaemias and to haemoglobinuria will be fully considered in the anatomical and clinical parts of this article (pages 93, 116, 125, and 130). The ways in which the red blood-corpuscles may be altered by the action of the malarial parasite are various. The extent of these changes varies with the variety and the virulence of the parasite. They are least in quartan infections, greatest in the sestivo-autumnal. The in- fected blood-corpuscle may appear otherwise normal. It may be swollen or shrunken or variously deformed. It may divide into two or more pieces. It may be partly or completely decolorized, or the haemo- globin may separate from the stroma and be dissolved in the plasma, or may be concentrated around the parasite. Especial significance in the aestivo-autumnal infections attaches to that alteration in the cor- gestive article on the malarial diseases ( Virchow's Handb. d. spec. Path. u. Therap., Bd. ii. Abth. 2, 2te Auflage, p. 41, Erlangen, 1864): "The cause of the periodicity of the fever cannot, therefore, be referred to the disposition of the nervous system to rhythmical vital actions, as many have formerly done, but it must, at least according to our present although very incomplete knowledge concerning the causes of heat, be attributed to some- thing periodically occurring in the blood, which is connected with the increased produc- tion of heat. It has been formerly conceived that a certain substance, a materia peccans, appears periodically in the blood and incites the febrile heat and reaction: this material requires for its production and complete development sometimes longer, sometimes shorter, periods, and herein lies the cause of the rhythm of the fever As an explanatory hypothesis this conception accomplishes more than the later attempts at explanation The continuous morbid process which causes the poisoning incites periodically changes in nutrition or in the blood which arouse the nervous apparatus to abnormal manifestations." 72 MAL ARI A. puscle which lias been repeatedly referred to as the brassy change, on account of the resemblance in the color of the shrunken corpuscles to brass, sometimes compared also to copper or old gold. Nor are the corpuscles which are actually infected by the parasite the only ones which may be altered. Uninfected corpuscles may also be changed in appearance, and may be destroyed, especially in cases of haemo- globinuria. These changes in the red blood-corpuscles, which must be regarded as degenerative and destructive, cannot be brought wholly into parallel- ism with the development of the malarial pigment. In fact, the most profound lesions and the greatest destruction of the red corpuscles occur in infections with the aestivo-autumnal parasite, which is characterized by the small amount or even the entire absence of pigment. To explain many of these changes we must have recourse again to the theory that toxic substances are produced by the parasite and directly damage the blood-corpuscles. These alterations in the red blood-corpuscles not only explain the malarial anaemias and the haemoglobinuria with their concomitant symp- toms and lesions, and the accumulation of malarial and other pigments in certain organs, but they are utilized, although less conclusively, to explain certain other malarial phenomena. We know from physiological observations that the physical integrity of the red blood-corpuscles is an important condition in the maintenance of their circulation within the blood current. It is reasonable to suppose that corpuscles as profoundly altered as are many of those infected with the malarial parasite will circulate with difficulty, and will tend to accumulate in certain situa- tions where local conditions of the circulation favor the lodgement of foreign particles which get into the circulation. Many writers, there- fore, attribute to these alterations in the physical properties of the in- fected red corpuscles the accumulation of the parasites within the vessels of certain internal organs, more particularly the spleen, the bone mar- row, the liver, and the brain, and they explain the absence of such accumulation in quartan infections by the comparatively slight lesions of the infected corpuscles, and the large accumulation in tertian, and still more in aestivo-autumnal, infections by the more serious damage inflicted upon the infected red corpuscles by the varieties of the parasite causing these latter infections. Doubtless these factors-changes in the infected red corpuscles and local conditions of the circulation-are important in determining the localization of the parasites in certain internal parts, but with our present knowledge we cannot explain the varying distribution of the parasites observed in different cases exclu- sively by their aid, any more than we can adopt a similar explanation for the localization of the micro-organisms in other infections. The localization of the parasites in some cases, more particularly in aestivo-autumnal infections, within definite vascular areas of internal organs stands in relation to corresponding symptoms and lesions. The comatose and the choleriform types of pernicious malaria are associated with an accumulation, which may be enormous, of the parasites in the capillaries and small vessels of the brain and of the stomach and intes- tine respectively. Other special localizations of the parasites will be mentioned in the subsequent part of this article. In these cases cap- PARASITOLOGY. 73 illaries and other small bloodvessels may be partly or completely plugged with parasites, chiefly within red blood-corpnscles. Swollen, degenerated, and desquamated endothelial cells, pigment, macrophages, and other phagocytes contribute to this occlusion of the vessels. Genu- ine thrombi also occur. Serious disturbances of the circulation must result from such exten- sive plugging of the vessels. It is not easy to determine how far these mechanical disturbances of the circulation are responsible for symptoms and lesions with which they are associated. Marchiafava and Bignami and others regard them as the essential cause of the grave nervous symptoms in comatose pernicious fever, and of other symptoms and of lesions. Many years ago Frerichs likewise attached much importance in the causation of cerebral symptoms to accumulations of pigment and the formation of coagula within the cerebral vessels. It appears, how- ever, to the writer that, aside from certain general pathological consid- erations and analogies with similar conditions in other diseases, this mechanical explanation is inadequate, and that here too the toxic prod- ucts of the parasite are operative. The promptness with which the grave cerebral symptoms may subside after administration of quinine is not easily reconcilable with the theory that they are due to plugging of the vessels. Even the focal necroses which are common in the liver in pernicious cases, and may occur in the spleen, the kidneys, and elsewhere, are best interpreted as due to the toxic products of the parasite, rather than as the result, as is claimed for the liver by Guarnieri, of plugging of the bloodvessels. These necroses do not differ from those observed in diphtheria, typhoid fever, and streptococcus and other infections, and that they may be purely toxic in origin has been demonstrated by Welch and Flexner.1 The capillary hemorrhages which have been observed in the brain in the comatose form of pernicious fever, and which may occur elsewhere, may be referred to the hyperaemia and stasis resulting from plugging of the vessels. The interesting fact has been observed that in these capillary hemorrhages the extravasated red corpuscles are without parasites, while the neighboring bloodvessels are filled with red corpuscles containing parasites. The explanation of this which is given by Marchiafava and Bignami and adopted by others is that the corpuscles containing para- sites on account of their greater adhesiveness stick to the walls of the vessels and thus are prevented from escaping. The writer offers another explanation as the more probable. The examination of these small hemorrhages shows that they are the result of diapedesis, and not of actual rupture of the vessels (rhexis). It is not difficult to comprehend that red corpuscles altered by the invasion of parasites would not par- ticipate in the process of diapedesis, whereas it is not easy to understand why they should not escape from ruptured vessels. It is evident from what has been said that, while occlusion of vessels and consequent disturbances of the circulation are common in severe malarial affections, and are doubtless of importance in causing some of the lesions and symptoms, the more important and characteristic symp- toms and lesions are, in the opinion of the writer, with our present 1 The Johns Hopkins Hospital Bulletin, March, 1892. 74 MALARIA. knowledge, better explained by the toxic theory of the pathogenic action of the malarial parasite than by any mechanical theories which have yet been offered. We have, however, no positive demonstration of the existence of spe- cific malarial toxins. The investigations as to the toxicity of the urine of malarial patients will be described on page 123. They have not led to any positive results as to the detection of specific malarial poisons. ' It is a very old conception that the febrile reaction of the malarial paroxysm is conservative in the sense that this response of the body to the presence of pyogenic agents in some way aids in the elimination or destruction of injurious substances. This conception is not altogether without support from the parasitological study of malaria. The fever begins at the time of the birth of a new generation of parasites. These young organisms before they have entered the red blood-corpuscles are, of all phases of development of the parasite, in the most vulnerable condition, as has been shown by investigations of the action of quinine. That a large number of them perish during the febrile paroxysm seems to be demonstrated, at least in quartan and tertian infections, by the contrast between the number of sporulating forms and the number of succeeding infected corpuscles. Especially suggestive of increased potency of parasiticidal agencies during the febrile paroxysm are cases, especially of quartan or tertian infection, in which, after a sharp paroxysm, the symptoms and the parasites disappear, perhaps perma- nently, but often to return after a long interval as a recrudescence of the fever (page 121). Similar H.ematozoa in the Lower Animals. Great interest attaches to the presence in the blood of certain lower animals of protozoan parasites closely resembling the malarial parasite. Attention was first called to this resemblance by Danilewsky (1885-86), who described more fully certain forms which were previously known, and added the discovery of new forms, especially that of hsematozoa in birds which bear close resemblance to the human malarial parasite. Since Danilewsky's first publications there have been a number of investigations on this subject by Kruse, Celli and Sanfelice, Grassi and Feletti, Laveran, Labbe, and others. In the blood of frogs, turtles, lizards, and some other cold-blooded animals hsematozoa presenting some points of resemblance to the mala- rial parasite are not uncommon. Of these the best studied and most interesting is the Drepanidium ranarum (Lankester), identical with Gaule's " Wurmchen," in the blood of frogs. It is, however, certain hsematozoa in birds which bear such close resemblance to the malarial parasite that their identity with the latter has been assumed by Dani- lewsky and Grassi and Feletti, who speak of the existence of malaria and of malarial parasites in these animals. Most of the observations thus far reported have come from Russia and Italy, but the parasites have been found in birds also in Germany and France, and recently in the United States. In birds thus infected have been found forms similar to those of the malarial parasite in man-viz. unpigmented and pigmented hyaline PARASITOLOGY. 75 bodies (which, however, in distinction from similar bodies in man, mani- fest little or no amoeboid movement), sporulating forms, crescents, and flagellated bodies. The bird's haematozoa are also parasites of the red blood-corpuscles, from which they produce black pigment: they pass through the same stages of development as the latter, and the same diversity of views exists as to the origin and significance of the crescents and flagellated bodies. The name H.emoproteus was introduced by Kruse to designate these so-called malarial parasites of birds, and various other names have also been suggested. Grassi and Feletti adopt the same names and the same classification for these parasite of birds as for the human parasites (page 38). There are differences between the haematozoa found in different species of birds, and in the same species apparently different varieties of the parasite have been observed, but there are at present no definite classification and no certainty as to the number of varieties which may exist. Although these haematozoa of birds evidently belong to the same class of organisms as the malarial parasite, there are several reasons which in- dicate that they are not identical with the latter. They present certain morphological and physiological differences which it would lead too far here to describe. Although found thus far chiefly in birds from mala- rial regions, it is not proven that they may not exist in birds elsewhere. The inoculation of uninfected birds with the blood of birds containing the parasites has been, in a large preponderance of the experiments, unsuccessful in the result. The inoculation of birds with blood from human beings affected with malaria, and the inoculation of human beings with the blood of birds containing the haematozoa, have been uniformly without positive result (Di Mattei). Large doses of quinine have no influence upon the parasites in birds. The presence of the haematozoa in birds is usually without recognizable disturbance of the health of the birds, although it may cause a chronic or an acute affec- tion. While, then, we must admit a close relationship between certain haematozoa of birds and the human malarial parasite, the existing evi- dence is opposed to their identification. DESCRIPTION OF PLATES I. AND II.1 The drawings were made with great care and skill by Mr. Max Broedel, with the assistance of the camera lucida, from specimens of fresh blood. A Winkel microscope, objective, 1-14 (oil-immersion), ocular, 4, was used. Figs. 4, 13, 23, 24, and 42 of Plate I. were drawn from fresh blood, without the camera lucida. PLATE 1. The Parasite of Tertian Fever. 1.-Normal red corpuscle. 2, 3, 4.-Young hyaline forms. In 4 a corpuscle contains three distinct parasites. •5, 21.-Beginning of pigmentation. The parasite was observed to form a true ring by the confluence of two pseudopodia. During observation the body burst from the cor- puscle, which became decolorized and disappeared from view. The parasite became, almost immediately, deformed and motionless, as shown in Fig. 21. 6, 7, 8.-Partly developed pigmented forms. 9.-Full-grown body. 10-14.-Segmenting bodies. 15.-Degenerative form simulating a segmenting body. 16, 17.-Precocious segmentation. 18, 19, 20.-Large swollen and fragmenting extracellular bodies. 22.-Flagellate body. 23, 24.-Degenerative forms showing vacuolation. The Parasite of Quartan Fever.2 25.-Normal red corpuscle. 26.-Young hyaline form. 27-34-Gradual development of the intracorpuscular bodies. 35.-Full-grown body. The substance of the red corpuscle is not visible in the fresh specimen. 36-39.-Segmenting bodies. 40.-Large swollen extracellular form. 41.-Flagellate body. 42.-Degenerative form showing vacuolation. PLATE II. The Parasite of jEstivo-autumnal Fever {Hcematozoon falciparum). 1, 2.-Small refractive ring-like bodies. 3-6.-Larger disk-like and amoeboid forms. 7.-Ring-like body with a few pigment granules in a brassy, shrunken corpuscle. 8, 9, 10, 12.-Similar pigmented bodies. 11.-Amoeboid body with pigment. 13.-Body with a central clump of pigment in a corpuscle showing a retraction of the haemoglobin-containing substance about the parasite. 14-20.-Bodies with central pigment clumps or blocks. Presegmenting forms. 21-24.-Larger bodies with central pigment blocks. Presegmenting bodies. Seen in the peripheral circulation during a severe paroxysm. 25-28.-Segmenting bodies from the spleen. Figs. 25-27 represent one body where the entire process of segmentation was observed. The segments, eighteen in number, were accurately counted before separation, as in Fig. 27. The sudden separation of the seg- ments, occurring as though some retaining membrane were ruptured, was observed. ' 29-37.-Crescents and ovoid bodies. Figs. 34 and 35 represent one body which was seen to extrude slowly, and later to withdraw, two rounded protrusions. 38, 39.-Round bodies. 40.-Pseudo-gemmation, fragmentation. 41.-Vacuolation of a crescent. 42-44.-Flagellation. The figures represent one organism. The blood was taken from the ear at 4.15 p. M. ; at 4.17 the body was as represented in Fig. 42. At 4.27 the flagella appeared ; at 4.33 two of the flagella had already broken away from the mother body. 45-49.-Phagocytosis. Traced with the camera lucida. 1 These plates are taken by permission from The Johns Hopkins Hospital Reports, vol. v., 1895. Four figures-viz. Figs. 21, 22, 23, and 24-have been added to Plate II., and are also from the draw- ings of Mr. Max Broedel. 2 The color of the pigment in these figures of the quartan parasite has too much of a reddish tint. 76 ETIOLOGY, PATHOLOGICAL ANATOMY, SYMPTOMS, DIAGNOSIS, PROGNOSIS, AND TREATMENT. By WILLIAM S. THAYER, M. D. Etiology. Distribution.-The malarial fevers are widely distributed, occur- ring in almost all regions of the earth. There are, however, certain principal foci where the disease is permanently endemic. These regions are chiefly in the warmer temperate and tropical countries. Generally speaking, the farther one departs from the equator the less common are the malarial fevers. A sharp line of delimitation cannot, however, be drawn. Occasionl cases have, according to Celli,1 been observed as far north as Irkutsk in Siberia, Haparanda in the Gulf of Bothnia (65° N. latitude), Juliushaab, Southern Greenland, and New Archangel in Alas- ka, while to the south malaria has been reported to exist as far as the isotherm of 60°. It must, however, be remembered in considering any statistics concerning the distribution of malaria that the diagnosis of malarial fever has been, until very recently-and is, alas I far too fre- quently today-made upon a very insufficient basis. In many regions today an intermittent fever with chills is without further investigation assumed to be of malarial origin, and even at the present time, in some of the large cities of this country, there are official statistics of mortality due to malaria-statistics showing thousands of deaths every year- which are almost absolutely incorrect. About the main foyers of malaria there is, however, little doubt. In Europe the disease is common in the low lands about the coasts of Italy, Sicily, Corsica, Greece, the Black and Caspian Seas, and in the lands bordering upon the Po, the Tiber, the Danube, and the Vol- ga. About the coast of certain parts of France, Spain, and in Denmark and Sweden, an occasional case is seen. In Holland and Belgium the milder forms of the disease are not uncommon, while a few cases of the same nature are seen in Germany about the mouth of the Elbe and along the Baltic coast of Prussia, in Silesia, the plain of the river Mark, and in Pomerania. In tropical Africa the disease appears in its most severe forms, especially along the West Coast. The chief foyers of the disease in Europe are in Italy and Southern Russia. In India, Ceylon, and in the East Indies it is particularly common, while in Southern and Southwestern China it is also endemic. In Japan the disease is rare. In the Western Hemisphere malaria is seen in the low- lands about the coast from New England to Florida, though above Vir- ginia the severe forms are rare. In the Gulf States and along the banks of the Mississippi and its tributaries, in most of the Southern States, the disease is almost always present. About some of the Great Lakes, both in the United States and Canada, malarial fevers are occa- 1 Verhandl. d. X. Internal. Med. Cong., Bd. v. Abth. xv. p. 68. 77 78 MALARIA. sionally seen, while a certain number of cases are reported from the Pacific coast. In Cuba, Mexico, and Central America some of the most fatal forms of the disease are met with. The much feared Chagres fever of the Isthmus of Panama is a pernicious malarial infection. About the low- lands of the eastern coast of South America, particularly in the Guianas and in Brazil, the disease is endemic in its most malignant forms. On the west coast it is less frequent, though its occurrence in Peru and Bolivia has been known for years. Indeed, it is from the Peruvian I ndians that we learned the value of the specific remedy for the disease. In Australia, New Caledonia, and the islands of the Pacific the disease is very rare, and in some regions, such as Hawaii, Samoa, New Zealand, and Van Diemen's Land, notwithstanding the existence of extensive low marshy tracts, it is quite unknown. In cases of malarial fever which occur sporadically in regions where the disease is uncommon the infection may often be traced to a previous sojourn in a malarious district. Extensive epidemics and pan- demics of malarial fever, spreading over the greater part of the earth, have been described. In most of these instances, however, consider- able uncertainty exists as to the true nature of the process. Physical Geography.-The physical geography of the country has much to do with the prevalence of malarial fever. In the words of Laveran, " The principal foyers of paludism are situated on the coast or along the banks of large rivers." High altitudes are usually free from malarial fever, and the mountains and plateaus in the neighbor- hood of malarial districts are often used as sanitaria by the inhabitants. The high altitudes may not, however, be a protection, as, according to Hertz,1 fevers occur in the Tuscan Apennines at a height of 1100 feet, in the Pyrenees at 5000 feet, on the island of Ceylon at 6500 feet, in Peru at from 10,000 to 11,000 feet. It is, however, by no means improbable that many of these fevers which have been called " mala- rial" are, in reality, of some other nature. This has been shown to be true in the case of the " mountain fever " of the Western States, which is for the most part, probably, typhoid fever. The Soil.-Low, marshy regions are particularly likely to be malarious; hence the term " paludism" which is so generally used. Mixed salt and fresh water marshes seem to be particularly favorable for the development of the disease. Low, moist, ill drained lands, rich in vegetable matters-lands which have been allowed to fall out of cul- tivation-are particularly dangerous. All marshy regions, however, even in tropical countries, are not of necessity malarious, an example of this being shown in some of the South Pacific islands, as already mentioned. And, while the disease is particularly common in marshy districts, it may occur in other regions in sandy or clayey soil, or, indeed, in rocky regions. An impervious subsoil is believed to be particularly dangerous. Effects of Turning up the Soil.-In many instances the denudation of a soil covered by forests or rank vegetation, or the turning up of the soil in a district which was previously free from the disease, may be fol- lowed by an outbreak of malarial fever, while in other regions where 1 v. Ziemssen's Cyclopedia of the Practice of Medicine, vol. ii. ETIOLOGY. 79 the disease already exists similar interference with the vegetation or the soil may greatly intensify the severity of the process. An example of this latter condition is shown in the severe outbreak of malarial fever which was associated with the excavation of the Panama Canal. In Paris, which for many years had been free from paludism, the digging of the Canal Saint Martin, and again, in 1840, the excavations for the fortifications, were, in each instance, followed by an outbreak of characteristic intermittent fever. Irrigation of low lying districts without proper drainage has been followed by an outbreak of mala- ria or an increase in the severity of the cases. Such a condition of things has been noted in some of the irrigated districts in Southern California. Effects of Drainage.-Efficient drainage of marshy districts which have been rich in malarial fevers has a marked effect upon the frequency and severity of the manifestations of the disease. Years ago malaria was common in the surroundings of London, which were marshy and ill-drained; today, thanks to good drainage, the disease is unknown. The low lands of Holland used to be the seat of very severe malaria; today, only occasional cases of the mildest forms of the disease occur. The effect of good drainage upon the Roman Campagna has been very striking, the severity of malarial fever diminishing materially. Cultivation.-The cultivation of many marshy, malarious districts has been followed by a marked improvement in the sanitary condition. The planting of trees has been supposed to have a particularly good effect, possibly because of the drainage of the soil which is thus accom- plished. For some time it was supposed that certain trees, particularly the eucalyptus globulus, had an almost specific effect in protecting the neighborhood against malarial fever. The advantages of this particular tree have, however, been much exaggerated. Malarial fever never orig- inates at sea. Those cases which have been reported date their infection, unquestionably, to some period before the voyage. There is much to suggest that the soil has some intimate connection with the development of the contagium of paludism. Variations in Distribution.-One of the most striking character- istics of malarial fever is the manner in which it leaves one region in which it has existed for some time, to appear in another which may, for a con- siderable period, have been quite free from any manifestations of the disease. This change in the distribution of the disease is in great part due to the activity of man. On the one hand, an outbreak may follow the abandonment or neglect of richly cultivated areas which have been well drained and taken care of, as, for instance, the Roman Campagna in the time of Augustus, while, again, in other regions the turning up of the soil may bring about an outbreak where it is least expected. But this explanation does not answer all cases. The appearance of malarial fevers in the New England States during the past fifteen years, after a long period of almost entire quiescence, is a striking example of these inexplicable changes in location. Again, in districts where malaria is permanently endemic there are often cycles in the severity of the disease which are impossible to explain. Climate.-Heat and moisture are important for the development of the fever. In malarious districts a very dry season is usually more 80 MALARIA. healthy. Laveran 1 states that in Algeria the rainy years show a more severe endemic than the dry, while the first " rains of the autumn give rise, almost always, in Algeria to a recrudescence of the fever." Season.-In tropical countries malaria exists usually throughout the year, but it is almost always most severe in the summer and fall. As one approaches the temperate climate the cases in winter and spring become very rare. Along the eastern coast of the United States, just as in Rome, the cases in the winter are very few, while with the spring a certain number of infections begin to appear. It is, however, not until July that the real malarial season begins. The height of the malarial season is reached in the months of August, September, and October. The following table, showing the number of cases of malarial fever treated at the Johns Hopkins Hospital between January 1, 1890, and January 1, 1894, gives a good idea of the variations in the occurrence of the disease to the seasons of the year: Jan. Feb. Mar. Apr. May. June. July. Aug. Sept. Oct. Nov. Dec. Total. 9 8 8 17 21 18 38 66 122 120 38 25 490 The earliest cases show also the mildest types of infection. Thus, in the spring the first cases are usually tertian or quartan infections. As the season advances double tertian infections become more frequent, while at the height of the malarial season the majority of cases are of the sestivo-autumnal type, the most severe form of malaria. Thus, out of 542 cases analyzed by Hewetson and the author,2 there were- First half year. Second half year. Regularly intermittent fevers 113 230 ^Estivo-autumnal fevers 5 183 Combined infections 3 8 121 421 = 542 At the height of the malarial season, during the months of September and October, there were- Regularly intermittent fevers 109 jEstivo-autumnal fevers 120 Combined infections 5 This observation concerning the variation of the types of the fever with the times of the year is as old as Hippocrates. It has long been popularly supposed that the early cases of fever in the winter and in the spring represent, in toto, relapses from infections of the preceding fall, the fevers of first invasion beginning only with the summer months. The analyses of our cases at the Johns Hopkins Hospital tend, however, to show that, while the proportion of fevers of first invasion is less in the spring than in the summer months, yet they do occur. Winds.-There is much which tends to suggest that the infective agent may be carried by the wind. It has been asserted, for instance, that along the banks of a stream in a malarious district the fevers are often more frequent and severe on the side toward which the prevailing winds blow. Again, in other instances it has appeared that strips of 1 Trait# des Fievres palustres, Paris, 1884, p. 8. 2 "The Malarial Fevers of Baltimore," Johns Hopkins Hospital Reports, vol. v. ETIOLOGY. 81 forest land have arrested the spread of the disease, suggesting that some infectious substance may be filtered out by the trees. Thus, Lancisi believed that it was through the influence of the winds that the Roman Campagna became more unhealthy after the removal of the sacred groves. These, he believed, acted as a protection by filtering from the air infectious substances carried by the winds which blew over the Pontine marshes. Altitude.-It has been repeatedly observed that in malarious districts the dangers of infection are much greater close to the ground. Sleeping upon the ground is particularly dangerous. The upper stories of a house are safer than the lower. Infection appears to take place more readily by night than by day. Drinking Water.-Many have laid, and still do lay, much stress upon drinking water as the source of the disease. The experiments, however, of Celli,1 Marino,2 and Zeri,3 who caused individuals to drink in large quantities water which was obtained from the most malarious districts, without any bad effects, and of Grassi and Feletti,4 who fed individuals upon dew collected from malarious regions, with similar negative results, are strong arguments against this idea. It should be remembered, however, that while these experiments are strong evidence that the malarial poison is not introduced through the drinking water, yet it is no proof that water may not contain the parasite, or, indeed, form an actual culture medium for some forms of the organism. We are wholly ignorant of the manner of entry of the parasite into the system, of the form in which it exists outside of the body, or of the changes which it may pursue in other media than the circulating blood. It is not impossible to imagine a body which might pursue a part of its development in water, reaching its truly infectious form only in a later stage and in some other medium. Grassi and Feletti have shown that the living parasite from the circulating blood does not, when ingested, cause fever. Thus, they caused an individual to drink the fresh blood of a malarial patient without result, while inoculation experiments with similar blood are almost always positive. (See page 34.) Race.- In many malarial districts the natives-negroes, Arabs, Indians, Tamils-appear to have a relative insusceptibility to the dis- ease, the degree of which varies in different localities and according to different authors. Our observations in Baltimore would tend to show that here the susceptibility of the negro is only about one third that of the white. Occupation.-The occupation has much to do with susceptibility to the disease. Soldiers and tramps who sleep upon the ground in malarious districts are particularly susceptible. Fishermen in the bays and inlets along the southern coast of the United States, as well as farmers and berry pickers in the same regions, are particularly open to infection. Age has apparently no effect upon the susceptibility, excepting in so far as the very young and the very old are less likely to be exposed. 1 Bull. d. Soc. Lane,, d. Roma, 1886, vi. 1, 39 (5 Dec., 1885). 2 Riforma Medica, 31 Oct., 1890, No. 251, 1502. 3 Bull. d. R. Acc. Med. di Roma, 1889-90, xvi. 244. 4 Centralblatt fur Backt., 1891, ix. 403, 429, 461. Vol. I.-6 82 MALARIA. Predisposing Causes.-It is generally believed that in malarious districts almost anything which tends to diminish the vitality of the patient acts as a predisposing cause to malarial infection. It is often asserted that where a previous attack has existed injuries of various sorts are particularly likely to be followed by a relapse of the malaria. It has been asserted, for instance, that an injury to the spleen in a patient who has formerly had malarial fever may call forth a relapse. With regard to the effects of traumatism, the observation of nearly a thousand cases during the last five or six years has not given any posi- tive answer, while the complications of malaria with other acute diseases have been, perhaps, rather surprisingly infrequent. It seems reasonable that trauma or operation, by reducing the condition of the patient, should render him more susceptible to a fresh malarial infection or more liable to a recrudescence of an already existing process. The fact, however, that in nearly seven years not a single case of post-operative malaria has occurred in the Johns Hopkins Hospital has led us to believe that many of the chills occurring under these circumstances, generally supposed to be malarial, are probably, in reality, septic in origin. Manner of Infection.-The discoveries of Laveran have revealed to us the infectious agent in malaria, while its specific action has been abundantly demonstrated by clinical observation and inoculation experi- ments. And yet it must be confessed that we are wholly ignorant as to the manner in which the parasite exists outside of the body or how in- fection takes place. The most important points of entry into the system which have been suggested are- (1) The respiratory tract; (2) The digestive tract; (3) The skin (insect bites, etc.). (1) There is a very general belief that infection may take place through the respiratory tract, though positive proof of its occurrence is as yet wanting. In favor of this view are the observations of Lancisi and others concerning the winds. (2) Many observers, as has been said, still believe that the parasite is introduced chiefly through the digestive tract. The observations, how- ever, of Celli, Marino, Zeri, Grassi and Feletti, already referred to, are very suggestive evidence against this idea. (3) The inoculation experiments referred to in the description of the parasites have given positive proof that infection may take place when the parasite is introduced beneath the skin. This renders more plausi- ble the old idea that insect bites may sometimes serve to convey the contagium. In this connection one may remember the remarkable observations of Theobald Smith,1 who has shown that the hsemocytozobn of Texas fever in cattle {Pyrosoma bigeminum) is conveyed from animal to animal by means of the cattle tick (Bobphilus boris). Experimentally it has been shown that although infection through the alimentary tract is improbable, subcutaneous infection is possible, while clinical observation is strongly in favor of the view that infection through the respiratory tract may occur. 1 U. S. Dept, of Agriculture, Bureau of Animal Industry, Bull. No. 1, Washington, 1892. PATHOLOGICAL ANATOMY. 83 In Summary.-The malarial fevers flourish in low, moist, hot regions, the borders of rivers and marshes, places where the water is brackish being particularly dangerous. High, dry, sandy, or rocky regions are rarely malarious. In a malarious district there is greater danger of in- fection near the ground, by night than by day. There is suggestive evidence that the contagium may be carried by the winds. Age has no marked influence on the susceptibility. The negro is relatively much more insusceptible than the white. The manner of existence of the parasite outside the body and the manner in which the infection takes place are still wholly unknown. Pathological Anatomy. (1) Anatomical Changes in Acute Malarial Infections ; (2) Changes following Repeated or Chronic Infections. Cases of the regularly intermittent fevers are so rarely met with upon the* autopsy table that our knowledge of the pathological changes present in the internal organs are largely based upon a study of the cases of pernicious sestivo-autumnal fever. Our knowledge of the pathology of the malarial fevers has been greatly increased in late years by the investigations made since the discovery of the parasite by Laveran, Councilman and Abbott, Guarnieri, Dock, Bignami, Barker, and Monti. One of the most interesting points which at once strikes the careful observer is the extreme variation in the distribution of the malarial parasites in the body, and the anatomical changes produced by them in different cases. This difference in the localization of the para- sites and in the seat of the important anatomical changes may bear, as has been pointed out in the description of the parasite, a direct relation to the symptoms which have existed during life. The most striking point in the appearance of the organs in malarial fevers is the melanosis which gives a characteristic slaty gray color to many of the organs. This results from the accumulation of the pigment produced by the parasites from the haemoglobin of the blood-corpuscles, and, while almost invariably present, its distribution, as in the case of the parasites, and the degree in which different organs are affected, varies considerably in different cases. The Brain.-The most striking changes in the brain are to be met with in the cases of comatose pernicious fever. The brain may be the seat of but few macroscopical changes. Melanosis may be entirely absent. At times, however, there may be a slight subpial oedema with hypenemia of the cerebral substance, and perhaps punctate hemor- rhages ; more commonly, however, the gray cortex shows a slaty or chocolate color, which may be quite deep. The vessels are markedly injected, and in places, as has been said, punctate hemorrhages may be found. In these instances the microscopical appearances are most striking. The cerebral capillaries are crowded with parasites, which are, for the most part, within red corpuscles, and may form an actual complete injection of many of the cerebral vessels. This is generally most striking in the gray substance. These parasites (usually of the restivo-autumnal type) may be in all stages of development, though generally one of the stages is most marked. Sometimes in cases where 84 MALARIA. death has occurred during the paroxysm actual thrombi of segmenting organisms may exist. Sometimes the organisms may not be so numer- ous, but evidence of their previous existence is found in free clumps of pigment and swollen pigmented endothelial cells, as well as leucocytes containing pigment and red blood-corpuscles. There is usually decided granular and fatty degeneration, and often pigmentation of the endothe- lium of the vessels-a change upon which the punctate hemorrhages probably depend. Some endothelial cells may be greatly swollen, almost occluding the lumen of the vessels : these, as has been demonstrated, especially by Monti, may contain a considerable number of apparently well preserved parasites in various stages of development; they may be within shrunken or brassy corpuscles or full grown and free. Occasion- ally large macrophages are seen almost occluding the capillary, which appear, according to Monti, to be endothelial cells which have broken loose and are free in the current. These lesions are particularly marked in the comatose form of per- nicious malaria. In some instances different parts of the central ner- vous system may be differently affected. In one case, for instance, studied by Marchiafava,1 where the patient died with symptoms of bulbar paralysis, a special localization of the changes was noted in the medulla. In other instances the cerebral lesions may be slight; the collections of parasites in the capillaries, as well as the degenerative changes in the endothelium, are not to be made out. Monti2 has recently studied the changes in the nerve cells in the gray cortex in pernicious malaria, according to Golgi's method, with interesting results. In some cases these elements were, so far as could be made out, quite normal, while in others interesting changes were noted : these cases were chiefly those showing grave nervous symptoms, such as coma, during life. The alterations were not uniformly diffused throughout the cortex, and never affected all the elements in a given zone. Usually cells more or less profoundly altered were found among other cells and fibres which were quite normal, although a tendency to a focal arrangement of these changes could be made out. The altera- tions affected chiefly the protoplasmic prolongations of the nervous cells of the cerebral cortex. Sometimes the prolongations appeared thinned and studded with fine nodes. Not infrequently these alterations were limited to the more delicate and distant branches, though it was not difficult to find cells of which all the dendrites presented the beaded appearance which is so well observed in the nerve cells of animals dead of inanition. In other points the alterations consisted of simple irregu- larities of contour in dendrites which were much thinned, extending from cells the bodies of which were sometimes normal, more often swollen, rarely thinned, shrunken, or atrophic. Coarser alterations were, however, not wanting. Cells were found whose dendrites showed coarse varicosities and very marked constrictions, so that they appeared as if formed of masses of protoplasmic matter connected only by the finest filaments of protoplasm. Similar changes were observed in the brains of animals in which embolisms were produced by the injection of lycopodium. 1 Lav. del. III. Cong. del. Soo. Itai, di Med. Int., Roma, 1890, 142. 2 Bull. d. Soc. Med.-Chir. di Pavia, 1895. PATHOLOGICAL ANATOMY. 85 In most of Monti's cases the axis cylinders were well preserved; the principal lesion appeared to consist in alterations of the protoplasmic prolongations. In some cases, however, especially in one severe case of comatose pernicious fever, certain alterations were to be made out in the axones. In this case the alterations of the nervous elements appeared more marked throughout the brain than in the other cases; the altera- tions in the dendrites were more frequent and marked, while the nervous prolongations also, had, in many points, lost their normal character. Instead of being smooth and regular as usual, they presented sometimes small nodes, more rarely larger swellings. Also, among the axones, as well in the cerebral cortex as in the cerebellum, there were occasionally varicosities. The alterations of the nervous fibres were, however, always less marked than those of the dendrites. Monti believes that these changes are due to the grave circulatory disturbances, the occlusion of capillaries, lesions of their walls, the stasis, and the hemorrhages produced by the malarial parasites, it may be noted that many of these changes are not dissimilar to those described by Dr. Berkley in animals after the injection of ricin. The Spleen.-The spleen is always enlarged ; there is a pronounced acute splenic tumor." The capsule is tense. The parenchyma is cyanotic and sometimes is of a markedly slaty gray color; it is soft and is often almost diffluent. In acute malaria death may occasionally occur from rupture of an enlarged spleen. Microscopically, the pulp contains enormous numbers of red corpuscles, many of which contain parasites. These parasites may be in various stages of development. Sometimes, in the same organ, different areas show separate groups of parasites in different stages of development. Generally the pigmented and segment- ing forms may be found in large numbers. Free forms of the parasite are relatively rare. One of the most striking appearances in the splenic pulp is, however, the presence of great numbers of phagocytes, some smaller and apparently leucocytic in nature, others very large cells, rich in protoplasm, containing a single large nucleus and occasionally a coarse granulation. These cells may reach an enormous size. They are laden with pigment, either in large clumps or spheres, in rodlets, or in very fine granules; the granules sometimes present the same arrange- ment which they had in the body of the parasite. The fine pigment may be distributed in delicate lines throughout the whole mass of proto- plasm of the phagocyte; it often seems to vary in its color in different parts of the cell, but on focussing this appearance is found to be due to differences in plane. These large cells also contain red corpuscles, which are often partially or completely decolorized and contain para- sites ; and, finally, entire smaller phagocytes with their included pig- ment or corpuscles, as well as clumps of haemoglobin of the color of old brass and fragments of degenerated red corpuscles. Golgi and Monti have called particular attention to the frequency with which these macrophages contain apparently well preserved parasites in different stages of development. They believe that the shrunken and brassy para- sitiferous red corpuscles are engulfed in the phagocytes as would be any foreign body, while the included parasites continue their development within. Some of these macrophages may show evidences of necrosis. In some cases one may find in the pulp actual focal necroses, very much 86 MAL ARIA. like those which may be seen in typhoid fever. These changes have been well described by Barker.1 There may be malarial pigment free in the intercellular spaces in the pulp. Pigmented polymorphonuclear cells are relatively rare; the small mononuclear elements and the lymphocytes of the follicles never contain pigment. The capillaries are usually filled with corpuscles con- taining parasites, while the splenic veins show relatively few, though they always contain phagocytes containing pigment and fragments of blood-corpuscles. The Liver.-The liver is often of an intense slaty gray color, which depends upon the enormous numbers of parasites and of pigment contained in the capillaries. The distribution of the pigment is different, as will be pointed out later, in this acute malarial infection from that cu wacteristic of repeated attacks. There is always a marked cloudy swelling. Microscopically, the capillaries are often crowded with leuco- cytes and contain numerous phagocytes; some of the largest macro- phages are here observed. Not infrequently the endothelial cells may be also observed to show evidences of phagocytic action. The perivas- cular tissue in the portal spaces may show numerous pigment bearing cells, while frequently liver cells may be found to contain clumps of pigment derived from the blood and altered red corpuscles. This con- dition, similar to that observed in pernicious anaemia, accounts, doubt- less, for the polycholia and the subicteric hue so commonly observed in the malarial fevers. Ordinarily relatively few parasites within red cor- puscles are to be found within the vessels : these are more numerous in the interlobular branches of the portal vein. In the intralobular veins one more often sees the macrophages. Among the most interesting changes to be noted in the liver are occasionally occurring disseminated areas of local necrosis of the liver elements with fragmentation of the nuclei, wandering in of leucocytes, and sometimes with evidences of proliferation of cells in the surround- ing tissue. These changes are very similar to those already noted in typhoid fever and other acute infectious diseases, and proven by Welch and Flexner2 to be produced in diphtheria, and by Reed3 in typhoid fever, by a circulating toxic substance. The occurrence of these foci in the liver was first described by Guarnieri,4 who ascribed them to the cut- ting off of the nutrition by the extensive blocking of the intralobular capillaries with pigment bearing phagocytes. Barker5 describes and pictures capillary thromboses in association with many of these areas. The Lungs.-The alveolar capillaries show, generally, large num- bers of phagocytes, which are, however, smaller than the largest macro- phages of the liver and spleen. Their substance may show evidence of necrosis. Occasionally pigment may be found in the endothelial cells of the capillaries and small veins, but much more rarely than in the capillaries of the brain or of the liver. Leucocytes containing malarial pigment are seldom found in the interior of the alveoli. Mono- nuclear phagocytes are much more frequent than ordinary polymorpho- 1 Johns Hopkins Hospital Reports, vol. v., 1895. 2 The Johns Hopkins Hospital Bulletin, No. 20, March, 1892. 3 Johns Hopkins Hospital Reports, vol. v., 1895. 4 Atti della R. Ace. Med. di Roma, 1887, s. ii. v. iii. 247-266. 5 Loc. dt. PATHOLOGICAL ANATOMY. 87 nuclear leucocytes, which, when present, contain, usually, finer, smaller particles of pigment. The macrophages are generally collected about the periphery of the smaller veins. The endoglobular parasites show, usu- ally, all stages of development. The endothelium of the capillaries and small veins rarely contains pigment, in sharp contrast to the condition existing in the brain. It is striking that the areas of bronchopneu- monia, which are not infrequently found, contain only the ordinary polymorphonuclear leucocytes and alveolar epithelial cells, pigmented elements being very rarely present. The capillaries of the septa may, however, be filled with pigment and macrophages. Bignami suggests that this fact is due to the diminished vitality of the pigment bearing cells, which have, to a certain extent, lost their motile power and are thus less able to pass through the vessels. The Kidneys.-The changes in the kidneys in acute malaria are usually much less marked than in the liver and spleen. Their gross appearance varies but little from the normal. Evidences of pigmenta- tion are usually wanting on gross examination. The malarial parasites and phagocytes are usually present in smaller numbers, the quantity being disproportionately small in comparison to the alterations of the parenchyma which are sometimes to be found. The glomeruli, how- ever, are ordinarily considerably pigmented, the pigment at times being seen within large white cells within the vessels, sometimes in the glomerular endothelium. Endoglobular parasites are rarely seen in the capillaries of the glomeruli ; they are more common in the inter- tubular vessels, but are rare even there. The most important lesions consist in exfoliation and degeneration of the epithelium lining the capsules. Albuminous exudates within the glomeruli were found by Bignami only in algid pernicious fever. At times, however, there may be marked alterations in the parenchyma-to wit, focal necroses of the epithelium, especially that of the convoluted tubules. The changes in the kidneys in cases of haemoglobinuric fever have been described by Pellarin,1 Benoit,2 Kiener, and Kelsch.3 The kid- neys are somewhat increased in size, the color varying from a deep reddish brown to a light yellowish brown coffee color in more anaemic individuals. When the color is pale, irregular pinhead points and blotches of a maroon color are to be seen upon the surface, some as large as several millimetres in area. They are also scattered through- out the cortex. These have been shown by Kelsch and Kiener to be due to pigment deposits; they are not visible in more congested kid- neys. The pyramids are of a deep red color from intratubular hemor- rhages. The capsule is easily detached; the consistency of the gland is normal. Microscopically, the epithelium of the convoluted tubules and of the large branches of Henle's loops are very opaque, the nuclei being scarcely visible. This is due to an infiltration of the protoplasm with a diffuse coloring matter and fine pigment granules which are rendered more evident by KOH. These granules are extremely small, and sepa- rately appear of a yellowish color, while en masse they have a brown shade. The epithelial cells are swollen and bulge into the lumen of the canal. Occasionally a cell shows a hyaline protrusion which seems on 1 Arch, de Med. nav., 1865. 2 Ibid. 3 Arch, de Phys., 1882. 88 MALARIA. the point of escaping. In some tubes the epithelial covering is repre- sented only by a thin protoplasmic layer with a homogeneous surface, appearing as if eroded down to the level of the nuclei. The lumen of the tubule is filled with clumps of amorphous material or casts mixed to a greater or less extent with this pigment. The brown specks and blotches seen macroscopically represent groups of tubules, the epithe- lium and lumina of which are crowded with similar masses of pigment; but pigment may also be found in larger granules-granules nearly as large as a red blood-corpuscle, and more or less spherical; they are refrac- tive, of a color varying from a yellow ochre to a deep brown, and are some- times accumulated in epithelial cells which bulge so as to almost occlude the lumen. Sometimes they occupy the lumen and form conglomerations, taking the shape of casts ; sometimes they are fused into a vitreoid mass. Between the opaque dark casts formed by the fine brown granulations and the almost vitreoid casts composed of the large orange colored granulations every intermediate stage may be seen in the same prepara- tion. Generally this pigment gives no reaction for iron, though Kelsch and Kiener have obtained this reaction from certain granules in one case. The finely granular substance is found, according to these authors, more particularly in cases where death has occurred in a pernicious paroxysm, while the larger forms of pigment are more frequent in cases of longer duration. In the glomeruli, as well as in the blood, Kelsch and Kiener have never seen the large variety of granules, though the finer granules are numerous. Between the glomerulus and capside, usually near the mouth of the tubule, there is often quite a collection of granules, which are also found sometimes in epithelial cells, sometimes free. In the glomerulus itself one may see fine gran- ulations disseminated in its substance and apparently included in the cells of the capillary walls. More rarely granulations may be accumu- lated in a capillary loop. In some cases there are small interstitial hemorrhages. The pyramids show few changes. The same varieties of casts as noted above may be found, and the same pigment collections. The epithelium is usually intact, though sometimes protruding and vesicular cells suggest that they may take part in the formation of hyaline material. Almost invariably a number of the tubes are found filled with blood-corpuscles. The Gastro-intestinal Tract. - The stomach and intestines show, under ordinary circumstances, few changes beyond the melanosis. It is to be remembered, however, that the intestinal mucous membrane may be of a dark steel gray color in conditions other than malaria. Microscopically, one may see a considerable number of parasites, espe- cially of the full grown and segmenting varieties, in the capillaries of the mucous membrane, together with numerous pigmented cells and apparently few pigment clumps. In most cases, however, the gastro- intestinal mucous membrane is not particularly sought by the parasites. In other instances, as pointed out by Marchiafava and Bignami, this region may be the seat of the main localization of the affection. Macroscopically, there may be intense hypersemia with punctate hemor- rhages in the gastro-intestinal mucosa. In one instance observed by the author there was a distinct dusky slaty tinge as well. Here the capil- laries throughout the gastro-intestinal tract may be crowded and blocked PATHOLOGICAL ANATOMY. 89 with parasites, free and contained in the red corpuscles or in phagocytes. As in the case of the brain, actual thromboses may exist with necrosis of the epithelial covering and ulceration. Cases of this nature are asso- ciated frequently with marked gastro-intestinal symptoms, some show- ing a clinical picture very similar to that of Asiatic cholera. The Bone Marrow.-The marrow is generally of a dark slaty color; it is often almost black. The small vessels are filled with endo- globular pigmented parasites, while numerous macrophages containing pigment and red blood-corpuscles may be found about the periphery of the lumina.of the vessels. At times, between the corpuscles, Bignami1 found numerous ovoid or round bodies which, from their size and stain- ing propensities, he believed to be free spores. Not only in the vessels, but also outside of these, the parasites are to be found in greater or less number. The macrophages are, however, especially numerous, even in the pulp. At times also free pigment clumps are apparently to be made out. The adrenal glands may be the seat of pronounced alterations. There are irregular areas of vascular dilatation, parasites being numer- ous in the distended vessels. Macrophages with varying contents may be present in considerable numbers. The endothelial cells of the ves- sels may be phagocytic, and malarial pigment and infected corpuscles may even be enclosed by true adrenal cells. In the other organs there is little that is characteristic. (2) Changes following Repeated or Chronic Infections.- Chronic Malarial Cachexia. While the above mentioned changes are found in the acutely fatal cases of malaria, interesting pathological changes may occur in various organs as the result of long continued or frequently repeated attacks. The most important of these changes occur in the spleen, the liver, the bone marrow, and the circulating blood. The Spleen.-The spleen is always considerably enlarged ; it may be enormous, reaching beyond the umbilicus and as low as the pubes. It is firm and hard ; the border is sharp. The capsule is usually much thickened, and white fibrous cartilaginoid plaques occur upon the surface. On section it has often a somewhat slaty color, while the trabecuhe are very prominent. The minute anatomy and development of the changes in the viscera, following repeated malarial attacks, has been followed with particular care by Bignami,2 upon whose valuable work we shall largely trespass in the following description. The acute splenic tumor is caused chiefly by the aggregation in the pulp of the spleen of an enormous number of red corpuscles which have become either shrunken and brassy colored or decolorized, and are found included in the colorless elements of the spleen as brassy colored fragments or hyaline masses ; by the continuous aggregation of colorless elements containing pigment, red corpuscles, or parasites, which collect from all parts of the body, and many of which are necrotic ; and, thirdly, by great numbers of red corpuscles contain- ing parasites, some of which apparently pass through the vessel walls 1 Atti d. R. Acc. Med. di Roma, Anno xvi. v., 1890. ' Bull. d. R. Acc. Med. di Roma, 1893, Anno xix. f. 4, p. 186. 90 MALARIA. by diapedesis and seek the columns of the pulp, where they are for the most part enclosed by the epithelioid elements. While, as a result of this proceeding, a considerable number of the proper elements of the spleen become necrotic, others, as well in the pulp as in the follicles, undergo karyokinetic division, while all this is followed by a marked hypersemia and acute tumor of the splenic pulp. Thus the spleen is converted into a place for the deposit of cadavers, while at the same time, during the same infection, processes of regeneration have begun to appear. When the actual infection is at an end and the acute hyperaemia of the spleen has ceased, the tissues in the neighborhood of these collec- tions of necrotic elements, or those surrounding the necrotic areas of the splenic pulp, show certain changes which, on the one hand, tend to pro- duce permanent alterations, and on the other to lead to a partial repara- tion of the part. In those parts where a considerable portion of the splenic tissue becomes necrotic or disappears, being carried away by the lymphatics, the splenic vessels become considerably dilated, forming a network of venous lacunae which are separated by thin layers of pul]). This results in a tissue simulating that of an angioma. In those cases where a more marked destruction of the splenic tissue has occurred, and where every trace of the pulp is gone, parts become represented by extensive areas of tissue which consist of wide cavernous sinuses, the septa of which are composed of a very delicate connective tissue, rich in giant cells, similar to that of the bone marrow. Some of the follicles be- come necrotic and fibrous. While this occurs a process of regeneration yet more extensive takes place, starting for the most part from the fol- licles, but also sometimes from the splenic pulp. The follicles become hyperplastic, reaching sometimes three or four times their normal size. This new form of lymphoid tissue, starting from the follicles, may be sometimes seen to surround necrotic areas of splenic tissue which be- come smaller and smaller and finally disappear. In the neighborhood of these hyperplastic follicles occurs a hyperplasia of the true elements of the pulp, while the reticulum becomes thickened so as to give rise, in preparations, to very beautiful and clear figures, such as are not to be seen in the normal spleen. The pigment and probably the greater part of the necrotic elements are carried on toward and collected about the periphery of the follicles, so that the diffuse melanosis of the pulp is followed by a perifollicular melanosis. The pigment then passes on into the lymphatic vessels of the sheaths of the arteries and of the con- nective tissue of the septa. This results, on the one hand, in thickening of the vascular sheaths and of the septa, and, on the other hand, in the appearance of single or multiple lymphatic cysts, giving sometimes the picture of a lymphangioma and resulting in chronic lymph stasis. When we consider that after each new infection fresh processes simi- lar to these must occur, it is easy to understand the gradual development of the enormous splenic tumors, in which, sometimes, it is difficult, even histologically, to recognize the original structure of the organ. The Liver.-The changes occurring in the liver in chronic malaria may in the same manner be traced from those occurring in the acute infection. In the acute infection an enormous number of phagocytes, pigmentiferous or globuliferous, coming in great part from the spleen, PATHOLOGICAL JTOMY. 91 invades the capillary network of the liver, while the parasites are gen- erally scanty. The circulation is slowed, the capillary network becomes dilated, while a certain amount of pigment is taken up by the endothe- lial cells of the vessels, and later by Kupffer's cells. The pigmented endothelium becomes swollen and in part necrotic. These vascular changes are followed by new areas of blood stasis. At the same time, as has been noted, many of the liver cells suffer alterations, either undergoing an acute atrophy from pressure or a coagulative necrosis. These areas are sometimes quite extensive. In other instances many cells are found to be filled with blocks of yellowish iron-containing pig- ment, resulting from the early death of many red corpuscles. At the same time a certain number of liver cells, Kupffer's cells, and endothe- lial cells multiply by karyokinesis. The result of all this is the acute hepatic tumor and the increase in functional activity-polycholia. But a small part of the great number of pigmented elements which enter the liver escape, passing through the branches of the suprahepatic veins. The greater part is taken up by endothelial and perivascular cells, so that the melanaemia is followed by a melanosis of the vessels. The pigment then passes forward out of the capillary network into the perivascular lymph channels, where it is collected in large blocks en- closed in white cells. These carry the pigment following the lymph channels to the periphery of the lobules, and perilobular melanosis follows thus the interlobular melanosis. This process then extends, and the masses of pigment are to be found three or four months after the end of the infection in large blocks, for the most part endocellular, in the perivascular lymphatic tissue of Glisson's capsule. While this migration of pigment is going on in the lobule there occur, on the one hand, permanent alterations, and on the other hand regenerative processes. Where the dilatation of the lymph and blood- vessels and the degeneration and pigmentation of the vascular elements is most marked and extensive, no regeneration may follow the atrophy and necrosis of the endothelial and liver cells. The dilatation of the vessels increases and becomes permanent. The greater part of the re- maining liver elements disappears; only a few remain in an atrophic condition, the tissue showing an angioma-like appearance consisting of ectatic vascular network, about which may be recognized a stroma consisting of Kupffer's cells. Where the dilatation of the lymph vessels is most marked there may occur small lymphatic cysts. In all parts of the liver, when the normal blood current has been restored after the disappearance of the pigment and the necrotic masses in general from the endothelial cells of the vessel walls, an active regen- eration of the tissue elements occurs about the atrophic or necrotic liver cells. The young hepatic cells become arranged with great regularity in lone- rows on both sides of the old elements. Thus, when the stroma remains intact, an interlobular regeneration may occur. These regene- rative processes are accompanied by the appearance of giant cells with budding nuclei, just such as are found in the embryonic liver. The regeneration never appears in parts of the liver that have not been entirely freed from the collections of pigment and parasites. The migration and collection of the pigment in the perilobular tissue is followed by a hyperplasia of this tissue, so that the surroundings of 92 MALARIA. the lobules are more distinct. These de- and regenerative changes result, then, in a marked increase in the size of some lobules and a diminution in size and an atrophy of others. As this process accompanies each acute infection, one can readily understand the chronic perilobular, mono- lobular hepatitis of malaria, which is characterized by the presence of zones of hyperplasia or of atrophy of the parenchyma, by chronic blood and lymph stasis, by the formation of areas of angiomatoid tissue, by lymphectases and lymphatic cysts. In this manner the large liver tumors which are so well known, with smooth surface and lobules of irregular size, have their origin. Bignami divides the processes in the liver into four stages : (1) The liver appears congested, while the lobules are not sharply distinguishable and show in severe cases a decreased melanosis. The macroscopical characters are about the same as those of the liver in acute malarial infections. Microscopically, at this period, a little after the ter- mination of the acute infection, it may be noted that the parasites have disappeared from the capillaries of the liver, the pigmented endovascular macrophages have in great part gone, and the pigment is entirely col- lected in the endothelium and in Kupffer's cells. Those parts of the hepatic lobules in which necrosis or degeneration has occurred undergo a marked atrophy ; the necrotic and degenerate elements are carried away in the phagocytes, while the vascular network becomes dilated. (2) In a more advanced stage on gross examination the lobules are distinct. The melanosis continues to be diffuse throughout the lobule, but is more marked at its periphery. The organ is still congested. The particular features of this stage are that, on the one hand, the hepatic lobule frees itself from the accumulation of pigment and the necrotic remains, which become collected toward the periphery of the lobule, while, on the other hand, an active process begins which tends toward a partial regeneration of the parenchyma. (3) In this stage the diffuse melanosis of the lobule, with the greater prevalence of pigment toward the periphery, is succeeded by an exclu- sively perilobular melanosis. The liver is enlarged, the consistency somewhat increased, the surface smooth. On section one may see that all the lobules are surrounded by a slate colored line, in the neighbor- hood of which the coloration of that part of the lobule is somewhat brown. In general, the slaty lines marking out each lobule form an exquisite network. The size of individual lobules varies greatly : some are two or three times the normal size, others are markedly diminished. Microscopically, it may be observed that the degenerative alterations of some lobules have led to the formation of false angiomata and of lacunae or cysts of lymphatic nature. Other lobules, by the process of regene- ration already described, have increased notably in volume. The pig- ment has become extravascular; its transport through the capillaries and perilobular lymphatics is brought about by white mono- and poly- morphonuclear cells. (4) In eases in which the acute infection has passed for several mouths (in one case three months only) the pigmentation is greatly diminished and scarcely visible to the naked eye. The liver is notably enlarged and congested. The surface is smooth. On section one may see the lobules distinctly marked, surrounded by a most delicate red- PATHOLOGICAL ANATOMY. 93 dish brown border; the consistency is somewhat increased. Micro- scopical examination shows that the melanosis has become exclusively perivascular. (5) Lastly, one arrives at the definite terminal form of the chronic malarial hepatic tumor. The macroscopical characters are the follow- ing : The liver is increased in size and in weight, sometimes enormously ; the surface is smooth, the capsule a little thickened. On section the appearance is finely granular, the lobules are distinct, a little prominent, and surrounded by a zone of slightly pinkish tissue. Microscopical ex- amination shows the disappearance of all malarial pigment. The altera- tions of the parenchyma are similar to those described in the last two stages. The lobules of varying size are surrounded by a hyperplastic perilobular connective tissue. The connective tissue of the larger septa is, on the other hand, of about normal volume. A notable dilatation of the capillaries, with stasis of the colorless corpuscles, persists. The hepatic cells are altered in form in the zones where the dilatation is most marked. There is considerable difference in individual cases in the extent of these various lesions. There are cases, for example, in which, despite the enormous increase in the weight of the organ, there may be no very marked dilatation of the capillaries, nor are false angiomata or lymphatic cysts to be found, while, on the other hand, the hyperplasia of the perilobular connective tissue and the increase in vol- ume of many lobules may be more marked : there may be an evident hyperplasia of the parenchyma (hepatic cells with many nuclei and nuclei rich in chromatic substance). In other cases, on the other hand, the cysts and false angiomata may be enormously developed, so as to constitute one of the chief factors in the enlargement of the liver. The Bone Marrow.-In individuals who have had numerous re- lapses of malarial fever the marrow of the long bones-for example, of the femur in the upper and lower fourths-is usually red and of a consistency greater than is generally seen in acute infections. The microscopical alterations are various; generally the signs of an active proliferation of the proper elements of the marrow are present. This leads to an increase in the haematopoietic activity. There are factors, however, such as the degenerative and destructive alterations which take place in the bone marrow during acute infections, which injure, to a varying extent and through a varying length of time, the haematopoi- etic functions of the marrow. In other cases, very rare indeed, the bone marrow presents the macroscopical and microscopical features which exist in acute pernicious anaemia, particularly the presence of a consid- erable number of megaloblasts. Lastly, there may be cases in which the new formation of the haematoblastic marrow is wanting or entirely insufficient. In these cases the post-malarial anaemia is of necessity progressive. The Blood.-Corresponding to the change in the bone marrow, Bignami and Dionisi1 distinguish four types of post-malarial anaemia: (1) Anaemiae in which the examination of the blood shows alterations similar to those observed in secondary anaemiae, from which they differ only in that the leucocytes are diminished in number. The greater part 1 Cent. f. Allg. Path. u. Path. Anat., 1894, V. No. 10, 422. 94 MALARIA. of these cases go on to recovery; a few, without any further change in the haematological condition, pursue a fatal course. (2) Ansemise in which the examination of the blood shows alterations similar to those seen in pernicious anaemia-presence of gigantoblasts (megaloblasts). These cases end fatally. (3) Anaemiae which are progressive, as a result of lack of compen- sation by the marrow for losses brought about by the infection. At autopsy the marrow of the long bones is found to be wholly yellow, while the marrow of the flat bones is also poor in nucleated red corpuscles. (4) Chronic anaemiae of the cachectic, which differ from the above- mentioned types by clinical and anatomical characters in that the special symptoms of malarial cachexia prevail, while one observes post-mortem a sort of sclerosis of the bone marrow. The marrow of the long bones is red and of an increased consistency ; the giant cells are very numer- ous, and many are necrotic ; the nucleated red blood-corpuscles are very rare, and the colorless polymorphonuclear corpuscles are present in small numbers. The Kidneys.-The kidneys in chronic malaria show usually no great changes. KiSner, however, describes two forms of kidneys met with in chronic paludism : (1) the congested form, and (2) the atrophic form. (1) The engorged kidneys are voluminous, increased in weight; the surface is smooth, the consistency firm, the color of a deep red. The congestion is especially marked in the pyramids. All the vessels are distended, and the congestion is sometimes so extreme that interstitial hemorrhages may result or hemorrhages into the interior of the tubules. The epithelium of the tubules is granular; there is often desquamation, and hyaline casts may be found. (2) The atrophic kidneys are small and irregular in surface. The capsule is adherent, the consistency increased. The kidneys show a maroon or mahogany color or a blotchy appearance. Small cysts are often to be found. The microscope shows alterations as well in the connective tissue as in the epithelium of the tubules. Amyloid degeneration occasionally follows chronic malaria. This has been noted in the kidneys by Laveran 1 in two instances, but in both of them the malarial cachexia was complicated with chronic broncho- pneumonia and bronchiectasis. Frerichs2 describes three cases, while Marchiafava and Bignami3 have carefully studied several instances. The clinical history of these cases showed that after a long period of febrile attacks (eestivo-autumnal or obstinate quartan) there followed the symptoms of nephritis and a rapid cachexia, in which the patients died in a few months. On autopsy the principal changes that were found were a grave aneemia, a marantic condition of the organs, a chronic nephritis, and a diffuse amyloid degeneration. The distribution of the amyloid substance in their cases was as follows : The degenera- tion was most prevalent in the kidneys, where not only the vessels of small and medium size and glomeruli were affected, but also, to a con- siderable extent, the walls of the renal tubules. The alteration of the 1 Traite des Figures palustres, p. 94. 2 Lehrbuch der Leberkrankheiien. 3 Riforma Medica, 1891, vol. i. p. 571. MALARIAL CIRRHOSIS. 95 interstitial tissue and the degenerations of the renal parenchyma are very grave. After the kidneys the amyloid degeneration is most severe in the intestines and the spleen. In the intestine the degeneration affects chiefly the vessels of the villi, but also the vessels of the submucosa, and to less extent those of the other intestinal coats. In the spleen the vas- cular network of the periphery of the follicles is particularly affected. Here one sees usually the deposition of great blocks of amyloid sub- stance, while in the trabeculae of the pulp the process is in its beginning or is entirely wanting. In the liver there is a less extensive and diffuse deposition of amyloid substance than in the kidneys. The degeneration affects islands of hepatic tissue which are irregularly disseminated, so that, for example, one may see an island of the size of a lobule or larger from which the hepatic tissue has entirely disappeared, the vascular net- work showing a most grave amyloid degeneration, while about this the hepatic tissue has a normal appearance. The first small zones of degeneration, according to Bignami, seek by preference the periphery of the hepatic lobules, from whence the process spreads. Malarial Cirrhosis.-The Relation of Chronic or Repeated Malarial Infections to Cirrhotic Processes. For many years certain authors have associated cirrhosis of the liver, certain chronic renal changes, and, in some instances, chronic inflamma- tion of the lung, endocardium, and central nervous system, with malarial fever. Indeed, in almost all works upon medicine malarial fever is in- cluded as one of the etiological factors in ordinary atrophic cirrhosis of the liver. This statement has been based almost entirely upon rough clinical observation, no one having definitely traced the development of the cirrhosis from the changes following acute or chronic malaria. Frerichs1 noted the rarity of cirrhosis in patients dying with chronic malaria, though in five instances this was the only etiological cause which he could discover. Laveran2 in his considerable experience has seen but two cases of atrophic cirrhosis following malarial fever. Welch has seen but one case of atrophic cirrhosis which appeared to follow malaria. Kelsch and Kiener give a longer description of hepatitis in malaria, distinguishing three forms of chronic malarial hepatitis and two groups of malarial cirrhoses : (1) Insular cirrhosis with nodular hepatitis and insular cirrhosis with diffuse parenchymatous hepatitis; (2) annular cirrhosis with nodular or diffuse parenchymatous hepatitis. The gen- eral appearance of the liver in these cases is that of ordinary atrophic cirrhosis. Bignami has recently discussed this subject in a very thorough man- ner. He concludes that there is little evidence to show that ordinary atrophic cirrhosis is a frequent follower of malarial fever. After describ- ing the development of the ordinary chronic hepatic tumor of malarial cachexia, he says: " It is easy to understand from this that it is not difficult to make a differential diagnosis between this form of chronic tumor-or of chronic hepatitis, as one might say-from the other forms 1 Loe. cit. 2 Traill, des Favres palustres, p. 90. 96 MALARIA. of cirrhosis. There are not facts or reasons sufficient to cause us to believe that ordinary cirrhosis can follow a chronic tumor. The struc- ture in the two cases is absolutely different. In the one we have an extensive new formation of connective tissue, multilobular in nature, retracting about the included lobules; in the other, a more scanty for- mation of perilobular connective tissue about a single lobule, not con- tracting, together with grave alterations of the lobules themselves, especially of their vascular and lymphatic system, not depending, as we have seen, upon the new formation of perilobular connective tissue, but due to lesions primarily local. Atrophic conditions of the liver exist in malaria, but are simple atrophies, and occur in patients who are exhausted, for example, by profuse diarrhoea, etc., or in cases which I have described as progressive post-malarial anaemia. They depend upon the complete want or almost complete absence of any process tending toward regeneration, resulting from grave and diffuse regressive alterations." Barker1 has recently ably discussed the relation of malarial infections to cirrhotic processes, and has emphasized the fact that many conditions exist in the organs in malarial fever which might well be the starting- point for extensive growth of connective tissue. Flexner,2 after the injection of blood serum from one animal into another, has seen the development of characteristic cirrhosis of the liver and of the kidneys in rabbits, following focal necroses not dissimilar to those found in the liver in acute malarial infections. In conclusion, then, it may be said that secondary sclerotic processes of greater or less degree in the liver, spleen, and bone marrow are not uncommon after repeated malarial infections. The question of the possibility of the development of a true atrophic cirrhosis of the liver, of malarial origin, is not settled; the development has never been actually traced and the condition, if it exist at all, is probably rare. The possibility of its occurrence cannot, however, be denied. Symptoms. Period of Incubation.-In the absence of definite knowledge as to how malaria is acquired, the ideas concerning the period of incuba- tion have varied very greatly. It has undoubtedly been observed that characteristic malarial fever may appear very shortly after exposure in a malarious district, many observers believing that this may occur with- in a shorter time than twenty-four hours. It is possible that the febrile attacks which occur sometimes immediately after exposure at night in damp, marshy, malarious districts may have some other cause than malarial infection. Thus, Plehn describes cases where, after exposure at night in very malarious districts in West Africa, there was an imme- diate paroxysm similar to a malarial attack, which, however, did not recur until the appearance, ten days later, of a true malarial fever, which doubtless dated its infection from the night of exposure. At the time of the first paroxysm the blood was negative, the parasite (aestivo- autumnal) not appearing until ten days later. The hypothesis of Plehn that the initial paroxysm was due to the absorption of some toxic sub- 1 Johns Hopkins Hospital Reports, vol. v. 2 The Medical News, Philad., Aug., 1894. SYMPTOMS. 97 stance produced, perhaps, by the parasite outside of the body, is ingeni- ous, but seems a little far-fetched. More commonly an interval of one or two weeks may be made out between the time of exposure and the time of the breaking out of the disease. Maillot1 considered the mean period of incubation to be from ten to twelve days, while Sorel2 esti- mated it at from seven to nine days. Hertz3 states that the period of incubation is commonly reckoned at from six to twenty days, but be- lieves that the disease may appear immediately after the reception of the injurious influence. A number of instances of prolonged incubation have been reported, many of which are open to doubt. Some of these, however, are hard to explain. Such, for instance, is the case of Blaxall,4 where, after spending five days in the harbor of Port Louis, two of the crew of a man-of-war were attacked, at the end of, respectively, twelve and four- teen days, with quotidian intermittent fever, while two others developed tertian fever at the end of, respectively, forty-eight and one hundred and eighty-four days after embarkation. It is probable, in view of our present knowledge, that many cases of prolonged incubation represent relapses of earlier attacks, the manifestations of which have been pres- ent and would have been evident on more careful examination. Of recent years, since the discoveries of the malarial parasite and the inoculation experiments of Gerhardt,5 Mariotti and Ciarrochi,6 Mar- chiafava and Celli,7 Gualdi and Antolisei,8 Angelini,9 Di Mattei,10 Calan- druccio,11 Bein,12 Baccelli,13 Sacharov,14 the subject has been considered in a much more intelligent manner. The period of incubation in these cases where the blood of one malarial patient was introduced intravenously or hypodermically into a healthy individual, have varied greatly. In in- dividual cases there was a variance in the period of incubation of from six to eighteen days, while the average duration was from eleven to twelve days. Recently, Bastianelli and Bignami15 have contributed four new cases to this list and have made a careful study of this subject. In their words, the period of incubation in these cases of artificial inocu- lation represents " the time necessary for the inoculated parasites to arrive, by multiplication, at the quantity necessary to determine the fever." . . . . " The period of incubation with a given variety of para- sites varies inversely to the quantity of material inoculated." . . . . " The mean and minimum period of incubation under equal conditions varies with the various groups of the fever: it is least with aestival fevers, a little longer with tertian fever, and yet a little longer with quartan fever." They believe that they are justified in concluding that " the period of incubation in experimental malarial infections is not a constant quantity, but varies in the same group of fevers and in differ- ent groups. In a given group of fevers it depends primarily upon the 1 TraitS des Figures, p. 263. 2 Arch, de Medecin milit., 1884, t. 3, p. 273. 3 Ziemssen's Cyclopaedia, vol. ii. p. 588. 4 Quoted from Mertz, loc. cit. 5 Zeitschr. f. klin. Med., 1884, 375. 6 Lo Sperimentale, 1884, s. iv. t. liv. 263. 7 Fortschritte d. Med., 1885, iii. Nos. 11 and 14. Rif. Med., 1889, Nos. 225, 264, 274. 9 Rif. Med., 1889, Nos. 226 and 227, pp. 1352, 1358. 10 Ibid., 1891, p. 544, and Arch, fur Hyg., 1895, 191. 71 Cf. Grassi and Feletti; Cent, fur Backt., 1891, ix. 403, 429, 461. 12 Charite Annalen, 1891, 181. 13 Deutsch, med. Woch., 1892, No. 32, 721. 14 Cent, fur Backt., 1894, xv. p. 158. la Bull. d. R. Acc. Med. di Routa, 1893-94, Anno xv., v. xx. 151. Vol. I.-7 98 MALARIA. quantity of material inoculated. In different groups of fevers it varies with the rapidity of the cycle of development of the parasites and with the special capacity for reproduction of the parasitic variety." They have constructed the following table from an analysis of all cases of experimental malarial infection which they could collect: Period of Incubation. Maximum (days). Minimum (days). Mean (days). Quartan fever ... 15 11 13 Tertian fever . . . 12 6 10 JEstivo-autumnal fever . . . ... 5 2 3 These researches, especially those of Bastianelli and Bignami proving that the incubation period in sestivo-autumnal fever may be as brief as two days, are of a great deal of interest. It is striking to see how well their conclusions agree with the deductions which have been drawn by other observers before the discovery of the malarial parasite. It is with the sestivo-autumnal variety of the parasite, that variety which is associated with the pernicious fevers, that the short periods of incuba- tion have been observed, while the older clinical observations of short periods of incubation relate usually to the same class of cases. We can- not, however, positively assume that these figures represent the period of incubation in infection as it ordinarily takes place, for we do not know how or in what form this occurs. The general results, however, of inoculations in tertian and quartan fevers agree quite closely with what might have been expected from clinical observation, while the demonstration that after small intra- venous inoculations in sestivo-autumnal fever the disease may appear in forty-eight hours makes it very easy for us to believe that, however the infection may occur, the true incubation period in some very malig- nant fevers may be extremely short. Plehn1 advances an ingenious hypothesis to account for certain early manifestations of fever. He asserts, as has been stated above, that he has noticed in several instances a well marked febrile reaction occurring within a few hours after exposure in a malarious locality and simulat- ing a single malarial paroxysm. The examination of the blood was negative. From nine to twelve days later, however, characteristic mala- rial fever developed, the parasites being readily found in the blood. He suggests that by exposure in extremely malarious districts the individual may absorb a sufficient quantity of a pyrogenic toxine to cause imme- diately a single paroxysm days before the true incubation period has been passed through ; there is, however, little which can be advanced as proof of such an hypothesis. Basing our conclusions, then, upon the comparison between clinical deductions and the accurate observation of inoculation experiments, we may say that it seems likely that the ordinary period of incubation in tertian fever is about ten or twelve days, in quartan fever a little longer, while in sestivo-autumnal fever the period may range from twenty-four hours or even less to ten days or two weeks, averaging probably a some- what shorter time than in the case of tertian or quartan fever. Types of Fever.-The malarial fevers may be divided into two 1 Virch. Archiv, 1892, cxxix. 285. SYMPTOMS. 99 main classes : (1) The regularly intermittent fevers, occurring through- out the malarial season; (2) the more irregular, often more or less con- tinued fevers, occurring in temperate climates, only at the height of the malarial season, the late summer and early fall. And under these two main classes one may separate three distinct types of fever, depending in turn upon infection with one of the three types of the malarial parasite which have been described previously. Thus, the first class, the regularly intermittent fevers, includes (a) ter- tian fever, with its combinations (double tertian fever), and (6) quartan fever, with its combinations (double and triple quartan fever). The second class of fevers, that including the more irregular varieties, de- pends upon infection with the third variety of parasite above described. Occurring, as it does, at the height of the malarial season (August, Sep- tember, October), it justly deserves the name (c) oestwo-autumnal fever applied to it by the Italian observers. Tertian fever is common in almost all malarial regions. Quartan fever is, however, rare in many districts where the other forms of infec- tion are frequent. In the United States quartan fever appears to be rare; in the last seven years, out of nearly a thousand cases observed at the Johns Hopkins Hospital, only nine cases of quartan fever have been seen. On the other hand, there are certain regions in which quar- tan fever is particularly common, as the neighborhood of Pavia in Italy and in certain parts of Sicily.1 These types of fever are the same wherever they exist. In tropical countries the severer types of sestivo-autumnal fevers are in excess. As one passes away from the equator only the milder tertian and quartan fevers are to be seen in the earlier part of the malarial season, while the sestivo-autumnal fevers appear in the later summer and early autumn. Lastly, in districts where malaria is very uncommon the milder forms, tertian and quartan fever, alone prevail. Tertian Fever.-(1) Single Infections-Tertian Intermittent Fever ; (2) Double Infections-Quotidian Intermittent Fever. (1) Single Infections-Tertian Intermittent Fever.-This type of fever depends upon infection with the tertian parasite, an organism which, as has been described, possesses the remarkable characteristic of existing in the blood of the infected individual in great groups, all the members of which are approximately at the same stage of development and pass 1 The interesting fact that districts closely adjoining one another and presenting the same general physical conditions may be each the foyer for a distinct type of malarial fever was noted by Trousseau some years before the discovery of the parasite. In dis- cussing the types of regularly intermittent fevers the great clinician says (Clinique medi- cale, vol. iii. p. 425, 2d. ed., 1865): "The types seem to depend upon the nature of the miasm, and especially upon the locality which it infects, rather than upon con- ditions relative to the individual who is affected. Tours and Saumur, both situated on the left bank of the Loire, appear to me to present the same climatic and telluric conditions, yet one observes at Tours only tertian fevers, while the several cases of quartan fever which I have met with there were individuals coming either from Saumur or Rochefort or from other regions where they had contracted it. One of the examples which has most impressed me in connection with the subject is the following: Fourteen soldiers imprisoned at Saumur came to Tours to testify before a court-martial. They had been scarcely ten days in the last town when nine of them were compelled to enter the hospital, affected with quartan fever, the germ of which they had evidently contracted at Saumur, since all the fevers which we observed with the inhabitants of Tours and the neighborhood were of the tertian type." 100 MALARIA. through their cycle of existence together, all the organisms composing the group undergoing segmentation within a period of several hours ; it requires, as has been said, approximately forty-eight hours to complete its cycle of development. In infections, then, with a single group of parasites segmentation occurs at intervals approximately forty-eight hours apart. As Golgi so clearly showed, the febrile paroxysm is always associated with the segmentation of a group of malarial para- sites, and, as one might expect, the chief characteristic of this type of fever consists in intermittent febrile paroxysms occurring every other day. The regularity with which these paroxysms recur is truly remarkable, the onset sometimes taking place at almost exactly the same hour day after day. More frequently there are slight differences, generally, how- ever, of not more than two hours, between the time at which succeeding paroxysms recur. Our observations of nearly a thousand cases would lead us to believe that slight anticipation in the hour of onset is more common than retardation. The Paroxysm.-The paroxysm is usually divided into three clas- sical stages: (a) the chill; (6) the fever; (c) the defervescence or sweat- ing stage. (a) The Chill.-This may begin without any premonitory symptoms. More commonly, however, for a period of from a few minutes to half an hour the patient complains of uneasy sensations, a slight headache, or perhaps a little giddiness or fatigue. Not infrequently the onset is preceded by yawning. If the temperature is carefully noted during this period, it will usually be found that a slight elevation has already begun to appear. Immediately after this the patient begins to complain of chilly sensations, usually up and down the back ; these increase, the patient begins to shiver, and soon a general shaking chill follows. The chill is often extremely violent: the teeth chatter; the whole body is thrown into so violent a tremor that the bed and often surrounding objects in the room are shaken. The skin is pale or often somewhat cyanotic and cool, though wholly disproportionately so in comparison to the intense feeling of cold complained of by the patient. It is often moist, while the erection of the hair follicles gives rise to the characteristic "goose flesh." The pupils are usually dilated. The patient complains often of headache, buzzing in the ears, vertigo, and sometimes of troubles of vision. The pulse is small and rapid and often of rather high tension. There may be nausea and vomiting. The duration of the chill varies materially in different cases ; it may last as long as an hour, though usually the period is considerably shorter -from ten minutes to half an hour. Not infrequently no actual shak- ing occurs, the patient complaining only of chilly sensations. Occa- sionally, though very rarely in this type of fever, the chill may be entirely absent. Thus out of 339 cases classified by Hewetson and the author at the Johns Hopkins Hospital, chills or chilly sensations were present in 95.5 per cent, of the cases. During the period of the chill the temperature of the patient rises rapidly, and at the end of the chilly sensations may have reached almost its height. Generally, almost the maximum point of temperature is reached within two hours after the onset of the paroxysm. (6) The Febrile Stage.-After a certain length of time the chilly sen- SYMPTOMS. 101 sations become less marked and are interrupted by flushes of heat, which be- come more frequent, and finally wholly replace the chill. Then begins the second or febrile stage of the paroxysm. The patient complains of an intense burning- heat; the skin is flushed, hot, and dry, the conjunctivae injected, the pulse becomes fuller, but remains rapid; it may be dicrotic. The patient com- plains bitterly of headache and often of vertigo and buzzing in the ears. The coverings for which but a short time ago he had begged are now thrown aside. Often there is in- tense thirst. The patient is frequently restless, throw- ing himself from one side of the bed to the other. In some instances there is active delirium. A case ob- served by the author jumped from the window of the ward during the febrile stage of a double tertian paroxysm, killing himself by the fall. In other instances the pa- tient is dull, drowsy, and typhoidal in appearance, complaining upon inquiry only of intense headache and aching pains in the back and the extremities. Not infrequently there is a slight cough. Sometimes there is vomiting or diar- rhoea. Bleeding- from the nose occasionally occurs. On physical examination the face is flushed, the con- junctivae are injected; the tongue is often dry and coated. There is often a dusky, yellowish-gray color Tertian intermittent fever. Fig. 1. 102 MALARIA. to the skin, while the lips and mucous membranes are pale. Herpes on the lips and nose is very common. Various cutaneous eruptions have been noted, usually erythematous in nature. In several instances the author has observed an extensive general urticaria. The respi- ration is not particularly accelerated, though the pulse is often rapid and sometimes dicrotic. The lungs are generally clear on auscul- tation and percussion, though, not infrequently, evidences of a general bronchitis-sonorous and sibillant rales-may be heard throughout the chest, more frequently in the back. The heart sounds are usually clear, though a soft systolic murmur may be heard over the body of the heart. The abdomen is generally natural in appearance. The area of hepatic dulness is often somewhat increased. There is frequently tenderness on pressure in the region of the spleen, while the area of the splenic dulness is almost invariably increased. In most cases the spleen is easily pal- pable. This has been the case in 73.4 per cent, of our cases in which notes were made. In fresh cases the border is rounded and soft; in older cases, where there have been numerous previous attacks, the bor- der is often sharp and firm, reaching sometimes a considerable distance below the costal margin. The splenic tumor is particularly striking in children. The most marked splenic enlargements occur, however, in the more irregular sestivo-autumnal fevers. Massuriany1 noted the presence of a soft souffle over the splenic area, which Bouchard has compared to the uterine bruit. During this period the temperature reaches its maximum point. Temperatures as high as 108° F. have been noted. The duration of the febrile period is usually four or five hours, though, not infrequently, considerably longer. (c) The Sweating Stage.-After the stage of fever has existed for four or five hours it is usually followed quite suddenly by the third or sweat- ing stage of the paroxysm. The patient begins to feel relief from the sensation of oppressive heat from which he has been suffering, and then, quite suddenly, breaks into a profuse sweat. The sweating is often excessive; the night-clothes and bedding may be soaked. In asso- ciation with this the temperature falls, usually quite rapidly. The pulse, which has been rapid, becomes slow and full, and the patient often passes into a refreshing sleep. The temperature falls, almost in- variably to a subnormal point. The duration of the sweating stage varies considerably. The defervescence is generally somewhat longer than the rise of temperature, though it may be very short and sudden ; it commonly lasts from two to four hours, though often somewhat longer. The average length of the entire paroxysm from the time the tem- perature passed 99° F. until it reached this point again averaged, in 173 cases observed by the author, about eleven hours. The paroxysms occur more frequently during the day than during the night, the onset being, perhaps, more commonly noted between midnight and noon, though it may occur at any hour of the day or night; indeed, paroxysms begin- ning in the afternoon are not at all uncommon. In children the paroxysm differs often from that observed in adults. Very commonly in young children both the first and third stages, the chill and the sweating, may be absent or abortive. The first stage is then generally represented by a slight restlessness. The face looks 1 St. Pet. med. Woch., 1884. SYMPTOMS. 103 pinched, the eyes are sunken ; the finger-tips and toes become cyanotic and cold, while the child may yawn and stretch itself. Nausea, vomit- ing and diarrhoea are particularly common. These may be the only manifestations of the first stage. Commonly, however, these symptoms are followed by grave nervous phenomena. The chill in malaria, as in other acute diseases, is not infrequently represented in the young child by general convulsions. These begin usually with a slight spasmodic twitching of the eyelids or of the extremities, the spasm soon becoming general. The febrile stage and the whole paroxysm are often shorter in the child than in the adult. The sweating stage may be wholly absent. In many instances, besides a slight coldness of the hands and blueness of the finger-tips, and a somewhat pinched expression of the face in the first stage, the first and third stage of the paroxysm may be entirely lacking. The Intermission.-In the period of intermission the patient often feels quite well, so much so that it is not uncommon for patients to pass through a number of paroxysms before consulting a physician, believing after each that the disease is at an end. The temperature after the sweating stage becomes almost invariably subnormal, and often remains so during the greater part of the next day. About forty-eight hours after the onset of the first paroxysm the fresh group of parasites proceeding from the segmentation of two days before having reached maturity and entered again upon segmentation, a fresh paroxysm begins. Often, as has been said, the time of onset of several successive paroxysms is almost exactly the same. More commonly, though, there are slight variations of an hour or two, anticipation or retardation. In these instances the parasite passes through its cycle of existence a little quicker or a little slower than in the typical forty-eight hours. Slightly anticipating paroxysms are very common, more so than retardation. The Blood. - The blood shows the presence of one group of the characteristic tertian parasites. These organisms arc to be followed through all the stages of their development. They are most striking and most readily observed several hours before the paroxysm, when they are large and contain most pigment. At the time of the par- oxysm and immediately before this the picture may not be so striking, as many of the parasites which, earlier in development, are to be found with great frequency in the general peripheral circulation, become accumulated in certain of the internal organs, where they remain during the period of segmentation. Segmenting parasites are usually to be found in the peripheral circulation, the first being seen several hours before the onset of the paroxysm ; at times they may be present in large numbers. Large swollen forms of the organism with very active pigment granules, or deformed and vacuolated forms, are also common during this period. Often the fragmentation of these bodies may be seen, and numerous small pigmented extracellular forms resulting from this fragmentation may be found. These swollen vacuolated and frag- mented forms appear to be more common where recovery is taking place, and there is every reason to believe that they represent full- grown parasites which, failing to undergo segmentation, have become degenerate and sterile. During and just after the paroxysm the pro- cess of phagocytosis may often be observed under the microscope, and 104 MALARIA. pigmented leucocytes are always present. The elements taken up are for the most part the free pigment clumps from segmenting forms, the segmenting form itself, fragmented extracellular bodies, and flagellate forms. (2) Double Infections.- Quotidian Intermittent Fever.-Single tertian infections are among the mildest forms of malarial fever which are observed in temperate climates ; more commonly the individual shows an infection with two groups of the tertian parasite. These groups reach maturity on alternate days. Segmentation, then, of a group of parasites occurs every day, and, as one might expect, daily paroxysms, quotidian intermittent fever, result. The paroxysms in these instances are similar in every way to those of single tertian infections. The manner of onset and duration are the same, while during the periods of intermission the temperature is likewise almost always subnormal. It is common, however, for the paroxysms on successive days to show slight constant differences in their hours of onset, one group of para- sites arriving at maturity at an hour slightly different from that of the other. These differences are usually not great, though they may be considerable, one paroxysm beginning in the morning, that upon the following day in the afternoon. Very commonly one set of organisms is more numerous than the other, causing thus a more severe paroxysm. The chart then shows alternate mild and severe attacks. These facts alone might lead us to recognize the dependence of this quotidian fever upon a double infection without the confirmation obtained by examina- tion of the blood. The blood shows the presence of two groups of the tertian parasite in different stages of development. Thus at the time of the paroxysm, Fig. 2. r- - Double tertian infection (quotidian fever). while one group is full grown and in the stage of segmentation, the other is represented by smaller, slightly pigmented, actively amoeboid bodies. The question of the origin of these double tertian infections is interesting and by no means wholly clear. Very commonly the first several paroxysms are tertian in nature, daily chills appearing only later on in the course. This may well be, and probably is due to the fact that at the time of the original infection there were two groups of SYMPTOMS. 105 parasites, one of which was so much smaller than the other as to take materially longer to reach a size sufficient to produce a paroxysm. On the other hand, some observers have suggested that the origin of double infections may be due to the lagging behind of certain parasites out of an originally single group, these retarded forms eventually forming a group of their own. If this be the case, however, it is remarkable that the retardation should be almost exactly twenty-four hours behind that of the original group. Indeed, the remarkable similarity in the hours of the paroxysms due to two different groups of the parasite is striking and not easily explained. Infections with multiple groups of parasites have been described. These result, naturally, in more irregular subcontinuous fever. This is, however, extremely rare. Only one doubtful case of this nature has been observed by the author. The examination of the blood in these instances shows organisms in all stages of development; there is great difficulty here in distinguishing separate groups. Quartan Fever.-(1) Single Infections.-Quartan Intermittent Fever; (2) Double Infections.-Double Quartan Intermittent Fever; (3) Triple Infections.- Quotidian (Triple Quartan) Intermittent Fever. (1) Single Infections.- Quartan Intermittent Fever.-This type of fever depends upon the presence in the blood of the quartan parasite, an organism which, just as in the case of the tertian parasite, possesses the remarkable characteristic of existing in the blood in great groups, all the members of which are, approximately, at the same stage of develop- ment. The cycle of development of the quartan parasite lasts approx- imately seventy-two hours, segmentation occurring every fourth day. The characteristics, then, of single quartan infections are quartan inter- mittent paroxysms, two days of complete intermission existing between. The paroxysm in quartan fever resembles in all its features that observed in tertian infection. The duration in the cases seen by the author averaged between ten and eleven hours. The same periods .of subnormal temperature, lasting often during the greater part of the two days of intermission, are observed. The regularity of the par- oxysms in quartan infection is the most remarkable characteristic of the disease. A tendency toward anticipation or retardation in the par- oxysms is less often noted than in tertian infection. The blood shows the presence of a quartan parasite. The develop- ment of the organism may be readily followed. It is most clearly demonstrated just before and during the paroxysm when the parasites are full grown. The tendency of the full grown and sporulating forms to accumulate in the internal organs-a tendency which has been noted in tertian fever, and exists, as will be stated later, to a greater extent in sestivo-autumnal fever-is not to be observed in the case of the quartan organism; all stages of development may be seen with equal frequency in the peripheral circulation. At the time when the parasite reaches maturity swollen, fragmented, and vacuolated forms may be seen as in tertian fever. They are, however, less frequent, as are also the flagellate bodies. (2) Double Infections.-Double Quartan Fever.-Often more than one group of quartan parasites may be present in the blood at the same time. When two groups are present segmentation usually occurs on two sue- 106 MALARIA cessive days, with a day of intermission following. Clin- ically, therefore, these double infections are characterized by chills upon two successive days, with a day of complete intermission following. The paroxysms in these instances are exactly similar to those observed in single infection. The examination of the blood, however, shows the presence of two groups of the quartan parasite. (3) Triple Infections.- Triple Quartan Fever.-Very commonly three groups of the quartan parasite may be pres- ent in the blood at the same time. These groups reach maturity on successive days, and cause, therefore, quo- tidian intermittent fever. The symptoms of quotidian fever depending upon a triple quar- tan infection differ often in no wise from those depending upon a double tertian infec- tion. Daily paroxysms, ex- actly similar in nature, occur in both instances. The same period of subnormal temper- ature may be noted, and the diagnosis, without the exam- ination of the blood, may be impossible. Examination of the blood in these instances shows, however, the presence of three groups of the quartan parasite, each in different stages of development. 2E S T I V O - A U T U M N A L Fever.-This type of fever differs materially from the regularly intermittent fevers of the early part of the malarial season. It depends upon the presence in the blood of the smaller organism first de- scribed by Marchiafava and Celli, the sestivo-autumnal Quartan intermittent fever. Fig. 3. SYMPTOMS. 107 parasite. This parasite, as has been previously stated, possesses to a much less marked degree the characteristic of existing in large sharply defined groups, while, as has also been noted, the length of the cycle of existence appears to vary considerably. At the beginning of many infections an arrangement in groups may, however, be made out, and this arrangement may exist for a certain length of time. Usually, however, before the process has lasted very long organisms in different stages of development may be found at any time during the fever. In some instances groups of parasites with a cycle lasting about twenty- four hours have apparently been made out, while in others fairly distinct groups appear to pass through a cycle lasting considerably longer, as long as forty-eight hours or even more. Clinically, sestivo-autumnal fever appears in very varied forms. Not infrequently it may be seen in the form of quotidian intermittent fever. Here the paroxysms may resemble very closely those of tertian or quartan fever, and in some instances, without the examination of the blood, the distinction from double tertian or triple quartan infections cannot be made. In these instances the process begins with a sharp chill and ends with a well marked sweating stage, the duration of the paroxysm being perhaps exactly similar to that in the regularly inter- mittent fevers. More commonly, however, the paroxysms are longer and more drawn out, lasting perhaps as long as twenty hours. Here the first stage often differs greatly from that in tertian or quartan fever. While in the regularly intermittent fevers the onset is rapid and usually associated with a chill, in these instances the rise may be much more gradual, while the chill is not infrequently altogether lacking. Often a slight transient chill may be observed some time after the beginning of the rise in temperature. The chill in aestivo-autumnal fever can by no means be called the initial symptom in the paroxysm ; the fever has often become well marked before the onset of the rigor. Usually, after a certain number of paroxysms, a distinct irregularity in the fever becomes evident. Either from the lengthening out of one of the paroxysms or from the anticipation of the following paroxysm the intermission between the two becomes, perhaps, completely obliterated or indicated only by a slight drop in temperature, until finally there results an irregular con- tinued fever in which all trace of the paroxysm has disappeared. Not infrequently the early paroxysms recur at greater intervals one from the other. These intervals are frequently forty-eight hours, more or less ("^stivo-autumned tertian fever; malignant tertian fever"- Marchiafava and Bignami). In these instances the paroxysms are usu- ally particularly long, lasting sometimes as much as thirty-six hours. The very gradual rise in temperature, which is often unaccompanied by a chill, and the slow fall, are in striking contrast to the chart of an ordinary tertian fever. Marchiafava and Bignami, who, as has been before stated, believe that they can distinguish two separate types of the sestivo-autumnal parasite, the quotidian and the tertian, have de- scribed minutely the fever curve in these cases with longer intervals. This class of cases they term " malignant tertian fever," in contradis- tinction to the milder regularly intermittent tertian fever. They de- scribe what they believe to be a characteristic fever curve, the more or less sudden onset of the symptoms, a pseudo-crisis, a precritical elevation 108 MALARIA. of temperature, which often reaches a point higher than has been pre- viously attained, and, finally, the actual crisis. Charts similar to this 2Estivo-autumnal fever (quotidian paroxysms). Fig. 4. have been observed by the author and reproduced in a recent publica- tion (see Fig. 5), though he has not seen a sufficient number of in- stances to justify him in believing that such a curve is characteristic of a particular, separate type of parasite. It is certainly true, however, SYMPTOMS. 109 that irregular oscillations in the curve of the fever produced by these parasites are very common. The periods of intermission between par- jEstivo-autumnal fever (paroxysms at intervals of forty-eight hours). $ p CH oxysms show, usually, a subnormal temperature. The periods of apy- rexia are, however, very brief, as one may readily conceive when he considers the length of the paroxysm, lasting, as it often does, thirty-six hours or over. 110 MALARIA. In those cases in which the paroxysms occur at intervals of approx- imately forty-eight hours, one from another, the irreg- ularity in the hour of onset of the paroxysms is partic- ularly striking. In some cases there is marked re- tardation, intervals of con- siderably more than forty- eight hours occurring be- tween the beginning of one paroxysm and that of its successor. More frequent- ly, however, there is antici- pation, the paroxysms re- curring at intervals of less than forty-eight hours. Now, if, as already stated, the individual paroxysm should last thirty-six hours or more, it may be readily seen how short the period of intermission in these cases would be. Often, then, there is an almost continu- ous high temperature, with occasional remissions or in- termissions lasting, per- haps, less than an hour- " malarial remittent fever." In many instances the new paroxysm begins be- fore the previous one has finished, owing either to an excessive prolongation of the first paroxysm or to an anticipation of the succeed- ing one. In these cases the result is, of course, a con- tinuous fever. Usually, the continuous fevers resulting from sestivo-autumnal in- fections, though the tem- perature may never reach the normal point, yet show indications of the parox- ysms and sometimes occa- sional abortive chills. In some instances, however, all evidence of paroxysms may be absent, the chart closely simulating that of typhoid fever. Such cases are probably often due to infections JEstivo-autumnal fever (showing the development of remittent and continued fevers). Fig. 6. SYMPTOMS. 111 with more than one group of parasites. It is probably true that the long duration of some of the paroxysms is accounted for by the fact that the segmentation of a given group of parasites occurs through an appreciably greater length of time than in the regularly intermittent fevers. The result of all this is that the chart of sestivo-autumnal fever presents very commonly somewhat the following picture : At the onset there are several intermittent paroxysms occurring at intervals of from twenty-four to forty-eight hours or a little more. After a few of these attacks the fever becomes irregular or continued. This may occur, as has been said, in several ways : (1) Through modifications of the curve in the individual paroxysm; (2) by modification in succession of the paroxysms. (1) The important modifications of the curve are the following: (a) The lack of a sharp initial elevation, so that the curve rises in a slow and continuous manner; (6) the occurrence of a pseudo-crisis, so that the attack tends to lose its individuality; (c) the prolongation of the paroxysm, which is usually associated with an exaggeration of the thermic oscillations during the fastigium. (2) The modifications in the succession of the paroxysms may be (a) the anticipation of the paroxysms; (6) the retardation of the paroxysms; (c) the prolongation of the paroxysms, by which apyrexia is made incomplete; (d) the occurrence of slight oscillations in temperature during the period which ought to be one of apyrexia; (e) the redupli- cation of the attack. Very often when the case first comes under observation it is already one of "remittent" or continued fever. The chills are frequently ab- sent ; the patient complains bitterly of headache and general pain in his back and extremities. He is usually dull, drowsy, and apathetic, though there may be marked delirium. The face is flushed, the con- junctivse are injected, the tongue dry and coated; there is sordes upon the lips and teeth ; the patient remains continuously in a condition similar to that described in the febrile stage of the ordinary paroxysm. In these instances it is often absolutely impossible, without examination of the blood, to distinguish the case from one of typhoid fever. The writer has repeatedly seen patients with sestivo-autumnal malaria placed under treatment as cases of typhoid fever, the attention being first drawn to the true condition of things by a sudden fall of the tem- perature to normal, or by the discovery of the small amoeboid hyaline parasites within the red corpuscles. Grave cerebral or abdominal symp- toms develop, often early in the course of these subcontinuous fevers, which frequently tend to become pernicious. Careful observations may show that these symptoms are paroxysmal. Delirium, drowsiness, stupor, coma, grave cerebral symptoms, local spasms, general convul- sive seizures may occur, or perhaps profuse vomiting or a choleriform diarrhoea with collapse. In fact, any of the symptoms which will be discussed under the Pernicious Fevers may suddenly develop in the course of subcontinuous sestivo-autumnal infection. These instances of more or less continued fever are occasionally referred to as " malarial remittent fever." They have been admirably described by Baccelli, who recognized their true malarial nature, under 112 MALARIA. Jistivo-autumnal fever; continued fever; "subcontinua typhoidea." (The fever after the 31st was due to an acute parotitis.) Fig. 7. SYMPTOMS. 113 the name of " subcontinua typhoidea." As has been previously stated, the tendency of the regularly intermittent fevers, when left to them- selves, is toward spontaneous recovery after a certain number of par- oxysms, and, while relapses are common and productive, perhaps, of grave secondary disturbances-anaemia, nephritis, etc.-the tendency to become pernicious is rarely observed. This is not true of aestivo- autumnal infections as a class. In many instances, to be sure, when placed under hygienic conditions the same tendency toward sponta- neous recovery, usually with relapses, is to be observed. Often, how- ever, an untreated infection becomes steadily more aggravated, until, finally, so-called " pernicious " symptoms appear and a fatal result ensues. In other instances an sestivo-autumnal infection may be associated with but slight irregular rises in temperature; there may be no sharp paroxysms, the patient complaining only of languor, anorexia, head- ache, pains in the back and limbs. Such instances may easily lead to errors in diagnosis. There is usually, if the case has existed for any length of time, a certain degree of anaemia, with the characteristic sallow hue to the skin, while the spleen is almost always enlarged. Such cases probably often pass into the condition which will be later described as " chronic malarial cachexia." Pernicious Malarial Fevers.-These very malignant forms of malarial fever have, in this and other languages, generally acquired the name " the pernicious fevers." It is quite true that the term " malig- nant fevers " used by the translators of Marchiafava and Bignami's1 work is, in the abstract, better, but the word " pernicious " is so firmly implanted in the general usage that its eradication appears to the writer injudicious. Pernicious fever depends, almost invariably, upon infection with the eestivo-autumnal parasite. In temperate climates these fevers are rare, but in the tropics they are extremely common. The pernicious nature of an attack depends, generally, as has been shown in the section on Pathological Anatomy (page 83), upon several causes : (1) The great numbers of parasites present and their capacity for rapid multiplication ; (2) the special involvement of certain vital organs by the parasites, which, as has been pointed out, show a remarkable tendency toward accumulation in certain definite organs, varying in different cases ; (3) possibly upon the greater or less virulence of the parasite. This latter statement is based upon the assumption that the malarial parasites pro- duce a specific toxic substance. Certain authors thus believe that, in the case of infection with a very malignant parasite, pernicious symp- toms may result, while but a small number of parasites are present, particularly if the chief seat of development of the parasite be localized in a particularly vital spot. This is, however, doubtful. While it is probable that a specific toxic substance may be produced by the para- site, and while there is very good reason to believe that there is a dif- ference between the malignity of the parasites in different instances, yet, in a general way, the severity of the symptoms, as demonstrated long ago by Golgi, appears to depend largely upon the number of parasites present. And in a general way it may be definitely stated that per- 1 The Parasites of Malarial Fevers, New Svdenham Society, 1894. Vol. I.-8 114 MALARIA. nicious fever never occurs without the presence of a considerable number of parasites, though in some of these instances very few organisms may be found in the peripheral circulation. Bastianelli and Bignami in a recent article1 well say: "The con- ditions through which a malarial infection becomes pernicious are : (1) That the infection be produced by one of the varieties of the sestivo- autumnal parasite. On this condition all today are agreed, and we shall not insist further.2 (2) The second condition relates to the abun- dance of the parasites, and it may be stated as follows : In pernicious fevers, if one takes into consideration not only the examination of the blood from the linger, but also the condition in the vessels of the various organs (Marchiafava, Celli, Bignami), it is a striking point that, how- ever the distribution of the parasites may vary in individual cases, their total number is always considerable. As regards the distribution, one may make the following distinctions : There exist (1) cases in which the number of parasites is most abundant, yes enormous, while all the organs are uniformly invaded. These are the most common forms of pernicious fever, and are usually accompanied by coma. There are some eases in this category in which the number of parasites in the blood of the finger, of the spleen, of the bone marrow, etc. is enormous, while the number in the brain is scanty ; clinically, the absence of cerebral phenomena is noted. (2) Cases in which the number of parasites is absolutely and relatively scanty in the bone marrow, in the spleen, in the liver, while there may be relatively few in the blood of the finger, yet other organs are crowded with parasites. Among these the following localizations are to be made out: (ci) The brain and the meninges are filled with parasites either in sporulation or in all their stages of development; in such cases it is difficult to find not only sporulating forms, but even young parasites in the spleen. Clinically, there are cerebral phenomena. (6) The stomach and intestine are chiefly invaded ; in these organs the mature forms of the parasite are usually found ; these are the cases of pernicious fever which present, clinically, .... intestinal phenomena." The pernicious symptoms may come on quite early in the course of the infection, though usually several paroxysms have existed before their appearance. In very malarious districts, however, almost the first paroxysm observed may be pernicious in nature. The Comatose Type.-The commonest form of pernicious malaria is that accompanied by coma. Here, in the earlier part of the paroxysm, the patient may be slightly delirious, but he soon becomes drowsy and somnolent, passing finally into a condition of profound coma. Not in- frequently, in grave malarious districts, the patient comes for the first time to the observation of the physician while in this condition. He is profoundly unconscious; the respiration is often stertorous, and occa- sionally of the Cheyne-Stokes type. The pupils may be contracted or dilated, sometimes perhaps unequal. There is often-a not unimportant point-a slight jaundice. Not infrequently there is hiccough ; the pulse 1 Bull. d. R. Acc. Med. di Roma, 1893-94, Anno xv., v. xx. 186. 2 There are exceptions, though rare, to this rule. Dr. Walter Reed of the Army Medical Museum in Washington has recently communicated to me his observation of specimens from a case of characteristic comatose pernicious fever due to a double tertian infection. This case has since been reported by Dr. Wm. B. French of Washington (N. Y. Med. Journal, 1895, vol. Ixiii. p. 674). SYMPTOMS. 115 may be full and slow and of high tension, though toward the end it is often rapid, irregular, and feeble. Local spasms of certain muscles may occur. Thus, in one of the author's cases there was a well marked spasm of the lower facial muscles on one side, which disappeared with the paroxysm. Recovery may result after the gravest symptoms, but without treatment the paroxysm is usually followed rapidly by a second, which generally proves fatal. Other Cerebral Manifestations.-In other instances most decided cerebral symptoms of a different nature may occur. Delirium which may be maniacal may be observed. Active delusions and halluci- nations are not uncommon, while in some instances tetanic convulsions have been noted. In a number of instances hemiplegia has been associated with the paroxysm, disappearing after the attack. At times distinct symptoms of bulbar paralysis may occur. In one of these cases carefully studied by Marchiafava1 the special localization of the parasites in certain foci in the medulla was confirmed post- mortem. Hemorrhagic Type.-In some instances of pernicious fever grave hemorrhagic symptoms may occur-epistaxis, haemoptysis, extensive cutaneous hemorrhages. Several of these cases are described by Mar- chiafava and Bignami.2 Algid Type.-This is sometimes extremely insidious and fatal. After several paroxysms which are in no way. remarkable the patient very suddenly passes into a condition of extreme collapse. This does not occur at the beginning of the paroxysm, but at the time when the stage of fever should exist. The temperature may be but slightly elevated ; indeed, in some instances it is subnormal. The condition is not unlike that in Asiatic cholera. The mind is clear, there is little suffering, but extreme collapse. The eyes are sunken; the features drawn and pinched ; the face expressionless; the tongue dry; the skin moist and covered with a cold sweat. The patient may be so quiet and uncom- plaining that it may be, as Laveran states, only through an accidental examination of the pulse that the true state of affairs may be discovered. The pidse is very rapid and feeble and thready, almost impalpable, be- coming imperceptible at the wrist before death. Physical examination of the thorax is negative excepting for the feeble action of the heart. The second sound at the base may be quite inaudible. The abdomen is usually retracted ; there is often tenderness on pressure in the region of the spleen, which is palpable. Sudoriferous Type.-A sudoriferous type of paroxysm has been described, in which, during the last stage, the sweating becomes exces- sive and the patient passes into a condition of collapse with a thready pulse and cold extremities. Without vigorous interference the case may end fatally. Bilious Type.-A type of paroxysm has been described by cer- tain observers, the chief symptom of which is the vomiting of large quantities of bile-stained fluid ; this is usually associated with stools of a similar nature. Gastralgic and Cardialgic Types.-Severe gastralgic parox- ysms associated with profuse vomiting, and often with hsematemesis, 1 Lav. d. III. Cong. d. soc. It. d. Med. Int., Roma, 1890, 142. 2 Loc. cit. 116 MALARIA. may occur without the existence of striking intestinal symptoms. An attack of this nature is well described by Laveran.1 Choleriform Type.-In certain instances in which the chief localization of the parasite is in the stomach and intestines the patients present a clinical picture strongly resembling that of Asiatic cholera. These cases have been particularly studied by Marchiafava.2 The paroxysm usually begins with profuse vomiting and diarrhoea ; the dis- charges may resemble those of cholera. The skin is cold, moist, and clammy. There is cyanosis of the lips and extremities; the pulse is rapid and thread-like. There may be cramps in the extremities. The condition closely resembles the algid stage of Asiatic cholera. If the paroxysm be not fatal, profuse sweating may follow, with an intermis- sion in the symptoms. Anatomically, the mucous membrane of the stomach and intestines is found to be filled with malarial parasites. These may produce actual thrombosis of the vessels of the mucous membrane with superficial necroses and ulceration. Pneumonic or Dyspnceic Type.-Baccelli3 and others have de- scribed a type of paroxysm the symptoms of which suggest strongly a pneumonia. This admirable observer, however, as long ago as 1866 recognized this condition to be distinct from a true complicating pneu- monia. There is intense thoracic pain, great dyspnoea, and a painful cough. There may be moderate dulness over the affected lung with coarse, sonorous, and sibilant and finer moist rales. Laveran 4 has seen a fairly abundant haemoptysis following an acute dyspnoeic paroxysm. In other instances, despite the extreme dyspnoea, physical examination may be quite negative. The sputum is mixed with dark fluid and clotted blood. The condition is certainly not a pneumonia; it is more probably an active congestion of the pulmonary vessels. In the absence of autopsy records in cases of this nature one can but suspect that they represent a special localization of the parasite in the pulmonary capil- laries. H^emoglobinuric Type-" Malarial ha^aturia."-Hemoglobi- nuria is a not uncommon symptom in the graver fevers in cer- tain malarious districts. In temperate climates it is rarely seen. The ultimate cause of its production is not yet settled. A con- tinual destruction of the red blood-corpuscles is going on throughout every malarial infection. This occurs in various ways : (1) The para- sites, developing within the corpuscles, form the black pigment, melanin, at the expense of the corpuscles in which they grow, the corpuscles becoming gradually decolorized and destroyed. (2) In many instances the red blood-corpuscles containing the parasite undergo a pre- mature necrosis, becoming brassy colored and shrunken. (3) Sometimes the decolorization of the corpuscles containing the parasite occurs quite suddenly, the corpuscles bursting, as it were, and setting free their haemo- globin in the blood current. Thus, during an ordinary malarial attack there is always a certain amount of haemoglobin set free in the serum, but, as this amount does not pass beyond the limit of the quantity which can be disposed of by the liver, it does not appear in the urine. 1 Traits des Figures palustres, Obs. xxxviii. 2 Cent. f. Allg. Path. u. Path. Anat., 1894, V. No. 10, 418. 3 Studien uber Malaria, Berlin, 1895. 4 Traite des Futures palustres. SYMPTOMS. 117 It is doubtless, in part, to this constant destruction of the red corpuscles, with the liberation of their haemoglobin, that the polycholia and slight jaundice so commonly obseryed in malaria are due. Ponfick estimates that up to one sixth the total number of the red blood-corpuscles may be destroyed and disposed of in the economy without the haemoglobin appearing, as such, in the urine. If this destruction of the red blood- corpuscles becomes unusually great, and the quantity of haemoglobin separated from the disco-plasma of the red blood-corpuscles exceeds the amount which can be taken care of by the liver, haemoglobinuria will result. It is not, however, oidy the infected corpuscles which lose their haemoglobin in these instances; great numbers of their uninfected fel- lows are equally affected, just as in the ordinary paroxysmal haemoglo- binuria. Some substance excessively toxic to the disco-plasma of the red blood-corpuscles must be present in the circulation, or some change has taken place in the blood serum by which it has lost its isotonicity, bnt what these changes are and to what they are due are by no means clear. There is much which might lead us to believe with Baccelli that some toxic substance, produced perhaps by the parasite itself, may be at the bottom of these changes. Why, however, haemoglobinuria should be so common in certain regions-as, for instance, Greece and West Africa-and so infrequent in many other more malarious dis- tricts is quite inexplicable in the present state of our knowledge. Clinically, these cases are among the severest forms of malarial fever. The same condition is known in Western Africa as "black water fever." By many observers, particularly by the French, the term bilious hcemoglobinuric fever has been used. Not infrequently the term " hcematuric" is used, and, indeed, as the interesting researches of Joseph Jones show, actual haematuria often occurs. The haemoglo- binuric attack is rarely the initial symptom of the infection. Usually the patient has had repeated attacks of malaria, the haemoglobinuria appearing suddenly with a relapse, or, if it be the first infection, the haemoglobinuric attack is preceded by several intermittent paroxysms. In cases where either in a relapse or in a primary infection the haemo- globinuria appears with the first actual paroxysm, there are often pro- dromal symptoms lasting for from several hours to sometimes several days. It is probable that these are associated with moderate fever and often represent abortive paroxysms. There are loss of appetite, head- ache, indefinite pains in the extremities and back. It may be remem- bered that in many paroxysms of the more ordinary types of aestivo- autumnal fever the gradual onset of the paroxysm without chill is fre- quent : this is not true in the case of the haemoglobin uric paroxysm, which begins almost invariably with a severe shaking chill. This is followed by intense pain in the back, head, and extremities, and by pro- fuse vomiting; the vomitus consists of a deeply bile-stained fluid. The face is flushed; the conjunctivae are injected; the pulse is rapid; the patient is usually in a condition of great anxiety and apprehension. There is a well marked icteric hue to the skin. There is usually profuse diarrhoea. The first urine that is passed, in the early stage of the paroxysm, has a somewhat rosy reddish hue. This, however, rapidly becomes deeper, and is finally an intense brownish black color with something of a greenish tinge, and a greenish yellow foam on shaking. The vomitus 118 MALARIA. becomes of a deeper color, at first yellow, then green, finally sometimes almost black. There may be diarrhoea, the dejecta being green or brown in color, while in other instances there is constipation. During the stage of fever the patient generally becomes jaundiced. There is usually little delirium, the patient being quite conscious and in a con- dition of great anxiety and agitation. He often complains of severe epigastric pain, which is possibly associated with repeated vomiting; in other instances the pains in the loins may be extremely severe, bearing, possibly, as Kelsch and Kiener1 suggest, some relation to the intense renal congestion. The fever is often high, the temperature touching, in some instances, 41° C. (106° F.) or even higher. The urine at the height of the process is of a deep brownish black color, and deposits on standing an abundance of reddish brown sediment. The amount varies considerably in different instances, in some being extremely scanty, in others amounting to as much as 1000 or 1500 c.c. The specific gravity varies inversely to the amount of urine passed. As the amount is generally somewhat reduced, the specific gravity averages above normal. The reaction varies ; it is generally feebly acid. There is usually an abundance of albumin. In some instances a test for the biliary coloring matters may be obtained. Kelsch and Kiener assert that this is the rule at the height of the process, while Plehn2 in eight instances was unable to obtain this test. The sediment consists of mucus, bladder epithelium, numerous granules and masses of pigment, renal epithelial cells, and, almost invariably, hyaline and granular casts with epithelial cells adherent. In many instances blood-corpuscles may also be found, actual hemorrhages taking place into the kidney. Often, however, besides the profuse sediment of a brownish granular material, occasional epithelial cells, and casts, not a sign of a red corpuscle may be found, the condition being a true luemoglobinuria. In the simplest and mildest attacks the temperature remains elevated nine or ten hours, and then falls quite suddenly to normal, the urine at the same time clearing up, excepting for a slight trace of albumin with occasional casts. In some instances a paroxysm of this nature is the last manifestation of the process, complete recovery following. In other instances there may be repeated intermittent haemoglobinuric par- oxysms, ending perhaps in recovery. Very frequently, however, the condition is more severe. The fever lasts much longer; the vomiting and diarrhoea continue ; the jaundice becomes more intense; there are perhaps occasional slight intermissions, but in the main the attack is continuous. The urine, as well as the fever, may show occasional tem- porary changes for the better, but these are of short duration, fresh ex- acerbations rapidly following. The urine becomes often scanty and more albuminous; the patient becomes emaciated and pale; the eyes are sunken, the tongue is dry, the pulse rapid and feeble, and eventually a fatal result follows. In some instances, however, recovery may occur when the patient is apparently almost beyond hope. Certain cases pursue an extremely rapid fatal course. The initial chill, fever, vomiting, and diarrhoea are associated with almost complete suppression of urine; that which is passed, often but a few drops, is in- tensely bloody. There is great agitation, intense prostration, the patient 1 Maladies des Pays chauds. 2 Deutsch, med. Woch., 1895, Nos. 25, 26, 27. SYMPTO MS. 119 falling into a condition of profound collapse and dying within several days. Nephritis almost invariably follows the haemdglobinuric attack. In the milder cases it is transient and slight. In many more severe cases, however, the end of the paroxysm is followed by the symptoms of a well marked nephritis, lasting sometimes for weeks and possibly even for months. In a certain number of instances this condition pur- sues a rapidly fatal course. The albuminuria and casts persist; the quantity of urine remains steadily below normal; the patient becomes uraemic ; and delirium, coma, and convulsions ensue with a fatal result. Malarial haemoglobinuria does not occur in all malarious districts. In some regions where pernicious fevers are relatively common luemo- globinuria is rarely seen. The cause for this is not apparent. In Rome, for instance, the disease is uncommon. It is not very frequent in most of the malarious districts of the United States. In Greece it seems to be unusually common, while in certain parts of Africa it is seen in its most fatal forms. The blood generally shows the aestivo-autumnal parasite.1 Predispos- ing causes appear to be any over-exertion or exposure, indeed anything which reduces the vitality of the individual. Extremely interesting is the widespread idea in certain regions that quinine, which has so specific an action upon the parasites, may yet have an unfavorable influence, indeed be the determining cause of the hsemoglobinuric paroxysm. In Joseph Jones' interesting memoirs2 a number of assertions of this nature appear. More recently Plehn3 in a valuable article upon the black water fever of Cameroon records his belief that in that climate, at least, the development of hemoglobinuria is often brought about by the ad- ministration of quinine, while the records of his cases of haemoglobin uric fever treated with and without the specific malarial remedy show that the more favorable course was pursued by those cases which were treated expectantly. This view, however, is not held by the majority of ob- servers. The tendency toward spontaneous recovery in many of these cases suggests, certainly, that the presence of the hemoglobinuria, de- pendent on whatever it may be, may have an injurious effect upon the life of the parasite. The Blood in the 2Estivo-autumnal Fevers.-The blood in the estivo-autumnal fevers shows the presence of the small form of the para- site described first by Marchiafava and Celli (" Hematozobn falciparum," Welch). As already noted in the description of the parasite, only the earlier forms in its cycle of existence are generally found in the per- ipheral circulation. These are the ring-like or amoeboid hyaline bodies, which are often quite free from pigment. As the later stages in the development of the organism are rarely found in the peripheral circu- lation, it is natural that the period shortly before and during the early part of the paroxysm should be that in which the smallest number of parasites is to be found on clinical examination of the blood ; and this 1 This has been the case in those instances observed by the Roman authors, and the descriptions of Plehn and others seem to point in the same direction. Owing, however, to the remarkable distribution of these fevers, to which reference has been made above, we should perhaps bear in mind the possibility that there may be certain fine differences between the parasites of the ordinary irregular fevers and those of the hsemoglobinuric variety, which may be brought to light by further study. 2 Medical and Surgical Memoirs, vol. ii., New Orleans, 1887. 3 Loc. cit. 120 MALARIA. is the case. There are cases of aestivo-autumnal fever where, at this period, a prolonged search must be made before parasites are to be found. Always, however, in the experience of the writer, parasites are present after a few hours have passed by. And I believe that it may be emphatically stated that there are no dangerous forms of malaria in which the parasite is not to be found after reasonably care- ful search. After the infection has existed for a week or two the crescentic and ovoid pigmented forms of the organism are usually observable. Phago- cytosis is very commonly to be noted, and pigment-bearing leucocytes are to be found throughout almost all periods of the fever. The period- icity in the phagocytic action is much less marked than in the ordinary intermittent fevers. This is due in part to the presence at all times of parasites in different stages of development, and in part to the early necrosis of the red blood-corpuscles which is so common in these fevers the dead fragments are speedily engulfed and carried away by the color- less elements. Occasionally, true macrophages, such as are seen in the spleen, may be found in the peripheral circulation ; these may be enor- mous, ten times the size of an ordinary leucocyte. They sometimes contain coarse granules, much larger than any ordinarily seen in the blood, having somewhat the appearance of eosinophilic granules. These cells may contain not only parasites, but red corpuscles, usually shrunken and brassy colored, including a parasite, and also entire smaller phago- cytes with their included pigment or parasites or corpuscles. Fevers with Long Intervals.-From the earliest times there have been described, besides the ordinary quotidian, tertian, and quartan intermittent fevers, other fevers with intermissions considerably longer; thus fevers with intervals of five, six, seven, eight, nine, ten, eleven, and twelve days, or even longer, have been believed to exist. Celsus, who distinguished quotidian, tertian, and quartan fevers, referred to the occasional occurrence of fevers with longer intervals, but noted their rarity.1 After Golgi's first researches concerning the life history of the quar- tan and tertian parasites, and after the fact became settled that a third variety of parasite existed, whose cycle, under some circumstances, lasted but twenty-four hours, the fever in every instance being definitely con- nected with the segmentation of a group of parasites, it is but natural that many observers should have suspected the existence of other varie- ties of parasites which in turn might be related to these rare fevers with longer intervals. And Golgi in 18892 advanced the hypothesis that the crescentic bodies which we know to be connected with the aestivo- autumnal parasite might bear a definite relation to these forms of fever. He believed that they represented a form of parasite which underwent a long, slow development, lasting from seven to twelve days-that, finally, segmentation of the crescentic forms occurred and paroxysms followed, just as in the case of the regularly intermittent fevers. This variety of parasite, however, differed in the greater length and the irregularity of the cycle of development, while the paroxysms, in like manner, recurred at irregular intervals, from seven to twelve days apart 1 " Interdum etiam longiore circuitu quaedam redeunt, sed id rare evenit." 2 Ziegler's Beitrdge, 1890, vii. 647. SYMPTOMS. 121 or even more. Canalis1 believed that the sestivo-autumnal parasite possessed two separate cycles-a shorter, lasting from one to two days, and a longer, associated with the crescentic and ovoid bodies, lasting an indefinite length of time, three or four days at least. Antolisei and Angelini2 also believed that this variety of parasite was associated with fevers with longer intervals. Clinically, however, one very rarely observes cases showing a regular recurrence of paroxysms at intervals longer than every fourth day. On the other hand, it is not so very unusual to meet with cases where a num- ber of paroxysms have recurred at intervals of, approximately, six to four- teen days. In all these instances one is generally compelled to depend largely upon the statements of' the patient. An analysis of those cases which have been observed since the recognition of the parasite and its different varieties shows that these fevers with long intervals may be associated with any of the varieties of parasite which we now know. Golgi noted the existence of such paroxysms in patients whose blood showed the sestivo-autumnal parasite. Bignami3 and Pes4 described cases occurring in connection with the tertian parasite, while Vincenzi5 has shown that they may be associated with the presence of any of the varieties of parasites which we now know, alone or in combination. The manner in which these fevers arise was described first by Bignami. As stated in the description of the parasite, the mere presence of the organism in the circulating blood is not sufficient to produce subjective symptoms. These appear first only when, from steady multiplication, the number of parasites contained in the circu- lation has reached a certain necessary quantity. With every period of segmentation their number appreciably increases. Not every fresh segment, however, continues to develop. Were this the case, every in- fection would become pernicious within a short period. With each par- oxysm a very considerable number of young parasites is destroyed-so great a number, in fact, that many, indeed the majority, of cases of ter- tian and quartan fever tend toward spontaneous recovery, though, to be sure, relapses often occur. To what thi^ destruction is due is as yet a matter of doubt. In how far it may depend upon the protective power of the blood serum or upon an active defensive phagocytosis on the part of the leucocytes, or, possibly, upon the deleterious effects of some toxic substance produced, perhaps, by the parasite itself at the time of segmentation, is as yet wholly a matter of speculation. It is, however, not an infrequent occurrence to see, more particularly in tertian or quartan infections, a severe paroxysm followed by a complete disap- pearance of the symptoms, while the blood shows a disappearance of the group of parasites. The author has previously published charts of this nature.6 In such instances, through some means or other, the greater part or an entire group of parasites is destroyed at the time of segmen- tation. In these cases the result is usually complete apyrexia for a certain length of time, from several days to two weeks or even more, and then, after, perhaps, a little warning, a repetition of the paroxysms. 1 Fartschritte d. Med., 1890, Nos. 8 and 9. 2 Rifarma Median, 1890, 320, 326, 332. 3Ibid., 1891, No. 165, p. 169. 4 Ibid., 1893, vol. ii. p. 759. 5 Bull. R. Acc. Med. di Roma, 1891-92, p. 631 ; Arch, per le Sc. Med., vol. xix. f. 3, p. 263. 6 The Malarial Fevers of Baltimore, loo. cit. 122 MALARIA. In some instances the first paroxysm may be followed by a period of apyrexia, lasting, as in one of the author's cases, eight days before the development of a second febrile attack, and that, in turn, by another intermission of approximately the same length of time, and so on, the chart thus showing an intermittent fever with intervals of, perhaps, eight or ten or twelve days. And yet the examination of the blood shows the characteristic parasites of tertian or of quartan fever. The explanation, then, of these fevers with long intervals is not to be found in a parasite whose cycle of development lasts an unusually great length of time, but in the fact that the first sharp paroxysm is followed by the destruction of so great a number of the parasites that a long period-sometimes practically that of the period of incubation of the disease-must be passed through before the group again reaches a size sufficient to produce symptoms. The recurrent attacks repre- sent, as Bignami pointed out, recrudescences from attacks from which complete recovery has not taken place. Single paroxysms with long intervals, or, more commonly, one or two paroxysms occurring to- gether with long intervals between them, may exist for a very consider- able length of time in tertian or quartan infections. Thus, the author has had occasion tv observe an individual who for over two years had had occasional chills at irregular intervals of two or three weeks, more or less, due to an untreated tertian infection. One or two paroxysms were almost invariably followed by an apparent complete spontaneous recovery, only to be succeeded in the course of from two to four weeks by another relapse. In another class of cases the paroxysms with long intervals are due to imperfectly treated malarial fever. Many patients living in mala- rious districts are in the habit of taking large single doses of quinine immediately following any outbreak of fever. Thus in an instance observed by the author a lady asserted that she had had paroxysms at intervals of ten days. The third or fourth paroxysm occurred under his observation, the blood showing the characteristic tertian parasites. In this instance the patient, by taking a single dose of quinine after each paroxysm, had accomplished the same end which nature accom- plishes in the other class of cases-viz. the destruction of the greater part of the group of parasites; and in each instance a relapse occurred about ten days after the previous attack. The same explanation is probably true in the cases occurring in sesti vo-autumnal infections. There is no evidence to show that there is any such thing as a regular type of fever occurring at intervals longer than every fourth day. The paroxysms in these instances differ in no way from those in tertian, quartan, or aestivo-autumnal fevers according to the variety of infection. Combined Infections with Different Varieties of Parasites. Combined infections with two or more varieties of the malarial para- sites may occur, though they are rather uncommon. In 542 cases of malarial fever classified by Hewetson and the author there were only 11 such instances. Clinically, these cases present usually the features of an ordinary tertian, quartan, or sestivo-autumnal infection, and without examination of the blood the presence of two varieties of parasites INFECTIONS WITH DIFFERENT VARIETIES OF PARASITES. 123 would often remain unsuspected. This is due to the fact that the two different varieties of the organism are rarely present each in sufficient number to produce symptoms at the same time. One type of the para- site almost always predominates, and is responsible for the clinical symptoms. Certain cases have been noted where a distinct alternation of symptoms has occurred ; a period of quartan fever, for instance, being followed by spontaneous recovery, and succeeded by a period of tertian fever, which, if untreated, pursues the same course, and gives way finally to a relapse of the quartan infection; the parasites of both varieties are present at the same time. In rare instances complicated fever curves may arise from a combined infection. This is, however, very unusual. The commonest combination in this climate is sestivo- autumnal and tertian fever. The Urine.-The urine in the malarial fevers has no special diag- nostic features. There are no constant changes in the amount or in the specific gravity of the twenty-four hours' urine. The color of the urine is somewhat increased, due probably to the increased quantity of urobilin which is derived from the haemoglobin of the red blood-corpuscles destroyed by the parasites. The amount of urea excreted during the paroxysms is increased, just as it is during any other acute febrile con- dition. Albumin is usually present in serious cases. Thus, out of 284 cases examined by Hewetson and the author, albumin was present in 133 instances, nearly one-half. In many of these instances casts of the renal tubules may be found. Actual acute nephritis may occur. Thus in 4 instances out of 335 of our cases evidences of a severe acute nephritis were present-a nephritis which, apparently, owed its origin directly to the malarial infection. In 3 of these instances the nephritis was hemorrhagic in nature ; in the other case, which resulted fatally, there was an extensive acute diffuse nephritis. Ehrlich's diazo reaction may be present; it was found in 5.5 per cent, of our cases. The Toxicity of Malarial Urine.-Extremely interesting researches have lately been made concerning the increased toxicity of the urine during malarial fever. Brousse,1 studying the effects following the injection of the urine of cases of malarial fever into animals, arrived at the following conclusions: "(1) The urotoxic coefficient calculated by Bouchard's formula, the mean coefficient being 0.464, rises during the paroxysm, and the physiological effects observed are those which usually follow the injection of urine-dyspnoea, myosis, falling of tem- perature, exophthalmos, and furthermore convulsions; (2) this toxicity is diminished during the period of convalescence in intermittent fever, very much below that of the urine during the paroxysm, and moreover below that of the normal urine."2 Roque and Lemoine3 studied the urine in 3 cases of malarial fever- one a case of tertian fever and two cases of pernicious comatose mala- ria. Their conclusions were as follows : " (1) The pathogenic agents of paludism form, in the blood, a large quantity of toxic products, a great part of which is eliminated by the urine. This elimination is at its maximum immediately after the paroxysm, and lasts, generally, twenty- 1 Quoted from Laveran, Du Paludisme, etc., Paris, 1891. 2 Societe de Med. et de Chir. pratiques de Montpellier, 14 Mai, 1890. 3 Revue de Med., 1890, p. 926. 124 MALARIA. four hours, at least in the paroxysms of tertian fever. (2) Sulphate of quinine acts by favoring the increase of this elimination. (3) Certain pernicious fevers, showing a complete absence of toxicity in the urine, depend probably upon alterations in the kidneys and liver, and the return of the urinary toxicity should be considered a good prognostic sign. (4) Finally, it may be noted that in two cases recovery has fol- lowed a more increased elimination of toxines than that observed after the preceding paroxysms." In discussing this paper Lepine justly remarked that injections should be made not only with the pure urine, but also with a solution of the salts of the urine made after calcination. This alone can give a reliable idea of the toxicity of the urine dependent upon organic compounds. More recently Botazzi and Pensuti1 have made an elaborate control research, and, while finding the same general results as Roque and Lemoine, dispute their conclusions. Their studies were carried out in ten cases. They collected urine during and after the febrile periods. They found that during the paroxysm the urine showed a less intense color than afterward. During the febrile periods examination of the urine with the ordinary reagents which are used in qualitative analysis showed always a diminished amount of alkaline and earthy phosphates, while that voided after the paroxysm showed sometimes a considerable quantity. The specific gravity of the urine passed after the paroxysm was higher than that during the paroxysm. They state that under other conditions the urotoxic coefficient has been shown to run parallel to the elimination of the potassium salts, while the presence of peptones in the urine increases appreciably its toxicity. Both these substances they found present in increased quantities in the urine passed after the paroxysm. The urobilin, as already stated, is present in increased quantities in the urine of malarial fever, and especially so in that fol- lowing the paroxysm. The toxicity of this substance has been demon- strated by these authors, who found that the urine passed after the par- oxysm, when decolorized, lost half its toxicity. They assert, in opposition to Roque and Lemoine, that " there is no need to suppose the presence of special toxic substances of the nature of leucomaines to account for the toxicity of malarial urine " [after the paroxysm] ; " the potassium, the phosphoric acid, the peptones, the urinary pigments, and especially urobilin, which are found in this urine in markedly increased quantities relatively to the normal urine and to that of the febrile period, are of themselves a sufficient explanation." The cause of the increased presence of these substances is not difficult to appreciate. The potassium salts and the pigments which they believe to bo the chief cause of the hypertoxicity result from the destruction of the red blood-corpuscles, and the phos- phoric acid and peptones are doubtless due to the disintegration and com- bustion of the albumins and nucleins of the cellular elements of the tis- sues. They have not found evidence of a marked retention of toxic sub- stances owing to disease of the kidneys, as asserted by Roque and Lemoine. Tn conclusion, they state : " We think that we have demonstrated (1) that in the malarial fevers the febrile urine is less toxic than that emitted during the apyretic stage; (2) that the urine emitted during the period of apyrexia is more toxic than normal urine ; (3) that the 1 Lo Sperimentale, Firenze, 1894, xlviii. 232, 254. INFECTIONS WITH DIFFERENT VARIETIES OF PARASITES. 125 toxicity of the urine of malarial patients augments constantly with the succession of febrile attacks, though in some cases this augmentation appears in the form of unexpected and irregular exacerbations ; (4) that, as there is nothing specific in the course of the intoxications produced in rabbits with malarial urine, there is no need to suppose the presence of specific toxins or substances of the nature of leucomaines, for the salts of potassium, phosphoric acid, the urinary pigments, the peptones, all of which substances are eliminated in increased quantities, are a sufficient explanation; (5) that the injection of febrile urine is followed by a slower intoxication, characterized by sopor, by increased diuresis, by diarrhoea, and mydriasis, while the apyretic urine produces a more acute effect, sometimes fulminating, characterized by clonic and tonic spasms and myosis, ' exhorbitisme,' spastic expiration ; (6) that to explain this different picture one may suppose that with febrile urine the polyuria and diarrhoea are due chiefly to the increased richness in the urea, while the peptones may contribute to the production of sopor. In the afebrile urines the salts of potassium, the phosphoric acid, the uri- nary pigments, and especially the urobilin, manifesting themselves as substances essentially convulsive, determine hypertoxicity. (7) Finally, besides the haemocytolysis and the destruction of the cellular elements of the tissues, and the formation and elimination of toxic substances, there must exist intermediate factors which account for the absence of increased toxicity after the first febrile paroxysms and the irregular ele- vation and diminution in the urotoxic coefficient in some other cases." Laveran speaks also conservatively concerning these experiments as a proof of the existence of a specific toxin. In conclusion, then, one may say that while a distinct increase in the toxicity of the urine has been shown to be present after malarial paroxysms, there is as yet no proof that this is dependent upon specific products of the action of the malarial parasite. The Blood.-Besides the presence of the parasites, the examination of the blood in malarial fever reveals certain other changes which are at times valuable from a diagnostic point of view. (A) The Regularly Intermittent Fevers.-An actual anaemia always occurs in malarial fever. Kelsch,1 Kalindero,2 Dionisi,3 all noted that a considerable fall in the number of red blood-corpuscles to the cubic millimetre occurred after each paroxysm, while similar results were obtained by Dr. Kirkebride in some counts made under the author's observation in 1893. The fall in the number of red corpuscles may be quite considerable, though in tertian and quartan fever the restitution to normal is very rapid. Always, however, after several paroxysms have occurred there is a certain degree of anaemia, which, if the disease be allowed to continue, may become quite marked. The percentage of haemoglobin falls with the number of corpuscles, but usually to a somewhat greater extent, while the return to the normal point, as noted by Rossoni,4 takes place more slowly than that of the red corpuscles. 1 Arch, de Phys., 1876, ii. s., t. iii. 490. 2 Jour, de Med. et de Pharm. J Algerie, 1889, xiv. 123. 3 Lo Sperimentale, 1891, t. iii. and iv. 284. 4 Lav. d. Cong. d. Soc. Itai. d. med. Int., IP Congresso, Roma, Oct., 1889, 121. 126 MALARIA. The behavior of the colorless corpuscles in malarial fever has been noted especially by Kelsch,1 Kalindero,2 Bastianelli,3 and Billings.4 It has been shown that the number of leucocytes in malarial fever is almost invariably subnormal. The smallest number of leucocytes is seen just after the paroxysm when the temperature is subnormal. From this time there is a gradual, slight increase, which becomes accentuated just before the paroxysm. A rapid diminution in number occurs again during the paroxysm. At no time is there leucocytosis. (B) The jEstivo-autumnal Fevers.-The changes in the blood in the sestivo-autumnal fevers are very similar to those in the regularly inter- mittent forms, differing only in their intensity. The red corpuscles show a marked diminution with each paroxysm. When the parasites are numerous this reduction amounts, sometimes, to as much as a million corpuscles during a single paroxysm. Between the attacks the corpus- cles do not show the same tendency to return to the normal number which is observed in the regularly intermittent fevers. The restitution is imperfect and incomplete. The number, however, rarely falls below one million to the cubic millimetre, although Kelsch has seen as small a number as five hundred thousand. The colorless corpuscles are almost invariably reduced in number. The changes in number follow the same course here as in the regularly intermittent fevers. There is a diminu- tion after the paroxysm, a slight rise just before the beginning of the succeeding attack, with a fall again later on. The haemoglobin follows the same curve as do the red corpuscles, falling, however, generally to a slightly greater extent. In certain instances a well marked leucocytosis has been noted in pernicious paroxysms. Bignami has noted the unfavorable inferences that one may draw from this symptom. In some instances this, very possibly, depends upon a secondary mixed infection. In other instances, however, it may occur where cultures from the organs are quite nega- tive. Thus, in one of the author's cases of the pernicious algid type the blood contained, one hour before death, sixty thousand leucocytes to the cubic millimetre. The leucocytes in malarial fever show certain other changes which are quite characteristic and interesting. Just as in the case of typhoid fever, where the number of leucocytes is ordinarily sub- normal, so in malarial fever, one finds upon a differential count a well marked reduction in the percentage of the polymorphonuclear neutro- philes, with a corresponding relative increase in the percentage of the large mononuclear forms. Thus the average numerical proportions of the various forms of leucocytes in sixteen cases analyzed in this clinic by Billings were as follows :- Small mononuclear 16.9 Large mononuclear 16.9 Polymorphonuclear 65.04 Eosinophilic 0.96 In the pernicious case above referred to, observed by the author, the relative proportions of the different varieties of leucocytes, notwithstand- ing the leucocytosis, were as follows : 1 Arch, de Phys., 1876, ii. s., t. iii. 490. 2 Loc. cit. 3 Bull. d. R. Acc. Med. d. Roma, 1890, Anno xviii., f. v. 297. 4 Johns Hopkins Hospital Bulletin, 1894, No. 43, 105. SEQUELAE AND COMPLICATIONS. 127 Small mononuclear 23 per cent. Large mononuclear and transitional forms 18.4 11 Polymorphonuclear 58.6 " The changes in the blood in malarial haemoglobinuria have been already referred to. The grave ansemise which may follow malarial fever will be con- sidered later among the sequelae. Sequels and Complications. There is no one point in the history of the development of our know- ledge concerning the malarial fevers where so much confusion and mis- apprehension has existed as in the appreciation of the nature of the sequelae and complications. The relation of chronic cachexia and grave anaemia to malaria has long been recognized, as well as the existence of an acute post-malarial nephritis. The grave cerebral, nervous, gastro- intestinal symptoms which may occur with acute malaria have been already referred to. Many observers, however, do, even today, ascribe to the malarial poison the capacity of producing of itself a considerable number of other complicating processes ordinarily dependent on other specific causes. These observers have in particular described a charac- teristic " malarial pneumonia," " malarial dysentery," etc. That such misapprehension should have arisen is not remarkable when we consider the many ways in which the simple malarial process may be masked or complicated. Ascoli1 states clearly the main possibilities in this direction as follows : " Finally, in conclusion, we may distinguish the following clinical forms : (1) Malaria which simulates another pathological process. (2) A disease, the [ordinary] course of which is known, which, in an indi- vidual suffering with chronic malaria, progresses and develops anomalies in its course according to the stage of the cachexia.2 (3) A fresh malaria develops in a subject who is at that time in an apyretic stage of the disease or suffering from the remains of a former infection (combinata'). (4) Different varieties of the heematozoa exist in the blood of a patient suffering from malaria alone (mista). (5) Two febrile diseases exist together and contemporaneously {concomitanti} : (a) exerting a recipro- cal influence detrimental to the organism (proporzionate)in certain of these cases the reciprocal influence is not manifest throughout the entire course ; (6) each preserving its more constant and common symptom- atology (associatd). (6) The malaria may prepare the ground for the development of another acute infection, or it may follow after another infection has run itself out (consecutiva)" The sequelse and complications of malarial fever may be divided into- (1) Those sequelse or complications due directly to changes produced by the malarial parasites or their toxic products; (2) true complications, mixed infections. 1. Sequelae and Complications due directly to Changes produced by the Malarial Parasites or their Toxic Products.-In the section upon the pernicious fevers the acute symptoms produced by the special 1 Bull. della Soc. Lane. d. Osp. di Roma, An. xii., 1891-92, 103. 2 " Una malattia di processo morboso noto che, attacando un malarico chronico, assume andamento e parvenze variabili secondo lo stadio della cachessia." 128 MALARIA. localization of the parasites in the brain, lungs, or gastro-intestinal tract have already been discussed. It is therefore unnecessary to refer again to the acute choleriform and comatose cases which might so readily sug- gest a mixed infection. Relapses.-The extreme frequency with which relapses are met in malarial fever has been referred to in the section on fevers with long intervals. Most cases, unless treatment be thoroughly carried out, show recrudescences in the course of one or two or three weeks. These are clearly proven to be due to the fact that all the parasites have not been destroyed by the treatment. The few which escape form a nucleus for the development of new groups, which in the course of a week or two arrive at a degree of development sufficient to result in a fresh outbreak of the symptoms. The recrudescences are, ordinarily, in every way simi- lar to the original attacks. There is, however, another variety of relapse which has been recognized for many years-viz. the reappearance of an infection many weeks or months after all symptoms have disappeared. Undoubtedly, many such cases are fresh infections. There are, however, cases where a fresh infection can be definitely ruled out, while the malarial nature of the process is undoubted. An interesting example of the reappearance of fever after a long period of perfect health is the case of a friend of the author, a physician himself, wholly familiar with malarial fever, clinically and pathologically. During the fall of 1880 Dr. suffered from a prolonged attack of tertian fever which reduced him to rather a cachectic condition. Recovery followed full doses of quinine. For twenty-one months after this the health was perfectly good, the patient living in non-malarious districts. On a hot afternoon of August, 1882, while making a pedestrian tour in the Tyrol, after a prolonged walk, during which the patient was subjected to great changes of temperature, there was a well defined characteristic malarial parox- ysm. The true nature of the attack was not suspected, but on the third day, at the same hour, while travelling in a railway-carriage, there was a second paroxysm. On the fifth day, again, at the same hour, a third characteristic paroxysm occurred. Convinced then of the malarial nature of the attacks, treatment with quinine was begun, which resulted in the immediate and permanent disappearance of the paroxysms. In the words of Dr. , "In this case there can be no question of a second infection. I had not been in a country where there was any malaria for two years, and for three weeks before the appearance of the first chill I had been in the mountains of the Tyrol." The absolute proof-the discovery of the parasite-is here wanting; there can be little doubt, however, as to the nature of the case. The explanation of these cases is difficult. It is highly improbable that the parasite has remained present in the blood, passing through its ordinary cycle of development, and yet some form of the parasite must exist throughout this time. Bignami, as was noted in the description of the parasite, suggests that some form of the organism-which perhaps we have not yet been able to discover, possibly a non-staining spore-may persist in some of the internal organs, possibly within the protoplasm of some of the cellular elements. Chronic Malarial Cachexia.-The commonest sequel to mala- rial fever is that which is generally known as chronic malarial cachexia. SEQUELS AND COMPLICATIONS. 129 In malarious districts many patients allow an infection to continue for weeks, months-nay, in some instances, even for years-without ever attempting a systematic or thorough treatment. The result is, natu- rally, a serious drain upon the vital resources of the individual. The course of such a case is commonly as follows : The patient has several paroxysms, and takes a few doses of quinine, which are followed by a disappearance of the fever, or after a week or so of paroxysms which have been untreated the fever disappears spontaneously. Fre- quent relapses occur which are improperly treated or allowed to take their own course. In some instances of restivo-autumnal fever a patient may remain for a long period of time with a slight, irregular fever, no sharp, definite, malarial paroxysms being observed. The first result of a continued process of this nature is the gradual development of an anaemia which usually becomes marked, and is sometimes extremely grave. The patient has a sallow, grayish yellow color; the lips and mucous membranes are blanched ; the tongue is often coated ; there is frequently oedema of the dependent parts. The spleen is usually greatly enlarged, sometimes reaching to the right of the median line. Indeed, some of the largest splenic tumors which occur may be seen in these cases. The hepatic flatness is increased in extent; the border is often palpable, reaching sometimes a considerable distance below the costal margin. The patient suffers greatly from exhaustion, severe headache, pains in different regions of the body. Severe supraorbital neuralgia may exist. Sudden motion or exertion is followed by vertigo or faint- ing. The gait is tottering and unsteady ; there may be a marked general tremor. The examination of the blood during an afebrile stage may be quite negative, excepting for the anaemia. More commonly occasional para- sites or pigmented leucocytes may be found, while in sestivo-autumnal infections the characteristic crescentic or ovoid pigmented bodies are usually to be seen. Chronic cachexia may follow any variety of infec- tion. In the majority of instances, however, it represents an untreated aestivo-autumnal infection, and in these instances the crescentic and ovoid forms of the parasite may be found. The same condition also follows frequently repeated attacks, even though the individual attack has been actively treated. The tendency toward dropsical transuda- tions is generally decided, and at times may give rise to confusion. Thus, in several instances the author has observed cases of moderate anaemia with quite marked oedema of the dependent parts and complete absence of fever, where, owing to an unsatisfactory history and the fail- ure to find parasites in the blood, the true nature of the process was wholly unsuspected until the appearance, within several weeks, of a re- lapse. Gastro-intestinal disturbances are very common in malarial cachexia, and the grave anaemia, with diarrhoea, oedema of the dependent parts, the enormous splenic tumor, reduce the patient to a most distress- ing condition of marasmus, where he is an easy prey to complicating infections of all sorts. Chronic malarial cachexia is not uncommon in children, where, owing to the irregularity of the symptoms, the true nature of the pro- cess is often unsuspected. It may lead to the most intense grade of infantile atrophy. The child becomes greatly emaciated ; the sallow, Vol. I.-9 130 MALARIA. grayish yellow, parchment-like skin hangs in folds; the mucous mem- branes are blanched. There are occasionally slight febrile attacks, the child becoming cold and blue, or, perhaps, showing now and then a slight eclamptic attack. There are persistent gastro-intestinal disturb- ances, vomiting, diarrhoea, as well as, perhaps, diffuse bronchitis. The spleen is always enormously enlarged. Post-malarial Anaemia.-The anaemia associated with malarial fever may assume various forms. Thus, Bignami and Dionisi1 have distinguished four types of post-malarial anaemia. (1) Anaemia, in which the examination of the blood shows alterations similar to those observed in ordinary secondary anaemia, differing from these cases only in that the leucocytes are diminished in number. These cases often show well marked oligocythaemia; oligochromaemia relatively greater; more or less poikilocytosis ; nucleated red corpuscles (normo- blasts). The leucocytes, as already stated, are diminished in number, while the relative proportion of the large mononuclear forms is increased at the expense of the polymorphonuclear cells. The greater number of these cases go on to recovery; a few, however without any change in the haematological condition, pursue a fatal course. (2) Anaemia in which the blood shows changes or alterations similar to those common in pernicious anaemia-i. e. marked oligocythaemia ; oligochromaemia relatively less; marked poikilocytosis; nucleated red corpuscles, for the most part gigantoblasts; leucocytes, diminished in number with an increase often in the small mononuclear forms, and a diminution in the polymorphonuclear varieties. These cases end fatally. (3) Anaemia showing the ordinary characteristics of secondary anaemia, excepting for the complete absence of regenerative forms (nucleated red corpuscles). These cases are progressive and fatal, the marrow, at autopsy, showing, as has already been stated, no evidence of regenerative activity. (4) Chronic secondary anaemiae occur in prolonged cases of malarial cachexia, and are remarkable for the small number of nucleated red corpuscles present and the marked reduction in the number of the leu- cocytes, particularly of the polymorphonuclear variety. There are, however, post-malarial anaemias which do show after the clearing up of the infection a leucocytosis similar to that in ordinary secondary anaemia. This is probably a favorable sign, pointing to a rapid regeneration. Malarial Nephritis.-The grave damage which the kidneys may suffer in certain acute, malarial infections, either from the direct action of some toxin produced by the haematazoa or from the presence in the circulation of injurious substances, due indirectly to the action of the parasite, is most strikingly brought to one's notice in the intense acute nephritis which, as described in a previous section, may follow mala- rial haemoglobinuria. The kidney, however, rarely escapes a certain amount of damage in any severe malarial infection. Thus, out of 284 cases analyzed by Hewetson and the author, albumin was found in nearly one-half, while severe acute nephritis was present in 4 instances. The nephritis following malarial fever is usually a mild acute, diffuse process similar to that observed in any infectious disease. In some instances, as stated in the section on malarial haematuria, the course 1 Loc. cit. SEQUELAE AND COMPLICATIONS. 131 may be rapid and fatal; in the majority, however, the prognosis is favorable and complete recovery occurs. It is not impossible that, in some instances, a fatal chronic diffuse nephritis may owe its origin to the malarial poison; however, definite proof of this is as yet wanting. There is nothing absolutely characteristic, clinically or pathologically, in these instances of malarial nephritis. Amyloid Degeneration.-Amyloid degeneration is an occasional sequel to malarial fever. Two cases were reported by Frerichs,' and several others have recently been studied by Marchiafava and Bignami.2 These cases have followed after a long series of febrile attacks, those which have been carefully studied having been sestivo-autumnal or obstinate quartan fever. The clinical symptoms are those of nephritis accompanied by an extremely rapid cachexia, ending fatally, as a rule, within several months. The blood in these cases may show the condi- tion first noted by Ehrlich as of grave portent-viz. complete absence of nucleated red corpuscles and eosinophilic cells, and reduction in the number of the leucocytes, with an excess of lymphocytes, while at autopsy the marrow of the long bones is found to be entirely fatty, showing no evidence of an attempt at proper regeneration. Atrophy of the Gastro-intestinal Mucosa.-Pensuti3 has reported a case of extensive atrophy of the gastro-intestinal mucosa fol- lowing, apparently, an acute malaria. Constant diarrhoea followed the attack, resulting in great exhaustion and death from broncho-pneumonia in three months. Though Baccelli was inclined to believe that the change was directly due to the action of some toxic substance connected with the malarial infection, the case cannot be said to be wholly convincing. Malarial Hepatitis; Malaria and Cirrhotic Processes.- As has been stated in the section on Pathological Anatomy, many ob- servers insist upon the occurrence of a true atrophic cirrhosis of the liver as a sequel to malarial fever. There are many reasons which would lead us to believe that this may, in some instances, occur, but clinically, in this climate at least, such cases are rarely met with. In few instances does one meet with a true atrophic cirrhosis of the liver in which other important etiological factors have not also been present. No such case has come under observation in the Johns Hopkins Hos- pital in the seven years since its opening. On the other hand, chronic hepatitis, resulting usually in an increase in the size of the liver, is com- monly observed in malarial cachexia and following repeated malarial infections. Distinct clinical symptoms due to the hepatic changes do not apparently exist. Malarial Paralyses.-Cerebral Paralyses.-Various paralyses have been described in association with malaria. The different forms which may occur in acute pernicious malaria have already been referred to. They are usually transitory, disappearing under treatment, and are due probably to circulatory disturbances induced mechanically by the parasites: they are almost always cortical in nature. The nervous symptoms in acute malaria are more commonly irritative than paralytic. Occasionally symptoms suggesting involvement of the spinal cord 1 Loc. cit. 2 Loc. cit. 3 Gaz. Med. di Roma, 1893, xix. 121. 132 MALARIA. may occur. Several Italian observers have reported cases where the symptoms strongly suggested disseminated sclerosis. In all these in- stances the parasites were found in the circulating blood, and recovery followed treatment by quinine. In one of Torti's1 cases there was, however, no fever, notwithstanding the presence of active parasites in the blood. In such instances it is easy to conceive that without exami- nation of the blood a diagnosis would be quite impossible. DaCosta2 has also reported a case of paraplegia with intention tremor, severe headaches, bitemporal hemianopsia, and mental symptoms, where the blood showed the aestivo-autumnal parasites. Recovery occurred under quinine. The cases of "acute ataxia" reported by Kahler and Pick3 were probably truly malarial. Bastianelli and Bignami4 have reported a case showing symptoms of the so-called " electric chorea" or " Dubini's disease." This was associated with a continued fever, the nature of which was not, at first, determined. Examination of the blood later showed it to be due to an sestivo-autumnal malarial infection. Recovery occurred under quinine. They believed that the process was due to " lesions secondary to the cerebral localization of the parasites." All of these processes coming on with acute malarial fever are essen- tially favorable in their course if treatment be begun in time. Accord- ing to Boinet and Salibert, however, permanent paralyses, both cerebral and spinal in nature, may follow malarial fever. Cases of peripheral neuritis following malarial fever have been reported, though definite proof that they were malarial in origin has not been obtained. From what we know, however, of the pathogenesis of the disease, we may readily believe that malarial fever as well as other acute infectious diseases, may be followed by acute degenerative lesions in the peripheral nerves. Some observers have believed that there was some predisposing rela- tion between malarial fever and Raynaud's disease (symmetrical gan- grene), though this is by no means proven. Poncet has described a retinitis and a retino-choroiditis, due to emboli of melaniferous leuco- cytes in the capillaries. Mental Diseases.-Various mental affections may follow malarial fever, just as may be the case with any acute infection. There is nothing especially characteristic in these cases. Thus, one of our instances of tertian malaria was followed by an attack of paranoia last- ing for several months. True Complications and Mixed Infections.-Malaria, like any other acute disease, is subject to various complications, many of which are a result of mixed infections with other pathogenic agents. As stated before, many of the symptoms caused by mixed infections were believed by the older observers to be due directly to the malarial poison. Of late, however, with our increased facilities for study and appreciation of these conditions, it has been recognized that in the majority of instances the complication is dependent upon a true mixed infection. Pulmonary Complications.-Pneumonia.-As has been stated 1 Bull. d. Soc. Lane. d. Osp. d. Loma, 1891, xi. 217. 2 International Clinics, Philada., 1891, iii. 246. * Beitrage z. Pathologic u. Pathologischen Anatomic des Centralnervensystem, Leipzig, 1879. 4 Bull. d. R. Acc. Med. di Roma, 1893-94, Anno xx. p. 221. SEQUELAE AND COMPLICATIONS. 133 in an earlier section, many observers have described pernicious fevers which during the paroxysm showed well marked pulmonary symptoms, dyspnoea, pain, haemoptysis. These symptoms, dependent probably upon the special localization of the parasites in the pulmonary capillaries, are to be sharply distinguished from true pneumonia, which may, and not un- frequently does, complicate a malarial attack. Again, in certain instances an ordinary acute pneumonia may present an intermittent fever which simulates quite closely the chart of intermittent malarial fever. These cases, however, may be readily recognized by. the absence of the parasite from the circulating blood. Such cases have been described by Wunderlich, Jaccoud, Bertrand, and Andrew Clark, while Ascoli1 gives an excellent chart. True acute pneumonia and malarial fever may, however, coexist. In these instances the course of the pneumonia may be but little in- fluenced by the coexisting malarial fever, while in other instances the exacerbations and remissions of temperature may be quite marked. Here the pulmonary process is a genuine croupous pneumonia, due, as has been shown by Marchiafava and Guarnieri,2 to infection with the diplococcus lanceolatus. Its course is quite uninfluenced by the admin- istration of quinine, and its connection with malarial fever is purely accidental, unless, as it may be in some instances, a preceding malaria has prepared the ground for the pneumococcus infection by reducing the vital forces of the individual. Pneumonia occurring in individuals suf- fering with chronic malarial cachexia appears to pursue an unusually malignant course, owing, doubtless, to the reduced condition of the patient. Retarded resolution and " organization " of the exudate are not uncommon in these instances (Ascoli). Broncho-pneumonia is also occasionally observed in association with malaria. The infection, how- ever, is purely secondary, in no way directly related to the malarial process. Pleurisy.-Certain observers have described symptoms in acute pernicious malaria suggesting pleural involvement where, on autopsy, nothing was to be found. In other instances pleurisy and malarial fever may coexist, although there is nothing whatever to show that this pleu- risy is not an entirely separate process from the malarial infection. There is nothing abnormal in the clinical or pathological course of such a pleurisy; it is uninfluenced by the administration of quinine. These cases are not to be confounded with the pleural transudations which may occur in cachectics. Quinine has no influence upon the process. Typhoid Fever.-The relations between malarial fever and typhoid fever have been much discussed, and are today probably more generally misunderstood in this country than any one point in connection with the febrile diseases. Since the discovery of the malarial parasite, with oui- modern means of diagnosis, there is no reason for the existence of any such confusion at the present day. The great similarity between the symptoms in certain cases of festivo-autumnal fever with typhoid fever has been pointed out in earlier sections. There is, however, no excuse whatever for the physician who today fails to recognize the malarial nature of such a fever after a few days' observation. The simple examination of the blood will invariably settle this question, the parasite being always present. 1 Loc. cit. 2 Bull. d. R. Ace. Med. di Roma, xv. 1888-89, 355. 134 MALARIA. Few are unfamiliar with the term so commonly employed, " typho- malarial fever." It was supposed that in malarious districts there ex- isted a continued fever which depended upon the combined action of two poisons, that of malaria and that of typhoid fever-true "pro- portionate!," in the sense of the old Italian observers. This fever was supposed to be markedly resistant to quinine and to betray its malarial nature by the frequency with which rigors occurred. We know today that " typho-malarial fever " as a distinct entity does not exist. Rigors occurring in the course of typhoid fever are by no means uncommon, but are of themselves wholly insufficient evidence on which to base a diagnosis of malaria. We know, on the other hand, that there exist, in this country at least, no malarial fevers 'which resist for more than three or four days the action of quinine. True complications of typhoid fever and malaria may occur, but they are rare, only one doubtful in- stance having been observed in seven years in the Johns Hopkins Hos- pital, where both typhoid fever and malaria are, unfortunately, very com- mon. Typhoid fever may be acquired by a patient suffering from acute or chronic malaria. A fresh malarial infection may break out or a slumber- ing infection may come to life again during the course of typhoid fever. But this condition is uncommon, and in no way justifies the term typho- malarial fever. There is little doubt that the enormous majority of cases referred to today as "typho-malarial " fever in this country and else- where are cases of typhoid fever, pure and simple. Too much stress cannot be laid upon this point, for the groundless assumption that there exists in this country a fever due to the combined action of typhoid and malarial poison, pursuing a fairly characteristic course and calling, from its malarial nature, for the continued use of quinine, has exercised in the past, and is exercising today, an extremely injurious influence upon the medical practice of this country. This influence cannot fail to be appreciated by the intelligent observer who has occasion to note the quantities of quinine which are systematically administered to many cases of uncomplicated typhoid fever in various districts of the United States. In the instances of true mixed infection of typhoid and malarial fever the picture may be most varied. If a fresh malarial attack or a relapse break out during the course of typhoid fever, well marked in- dications of the paroxysms, varying according to the type of parasite present, may be observed, as shown admirably by the charts recently published by Gilman Thompson.1 In these instances the blood shows the presence of the parasites; these, with the symptoms dependent upon them, disappear immediately after ordinary doses of quinine. If, on the other hand, the typhoid fever develop in the course of latent or chronic malarial infection, the symptoms on the part of the malarial parasite may be almost absent. Intestinal Complications.-The occurrence of diarrhoea, partic- ularly in children, during acute paroxysms is well known. The changes produced by the malarial parasite in the intestine in certain acute per- nicious cases have already been considered; the acute choleriform per- nicious paroxysm is truly malarial in nature. There is nothing, how- ever, to show that the more chronic dysenteries and diarrhoeas often 1 Trans. Ass. Am. Phys., 1894, 110. SEQUELS AND COMPLICATIONS. 135 associated with cachexia are in any way directly connected with the action of the malarial poison, excepting in so far as this may have pre- pared the ground. It is not impossible to conceive that severe infec- tions might follow directly upon an acute choleriform attack. Partic- ularly interesting are several cases noted in the medical clinic of the Johns Hopkins Hospital, where the Amoeba coll has been found in the dejecta of patients suffering simultaneously with acute malaria and dysentery. In all of these instances the intestinal process might well have been directly ascribed to the malarial poison. The frequency with which the Amoeba coli is associated with tropical dysenteries makes it exceedingly probable that many of these post-malarial intestinal affec- tions in tropical climates may be in reality due to a mixed infection with the two protozoa, as in our instances. Tuberculosis.-Numerous observers, and particularly Boudin,1 have asserted that tuberculosis was directly antagonistic to malarial fever and the converse. Boudin pointed out that tuberculosis was rare in countries where malaria existed, and that where tuberculosis was common malaria was rare. This assumption has exerted a certain influence on the minds of many. Experience, however, has shown that it lacks foundation. In many of the districts where malaria is common it is true that tuber- culosis is unusual, owing to certain climatic influences. In the northern regions, where tuberculosis is more common, malaria, as is well known, is relatively infrequent. In other regions we find malarial fever and tuberculosis side by side, intimately associated, occurring, by no means infrequently, in the same patient. Marchiafava,2 indeed, is inclined to believe from his observations that chronic malaria is not an unimportant predisposing cause to pulmonary tuberculosis. It is, how- ever, really interesting that among the 614 cases analyzed by Hewetson and the author in not a single instance was pulmonary tuberculosis present. Other Infections.-Infection with the other pathogenic organisms is not so very rare ; thus the author has observed furunculosis, parotitis, tonsillitis, and acute rheumatism, while in one fatal case, admirably studied by Barker, there was a general infection with the Streptococcus pyogenes. Antolisei and Laveran have observed cases of variola complicated dur- ing convalescence by characteristic malarial fever, while Baccelli has observed the same in cases of other exanthemata. Post-partum and Post-operative Malaria.-One hears not in- frequently of post-partum and post-operative malarial fever, and it is, alas ! only too common today to ascribe elevations of temperature during the first few days after operation and during the puerperium to malarial fever. This condition is probably rare. There are few such instances in literature where the malarial nature of post-partum paroxysms was def- initely proven. In the seven years since the opening of the Johns Hop- kins Hospital not a single case of post-operative malaria has occurred. Undoubtedly, the reduced condition of the patient during these periods might, and probably does, favor a recrudescence of the latent malarial infection. It is, on the other hand, probable that the majority of instances of supposed post-partum and post-operative malaria have no 1 Trade des Fievres intermittentes, Paris, 1842. 2 Bull. d. Soc. Lane. d. Osp. d. Roma, 1891, Anno xv. 186. 136 MALARIA. connection whatever with true malarial fever, but represent simply a septic infection. This has been the case in every instance of suspected post-operative malaria which has come under the author's observation. Insolation.-The complication of an active or chronic malarial fever with insolation is probably not very uncommon. Bastianelli and Bignami1 have recently demonstrated in an interesting manner the fre- quency with which such cases have, in Italy, been considered as essen- tially malarial in nature. The pernicious malarial fevers are particu- larly common at the hottest season of the year, while the individuals most subjected to malarial infection are also often those who work bareheaded in the fields, exposed directly to the sun's rays. These observers called attention to the fact that a number of instances of what has been considered pernicious comatose malaria have been reported in which, at autopsy, only cerebral hypersemia, pulmonary hypostasis, and slight degenerative changes in other organs were observed. In some of these cases no malarial parasites were to be found ; in others, evidences of a recent infection ; in others, perhaps the evidence of a recent infec- tion with the presence of a small number of active parasites-far too few, however, to account under ordinary circumstances for such grave symptoms. Cases of this nature have led some observers to assume that a very small number of parasites might give rise to severe per- nicious symptoms, owing to their excessive malignancy. It is much more probable, as Bastianelli and Bignami state, that the process repre- sents a complication of malarial fever with insolation which might occur in an individual with active malarial fever or in one who has recently recovered from an attack. Indeed, it is not impossible that a preceding malarial infection, by reducing the strength of the individual, may render him more subject to such attacks. Diagnosis. (1) The Regularly Intermittent Fevers.-The diagnosis of the regularly intermittent, tertian, and quartan fevers is generally a rela- tively simple matter. The regidar paroxysms with their three stages of chill, fever, and sweating arc so characteristic as to leave little doubt in most instances concerning the nature of the process. The amemia and the enlarged spleen which are present in the vast majority of instances are also important from the point of view of differential diagnosis. Occa- sionally paroxysms very closely similar to the malarial access may occur from other infectious causes, and sometimes the regularity with which the individual paroxysms may succeed one another may lead to errors in diagnosis. The paroxysms, however, in malaria differ in certain respects from those occurring in most other acute infections. Thus, the average duration of the malarial paroxysm, if we estimate the course from the time the temperature passes 99° until it again falls below this point, is from ten to twelve hours, while in other infections the course is often materially shorter. There may, of course, be mild mala- rial paroxysms which last but four or six hours, but in these the tem- perature is correspondingly moderate. One rarely observes in malarial fever temperatures of 104°, 105°, or 106° in a paroxysm lasting as short ' Bull. d. R. Arc. Med. d. Roma, 1893-94, Anno xx. p. 151. DIAGNOSIS. 137 a time as six hours or even less. The writer has seen cases of septic in- fection in which, for a considerable length of time, chills closely simu- lating those of malarial fever occurred, while the anaemia and enlarged spleen were also present. The chief difference to be noted was the marked difference in the length of the paroxysms, which were some- times as short as four or five hours, the temperature reaching, perhaps, within this time a point as high as 106°. The same may be true of the chills which are not so infrequently seen during the course of typhoid fever-chills caused, doubtless, by auto-intoxications as yet not under- stood. Whenever the temperature rises as high as 104° and the par- oxysm lasts no longer than six hours, one is justified in the suspicion that the fever is not malarial in origin. At times, however, other infections may give rise to paroxysms most closely simulating those of malarial fever. Thus, in two instances the writer has observed typical quotidian paroxysms lasting from ten to twelve hours, and beginning nearly at the same hour on two successive days, which were considered to be malarial in nature, but which, upon examination, turned out to be due to acute otitis media (in one instance due to the diplococcus lanceolatus). The intermittent fever which is most commonly confused with mala- ria is that associated with pulmonary tuberculosis. It is probably no exaggeration to say that the majority of cases of pulmonary tubercu- losis arising in the malarial districts of this country are, at some time in their course, mistaken for malarial fever. Intermittent fever, recur- ring often at fairly regular hours on succeeding days, is the rule at some stage, earlier or later, of pulmonary tuberculosis, while actual chills may occur. It is natural that the patient should ascribe such symp- toms to malaria; there is, however, no excuse today for such error on the part of the physician. The sallow color, the anaemia, the enlarged spleen will serve to distinguish the malarial process from the tuberculo- sis, where, though the face be pale, the lips and mucous membranes show usually a good color, while splenic enlargement is rare. The examina- tion of the lungs, sputa, and blood will determine the diagnosis. The chills which often occur in the course of gonorrhoea or those following catheterization or the passing of sounds may be confused with malarial fever. The urethra should always be examined in doubtful cases. In some cases of grave septicaemia following gonorrhoea there may be little or no evidence of an actual urethritis. Here the exami- nation of the blood will immediately settle the question. Tn the one instance there is leucocytosis without malarial parasites; in the other, a normal or reduced number of leucocytes with the presence of the ma- larial organism. In all these cases the final decision must be arrived at from an examination of the blood. It is through this alone that a positive diagnosis of malarial fever can be made. Method of Examination of the Blood.-For the satisfactory examination of the blood an oil-immersion lens is absolutely necessary. No physician today can consider himself equipped for practice without a good microscope and an oil-immersion lens. Though much valuable work has been done with dry lenses and lower powers, it is folly to attempt careful work without better means. The simplest and best method of studying the malarial parasite is in the fresh blood at the 138 MALARIA. bedside or in the consulting room. The steps toward the preparation of the specimen are quite simple, though certain precautions must be rigidly adhered to. The cover-glasses and the slides must be carefully washed in alcohol or alcohol and ether in order to remove all fatty sub- stances ; they should always be washed immediately before use. The blood may be taken from any part of the patient's body, though the lobe of the ear is perhaps preferable, inasmuch as it is less sensitive and more readily approached than the finger-tip, while a smaller puncture will draw more blood. This method is also more satisfactory than the puncture of the finger, in that the patient cannot so readily observe the proceeding-a point of considerable importance in nervous patients and in children. The ear is first thoroughly cleaned; the lobe is then punctured with a small knife or lancet. For the most careful pro- cedures it is advisable to wash the ear with soap and water, and after- ward with the alcohol and ether. But, practically, it is often advisable to make as few preparations as possible, and unless the ear or finger be extremely dirty one may proceed at once. A pin or needle will, of course, answer the purpose, but it is well to remember that a stab made by a round blunt-pointed instrument is much more painful than that by a sharp cutting edge, while a considerably deeper stab is required to draw a given quantity of blood. If a very sharp spear-pointed lancet be used, and the lobe of the ear taken firmly between the fingers so that the skin is held tense, very slight pressure with the tip of the lance will cause an incision deep enough for all purposes. This process is almost without pain to the patient. By proceeding carefully blood may often be obtained in this manner from a sleeping infant without its awakening. After the first several drops of blood have been wiped away the freshly cleaned cover-glass is taken in a pair of forceps and allowed to touch the tip of a minute drop of blood. It is then placed imme- diately upon a perfectly clean slide. It is well, if a third person be present, to allow the slide to be vigorously rubbed with a clean linen cloth just before the application of the cover-glass. The spreading out of a drop of blood will be thus considerably facilitated. If the slide and cover be perfectly clean, the blood will immediately spread out between them, and, unless the drop of blood be too large, the corpus- cles may be seen lying side by side entirely unaltered in their main cha- racteristics. The drop of blood which is taken should be very small unless the patient be very anaemic, and care should also be exercised that the tip of the drop only touch the cover. If the cover be placed rudely against the drop and pressed perhaps also against the ear, the blood may so far spread out that the process of drying may have begun at the edge of the drop before the glass is laid upon the slide. If this be the case, the immediate spreading out of the blood between the slide and the cover does not occur. No pressure whatever should be exerted upon the cover, which should not be pushed or allowed to slide. The specimens will remain in good condition for a considerable length of time, an hour or more-long enough to be thoroughly examined. If one desire to observe the specimen for a greater length of time, the per- iphery of the glass may be surrounded by paraffin or vaseline. In this manner we may see the parasites living and in active motion, while DIAGNOSIS. 139 the most exquisite examples of phagocytosis may be observed. By enclosing the specimen in paraffin or vaseline the preparations may, if handled carefully, be carried from the residence of the patient to the consulting room and there examined, but under these circumstances one must generally rely upon dried and stained specimens. The preparation of specimens for staining is quite simple, requiring only a little experience and practice. Stained specimens are of especial assistance in the detection of the unpigmented hyaline bodies, particu- larly the pale tertian forms and those of the aestivo-autumnal parasites. A small drop of blood flowing from the lobe of the ear or the finger-tip is collected upon a perfectly clean cover-glass, which is immediately placed upon another glass. The drop of blood, if the two covers be perfectly clean, spreads out immediately between the glasses. The cover-glasses are then drawn apart. If neither glass be lifted or tilted during this process, they will slide apart readily without sticking. If the glasses have remained together so long that they have begun to adhere, one may be sure that the specimen will be no longer perfect. The glasses, thus prepared, are allowed to dry in the air, which they do usually in the course of a few seconds, and may then be preserved for an almost indefinite length of time. To prepare them for staining the glasses should be heated upon a copper bar or in a thermostat at a temperature of 100° to 120° C. for two hours, according to the method of Ehrlich, or they may be placed in absolute alcohol and ether, equal quantities, for two hours or more (Nikiforov's method). The malarial parasite is readily stained by most of the basic nuclear dyes. The simplest method is perhaps to stain with a concentrated aqueous solution of methylene blue or Loffler's methylene blue: Concentrated alcoholic solution of methylene blue, 30 c.c. Solution of caustic potash 1 : 10,000 100 " In either instance, the specimens should be stained for from thirty seconds to a minute, washed in water, dried between filter papers, and mounted in oil or balsam. The red corpuscles then will be un- stained, while the nuclei of the leucocytes and parasites will be stained a clear blue. A contrast stain may be obtained by the following method : The cover-glass specimen, after fixing in absolute alcohol and ether from four to twenty-four hours, is placed for a few seconds (thirty seconds to five minutes) in a 0.5 per cent, solution of eosin in 60 per cent, alcohol, washed in water, dried between filter papers, and placed for from thirty seconds to two minutes in a concentrated aqueous solution of methylene blue, or in Liiffler's methylene blue, washed in water, dried between filter papers, and mounted in Canada balsam. The red corpuscles and the eosinophilic granules are stained by the eosin, while the nuclei of the leucocytes and the parasites take a blue color. Admirable results may be obtained by a modification of Romanov- sky's method. Two solutions are necessary-a saturated aqueous solu- tion of methylene blue and a 1 per cent, watery solution of eosin. The older the methylene blue solution the better the results. The staining mixture should be made just before it is to be used. To one part of the filtered methylene blue solution about two parts of the 140 MALARIA. eosin solution are added. This is carefully stirred with a glass rod and poured into a watch-glass ; it should not be filtered after the mixture has been made. The cover-glasses, fixed according to the methods above described or by hardening in alcohol for from ten minutes up- ward, are allowed to float upon the top of this fluid. The specimens are covered by another inverted glass, and the whole by an inverted cylinder which is moistened on the inside. In from half an hour to three hours-best in two or three hours-good specimens are obtained. For quick work in the consulting room the simple stain with methy- lene blue alone is perfectly satisfactory, though the observer must of course have sufficient experience to be able to distinguish precipitates which may be present in the staining solution from parasites.1 The discovery of malarial parasites in the red blood-corpuscles is, of course, a positive sign of the malarial nature of the process. In some instances where the parasites may be very scanty or absent the presence or absence of a leucocytosis is an important diagnostic sign. As will be remembered, the leucocytes in malarial fever are normal or dimin- ished in number, whereas in almost all processes with which the acute intermittent malarial fever may be confounded there is a well marked leucocytosis. This is the case in all the septic infections which are most likely to be confounded with tertian and quartan fever; it is also true of tuberculosis, at least when accompanied by intermittent fever. The presence of a marked leucocytosis is strong presumptive evidence against the existence of malarial fever. In some instances where very few parasites are present the finding of pigment-bearing leucocytes may be an important aid in diagnosis. Tertian and quartan infections where multiple groups of parasites are present may occasionally be confounded with typhoid fever. Well marked remissions and, almost invariably, actual intermissions, usually occur, while the examination of the blood will readily clear up the diagnosis. The differential diagnosis between tertian and quartan infections may be readily made in the fresh specimen, less distinctly in the stained. The larger and more actively amoeboid, pale tertian para- site with fine brownish, actively dancing pigment granules may be readily distinguished from the smaller, less active, more refractive quar- tan parasite with its coarser, more slowly moving, darker granules. In the case of the tertian parasite the red corpuscles may be seen to become expanded and pale with the growth of the organism, while in the quar- tan parasite the corpuscle is shrunken and of a deeper, more brassy color. If the blood be examined just before or during the paroxysm, the more irregularly segmenting tertian organisms with their numerous (twelve to thirty) segments may be clearly distinguished from the smaller regular forms in quartan fever with their fewer (six to twelve) segments. The presence, in either instance, of one or more groups of parasites may usually be readily determined. Combined infections with quartan and tertian parasites-which, though very rare, do exist-may also be readily made out. In the stained specimen the size of the pigment and the parasite 1 The experienced observer may obtain sufficiently good specimens for diagnosis in many instances by rapid heating of the cover-glass over the flame for a few minutes ; the results, however, are uncertain. DIAGNOSIS. 141 and the behavior of the red corpuscle, pale in one instance, taking a deep eosin stain in the other, and the characteristics of the segmenting forms, should enable us also to make a differential diagnosis. If it be impossible to make a microscopical examination of the blood, the therapeutic test is usually sufficient; thus, in the regularly intermittent fevers there is rarely any recurrence of the fever after forty-eight hours from the beginning of the administration of quinine. In the majority of instances of tertian infection in this climate all traces of fever disappear within twenty-four hours. (2) The AEstivo-autumnal Fevers.-While the diagnosis in the regularly intermittent tertian and quartan fevers is a relatively simple matter, the same is not true of the more irregular sestivo-autumnal forms of malaria. In some instances, where the paroxysms are of shorter duration and occur at regular intervals, usually quotidian, the diagnosis may be as self-evident as in the regularly intermittent fevers. The longer paroxysms, occurring at intervals of approxi- mately forty-eight hours one from another, with their less rapid rise, but with a complete intermission between them, are also generally easily recognized when we take into consideration the anaemia, the en- larged spleen, and the herpes labialis which are so commonly present. When, however, from any of the various causes above mentioned the separate paroxysms become more or less complicated or merged one with another, so that at first but slight transient intermissions, then perhaps only irregular remissions, and finally a continued high fever, result, the diagnosis becomes often more difficult. Such a case often presents itself in the form termed by Baccelli " subcontinua typhoidea." The general clinical appearances are so similar to those of typhoid fever that a dis- tinction without examination of the blood may be quite impossible. In a certain number of instances vestiges of the paroxysms still may be made out, a well marked acme in the fever being reached at approximately the same hour at quotidian or tertian intervals, though in other instances all traces of the individual paroxysms may have disappeared. Sometimes the history of several sharply intermittent paroxysms in the beginning of the illness may lead us to a correct diagnosis. Again, the prodromal symptoms are much less frequent and severe, as a rule, in malaria than in typhoid. Herpes is common in sestivo-autumnal malaria, unusual in typhoid fever. Delirium may appear quite early in a malarial attack ; it is rare during the first few days of a typhoid. Bronchitis is more common in typhoid than in continued malarial fever. Marked abdominal symp- toms, though they may occur, are unusual in malaria ; the rule in typhoid fever. Certain erythemata, and especially, urticaria, may be present in malarial fever, while the characteristic typhoid roseola does not occur. In both instances the spleen is usually enlarged. An important diag- nostic sign is the anaemia which is almost invariably present if the ma- larial fever has lasted more than a few days, while in typhoid fever anaemia during the first two weeks is rare. Another important sign is the slight icteric hue which is usually present in malaria ; rare in typhoid. Ehrlich's diazo reaction is unusual in the urine in malarial fever; it was found in but 6 per cent, of the cases classified by Hewetson and the author, while it is almost invariably present in typhoid.' Here, however, as in all other forms of malaria, the final decision 142 MALARIA. is to be reached only by examination of the blood, where the small, amoeboid, and ring-shaped, hyaline sestivo-autumnal parasites are to be found. If the process has lasted a week or more, the pigmented ovoid and crescentic bodies are also usually present. In rare instances quite severe febrile symptoms may be present, while the peripheral circulation may at times show but a small number of parasites. Here the discovery of pigment-bearing leucocytes may often be of assistance. The dimin- ished number of leucocytes which one finds under these circumstances does not help us in the differential diagnosis from typhoid fever, where also the leucocytes are almost invariably subnormal in number. If the ease occur in a neighborhood where it is impossible to obtain the aid of the microscope, the diagnosis may be definitely made by the therapeutic test. No malarial fever now known resists good doses of quinine for more than three or four days. It is generally safe to say that if the process be malarial the temperature will be practically normal by the fourth day. If quinine fails to influence the fever, we may rest assured that the process is either non-malarial or a mixed infection. The confusion with typhus fever might occur in some instances, but here, again, the examination of the blood will settle the question. As in the case of the regularly intermittent fevers, the process may be confounded with tuberculosis or other various septic infections. The one safe method of differential diagnosis is the examination of the blood. Pernicious Malaria.-The diagnosis in some pernicious paroxysms may be at times confusing. Comatose Pernicious Fever.-This type of fever must be distinguished from sunstroke, uraemia, cerebral hemorrhage. The differentiation of such an attack from sunstroke is by no means simple. As Bastianelli and Bignami have pointed out, individuals who are subjected to mala- rial infection are often those working in the fields and most exposed to the rays of the sun at the hottest season of the year, while the clinical symptoms of the two processes may be closely similar. It is interesting to note that the case of comatose pernicious fever referred to above as occurring in a tertian infection was at first mistaken for sunstroke. The slight jaundice, the anaemia, the enlarged spleen would serve to sug- gest the malarial nature of the process, while the examination of the blood gives a positive clue to the diagnosis. In the tetanic, meningeal, eclamptic, and hemiplegic types the same symptoms may lead to a cor- rect diagnosis. The Algid Type.-In this type of paroxysm, where the temperature may be normal or subnormal, and where often (from the actual conden- sation of the blood) the anaemia may not be as apparent, the diagnosis may be considerably in doubt. Here, however, icterus and enlarged spleen are suggestive, while examination of the blood will give posi- tive diagnosis. It is in cases of this nature that the physician who makes systematic blood examinations in all doubtful cases will be enabled at times to gain information which will save the life of his patient. The Hemorrhagic Type.-The diagnosis in some of the instances of this nature must be made between malarial and yellow fever. The early appearance of albumin and casts in yellow fever is suggestive, while the spleen is often but little enlarged in this affection. DIAGNOSIS. 143 The examination of the blood may in some cases be the sole reliable method of differentiation. Malarial Haemoglobinuria.-The diagnosis here lies usually between yellow fever, the ordinary paroxysmal haemoglobinuria, and acute nephritis from some other toxic origin. And here, again, the chief reliance must be placed upon the examination of the blood. Post-partum and Post-operative Malaria.-A diagnosis of these con- ditions can only be made upon examination of the blood. The malarial paroxysms differ from the paroxysm due to septic infection chiefly by their greater regularity and by their average longer duration. The blood, apart from the presence of the specific parasites and pigment, shows in the one instance diminution in the number of leucocytes, and in the other well marked leucocytosis. Chronic Malarial Cachexia.-The diagnosis of chronic malarial cachexia is usually relatively easy. It is chiefly to be confounded with grave primary or secondary anaemia or with leukaemia and pseudo- leuktemia. The malarial process may usually be distinguished from splenic anaemia by the presence of pigment and parasites in the blood. In some instances, however, where these are not to be found, the en- larged spleen, the grave anaemia, the hemorrhagic tendency, the drop- sical effusions present in both conditions may render the diagnosis almost impossible without appealing to the history of the patient. The progress of such cases under proper treatment is usually, however, decisive. The malarial cachexia responds generally, slowly but progress- ively, to treatment. Thus, the author has seen a spleen which reached beyond the umbilicus and almost to the pubes diminish under treatment until it was only just palpable, while the blood returned from 1,000,000 red corpuscles to the cubic centimetre to the normal condition, the patient remaining in perfectly good health in a non-malarious district. The diagnosis from leukaemia is readily made by examination of the blood. Post-malarial Ancemia.-An absolute differential diagnosis between post-malarial anaemia and some other secondary amemiae is impossible. The tendency, however, in the post-malarial anaemia to a diminution in the number of leucocytes is always marked, while a relative increase in the large mononuclear elements is very suggestive. As has been said before, there is nothing characteristic in the nephritis which follows malarial fever. Other Complications and Mixed Infections.-In some of the mixed infections to which reference has been made above a certain diagnosis can only be made by the discovery of the parasites and the persistence of the complicating process after the disappearance of the organisms under quinine. Thus, the diagnosis of typhoid fever may be made if the characteristic symptoms continue after the clearing up of the complicating malarial process. In the case of pneumonia the diagnosis depends more upon the physical examination, knowing as we do that the malarial parasite is of itself incapable of producing actual pneumonic consolidation. The same is true of pleurisy. The occurrence of diarrhoea or dysentery during the active malarial process may or may not be directly due to the malarial poison. The 144 MALARIA. presence of the Amoeba coli in the stools is evidence of a complicating process, while in other instances of diarrhoea in acute malaria the result of the specific treatment must be awaited before one can form a definite diagnosis. Parotitis, tonsillitis, acute rheumatism, the exanthemata, occurring in connection with malarial fever, may be recognized by their usual symptoms. Prognosis. The Regularly Intermittent Fevers. - The prognosis in tertian and quartan fevers as for ultimate recovery is almost invariably good. The writer knows of but one instance in which actual pernicious symptoms were present in tertian or quartan infection. Without systematic and careful treatment relapses and grave cachexia may, however, follow- a cachexia which may well lay the patient open to the gravest second- ary complicating processes. It is not improbable that in certain of these instances a fatal chronic nephritis may follow repeated malarial infections. ^stivo-autumnal Fever.- In ordinary cases of aestivo-autumnal fever which come early under treatment the prognosis is perfectly good. Treat- ment must, however, be more active and longer carried out than in the regularly intermittent fevers. Imperfectly treated cases are more likely to be followed by cachexia and grave post-malarial anaemia. Pernicious Fevers.-Wherever pernicious symptoms have developed the prognosis is extremely grave, and, unless active treatment be insti- tuted, usually wholly unfavorable. In a patient first coming under obser- vation in a pernicious paroxysm an entirely favorable prognosis can never be given for at least forty-eight hours after the beginning of treatment. It is always possible that a single pernicious paroxysm may be succeeded, despite treatment, by another upon the following day. If active treat- ment has been begun during a pernicious paroxysm and no succeeding paroxysm has occurred within forty-eight hours, the prognosis is usually favorable. Malarial Hcemoglobinuria.-The prognosis here is always extremely grave; indeed, the dangers of a fatal outcome are not past until several days after the complete disappearance of fever and of symptoms on the part of the urine. Chronic Malarial Cachexia.-In the milder grades of chronic malarial cachexia the prognosis is good if the patient can be compelled to adopt a properly hygienic life. In the more severe grades recovery is ex- tremely slow, and at times almost impossible, unless the patient be transferred into a more healthy region. Post-malarial Ancemia.-The anaemiae following malaria are often extremely grave. In those instances where the nucleated red cor- puscles are scanty or absent and the leucocytes are diminished in num- ber, and in those cases where the blood shows the characteristics of true pernicious anaemia, the prognosis is extremely grave. The prognosis in the various complications of malaria is influenced only by the possible unfavorable effect of the coexisting malarial in- fection. Secondary infections occurring in individuals suffering from malarial cachexia appear to pursue an unusually unfavorable course. TREATMENT. 145 Treatment. General Measures.-Certain general hygienic measures are advis- able, and sometimes very important, in the treatment of malarial fever. Rest in Bed.-It is always prudent, if possible, to keep a patient with malarial fever in bed for twenty-four or forty-eight hours; in the more severe aestivo-autumnal fevers it is absolutely necessary. The simpler regularly intermittent fevers often show a temporary and sometimes permanent spontaneous recovery following rest in bed, without further treatment. In hospital practice it is our rule to keep a patient with malaria in bed until the entire disappearance of fever, whether it be intermittent or subcontinuous. It is not impossible that the more satis- factory results of hospital treatment may, in part, depend upon the fact that the patients are so much more readily kept at rest. Change of Surroundings.-If the patient's dwelling be in a malarious district, it is always important, if possible, that the individual be removed into more healthy surroundings. Thus, recovery from chronic cachexia is greatly favored by the removal into higher, more healthy regions. In some instances of advanced cachexia the removal may be absolutely necessary. In the ordinary acute malarial fevers it is, however, gen- erally perfectly possible to treat the case in the malarial district itself. The patient should be kept, while under treatment, in one of the upper stories of the house; he should be warned against remaining out of doors at night during convalescence, and prevented, as far as possible, from subsequent exposure to infection. Diet.-In the simple intermittent fevers the patient may be given an ordinary nourishing general diet. During the paroxysms, which last but ten or twelve hours in all, the patient need not be forced to eat; it is, however, generally well that liquids, milk, broths, soups, should be taken in small quantities. Stimulants may be administered symptomatically. In the more severe subcontinuous fevers, where there is usually com- plete anorexia, the patient may be given liquids of all sorts, soups, milk, broths, at short intervals ; while, if he be hungry and there be no gastro- intestinal symptoms, there is no contraindication to soft solids and eggs. In cases where there are marked gastro-intestinal symptoms great care must, of course, be exercised with the diet. Easily digested liquids, such as boiled milk, albumin-water, and broths should alone be given. Exposure to the Air.-There are districts where experience has led the inhabitants to believe, probably justly, that exposure to the night air is injudicious. It may be unwise in such regions for the patient to be allowed to sleep with his window open. If, however, the patient be in a healthy district and be accustomed to living and sleeping with open windows, there is no reason why a change should be made during the existence of the fever. There is no fever which we know today which is unfavorably influenced by fresh air and open windows, provided the individual be accustomed to such air beforehand. Quinine.-Malarial fever is one of the few diseases against which we possess a remedy which truly deserves to be called specific. This remedy, in the form of cinchona bark, was introduced into Europe in 1640 by the countess del Chinchon (wife of del Chinchon, the Spanish governor of Peru), who had recovered from a severe attack of intermit- Vol. I.-10 146 MALARIA. tent fever after taking a powder administered by a corregidor of Loxa. As far as is known, tins substance was first used by the Indians in this region as a remedy against malarial fever. The powder, which was known at first as " the powder of the countess," and afterward as "the Jesuits' powder" for the reason that it was introduced into gen- eral use by the Jesuits in Rome in 1649, was prepared from the bark of a Peruvian tree. This was for years known as Peruvian bark, though its officinal name, Cinchona, is derived from that of its intro- ducer to the Eastern hemisphere. It was at first administered in the form of the pulverized bark, the cinchona powder, which contains, in addition to various alkaloidal substances, a considerable quantity of tannin. Today, however, the pulverized bark is no longer in general use, its place having been taken by various salts of its active principle, quinine. Action of Quinine on the Malarial Parasite.-For centuries after the introduction of quinine and after its specific action in malarial fever had been noted the exact mode of action remained unknown. As long ago as 1867, Binz1 correctly concluded that the efficacy of quinine in paludism depended upon its action as a protoplasmic poison upon some lower organism which he assumed to be the cause of the process. The extremely toxic action of quinine upon the infusoria was at that time clearly demonstrated. Since the development of our knowledge con- cerning the malarial parasite it has been possible to study, to a certain extent, the direct action of quinine upon the luematozoa. Laveran noted the immediate disappearance of the parasites following the ad- ministration of quinine, and in 1881 asserted that " it is because it destroys the parasite that quinine causes the disappearance of the man- ifestations of paludism." He showed that by allowing a 1 : 10,000 solu- tion of quinine to run under the cover-glass the movements of the para- site were immediately arrested, as they are upon subjecting the organism to any other protoplasmic poison. Golgi2 has studied the action of quinine on the tertian and quartan parasites. He noted that after the administration of quinine the quar- tan organism, in its endoglobular stage, shows a coarser granulation with a metallic reflex, while the protoplasm shows a certain cloudiness. At times one may see abortive segmenting forms which are smaller than the normal, with a lack of regularity and fewer segments. The pig- ment also may not collect as sharply in a clump in the middle of the parasite. In the tertian parasite the changes are more marked, owing to the greater normal activity of the organism. The body is round and immovable, and shows a sharper outline than usual, while the pigment has a peculiar metallic reflex and tends to collect in clumps. Full grown tertian forms may present a large transparent swollen condition with very active movements of the pigment granules. Sometimes the pigment may collect toward the periphery, leaving an hyaline space in the middle. Mannaberg3 asserts that three hours after the administration of 0.5 of quinine the amoeboid forms of the tertian parasite show a marked diminution in their activity. In several hours more the number has greatly diminished, while many of those present 1 Centralblatt f. d. med. IFiss., 1867, p. 308. 2 Deutsch, med. Wock., 1892, 661, 695, 707, 729. 3 Doc. cit. TREATMENT. 147 are fragmented, resulting in the presence of several separate spherules in the red corpuscle. Full grown forms show a cessation of the move- ments of the pigment, the body having a somewhat refractive homoge- neous appearance. Large hydropic forms with active pigment may also be seen. These two latter forms may occur normally during the par- oxysm, as Golgi and Mannaberg also assert; they are probably degen- erate forms. The writer has also observed in the case of the tertian parasite the somewhat greater refractiveness of the organism, the col- lection of the pigment into clumps, and the cessation of active move- ments, as well as the presence of a greater number of fragmenting forms. Romanovsky1 and Mannaberg2 have made interesting studies with stained specimens. Both observers note the loss of affinity for coloring matters in the chromatin substance of the nucleus. They also note that in the segmenting forms, after quinine has been given, the greater number of the segments show no nucleoli. These changes in the nucleus they believe to be evidence of a necrotic process. The segments without nucleus Mannaberg terms " still-born." Baccelli3 noted that in restivo-autumnal fever after the intravenous injection of quinine there was an increase in the activity of the small amoeboid forms, which, often inside of twenty-four hours, disappeared without showing any outward signs of degeneration. Marchiafava and Bignami,4 studying the aestivo- autumnal fevers, note that the administration of quinine is followed by an increase in number of shrunken, brassy colored corpuscles. They believe that the included parasites are incapable of further develop- ment. Most observers who have been able to test the action of quinine upon the malarial parasite will agree with Golgi that in tertian and quartan fever quinine acts most markedly on the free young segments, less upon the more advanced forms where the red corpuscle is in greater part de- stroyed, and least upon the young endoglobular forms. If quinine be given several hours before the paroxysm, it will not prevent segmenta- tion, but it will destroy the new group of parasites, the fresh segments. Segmentation takes place, toxic substances are produced and enter into the blood serum, and the chill follows, being at most a little modified or retarded. The further development of the new group of organisms is, however, prevented, and on the following day no parasites whatever may be observed. Marchiafava and Bignami5 arrive at the same conclu- sion in the case of the sestivo-autumnal parasite. They state " that the maximum and most rapid action of the remedy is exercised on that phase of the extraglobular life of the parasite which follows the com- pleted segmentation." They note, as does Golgi in the case of the ter- tian and quartan organisms, that the segmentation cannot be prevented if quinine be given when the parasite has reached the preparatory stages. " Quinine," they say, " acts on the amoeba of malaria during those phases of its life in which it absorbs nourishment and develops ; when the nutritive activity comes to an end, the transformation of haemoglobin into black pigment having been accomplished, and the phase of repro- duction begins, then quinine becomes inefficacious against this process." 1 Cent, fur Backt., 1892, xi. Nos. 6 and 7, 219 ; and St. Pet. med. Woch., 1891, Nos. 34 and 35. 2 Loe. cit., and Cent, fiir kiln. Med, 1891, No. 27. 3 Deutsch, med. Woch., 1892, No. 32, 721. 4 Loc. cit. 5 Loc. cit. 148 MALARIA. To best combat the further development of a group of malarial parasites quinine should be in solution in the blood at the time of the setting free of the fresh parasites-i. e. during and several hours before the parox- ysm. In ordinary tertian or quartan fevers, with moderate regular daily doses of quinine, the parasites will usually wholly disappear from the peripheral circulation inside of three days. In sestivo-autumnal fever the time may be a little longer. All observers agree that the crescentic bodies are affected slowly if at all by quinine; they remain in the blood long after all other forms of the parasite have disappeared. Effects of Quinine upon the Human Being.-In small doses, such as are ordinarily required therapeutically, quinine causes no subjective symptoms. In somewhat larger doses, however, it produces at times a ringing in the ears, roaring or sometimes tinkling noises, and, finally, more or less deafness. Larger doses are followed by a dimming of the vision, even to complete blindness. Ringer has noted that this may sometimes begin in one eye, and, indeed, exist for considerable time upon one side alone. The pupil is usually dilated. In larger doses a severe frontal headache, with giddiness and staggering gait, delirium,, and great muscular weakness, may follow, and, finally, in still larger doses, convulsions and death. At times large doses of quinine are fol- lowed by certain cutaneous disturbances. Ringer describes an intense general erythema similar to a scarlet fever rash and followed also by desquamation. Urticaria also at times occurs. Manner in which Quinine should be Given.-Like another commonly used and extremely valuable drug, digitalis, quinine, which is our main stay in malarial processes, is very frequently abused. Laveran well says : " In a general way it may be said that in malarial districts far too much sulphate of quinine is given to patients who have no need of it, while a sufficient quantity is not given to patients suffering from paludism." The very degree of its efficacy, as in the case of mercury and iodide of potassium in syphilis, is probably accountable for the lax manner in which it is frequently given. When one or two doses are followed by a complete disappearance of symptoms, the immediate relief is so great that the patient fails to recognize the importance of continued treatment, and, by abandoning the regular regime, lays himself open to repeated relapses. It is of considerable importance to determine in an individual case how and in what form quinine should be given. The following tables, taken from Laveran, show the percentage of quinine which the different salts contain, as well as their relative solubility : Salts of Quinine classified according to the Percentage of the Alkaloid which they contain. Quinine. 100 parts of the basic muriate of quinine contain 81.71 per cent. P " neutral " " " 81.61 " " " basic lactate " " 78.26 " " " " hydrobromate " " 76.60 " " " " sulphate " " 74.31 " " " sulphovinate " " 72.16 " " " neutral lactate " " 62.30 " " " " hydrobromate " " 60.67 " " " " sulphate " " 59.12 " " " sulphovinate " " 56.25 " TREATMENT. 149 Salts of Quinine classified according to their Solubility in Water (Regnaidd and Villejean). Water. 1 part of the neutral hydrochlorate of quinine is soluble in 0.96 " " " sulphovinate " " " 0.70 " " " lactate " " " 2. " " basic sulphovinate " " " 3.30 " " neutral hydrobromate " " " 6.33 " " " sulphate " " " 9.00 " " basic lactate " " " 10.29 " " " hydrochlorate " 11 " 21.40 " " " hydrobromate " " " 45.02 " " " sulphate " " " 581.00 The ordinary method of administering quinine is by the mouth; the common form in which it is given in this and most countries is as the sulphate. The sulphate of quinine is very slightly soluble in water, but quite readily soluble in dilute acids. The best manner to administer this form of quinine is in water containing a sufficient quantity of dilute hydrochloric or sulphuric acid to hold the salt in solution.1 The ex- tremely bitter taste is sometimes an objection in sensitive patients : this, in the case of the quinine powder, may be partly obviated by mixing with an equal quantity of powdered ginger. The drug may also be administered in the form of pills or in capsules. Quinine pills are con- venient, but are open to the common objection that in many instances the commercial pill is an highly insoluble object. Thus, it is not at all infrequent in dispensary practice for the physician to be consulted by patients with simple intermittent fever who have taken quinine pills2 without effect, while the solution or the powder has an immediate result. For more rapid action the quinine may be administered hypodermically or, according to the method of Baccelli, intravenously. For these pur- poses more soluble salts than the sulphate must be used. Thus, for subcutaneous use the neutral hydrochlorate of quinine is an excellent salt. De Beurmann and Villejean 3 use the following formula : If. Bihydrochlorate of quinine, 5. Distilled water, q.s. ad 10. 1 e.c. (U[xv) of this solution contains 0.5 (gr. vijss) quinine. If the hydrochlorate of quinine is not to be obtained, one may make use of the ordinary sulphate, as follows : Sulphate of quinine, 1. Tartaric acid, 0.5 Distilled water, 10. The officinal bisulphate of quinine is soluble in about 9 or 10 parts of water, and may be used hypodermically if a more soluble salt cannot be obtained. 1 The druggist customarily adds about 1 drop of the dilute acid to 1 grain (0.65) of the salt. 2 My colleague, Dr. L. F. Barker, has actually observed the discharge of well preserved quinine pills from faecal fistuke in three instances. 3 Quoted from Laveran, Du Paludisme, etc. 150 MALARIA. Baccelli1 uses, as an intravenous injection, the following mixture, which he has found to act with the greatest rapidity and the most marked effect: 1^. Quinime hydrochloratis, 1.0 Sodii chloridi, 0.075 Aquae destillatse, 10.0 The solution is perfectly clear and should be injected lukewarm. The procedure is described by Baccelli as follows : " After the veins of the forearm have been made turgescent by means of a circular tourniquet above the elbow, we introduce a Pravaz needle in a direction from below upward into the lumen of the vein. We select a small one in order to avoid hemorrhage afterward. Generally, we are accustomed to select one situated upon the flexor side of the forearm. The syringe holds 5 c.c., and is filled according to the dose which is to be given, and con- nected with the needle before its introduction." The most rigid anti- sepsis must be observed. The stab wound is closed with collodion after the needle has been withdrawn. The bimuriate of quinine and urea, which contains nearly 80 per cent, of quinine and is soluble in less than its own bulk of water, is another convenient form in which to administer the drug. The hypodermic use of quinine is attended by considerable pain and real danger of a subsequent abscess or necrosis. If the solution and the instruments be carefully sterilized, there is little danger of abscess, but at times a considerable area of necrosis may result. It is always import- ant to introduce the needle well into the subcutaneous tissue ; if this be neglected and the solution be introduced into the deeper part of the cutis, necrosis usually follows. Quinine may be given by rectum ; this is, however, a last resort, and is practically never necessary excepting, at times, in children. The Time at which Quinine should be Given.-If one but remember the studies of Laveran, Golgi, Mannaberg, and others concerning the effect of quinine upon the parasite, and then consider the close rela- tion between the development of the parasite and the symptoms of the malarial infection, one may readily perceive the time at which, theo- retically, the drug should be best administered. Inasmuch as it has been shown that quinine acts most effectually upon the young extracorpus- cular parasite, it would seem fair to conclude that the period just before or during the paroxysm should be that at which quinine might be ad- ministered with most effect, and, as has been clearly shown, this is the case. A dose of quinine shortly before a paroxysm in the regularly intermittent fevers will not affect that paroxysm, but will prevent a recurrence of the succeeding one dependent upon that group of organ- isms. Thus, a single moderate dose of quinine given just before or during a paroxysm in single tertian or quartan infection will cause generally a total disappearance of the symptoms, while in the case of a double tertian infection it may often be seen to change the type of the fever from quotidian to tertiam Thus, in such an instance the par- oxysm expected upon the following day will occur, but that expected 1 Studien uber Malaria, Berlin, 1895. TREATMENT. 151 in forty-eight hours will not appear, the greater part of the group of parasites having been destroyed. The same has been shown to be true in sestivo-autumnal fever, though the parasites are much more resistant to the action of quinine than those of the regularly intermittent fevers. Administration of Quinine in the Regularly Intermittent Fevers.-Here it is generally best to place the patient upon regular continued treatment with quinine. If it be possible to keep the patient in bed, very small doses will often be sufficient. Thus, 0.065 (gr. j) three times a day will, in many instances, be followed by a disappearance of the symptoms. In practice we may give, according to the severity of the case, from 0.13 to 0.325 (gr. ij-gr. v) three times a day. If in tertian fever the patient be seen on the day between the paroxysms, 0.325 (gr. v), three times a day will generally, if the patient be confined to bed, prevent even any suc- ceeding paroxysm. One may predict, almost with certainty, the entire disappearance of the fever after this. If the patient be seen first just before an expected paroxysm or during the attack, it may be well to give a single large dose, 0.325-0.65 (gr. v-gr. x), and follow this by smaller doses, 0.13 (gr. ij), three times a day. If the paroxysms have been severe, it is sometimes wise to give large doses of the drug (0.325- 0.65 (gr. v-gr. x)) during the first days of treatment at the hour when without treatment the paroxysm might have been expected. The para- sites in tertian and quartan infections disappear from the blood generally within three days, but treatment with small doses, 0.4 (gr. vj), in twenty- four hours should be continued for at least three weeks. AEstivo-autumnal Fevers.-In the treatment of sestivo-autumnal fever larger quantities of quinine must, as a rule, be given. In ordinary cases where no pernicious symptoms have developed one may start treat- ment with 0.325 (gr. v) every four hours. In most cases under such treatment fever will entirely disappear inside of three days. If symp- toms of cinchonism develop, the dose may be reduced. If the patient come under observation during a paroxysm, or if the history be obtained of a severe paroxysm having recently occurred, it may be well to begin with larger single doses. Thus, during or just before a paroxysm 0.65 (gr. x) may be administered, followed by 0.325 (gr. v) every four hours. If severe nervous manifestations accompany the paroxysm and the de- velopment of pernicious symptoms be feared, it may be well to adminis- ter the quinine hypodermically or intravenously. It is rarely necessary to give doses larger than 1.0 (gr. xv). It may rarely be necessary to give several doses of this size at intervals of several hours during a long- continued paroxysm ; usually two or three doses at intervals of four hours are sufficient, while afterward it will be possible to give smaller quantities (0.325) every four hours. Such doses will usually prevent the recurrence of a paroxysm due to this group of parasites. It is, however, possible that a second large group of parasites, which all treatment has failed to influence, may on the following day produce a fatal paroxysm. The same course should be pursued during the suc- ceeding paroxysm. It has long been a well recognized fact in malari- ous districts that if the patient survive the second paroxysm after the beginning of treatment, ultimate recovery is usually assured. In true pernicious paroxysms the experience of Baccelli would seem to show that intravenous injections of quinine are by far the most efficacious. 152 MALARIA. Buccelli has used successfully the solution of quinine described on page 150. It is apparently unnecessary to use doses larger than 1.0 (gr. xv). Malarial Hemoglobinuria.-The same general rules which apply to the treatment of the other pernicious fevers hold good in the case of malarial haemoglobinuria. It should, however, be noted that cer- tain observers believe that large doses of quinine exert a distinctly injurious influence upon the blood, aggravating often the destruction of the red corpuscles. Thus, Plehn 1 in a recent article goes so far as to advise an expectant treatment in these cases, asserting that recovery is more likely to result under careful nursing and general treatment than under the administration of quinine. This view is not held by the majority of observers. Cinchonism.-Contraindications to Quinine.-1There is a great dif- ference in the susceptibility of different individuals to quinine. Rela- tively small doses produce cinchonism in some individuals, while others are extremely tolerant of the drug. In the majority of instances, how- ever, in which complaint is made it is based upon the fact that the drug has been administered in injudiciously large doses. The writer has never observed but one case in which it was impossible to administer quinine in sufficient doses to combat ordinary malarial manifestations without serious symptoms. In this instance, occurring in a colleague, the symptoms produced by quinine or other cinchona derivatives are interesting enough to mention here. After taking 0.13 (gr. ij) of the sul- phate of quinine, in half an hour the patient had a feeling of oppression in the epigastrium, followed by nausea, vomiting, and then soon by "a hot prickling sensation over the entire skin." On one occasion, without extreme itching, there was an intense scarlatinoid erythema, lasting for hoursand followed by desquamation; on another occasion, after 0.195 (gr. iij) of salicylate of cinchonidia, a most intense general urticaria. Cases of this nature are extremely rare, and there are few in- stances probably in which individual susceptibility is any true contra- indication to the administration of quinine in malarial fever. The prejudice against the drug is very strong in the mind of some in- dividuals, and it is not infrequently wise for the physician to intro- duce quinine in a form unfamiliar to the patient. Other Cinchona Derivatives.-Various other cinchona deriva- tives have been used as substitutes for quinine in the treatment of malarial fever. Thus, einchonin, cinchonidin, quinidin, and quinoidin have been recommended. The efficacy of these drugs is, however, so far below that of the various salts of quinine that their employment is inadvisable. Methylene Blue.-Next to quinine, the most valuable remedy in malarial fever is, probably, methylene blue. This substance was first employed in 1891 by Gutmann and Ehrlich,2 who were led to its use by the observation of Celli and Guarnieri that the malarial parasites were stained while yet living by this substance. They found that in small doses quite a marked effect was obtained in several cases of intermittent fever. Since this time the drug has been used by a number of different observers, most of whom agree in the conclusion that methylene blue 1 Loc. cit. 2 Berliner klin. Woch., 1891. TREATMENT. 153 possesses a well marked antimalarial action, the parasites often disap- pearing from the blood and the patient recovering after its administra- tion. As an antimalarial agent it is, however, as the observations of the author1 have shown, far below quinine in efficiency, while the parasite acquires, apparently, a certain tolerance to the drug after its continued use. In certain mild cases of the regularly intermittent fevers it may be given in doses of 0.13 every four hours in capsule, with possibly a cura- tive effect. Larger doses have been given without ill effect-doses as high as 3.0 (gr. xlv) in twenty-four hours. The only unpleasant symptom following its use is, apparently, strangury, which may be prevented by the administration of small quantities of powdered nutmeg at the same time. After ingestion of methylene blue the urine has a deep blue color ; the faeces become blue on exposure to the air. While in certain instances methylene blue may have a curative effect, it is so far inferior to quinine that its value is certainly extremely limited. Phenocoll.-Within the last few years several Italian observers have reported moderate successes from the treatment of malarial fever with the hydrochlorate or acetate of phenocoll, a derivative of phenace- tin. It may be given in doses of 1.0 (gr. xv). It has been prescribed in the treatment of malaria in children. Other Remedies.-A large number of other drugs have been at one time and another employed in the treatment of paludism. Thus iodine, strychnine, sulphur, arsenic, alum, preparations of eucalyptus and helianthus have been recommended. With the exception of arsenic, which, as will be said, is often of use in anaemia and chronic cachexia, the value of these substances is slight. Further Treatment.-Besides the treatment with the specific drug, certain accessory and symptomatic measures are often important. The value of purgation has long been insisted upon, and the old custom of beginning the treatment of malarial fever by administering a mercu- rial purge is probably in some instances of value. In cases where there are grave intestinal symptoms it should be avoided. Profuse vomiting or purging during a paroxysm should be controlled, as far as possible, by morphia administered hypodermically. Excitement and active de- lirium during the fever may also at times require the use of morphia. In the collapse in pernicious fevers most active stimulation must at times be resorted to ; alcohol, strychnia, and ether may be freely admin- istered hypodermically. In the algid forms external heat should be applied, as well as encmata of warm water. In continued high fever, particularly if there be delirium, cold sponging or the actual cold bath may be of value. During convalescence the most serious symptom with which we have to deal is the ancemia. In these cases iron and arsenic are our mainstays. In most instances iron alone, either in the form of Bland's pills or as the tincture of the chloride, in full doses, will be followed by good results. In severe cases arsenic may be resorted to; it is best given in Fowler's solution (liquor potassii arsenitis). It is well to begin with small doses (gtt. iii, t. i. d.), and to increase the dose steadily, one drop every other day, until the physiological effect is observable- slight suffusion and injection of the conjunctivae, gastro-intestinal symp- 1 Johns Hopkins Hosp. Bulletin, 1892, No. 22, 49. 154 MALARIA. toms. The dose should then, after a few days' pause, be reduced and maintained at the highest possible limit. Some very grave anaemiae which closely simulate true pernicious anaemia and react but little to iron may show marked improvement after vigorous treatment with arsenic. It should be borne in mind that in rare cases arsenical neuritis may follow. In some instances it is well to continue the use of strychnia in some form as a bitter tonic during convalescence. Treatment of Chronic Mala ri ae Cachexia.-The treatment of chronic cachexia is often a very difficult matter. Active treatment by quinine will readily remove the parasite from the circulation and put an end to acute symptoms, but the extreme debility and the grave anaemia are often very obstinate. Owing to the great susceptibility of such patients to fresh infections or to a reappearance of an old infection after the cessation of treatment by quinine, it is sometimes almost neces- sary to remove the sufferer to a non-malarious district. The anaemia, which is usually the gravest symptom, should be treated according to the suggestions given above. It is in these cases that persistent and vigorous treatment by arsenic is especially valuable. The patient should be kept from all undue exertion; if the anaemia be very grave, rest in bed is important. The diet should be most nourishing, and the patient should be allowed to sit in the sun and fresh air in the middle of the day if the climate be not too hot. Bitter tonics are often valuable, par- ticularly strychnia. Most cases of this nature will recover, even in a malarious district, if treatment be properly carried out. The majority of cases of malarial cachexia owe their origin to the carelessness of the patient, who does not carry out proper treatment with quinine and fails to observe the ordinary prophylactic measures. Prophylaxis. - General public prophylactic measures, such as proper drainage, cultivation of the soil, and so forth, cannot be con- sidered here. The individual, however, may adopt certain measures which may protect him in the most malarious districts. If it be neces- sary to visit, temporarily, notoriously malarious districts, let him, so far as possible, choose the season at which the fevers are least prevalent. The dwelling should be sought upon ground as high and dry as possible. Exposure at night in dam]) or marshy districts should be avoided; the sleeping apartment should be an upper story of the house. Despite the experimental evidence against the idea that infection occurs through the gastro-intestinal tract, it is prudent to boil all drinking water com- ing from malarious districts. Medicinally, quinine in small doses will often prevent infection. If the district be extremely malarious, the various simple wines containing cinchona are insufficient protection, and it is prudent to take several grains of quinine daily. Monti1 has recently reported good results from the administration of the sulphate of quinine in doses of 0.40 (gr. vj) every other day. Sezary2 believed that a smaller quantity, 0.15 (a little over gr. ij), daily was sufficient to protect the individual under most circumstances. 1 Loc. cit. 2 Medecine moderns, 1892. DENGUE. By HAMILTON A. WEST, M. D. Definition.-Dengue, Break-bone Fever, Knockel K oorts, Rheu- matic Scarlatina, Eruptive Rheumatic Fever, are the principal names applied to an acute, benignant, specific fever of short duration, preva- lent usually in extensive epidemics in tropical and subtropical regions. It consists of two paroxysms of fever separated by an interval either of complete apyrexia or a decided remission of temperature, and attended by severe muscular and articular pains, and, in a considerable proportion of cases, also by an eruption of variable character. History.-Dengue first attracted attention by the extensive preva- lence of an epidemic in the West India Islands in 1827; previously, in 1779, an account of its occurrence in Java was given by David Brylon, and in the subsequent year Benjamin Rush described an epidemic preva- lent in Philadelphia. The West India epidemic began in September, 1827, in the island of Saint Thomas, rapidly extending southward over the Caribbean Islands to Colombia, and northward to various cities in the United States, notably Pensacola, Charleston, Mobile, New Orleans, and Savannah, a few cases occurring as far north as Boston, Philadel- phia, and New York. The next extensive epidemic took place from 1848-50 in various large cities in South Carolina, Georgia, Alabama, Louisiana, and Texas. Reliable observers state that as many as eight- tenths of the population of such cities as Augusta and Charleston would have the disease during a period of six weeks, showing such rapid and gen- eral dispersion as hardly to be equalled in this regard by any other malady. After about two decades dengue appeared in Arabia in 1871, extend- ing southward by the routes of travel to Zanzibar and other towns on the East African coast; thence to Java, reaching and spreading over India in 1872, invading several English stations in China and Burmah, and extending to the Gulf States in 1873. This epidemic was not only widespread, but intense, in some places hardly a person escaping. In Madras it is said that every house was invaded. In 1880 another epi- demic occurred, beginning in Cairo and spreading over the whole of Egypt, and extending afterward to many towns in North and South Carolina, Georgia, Florida, Mississippi, Louisiana, and Texas. In 1883 an epidemic of dengue appeared in Syria, first observed at Latakia on the northern coast. It spread by importation, but never reached beyond two thousand feet above the level of the sea, the high and dry mountain air seeming to be unfavorable to its propagation. Its prevalence in Beyrout was almost universal. This epidemic pre- vailed in Egypt also, and was marked by the same characteristics of pandemicity. In 1885 there was a severe epidemic in the State of Texas, 155 156 DENGUE. visiting many of the larger towns, not confined to those upon the Gulf Coast, as Galveston and Houston, but extending far into the interior, to San Antonio, Austin, Dallas, as well as to many smaller places, reach- ing an altitude of nine hundred feet above the sea level, and attacking a large proportion of the population in the infected localities. So far, with exception of the southern provinces of Spain, Europe has escaped. Dengue occasionally occurs sporadically in the places most subject to it, as in India, Northern Egypt, and various localities in the Gulf States. In Galveston sporadic cases or mild epidemics are not infrequent. Etiology.- Climate.-It will be observed from the above imperfect historical sketch that the disease is restricted to quite definite territorial limits, its latitudinal range extending from about 32° N. to 22° S., and, though in rare instances it may have occurred as far north as Boston, New York, and Philadelphia, such events are exceptional. Season.-The influence of heat as a predisposing factor is shown not only by the above facts, but by the occurrence of the disease in colder climates during the summer and autumn seasons, and its prompt disap- pearance upon the advent of winter. In strictly tropical climates, as in the West India Islands, it may prevail every month during the year, and does not seem to be affected by weather changes. In semi-tropical regions its extension into the winter months is apparently favored by an unusual prolongation of summer heat. In December, 1894, sporadic cases occurred in Galveston, as the month was unusually warm, reaching within two degrees of the highest mean temperature for twenty years. The question arises as to what influence high temperatures may have in the development of dengue. That no extraordinary range of tempera- ture occurred during the years of most extensive epidemics in Texas is shown by the following : In August, 4873, the average temperature for the month was normal; September, 1 ° above; October, 2° below; No- vember, 2° below; December, 1° below. In 1885, August, 1° above; September, 1° below; October, 2|° below; November, 1° above; De- cember, normal. A humid atmosphere appears generally to be favorable to the propa- gation of dengue fever, as will be noted by this condition prevailing in the localities where it has occurred with the greatest frequency. Such local influences are, however, not essential, as has been repeatedly shown by the occurrence of epidemics at altitudes of from six hundred to nine hundred feet above the sea level and in climates ordinarily dry and salubrious. Influence of Race, Sex, and Social Condition.-The susceptibility to this disease appears to be almost universal. During the time of its epidemic prevalence it attacks with peculiar impartiality all ages and all classes of the population. There is hardly any infection, if we except epidemic influenza, which is so indiscriminate, so general, and so rapid in its march and progress. Specific Causes.-Although the clinical history of dengue, and its apparent spread by air currents, individual contact, and fomites, point to a specific pathogenic micro-organism as its essential cause, no effort, so far as the writer knows, was made looking to the dis- covery of such causative agent until 1885. At this time, during the prevalence of an epidemic in Austin, Texas, Dr. J. W. McLaughlin ETIOLOGY. 157 macle a series of observations by which he was finally convinced that he had isolated the micrococcus of dengue. The results of these investiga- tions were reported to the American Medical Association at its meeting in 1886, were afterward briefly referred to at the International Medical Congress in 1887, and photographs of pure cultures were exhibited at the Pan-American Medical Congress in 1893. Dr. McLaughlin states : " 1. That he examined microscopically the blood of twenty persons suffering from dengue in its various stages, taking it directly from the veins, and found in all a peculiar staphylococcus. 2. Using necessary precautions to exclude alien germs and obtain chemical cleanliness, he introduced upon the point of a sterilized platinum wire a small fraction of a drop of dengue blood into test-tubes containing sterilized culture jelly, and grew upon it the same micro-organisms which the blood con- tained. 3. Using requisite precautions against the introduction of any foreign element, he aspirated into a series of Liebig's potash bulbs the blood directly from the arm of a dengue patient. The bulbs were then hermetically sealed, and those micro-organisms which the blood con- tained allowed to grow upon the contents of the bulbs as a nutritive medium. The temperature was constantly maintained at 100° F. At the expiration of six months the contents of the first bulb was examined under high power, with the result of finding the same micro-organism as was present in the blood drawn directly from the arm of the fever patient and that had been grown pure on the culture media." Dr. McLaughlin thus summarizes the results obtained from the preceding methods of examination : " I found a species of micrococcus, of un- usually small size, in the blood of all persons having dengue whom I examined, which has unique biological characteristics that distinguish this from all other species of pathogenic micrococci, and make it highly probable, at least, that this microbe is causative of dengue. The unique biological habit of this micro-organism is displayed by it in the group forms that occur when it is grown in artificial culture media. These are as follows : When a culture preparation of this micrococcus is suit- ably stained and examined with a high power (say a y^th homogeneous immersion lens), the picture that is presented to the eye will be made up of (1) circular groupings of cocci around a larger coccus (arthrospore) that is located in the centre of the group ; (2) surrounding and imbed- ding the cocci will be seen a gelatinous substance-microprotein-of definite form and shape; (3) these squares of microprotein in which the cocci are imbedded join similar squares, side to side, and thus form clear and distinct filaments. The separate segments of the filament, and the micrococci grouped around a larger, centrally located coccus in each segment, can all be distinctly seen in stained preparations when exam- ined with high-power objectives. " Not all the filaments that can usually be seen in the same micro- scopic picture are perfect in form like these described. Others will be seen that are undergoing a process of disintegration, the end of which is to liberate the cocci they contain, and filaments in all stages of disinte- gration, from the beginning of the process to its ending and the complete liberation of the cocci, will be observed. At the beginning of disinte- gration the filaments appear swollen, lose their distinct outline and the markings that differentiate their parts. Then the filaments fall away, 158 DENGUE. enlarge, and assume an imperfectly circular form, and finally coalesce and spread out, so that the picture they present (in stained preparations) is that of an irregular mosaic. The circular grouping of the cocci is still retained, while the microprotein which formed the principal mass of the segments retains sufficient of its outlines of these, at their points of coalescence, to produce the mosaic. Finally, as disintegration con- tinues, all order in the grouping of the cocci disappears, and these bodies are seen scattered irregularly over the microscopic field. But it will now be observed for the first time that each coccus is surrounded by a capsule-a covering of microprotein which it brought with it from that of which the segments were composed. All the free micro- cocci that were seen, whether obtained directly from the blood or from artificial cultures, were encapsulated. No filaments were found in the blood that was obtained direct from the veins, and I cannot be sure they were in the blood cultures made of this micrococcus. I found many bodies having the outlines of filaments, but as I found no differentiating stain that the coccus would hold when it was washed out of the blood cells by the decolorizing washes, I cannot be sure that the bodies seen in the blood cultures were the filament-group form of this coccus ob- tained from other artificial cultures. " Blood as a culture medium for this micrococcus was obtained by aspirating it directly from a vein of a dengue patient into sterilized tubes and bulbs. These were then placed in a culture oven at 100° F. and examined microscopically at different periods. All contained large numbers of the micro-organisms." As dengue is a mild disease, it will be comparatively easy to confirm these observations of McLaughlin by inoculations upon the human sub- ject. The question will doubtless be determined upon the advent of another epidemic. Communicability.-The query as to the communicability of this disease has been so far unsettled. Its rapid and widespread diffusion seems to preclude its exclusive extension by contact of individuals. On the contrary, positive facts in evidence of its conveyance along routes of travel and from one person to another point to its being communicable. The evidence goes, to show that the micro-organism which produces the disease may escape from the body of a person sick with dengue and infect another individual. Dr. Dickson states that immunity is conferred by previous attacks. He observed in Charleston that in 1850 only those escaped the disease who had suffered from it in 1828. Upon this point, however, there is no unanimity of opinion. Poggio expresses astonish- ment that one attack should protect so little from another. Thomas considers that once having had the disease a person is more liable to suffer from it than before, at least during an epidemic. The same author cites instances of patients who had dengue in Savannah in 1880 whom he had treated for the same disease previously. The truth appears to be that immunity from previous attacks is much less often conferred than in most other infectious diseases. Pathological Anatomy.-Dengue being, in the vast majority of cases, a non-fatal disease, no structural changes have been noted as characteristic. In the epidemic in Galveston of 1885 my colleague, Dr. Paine, observed a localization of inflammation upon the serous SYMPTOMS AND CLINICAL HISTORY. 159 membranes, especially the pleura and peritoneum, but these are to be regarded as complications rather than as usual anatomical changes. Symptoms and Clinical History.-The period of incubation varies from two to five days. The onset is usually sudden. The initial symp- toms are rigors or chilly sensations, headache more or less intense, pains in the muscles of the limbs and back or apparently deeper seated in the bones and joints. Coincidently there is a rise of temperature, which varies from 101° to 106° F. Anorexia is usually complete; nausea and vomiting are common ; the tongue is moist and acquires a yellowish coat. The pulse and respiration are quickened in proportion to the extent of the fever, the former ranging from 95 to 120 per minute. In children convulsions may occur at the outset, and with a high tempera- ture they are frequently delirious. The face is turgid, the eyes red and watery. The urine is rather scanty and high colored, but is rarely albu- minous. Lassitude, weakness, and restlessness are usually present and proportionate to the severity of the attack. The joints are not only pain- ful and stiffened, but in many instances swollen. These symptoms, after persisting several days, are followed in a considerable number of cases by an eruption which varies very much in appearance. Dickson describes the exanthem as appearing usually on the fifth or sixth day, and consist- ing of minute papulae, somewhat elevated, of a florid red color, distributed in irregular patches. It is noticed first in the face, then on the trunk and thighs, gradually spreading to the extremities. When fully devel- oped it is attended with some itching and burning, and generally dis- appears in two or three days with some desquamation. The eruption sometimes resembles urticaria or measles; ordinarily it is scarlatinous in form, but is less diffused than that of either rubeola or scarlet fever. The exanthem, according to the writer's experience, is absent in many cases. In all probability it varies in frequency in different epi- demics. During the progress of these symptoms the fever continues, the temperature rising on the second or third day to 102°, 103°, or even 105° F. It then declines and returns to normal on the fifth day. According to the observations of D'Aquin of New Orleans, "the tem- perature curves of dengue showed a continuous and steady rise until the highest point was reached on the first, second, or third day of the attack. Then comes a short stadium of a few hours, and then a remission, even to be followed by another rise of temperature, which, however, never reaches the maximum point of the first." The eruption generally ap- pears with the second access of fever, and simultaneously there is inflam- matory enlargement of the suboccipital, cervical, axillary, and inguinal lymphatic glands. A disposition to hemorrhages from the mucous membranes has been noted in a considerable proportion of cases. Bleeding may take place from the nose, gums, stomach, intestines, and uterus. Menorrhagia, metrorrhagia, abortions, and miscarriages are likely to occur. Convalescence is usually slow, and is characterized by an amount of prostration and weakness apparently out of proportion to the severity and gravity of the disease. The stomach is left in a weak and irritable condition ; there are anorexia, nausea, and vomiting. Not infrequently one or two weeks elapse before a restoration to the normal vigor of mind and body is established. A better idea of the symptomatology of the dis- 160 DENGUE. case will be obtained by a brief analysis of the more important clinical events. The Muscular and Arthritic Pains.- Every author who has ever described dengue has called attention to the severity of these symp- toms ; especially is this the case if he himself has been the victim. The various names which have been given to the disease are significant as to the prominence of the rheumatoid manifestations. It is hardly necessary to remark that such events should be differentiated from true rheumatism. We have in dengue an exaggeration of what is observed in many other of the infectious diseases ; that is, a predilection upon the part of the specific pathogenic agent to affect the muscular structures. There are many of the milder cases where the pain is located in the muscles, chiefly of the neck and limbs, the joints not being especially involved. Course of the Fever.-The statement that there are two paroxysms of fever separated by an interval of complete apyrexia requires modi- fication. It was founded, doubtless, upon the accounts of the earlier writers before careful thermometric observations had been made, the period of decided remission being taken for complete intermission. Thus Eugene Foster states that out of 500 cases seen by him in the epidemic at Augusta, Georgia, in 1880, there was but one paroxysm, lasting from four to seven days. Confirming the statement of Dr. D'Aquin, already quoted, that there was a continuous and steady rise of temperature until the highest point was reached, most frequently on the second day, then a short stadium of a few hours, then a remission, soon to be followed by another access of fever, which, however, never, reached the first maximum of heat, Dr. John Wortabet1 in his descrip- tion of the epidemic of 1883 in Syria says that the fever was continuous from three to five days, ranging from 99.5° to 104.5° F., being higher in the forenoon than in the afternoon, and that the paroxysm occurring on the sixth day was very rarely observed in the Syrian epidemic. The observations of D'Aquin have since been confirmed by Vauvray, who studied the disease in Egypt, also by Dr. Brun, who observed the epi- demic which prevailed in 1888-89 in Beyrout, Syria. There are, doubt- less, however, some cases, as described by Martialis of India, Thomas of Savannah, and Holliday, where there is a distinct interruption of the fever, followed by a milder secondary thermic paroxysm. The Eruption.-During the first febrile paroxysm the initial rash is observed. In India this rash has been noted by Martialis and Charles as present in from one-half to two-thirds of the cases. It is usually transitory, lasting only during the first febrile period, and varies in appearance from a slight blush to a well marked erythema. The ter- minal rash is more constantly present than the primary one. It has no uniform appearance, and may be erythematous, miliarial, urticarial, or herpetic, and is indicative, should there be no relapses, of the decline of the disease. Upon its first manifestation there is often a slight rise of temperature ; sometimes there are successive crops, and desquamation is coincident with convalescence. The frequency with which any erup- tion at all occurs varies in different epidemics. Unquestionably there are many cases where it is entirely absent. 1 Transactions Ninth International Medical Congress, vol. iv. p. 467. REMARKS on dr. brown's paper on trichinosis. Dr. Thayer.-The evidence offered by Mr. Brown in favor of the origin of the eosinophilic cells by transition from the soaoalled neutro- philes is very suggestive. The total number of polymorphonuclear cells found in the circulating blood was practically what one would expect in a leucocytosis of that extent. And yet, examining this percentage which normally should consist almost absolutely of so-called neutrophilic leu- cocytes, we find the great majority represented by eosinophiles. The fact also that in the effected parts the blood-vessels contained the same relative pr portion of eosinophiles and neutrophiles as did the peripheral vessels, while the tissues round about contained an enormously greater percentage of eosinophiles, is very interesting. That the so-called neutrophilic granules stain often with acid coloring matters is well known. With good acid dyes these granules almost always take a slight stain, and by some observers both eosinophiles and neutrophiles are classed as acidophilic cells. They stain, however, much better in fluids consisting of a mixture of acid and basic coloring matters. As Mr. Brown has sharply pointed out, this acid staining of the smaller granules was not to be made out at all in the specimens of blood and in the blood-vessels in the tissues, and the fact that outside of the vessels in the effected parts numerous apparent transitional forms between the non-granular polymorphonuclear wandering cells and the true eosinophiles existed is very suggestive* That these cells were true eosinophiles in the sense of Ehrlich, Mr* Brown h- s proven by careful tests with a number of differ- ent acid coloring matters. The idea that the eosinophiles represent a further change in the cell which we know as the neutrophile is, as Mr* Brown has said, not a new one, but I am not aware that any argument is favor of this view as forcible as that which he presents has yet been published. With regard to the actual blood condition-the increase of the eosinophiles-no similar case exists in the literature; the percentage of eosin- ophiles in this instance is more than twice as large as has been reported in any other case. AN ADDRESS ON MALARIAL FEVER DELIVERED BEFORE THE CLEVELAND MEDICAL SOCIETY BY William Sidney Thayer, M. D. Associate Professor of Medicine in the Johns Hopkins University Reprint from the Cleveland Journal of Medicine June, 1897 AN ADDRESS ON MALARIAL FEVER Delivered before the Cleveland Medical Society By William Sydney Thayek, M. D. Associate Professor of Medicine in the Johns Hopkins University GENTLEMEN: In the few words I wish to say tonight I shall endeavor to bring together some of the more important points which have been added to our knowledge concerning malarial fever since the discovery of the specific parasite sixteen years ago, and to emphasize their practical significance. I am aware that in Cleveland the disease is relatively rare, and yet its occasional occurrence and its interesting relations from a point of view of diagnosis with various other affections which are common with you here, as well as with us farther south, have suggested to me that a brief discus- sion of the subject might not be without interest. Let us first consider the pathogenic agent. From time immemorial the prevalence of fevers in damp and marshy districts has been known. In old times, however, the malarial fevers were not sharply differentiated from vari- ous other febrile processes; in particular,typhus,typhoid, relapsing fevers and other septic infections. After the introduction of quinine, Torti, in 1712, differentiated a special class of fevers which yielded to treatment by this drug. These fevers, which occur especially in warm and tropical countries, and in damp, marshy regions, showed frequently an intermittent character, and to them the term "malaria" came to be applied. It is very remarkable how early the infectious nature of malaria was sus- pected. Varro (B. C. 118-29) says: " Advertendum etiam si qua erunt loca palustria et propter easdem causas, et quod arescunt, crescunt animalia quaedam minuta, quae non possunt oculi consequi, et per aera intus in corpus per os, ac nares perveniunt atque efficiunt difficiles morbos." Thus, we see that not only was the infectious nature of the process sus- pected, but further, the infectious agent was believed to be an animal parasite. These views were maintained in 1716 by Lancisi, and later by Rasori and a number of other Italian observers. The general idea which was held concerning the manner of entrance of the infectious agent into the organism is reflected by the popular term whi.ch has since become definitely attached to the disease. The word "ma- laria" is nothing more than the Italian expression "mat' aria"-bad air. But these older ideas concerning the animate nature of the virus of ma- laria gave way gradually, especially during the early part of this century, to the theory that the parasite was of vegetable origin, this view having been especially put forward by Mitchell and Salisbury in this country. In 1879 Klebs and Tommasi Crudelli described a bacillus which they believed to be the infectious agent of malaria. This they obtained from the 2 earth in malarious districts. Their observations, though incomplete and soon disproven, gained considerable credence; so much so that fifteen years after the discovery of the true parasite one of the leading medical journals, published in the English language, referred in an editorial to the opinions of these authors as settled facts. In 1880 Laveran, a French army surgeon in Algiers, discovered in the blood of patients with malarial fever living organisms, which develop in the red blood-corpuscles of the affected individual, at the expense of which they grow and accumulate dark pigment-granules. These organisms are readily demonstrable microscopically, either in the fresh blood or in dried and stained specimens. From the universal presence of these parasites in the blood of patients with malarial fever, their immediate disappearance with recovery, either spontaneous or under treatment by quinine, Laveran believed himself justified in assuming that they represented the true pathogenic agent of the malady. Despite the opposition which the discovery of Laveran met with at first, you well know how universal has been its confirmation by all observers who have had opportunity to properly study the disease. The great value of this advance, apart from the light which it has thrown upon the general pathology of malarial fever, is readily appreciated when we consider that it has furnished us with a simple and certain method of diagnosis of the disease. Now, though the discovery of the presence of a living animal parasite in the blood of all patients with malarial fever-a parasite which disappears with the recovery-is strong presumptive evidence of the intimate relation between the symptoms and the organism; yet we must acknowledge that only one of Koch's three postulates essential to determine the causal relation between the parasite and the disease has been fulfilled. For the absolute proof of this causal relation we need in addition: (a) To obtain the organism in pure culture outside the body; (0 To transfer the disease by inoculation from the pure culture into healthy individuals. The cultivation of the parasite outside the body has never yet been accom- plished, but we have in the blood of the infected individual, which is other- wise sterile, essentially an already prepared pure culture; and repeated experiments by Italian, Russian and German observers have shown that intravenous or hypodermic inoculation of the blood of an infected individual will always transfer the infection. As has already been said, Laveran's discovery has been almost univer- sally confirmed by all observers who have had opportunity to properly study the disease. And to our credit be. it said that our countrymen have been among the foremost in continuing his work-Councilman and Abbott, Stern- berg, Osler, James and Dock having early recognized the importance and value of the discovery. 3 After Laveran, the next great advance was made by Golgi, who, in 1885, studied the parasites observed in quartan and tertian fever, tracing all the steps in their life-history and reproduction, and noting the remarkable rela- tion which exists between the development of the parasites and the clinical manifestations of the fever. Further studies by Roman observers and also by Golgi of the more irregular and pernicious fevers occurring in the tropics, and during the later summer and fall in temperate climates, have led us to recognize today three main types of the fever, each of which is associated with a special type of the malarial parasite: (1) Tertian fever. (2) Quartan fever. These may be classed as the regularly intermittent fevers; they occur in temperate climates throughout the malarial season, forming the only cases in the earlier part of the year. (3) The more irregular fevers which have been termed by the Italians the "acstivo-autumual" fever. This type of the disease occurs commonly in the tropics, but in temperate climates it is observed only during the height of the malarial season; that is, during the later summer and early fall. * * * The Parasites of the Regularly Intermittent Fevers; the Tertian and Quartan Parasites. We now know that in tertian and quartan fever the parasites exist in the blood in enormous groups, all the members of which are approximately at the same stage of development. The parasites constituting such a group enter the red corpuscles as small, clear, amoeboid, hyaline bodies, which de- velop within the corpuscles, increasing in size and accumulating dark pig- ment-granules as a result of the destruction of the hemoglobin of the contain- ing element. When the parasite is fully developed the pigment gathers into a single block or a clump of coarse granules, and the organism breaks up into a number of small, round hyaline bodies, each of which represents a fresh young parasite. These small hyaline bodies enter fresh red blood-corpuscles and pursue again their cycle of development. The length of the cycle of development of a group of tertian parasites lasts almost exactly 48 hours; so that, if one group be present in the blood, sporulation will occur every other day. On the other hand, the cycle of existence of the quartan parasite lasts approximately 72 hours, sporulation ■occurring every fourth day. Now, the remarkable fact was discovered by Golgi that the malarial paroxysm is always associated with the sporulation of one of these groups of parasites. Thus, if one group of tertian parasites be present in the blood, sporulation will occur every other day, and with every period of sporulation there will occur a typical malarial paroxysm-tertian intermittent fever. In infection with quartan organisms, whose cycle of existence is longer, lasting 72 hours, sporulation and the resulting paroxysm occur only every 4 fourth day-quartan intermittent fever. Furthermore, it has been shown that, all things being equal, the severity of the manifestations of the infec- tion depends largely upon the number of parasites actually present. The mere existence of parasites in the blood is not sufficient to produce fever; the group must reach by multiplication a certain sufficient size. Thus, ordinarily, a considerable period of incubation is required for the develop- ment of malarial fever, during which time a group of parasites is passing through its regular cycle and reaching over larger proportions by its gradual multiplication. In experimental infections it requires usually about ten days or two weeks for the parasites inoculated to reach by multiplication a number sufficient to produce well marked manifestations. Not infrequently more than one group of the tertian or quartan organ- isms may be present, but more than two groups of the tertian or three of the quartan are extremely rare. In infections with two groups of the tertian organisms the parasites reach maturity, almost invaribly, upon successive days; the result thus is quotidian intermittent fever. When two or three groups of the quartan organism are present, they also arrive at maturity usually on successive days, so that there follow either two days with intermittent parox- ysms, followed by one day of complete intermission, or a quotidian fever due to three groups of the parasite. The morphological differences between the tertian and quartan parasites it is impossible to enter into at length in so short a space as is allotted to me tonight. You will observe upon the chart the main points of difference, which are well marked. The most important are the greater size of the tertian organism, its greater amoeboid activity, the larger number, greater activity and smaller size of the pigment-granules; the fact that it breaks up into a larger number of spores than does the quartan organism, while the containing red corpuscle becomes gradually expanded and decolorized. The quartan parasite as you see is smaller: the granules are less motile, less numerous and coarser; the parasite breaks into a smaller number of segments, while the containing red corpuscle becomes rather contracted and deeper colored. The Aestivo-autumnal Parasite. The third variety of fever, the aestivo- autumnal fever, is associated with the presence of organisms which possess distinct morphological and biological differences from those described above, the chief being their much smaller size. There are, however, certain other important biological variations. They develop, for instance, largely in the internal organs, appearing in the peripheral circulation only during the earliest stages of their existence, when they are represented by small amoeboid, non-pigmented, hyaline bodies. The larger forms, forms containing more than a few scattered granules of pigment, are relatively rare in the peripheral circulation; the segmenting bodies are only found in the blood of certain internal organs, especially the spleen, bone-marrow, brain and liver. I have 5 seen segmenting bodies in the peripheral circulation but three times in this type of fever. In this type of malaria there appear, also, after the infection has lasted about a week, larger pigmented crescentic or ovoid bodies, which do not apparently pursue the ordinary cycle of development, bodies which are very resistant to quinine. They represent probably sterile forms as long as they remain in the blood, though it cannot be denied that, as some maintain, they may be capable of further development outside the body. A striking biological feature of the aestivo-autumnal parasite, or, as Dr. Welch has happily termed it, ''Hacmatozoan falciparum," is the fact that the organisms are often accumulated in great numbers in certain special parts of the body. These special localizations of the parasite in various internal organs may give rise by the changes there produced to distinct clinical symptoms. Another difference from the organisms of the regularly intermittent fevers is the fact that they are often present in multiple groups or sometimes in great numbers, apparently at almost all stages of development, so that the regular arrangement in groups is lost. In those cases in which distinct groups may be made out the length of the cycle of existence appears to vary from 24 to 48 hours, or a little more. Marchiafava and Bignami believe that they can distinguish morphologi- cally and biologically two varieties of these parasites, one with a shorter and the other with a longer cycle, a view, however, which we have been unable to confirm. The fevers with which these organisms are associated show, as one might expect, a much more irregular course than do the tertian and quartan fevers, and, not infrequently, there may be an irregularly remittent elevation of temperature. In summary, then, we may say that we must now recognize: (a) That malarial fever is due to infection with hemocytozoa, which de- velop within the red corpuscle; (&) That three varieties or more probably species of these organisms are to be distinguished, each associated with a distinct type of fever-namely, the tertian, the quartan, and the aestivo-autumnal parasites. (c) That these parasites, in the regularly intermittent fevers, are present in great groups, all the members of which are approximately at the same stage of development. (d) That the same is often true of the aestivo-autumnal parasite, though the tendency toward multiplication and the obliteration of sharply distin- guishable groups is much more marked. (e) That the malarial paroxysm occurs always in association with the sporulation of a group of parasites. iperature. 6 (f) That the severity of the symptoms in any given infection depends to a great extent upon the number of parasites present. * ★ * We have seen that the causal relation of the parasites to malarial infec- tions may be regarded as a settled fact. Let us now consider more intimately the manner in which the parasites bring about the clinical manifestations. The Febrile Paroxysm.-The observations of Golgi which have been al- most universally confirmed, show that the malarial paroxysm is always coin- cident with the sporulation of a group of parasites. The intermittent fever is thus easily accounted for by the remarkable arrangement of the parasites in groups sporulating at regular intervals, as has been already referred to. In infections with the aestivo-autumnal parasites, in which the groups are so fre- quently multiple, or in which, indeed, this arrangement may be absent, the fever, as one might expect, is often irregular or continuous. But why should the sporulation of a group of parasites be followed by fever? Golgi first suggested that the fever was the result of the invasion of the red corpuscles by the fresh young spores arising at the time of segmentation. But Antolisei, by a simple clinical observation, which may be confirmed at any time by the bedside, showed that this could not be the case. He called attention to the fact that if a large dose of quinine be given just before a malarial paroxysm, the segmentation of the ripe group of parasites will not be hindered, but the new organisms will all be destroyed before they enter fresh red blood-corpuscles; no fresh invasion of red elements takes place and the parasites disappear from the blood. The impending paroxysm occurs just the same, but no further symptoms follow. It cannot then be the invasion of fresh red corpuscles by the young parasites which is re- sponsible for the paroxysm, but rather something which occurs at the time of sporulation. Baccelli was the first to suggest, from analogy with other infectious processes, that the paroxysm is due to a circulating toxic substance set free by the parasites at the time of sporulation. This view, which seems most rational, has been accepted by most observers, and, indeed, there is much to support it. That the chill and fever are produced by toxic substances in the circula- tion is strongly suggested for the following reasons: 1. Analogy with other infectious processes. 2. The fact that observations by Brousse, Roque and Lemoine, Botazzo and Pensuti have shown that there is a marked increase in the toxicity of the urine passed during and just following the malarial paroxysm. 3. The greatly increased toxicity of the sweat obtained during the malarial paroxysm as compared with that of normal individuals, as shown by the observations of Queirolo. 4. The strongest evidence, however, of the existence of a circulating toxic substance is found in the presence in the organs of patients dead of acute malarial infection of areas of disseminated focal necrosis, closely simi- lar to those which occur in various other severe infectious diseases. These areas have been clearly shown by Flexner to be pathognomonic of a general toxemia. We have thus practically conclusive evidence of the existence of some toxic substance circulating in the blood. Is this a specific toxine set free by the hematozoa, or may it, perhaps, be the result of changes produced in the organs or tissues by the action of the parasites, such as, perhaps, the destruc- tion of numerous red corpuscles, with the setting free of a considerable quantity of hemoglobin? Let us consider what happens at the time of the paroxysm. The par- oxysm, as has been said, immediately follows and is intimately associated with the sporulation of a group of malarial parasites. There occurs at this period: 1. The segmentation of a large number of full-grown parasites into fresh young organisms, while the pigment (and possibly some small quantity of the cytoplasm of the parasites) are left behind. 2. The liberation of a large number of full-grown and segmenting organisms, while the including red corpuscles are disintegrated and de- stroyed, and the remains of these, together with a certain amount of hemo- globin which they yet contain, are left to be cared for in the circulation. 3. The escape from the red corpuscles of a considerable number of full-grown parasites which become degenerated and fragmented. These, with the remnants of the segmenting forms are usually engulfed by phago- cytes. 4. The rupture of a certain number of uninfected red corpuscles which ?et free their hemoglobin in the general circulation. We might imagine that these toxic substances arising at the time of the paroxysm result from the destruction and disintegration of a large num- ber of red blood-corpuscles; or that they are liberated by the parasites themselves at the time of sporulation, and possibly also by the fragmenting full-grown forms which are usually to be seen at this period; or we may imagine that both these factors play a part. It may be that the destruction of a large number of red corpuscles exerts a toxic influence upon the organism. In other conditions, however, in which this occurs, it is difficult to separate the effect of the blood-destruction from that of the exciting cause, while extensive blood-destruction is by no means always associated with a sharp febrile paroxysm. Thus, in poisoning by chlorate of potassium or carbon monoxide, when great numbers of red blood- corpuscles are destroyed, with consequent hemoglobinuria, fever may be practically absent. 7 8 There are, then, many reasons which might induce us to believe that Baccelli's supposition is true; that the toxic substance or substances responsi- ble for the paroxysm are liberated by the sporulating parasites. The remains of the disintegrated red corpuscles may exert a toxic effect, but it is scarcely probable that they play the primary part in exciting the paroxysm. The Anaemia.-The discovery of the malarial parasite has enabled us easily to account for the anaemia which is so characteristic of malarial infec- tions. This depends not only upon the constant destruction of the red blood- corpuscles in the circulating blood, but in more chronic cases upon the ex- tensive changes in the blood-forming organs which are brought about by the infection. The jaundice also is a direct result of the extensive blood-destruction. It is not, strictly speaking, hematogenous. The remains of the destroyed red blood-corpuscles and the hemoglobin set free are disposed of ordinarily by the liver through the bile; the increased blood-destruction results in so extensive a polycholia that from the inspissation of the bile and the over- crowding of the bile capillaries, absorption of bile with jaundice occurs. Pernicious Symptoms.-But among the most interesting results which have followed the recent studies of malarial infections have been the explanations which we have found for some of the pernicious symptoms which are especially common in aestivo-autumnal infections. These symp- toms have been shown to be in many instances directly due to the special localization of the parasites in certain internal organs. Cerebral Symptoms.-The frequency of cerebral symptoms in pernicious malaria is well known. Often, probably, the delirium and other manifesta- tions are due to circulating poisons, but in many cases with symptoms refer- able to disturbed brain functions, coma, general or local convulsions or paral- yses, post-mortem examinations have clearly demonstrated their dependence upon local disturbances produced by the accumulation and development of enormous numbers of parasites in certain parts of the central nervous system. In many cases of fatal comatose malaria the capillaries of the grey cortex throughout may be crowded with parasites free and in red corpuscles. In some instances actual thromboses may occur, resulting in serious local changes. Sometimes definite local symptoms have been shown post-mortem to be due to changes resulting from the special accumulation of parasites in small areas of the brain or cord. Thus, in one instance of pernicious fever, with symptoms of bulbar paralysis, Marchiafava was able to demonstrate post-mortem a special localization of the parasites, with quite extensive sec- ondary changes in the medulla oblongata. In like manner the well-known choleriform type of pernicious paroxysm has been shown to be due to the special localization of enormous numbers of parasites in the gastro-intestinal mucosa. 9 It may be that those instances of pernicious fever, which I have never had the opportunity to observe, but which have been well described by Baccelli in particular, those cases associated with marked pulmonary symp- toms, are due to a special localization of the parasites in the capillaries of the lungs. * * * Manner of Infection.-From what I have said it is easy to appreciate how deep an insight we have gained into the causes and nature of this important disease, and yet much remains to be done. For instance, we have no idea as to the form in which the malarial parasite exists outside the human body, nor of the manner in which infection occurs. Owing to our ignorance of the former condition we are naturally more or less at sea in our attempts to eluci- date the manner of infection. Does infection occur through the'respired air, or through the gastro-intestinal tract? Or may it possibly be transmitted subcutaneously by means, perhaps, of insect bites? You well know how general the idea is that malarial infection takes place by means of the inspired air. Indeed, there seems to be almost overwhelm- ing evidence in favor of the view that infection may take place in this manner. And yet definite proof we do not possess. In like manner many observers believe that malaria may be a water- borne disease. It must, however, be said that numerous attempts by Celli, Marino and Zeri to produce infection by the administration of water from the most malarious districts, by the mouth, by rectum and as an inhalation, have failed. Grassi and Feletti have furthermore caused patients to drink dew collected from malarial districts, and, indeed, fresh human blood con- taining malarial parasites, and in every instance with a wholly negative result. That malaria may be transmitted by hypodermic or intravenous inocu- lation has been indisputably proved by a large number of carefully carried out experiments. And recently a considerable impetus has been given to the idea that malarial infection may be brought about by the bites of certain insects, especially the mosquito. Laveran, Bignami and others have called attention to the fact that many of the precautions adopted in severely malarious districts against infection are just such as might be directed against the bites of insects, and especially mosquitoes. The discovery of Theobald Smith that the hemocytozoon {pyrosoma bigeminum) of Texas cattle fever is conveyed from one animal to another by means of the cattle-tick, and that of Bruce, that the cause of the tsetse-fly disease is an hemocytozoon which is introduced by bite of the insect, are certainly suggestive, relating, as they do, to parasites so closely allied to the malarial organism. The theory recently put forward by Manson, who suggests that the mosquito may represent an intermediate host of the malarial parasite, 10 playing the same role that it does in the case filaria sanguinis hominis, is very interesting but purely hypothetical. Much of this idea Manson bases upon the discovery that flagellate bodies may develop from crescentic forms within the stomach of the mosquito; but this fact, though very interesting, is not remarkable, when we consider that they develop outside of the body upon the fresh slides of blood. That malarial infection may take place through the bites of insects is an interesting possibility, but it is by no means proven. * * * Now, what practical results have we gained from these interesting ad- vances of the last fifteen years? The most important certainly is the estab- lishment of a positive diagnostic criterion; but further, as a direct result of this we have learned much that is important with regard to the methods and effects of treatment. The only positive diagnostic sign of malarial fever is the discovery of the parasites in the circulating blood. The search for the organism is a relatively simple matter to anyone who is familiar with the use of the micro- scope and the examination of the blood. It is, however, just as impossible for one who is not familiar with appearances of fresh blood, as well as of its more important pathological changes, to determine the presence or ab- sence of certain forms of the malarial parasite, as it is for one who is ignorant of the kidney to determine fine structural changes in a microscopical section of that organ. This is a point which should not be forgotten. The study of the blood has until very recently been neglected in our medical institutions, and there are but few who have not paid especial attention to this subject who are capable, without a certain amount of practice and study, of forming an en- tirely reliable opinion concerning certain forms of the malarial parasite in a specimen of blood. For one who has not paid particular attention to the appearance of fresh or stained specimens of blood, not days, but weeks, nay, even months of study may be necessary before he becomes capable of posi- tively deciding upon the nature of various changes which are not infre- quently met with in the circulating blood, changes which sometimes very closely simulate malarial parasites. On the other hand, it should be said that the large tertian and quartan organisms and the crescentic and ovoid forms occurring in aestivo-autumnal fever are readily recognizable by anyone who has seen them a few times. The positive diagnosis of such cases is easy. In the case, however, of certain of the smaller forms, especially of the aestivo-autumnal parasite, the opinion of a skilled observer alone is reliable, a statement which is, unfortunately, daily proved in current medical literature. Many physicians who are in active general practice are as unable to give proper time for such examinations as they are to satisfactorily examine the sputa in many doubtful cases of tuberculosis, but it is always possible for such a physician to prepare dried smears of blood and to send them to- an individual who is capable of properly studying them. Far be it from me to say that the examination of the blood is always necessary for a practical diagnosis of malarial fever. In the vast majority of instances the therapeutic test is sufficient, and one of the greatest benefits which the discovery of the parasite has brought to us has been the definite proof of this fact. This is one of the most important services which the discovery of the parasite has rendered to us. How often previously in fevers which have not presented all the ordinary clinical manifestations of typhoid has the physician remained in doubt as to their possible malarial nature, even after they have failed to yield to quinine! The discovery of the parasite has taught us that the failure of such a fever to respond within three or four days to the drug is absolute proof of its non-malarial nature. The importance of this fact cannot be overesti- mated, and no one feels it more than the physician who has practiced for any length of time in a district where both malaria and typhoid fever are common. There is no excuse today for cinchonizing a patient with typhoid fever; if treatment by sufficient doses of quinine prove ineffectual after four days we may abandon our diagnosis of malarial fever. Another point which the discovery of the parasite has assisted in elu- cidating is the subject of the so-called "typho-malarial" fevers. Improved methods of observation have shown that the complication of typhoid and malarial fevers is relatively rare. It would indeed be extraordinary if occa- sional cases did not occur, and such cases are observed, but in these instances the case presents features of a simple complication of two distinct and sepa- rate diseases. There is nothing characteristic in the course of such infec- tions. The malaria is as readily amenable to treatment as under other con- ditions. The great majority of chills occurring in typhoid fever have nothing whatever to do with malaria; the parasites are not present in the blood and the manifestations are unaffected by quinine. Such chills represent in most instances, probably, secondary infections or auto-intoxications of intestinal origin. There is no such disease as "typho-malarial" fever, and the sooner we cast aside the term the better. Certain forms of aestivo-autumnal continued malarial fever may, how- ever closely simulate typhoid, and it may not be out of place here to enter for a moment more minutely into the points in differential diagnosis. I have upon the chart a table, taken from a publication now in press* which presents in parallel columns the more important points of difference between the re- mittent aestivo-autumnal fever and typhoid fever. 11 12 REMITTENT FEVER Onset generally intermittent. Irregular remissions. The temperature may arrive at 40° (104°) within twenty-four hours. Headache rare in the beginning; of a neuralgic character, pulsating, vari- able in its position and intensity. Sclera subicteric from the onset. The apathetic expression of the face, the dryness of the tongue, sordes upon the teeth are not very marked. Breath foul. • The delirium may come on in the early days; it is recurrent but changes with the exacerbations of temperature and other symptoms, and may give way to grave symptoms related to other organs. If there be pulmonary congestion the cough and other symptoms come on suddenly; the areas affected change from one to the other lobe or lung and may disappear and reappear again with varying intensity; dyspnea is very pro- nounced; circulatory disturbances are marked, even syncope. There is usually restlessness and anxiety, (jactatatio corporis). Peculiar greyish yellow color of skin; sometimes a slight jaundice. Herpes common. Anaemia more or less marked early in the course. No characteristic exanthem; urticaria not uncommon. At times there may be transient tympa- nites or ileo-cecal gurgling; they are but slightly pronounced and paroxys- mal; diarrhoea is slight or absent and has not the characters of that in ty- phoid fever. No distinct course. Urine, high-colored; may show a trace of bile; Ehrlich's diazo reaction rarely present. Blood shows no leucocytosis; eosino- philes not notably diminished; serum does not cause agglomeration of ty- phoid bacilli (Pfeiffer, Durham and Widal); malarial parasites and pig- mented leucocytes present. Fever disappears under quinine. Is an endemic disease occuring particu- larly in rural districts; rarely epidemic. TYPHOID FEVER Onset gradual and progressive. Regular, though very slight morning re- missions with evening exacerbations of temperature. The temperature does not reach 40° (104°) before the third or fourth day. Headache from the beginning; perma- nent, severe, frontal. Sclera white. These symptoms are well marked and progressive. Breath has a peculiar mouse-like odor. Delirium appears only when the disease is well pronounced; it is often persis- tent and variable only in degree. Pulmonary congestion is gradual and persistent; always hypostatic (the bases and dorsal surfaces of the lungs); the dyspnea is less pronounced, and later in appearing, depending more upon the abdominal conditions (tympanites, &c). There is usually relaxation, prostration, stupor. No jaundice. Herpes rare. Anaemia absent excepting in later stages. Characteristic roseola. Tympanites, gurgling, diarrhoea appear slowly and may become well marked. Has a fairly characteristic course. Urine high-colored; bile absent; diazo- reaction present during the height of the process. Blood shows no leucocytosis; eosino- philes diminished or absent; serum causes agglomeration of typhoid bacil- li; malarial parasites and pigment ab- sent. Fever uninfluenced by quinine. Usually epidemic; prevailing commonly in cities. ♦Lectures on the Malarial Fevers. 8vo. D. Appleton & Co. 13 I doubt if the medical public realizes altogether how much the discovery of the parasite has taught us with relation to this one point in the differential diagnosis of malarial fever. We are carried slowly onward on the river of medical progress into new ideas and theories, and gliding almost uncon- sciously out of the old forests of obscurity into the ever-widening clearings opened by science, we often forget how much we have learned in a rela- tively short period of time. We know today that in Baltimore, for instance, a district where malarial fever is extremely common, fatal malaria is a rare occurrence; we know that, barring a few imported pernicious cases, fatal malarial fever is almost un- known in such a city as New York or Brooklyn, and yet, gentlemen, let me call your attention to a few statistics taken from the United States census for the six years ending in 1890, statistics to which attention has already been called by Dr. Osler. In the city of New York during these six years there were reported: Deaths from malarial fever, 2,060, or 24.26 per 100,000 of average population. Deaths from typhoid fever, 2,031, or 24.27 per 100,000 of average population. In Brooklyn for the same period there were reported: Deaths from malarial fever, 1,413, or 32.62 per 100,000 of average population. Deaths from typhoid fever, 1,002, or 23.13 per 100,000 of average population. In the city of Baltimore during the same period of time there were reported: Deaths from malarial fever, 934, or 41.51 per 100,000 of average population. Deaths from typhoid fever, 904, or 40.17 per 100,000 of average population. Now, gentlemen, during the seven years since the Johns Hopkins Hos- pital was opened, two of the years being included among those in which these census statistics were compiled, there occurred in the hospital: Deaths from malarial fever, 3; deaths from typhoid fever, 48; a proportion of one death from malarial fever to sixteen from typhoid. It is wholly safe to say that at least nine-tenths of these reported statistics are incorrect, the vast majority of the so-called cases of malarial fever being doubtless typhoid. And we forget that as short a time as seven years ago we regarded such statistics as these with complacency. But if the Baltimore statistics are surprising, in Brooklyn and New York, where it is extremely doubtful whether a single case of pernicious malarial fever occurs, apart, perhaps, from a few coming from the tropics, the statistics are simply appalling; and let me repeat, there is no excuse for such statistics today, for the discovery of the parasite has not only given us in itself a sure method of diagnosis, but it has taught us to realize with what complete confidence we may rely upon the therapeutic test with quinin in the differential diagnosis of malarial fever. The discovery of the malarial parasite has been of invaluable assistance in the differential diagnosis of a number of other manifestations of malaria 14 which might otherwise be overlooked. This is especially true in certain pernicious paroxysms, particularly the comatose form which is frequently confounded with sunstroke. In algid and choleriform paroxysms, which may occur indeed without a chill and with sub-normal temperature, the examination of the blood may often save life by giving us an immediate diagnosis. The examination of the blood is also of considerable assistance at times in helping us to make a ready diagnosis between early tuberculosis and certain septic conditions associated with intermittent fever. Had we in private practice a carefully-kept two-hourly chart to show us the exact hour of onset and the exact duration of paroxysms in all these instances, our diagnosis might be relatively simple, but we know too well that this is not the case, and confusion between early tuberculosis and malaria in the neighborhood, for instance, of Baltimore is excessively common. A ready means of differential diagnosis between malarial fever and various post-partum and post-operative infections is afforded us by the pres- ence of the parasite in the blood. Careful observation tends to show that the majority of post-partum and post-operative chills are not malarial in nature, and the early recognition of this fact, as permitted by blood exam- ination, should put us on the lookout for some other septic complication. Now, gentlemen, can we say with assurance that the malarial parasite is always to be demonstrated in the circulating blood in every malarial infec- tion? May we positively deny the existence of a malarial infection from the absence of the parasite in specimens of the circulating blood? Literally speak- ing, we cannot, for there are instances of malarial infection in which careful search of the blood fails to show the parasite. Practically, however, we can, for such cases are rare and unimportant. In any case of tertian or quar- tan fever of sufficient severity to produce symptoms, reasonably careful ex- amination of the blood will always show the malarial parasite. Occasionally, in aestivo-autumnal fever, in which, as has been before noted, the parasites tend often to gather especially in the internal organs, particularly at a period during or just before a paroxysm, the number of parasites in the peripheral circulation may be extremely small, and rarely, though occasionally, a single careful examination may prove negative. Almost invariably, however, a subsequent examination will reveal the parasite. There are no cases of pernicious malaria in which the parasites are not present in the blood in sufficient quantities to immediately call our attention to the nature of the case. What have we learned with regard to the treatment of the disease? Much. We have learned, in the first place, that quinine is a true specific. We have definite proof that those occasional cases in which quinine has ap- peared to be inefficacious are clearly not cases of malaria, or at least are cases in which there is a complicating disease. 15 We have been confirmed in our ideas as to the time when quinine should be given to the most efficacious, by the explanation of the cause of its action. It has been shown that the organisms are most readily affected at the time when they are free in the circulation, and that period only occurs at the time of sporulation, namely, just before and during the paroxysm. In ordinary intermittent fevers a sufficient dose of quinine, given just at the time of the paroxysm, will almost entirely destroy the group of para- sites then segmenting, and will prevent, for some time, at least, further mani- festations on the part of that group of parasites. Continued treatment, however, is usually necessary to entirely destroy the infection. We have then a practical foundation for the fact already made out that the time at which the best result is to be obtained from the administration of large doses of quinine is just at the period of the paroxysm, or at the time when the parox- ysm would have occurred, had previous treatment been omitted. * * * But I have already passed beyond my proper limit of time. Let me remind you, however, in conclusion, that Laveran's discovery of the parasite, which has done so much to bring order out of the chaos of our continued fevers, was not made by chance; it was the result of carefully planned in- vestigation. Such results as this do more to prove the value of careful, scientific clinical and laboratory observation than books of argument. We now know the pathogenic agent of malarial fever; we possess a simple and certain method of diagnosis; we have in quinine a true specific remedy for the disease. But we have yet a higher goal to reach. We must discover a means of prevention, and the first step toward this is to discover the method of infection. It may well be that we are not far from this discovery. It is one of the most hopeful fields for research which is now open to us, and it is a field in which our climate offers us unusual opportunities for study. Let us hope that we in America may play as honorable a role in the clearing up of the obscure questions connected with malaria as did our illustrious predecessors, the little group of students of Louis, in the differ- entiation of typhus and typhoid fever. COMPTES-RENDUS DU XII CONGRES INTERNATIONAL DE MEDECINE MOSCOU, 7 (19)-14 (26) 40UT 1897. EXTRAIT MEMOIRE Par MOSCOU. Societe de rimprimerie „S. P. Yakovlew", Saltykovski pereoulok, 9. 1OOO. A. Mosse, Excretion urinaire apres les acces palustres. 125 ree (44 gr., 56 gr. et meme 58 gr. d'uree en 24 heures), comme nous i'avons signale alors quo le malade n'a pas encore regu une alimen- tation tres azotee. b) L'excretion de l'acide urique, chez trois malades observes pen- dant un certain temps apres les acces febriles, a ete sensiblement aug- mentee dans les 24 heures. Proportionnellement, l'augmentation de cet element etait bien plus accentuee que celle d'uree. De plus, la courbe de l'excretion de l'acide urique et celle de l'excretion urinaire affectent un parall^lisme plus regulier que celui des courbes de l'excretion ureique et urinaire. Le graphique fourni par un de nos malades frappe a nouveau de plusieurs acces (type tierce) tant qu'il etait en convalescence deja depuis quelque temps, permet de saisir d'un coup d'ceil et failure generale du phenomene et le pa- rallelisme que nous venons d'indiquer. c) L'excretion de l'acide phosphorique total, diminuee au mo- ment de l'acces, comme Rem Picci l'a deja signale *), subit pendant les jours suivants une augmentation parfois tres sensible. L'un de nos graphiques montre un parallelisme tres apparent des courbes de 1'ex- cretion urinaire, ureique et phosphorique, pendant la polyurie aigue. Mais Failure du syndrome urologique n'est pas toujours aussi regulier que dans ce cas. d) Nos dernieres recherches sur 1'elimination des chlorures confirment et completent ce que nous avions deja constate a ce sujet. Diminuee, ordinairement mais non toujours, au moment des paroxis- mes febriles, l'excretion chlorurique se releve assez rapidement apres l'acces. Pendant la polyurie elle peut atteindre des chiffres treseleves (30 gr. a 40 gr., et meme le chiffre colossal de 65 gr. en 24 heures). Les chlorures sont 1'element dont l'excretion subit habituellement la plus grande augmentation au moment de la polyurie. L'alimentation peut favoriser cette augmentation, comme nous sommes parvenu a en avoir la preuve experimentale dans une de nos dernieres observations, mais 1'influence du regime alimentaire, quoique sensible et tres reelle, est insuffisante pour expliquer cette hyperchlorurie qui peut d'ailleurs se produire independamment de l'alimentation. e) Toxicite urinaire.-Nos recherches sur ce point ne nous ont pas donne de resultats absolument concordants. Comme Brousse, Ro- que, Lemoine, nous avons trouve parfois la toxicite urinaire augmen- tee, et cette augmentation a pu coincider avec la polyurie. D'autres fois les resultats ont ete moins nets, parfois meme le coefficient uro- toxique a ete inferieur a la normale. La raison de cette discordance parait tenir a deux causes: 1° difference de resistance individuelle a 1'intoxication presentee par les divers animaux sur lesquels on expe- rirnente 2); 2° difference dans la proportion des divers elements toxi- ques contenus dans les urines, suivant les sujets. Nous n'apprecions que 9 Sulla eliminazione dei fosfati nolle urine dei malarici („Policlinico" 1894., f. 4). - La secrezione urinaria nella infczion • malarica (1896 p. 76). 2) Avec une meme urine injectee dans les memes conditions et presque au meme moment a deux'lapins que 1'on nous assurait etre de la meme portee, nous avons constate une difference de 1ji environ dans les chiffres obtenus comma coeffi- cient urotoxique. Mrs Bouchard & Charrin ont d'ailleurs fait mention de cette variability du reactif vivant. 126 Section V: Maladies internes. la toxicite totale, in gio bo, de tous ces elements toxiques, mais, ainsi que l'a parfaitement fait remarquer Mr. Ie Professeur Bouchard, leur individuality physiologique se revele par la fa^on dont ils agissent sur les diverses appareils de 1'organisme intoxique (pupille, glandes sali- vaires, rein, systeme nerveux). Nous avons observe plusieurs fois au cours de ces recherches experimentales que les animaux qui urinent frequemment pendant que 1'on pratique 1'injection intra-veineuse (toutes les conditions de 1'injection restant sensiblement les memes: tempera- ture, vitesse, etc.), peuvent recevoir impunement dans les vaisseaux une quantite d'urine beaucoup plus considerable que ceux chez les- quels cette diurese protectrice ne se produit pas. Ainsi nous parait se trouver confirmee 1'opinion que nous emet- tions il y a quelques annes deja: que si la polyurie aigue malarique, dont nous avons fait connaitre 1'existence, presente plusieurs caracte- res d'un syndrome critique dans bien des cas, sa nature la rapproche des polyuries aigues observees au debut de la convalescence des ma- ladies infectieuses. Meritant bien nettement dans quelques cas le nom d'eliminative, propose par Rem Picci, elle parait, dans d'autres, n'entrainer au dehors ni exces de dechets organiques, ni forte proportion d'elements toxiques, elimines parfois avaut que la polyurie se produise. Prof. Thayer (Baltimore). On the Increase of the Eosinophilic Cells in Trichinosis. In the April number of the „Bulletin of the John's Hopkin's Hos- pital " Brown reports some extremely interesting studies upon trichino- sis made chiefly upon specimens of the blood and muscles of a case, which occured in the medical clinic under our observation. In this communication the very remarkable fact was pointed out, that the blood showed an enormous percentage of eosinophilic cells, the proportion reaching at one time as high a point as 68,2% of the entire number of leucocytes. Brown remarks justly, that „the presence of such quan- tities of eosinophiles suggests their possible diagnostic value in trichin- osis". The occurrence of a second case with similar manifestations would appear to entirely justify our suspicions as to the great dia- gnostic importance of this increase in eosinophilic cells and it has seem- ed to me advisable to present here a brief summary of these two in- stances. The careful studies of Dr. Brown will appear at length in an early number of the Journal of Experimental Medicine. Case I. R. T. aged 28; Englishman by birth; was admitted to the John's Hopkin's Hospital on the third of March 1896, complaining of general muscular pains and weakness. The patient, who was a repor- ter by occupation, had been leading the life of a tramp for some time before entry, sleeping at times out of doors and often deprived of sufficient nourishment. His family and previous history had no relation to his complaint at that time. Present Illness: For six weeks he had complained of .,irregular indefinite pains'1, as he expressed it, in his joints, bones and muscles Thayer, Eosinophilic Cells in Trichinosis. 127 and for two weeks before entry had been so much worse, that he had had great difficulty in moving about. There was a feeling of fulness in the head, and great muscular tenderness and weakness, so much so that he had to be assisted in putting on his clothes. He was un- aware of having had fever. There had been no oedema. The physical examination showed a well nourished man of medium size, tongue thickly coated; slight pallor of the lips and muc- ous membranes; temperature on admission 102 F.; pulse 104; respirat- ion 24. The thyreoid gland was rather large, particularly the left lobe. Examination of the thorax and abdomen was negative; the lungs were clear on auscultation and percussion; cardiac area was normal. There was a soft systolic murmur over the heart, most marked in the pulmonary area, heard a short distance out into the axilla. The spleen was not palpable; there were no rose spots. There was great muscular tenderness and lameness. Light touches upon the skin and pinching of the skin causes no distress, while deep- er pressure upon the muscles were followed by considerable pain, especially in the muscles of the arm, thighs, legs and gluteal regions. There was no tenderness felt in the course of the long bones. The muscular tenderness was general. The patient lay quietly in bed, any voluntary motion being accompanied by considerable pain. The fever remained continually elevated for the first five days ranging between 100° and 104,3°. From the 8th of March on the tem- perature began gradually to fall, reaching a point under 100° upon the 18th, after which it remained normal. The urine was slightly reduced in quantity; there was a well marked diazo-reaction; the sediment contained a few granular casts. The blood, examined on the 6 th of March showed: Red blood corpuscles 4232000 Leucocytes 16500 Differential count of the leucocytes: Small mononuclear leucocytes 5°/0 Large mononuclear and transitional forms. 7°/0 Polynuclear neutrophiles 5O°/o Eosinophiles 38% Though the continued high temperature and general pains at first suggested typhoid fever, the absence of any abdominal symptoms, the leucocytosis and the extraordinary increase in the eosinophilic cells rendered the diagnosis improbable. On the other hand, the extreme muscular tenderness on movements or on pressure pointed directly to a myositis and a diagnosis of trichinosis was made. This was confir- med by the removal of a small piece of muscle from the right biceps on the 12th of March, and the demonstration of active living trichinae and others just beginning to be encapsulated. After the 18th of March the patient improved steadily and was discharged on the 13th ot May well. About the 10th of April the patient first left his bed and for some days afterwards there was slight oedema of the ankles, the only oedema, which had at any time been noted during his illness. 128 Section V: Maladies internes. The examination of the blood was made daily by Mr. Brown during the patient's stay in the hospital and the beautiful charts, which he has prepared, will appear shortly in his detailed studies upon the case. The total number of leucocytes per cubic millimetre ranged bet- ween about 13,000 upon the 16th of May to over 35,000 on the 18th of April, being for the greater part of the time above 15,000 in number. The percentage of eosinophilic cells, which was 37% upon the day of entry, fell to a little over 8% on the 22nd of March and then rose gradually, reaching the extraordinary level of 68,2°/0 on the 23rd of April. The small and large mononuclear elements remained throughout at a percentage slightly higher than one would hove expected with the degree of leucocytosis existing, that is at a little below their normal percentage, while the number of polymorphonuclear neutrophiles was in directly inverse proportion to that of the eosinophiles. Thus upon the 23rd of April with a leucocytosis of 17,700, the differential count of leuco- cytes was as follows: Small mononuclear leucocytes 19,6% Large mononuclear 5,2% Polymorphonuclear neutrophiles 6,6% Eosinophiles 68,2o/o Case II. E. B. 29 years old; German by birth was admitted to the John's Ilopkin's Hospital on the 15th of April 1897, complaining of chills and fever, muscular pains and weakness. The patient was a sailor, having recently arrived upon a steamer from Cuba. Several of his shipmates had, during the trip, developed intermittent malarial fever of the aestivo-autumnal type. His family and personal history were negative. Present Illness: For about ten days, or two weeks, the patient had noticed a loss of appetite and general muscular weakness.* Six days before entry he began to complain of continuous frontal headache, and he had had for four days considerable pain in the calves of the legs and in the back. For five days there had been slight general abdominal pain. On the morning of the day of entry the patient had two fluid stools. Five days ago the patient noticed a sudden oedema of the eyes, and face. This was so marked, that the eyes were opened with diffic- ulty, the movements of the lids being accompanied by some pain. For the last several days he had had slight pain on mastication, and on deep inspiration. There had been shaking chills and considerable fever. Physical Examination, showed a well nourished man; lips and mu:ous membranes of good color; a slight fulness of the eyelids, which, however, was not very marked; the tongue had a pasty white coat. The abdomen was natural in appearance. There was slight tender- ness on pressure in the right iliac fossa. The spleen was just palpable. The border of the liver was to be felt on deep inspiration. There was no general glandular enlargement. There were a few small pinkish pa- pules on the trunk suggestive of a typhoid roseola: The urine was reduced in quantity; of a normal color; specific gravity 1018; slight trace of albumen; diazo-reaction not present; sedi- ment slight; no casts. Thayer, Eosinophilic Cells in Trichinosis 129 Blood. Red corpuscles 5000000 „ Colorless „ 13000 Differential count of the leucocytes. Small mononuclear forms 11% Large „ „ and transitional forms.... 5% Polymorphonuclear neutrophiles 37n/0 Eosinophiles 44% Examination of the stools, which were fluid, and of a deep brown color showed no mucus or blood; no evidence of parasites or ova. The temperature pursued a remarkable course, daily elevations occurring at about noon, the temperature rising to a point as high as 105 and falling during the morning hours to a subnormal point. The paroxysms very closely resembled those of aestivo - autumnal malarial fever. Repeated examinations of the blood were made without showing t he presence of parasites or pigment, and on the 18th of April I aspirat- ed the spleen in order to exclude absolutely the presence of malarial infection. No pigment or parasites whatever were to be found in the splenic juice. Regular examinations of the blood were made by Mr. Brown with the following result: The number of leucocytes varied between 6000 on the 23rd of April to 13000 on the 15th of April and 3rd of May, while the percentage of eosinophiles varied between 14% on the 29th April and 42,8% on the 15th. In this case as in the former the same in- verse proportion existed between the number of neutrophilic and the eosinophilic leucocytes. Thus, on the 29th of April with a leucocytosis of 12000 there were only 14°/0 of eosinophilic cells and 67% of polymorphonuclear neutrophiles; while on the 15th of April with 42,8% of eosinophiles there were 43,1% only of polymorphonuclear neutrophiles. It is extrem- ely interesting, that here the mononuclear forms represent exactly the percentage of the total number of leucocytes, which they would normally in so great a leucocytosis. The results then of blood examination were practically the same, as those obtained in the above described case of trichinosis. The enormous number of eosinophilic cells present in the blood in connection with our former experience led us to suspect the possibil- ity of the existence of trichinosis in this instance, and small piece of muscle was removed from the calf of the right leg. Pieces of this muscle were examined in fresh salt solution without the discovery of any tri- chinae. The remaining bit of muscle was hardened in alcohol, embed- ded in paraffin, and cut. In the specimens stained in haematoxylin and eosin the characteristic degenerative processes, described by Mr. Brown in the former case of trichinosis, were discovered and also in one portion of the muscle a characteristic young trichina embryo, as yet not encapsu- lated, which had evidently just entered into the muscle fibre. The pa- tient made a good recovery and left the hospital feeling perfectly wel on the 18th of May, since which time he has escaped our observation. Thus, in two instances of acute trichinosis we have discovered the remarkable fact, that the blood contained a larger percentage of eosi- nophilic cells, than has ever heretofore been noted. This increase in XII Congres internat. de Medecine a Moscou. Section V. 130 Section V: Maladies internes. eosinophilic cells, so striking in the first instance, led us to suspect the existence of trichinosis in the second milder case, in which the clinic- al symptoms would scarcely have justified a diagnosis. This observ- ation, we are inclined to believe, may possess a considerable diagnostic importance. It is important and interesting to note, that this increase in eosin- ophilic cells occurred always in association with a leucocytosis and that the increase in eosinophiles was invariably associated with a correspon- ding decrease in the polymorphonuclear neutrophilic elements. The small mononuclear elements and the large mononuclear and transitional forms preserved always either their normal proportion or a somewhat reduc- ed percentage, as might have been suspected in connection with a leu- cocytosis of the extent present; the percentage of the polynuclear and eosinophilic cells together form nearly or quite the proportion com- monly represented by neutrophiles alone. These cells were always pres- ent in inverse proportion one to the other, an increase in the one vari- ety being invariably associated with a decrease in the other. This remarkable fact points certainly to a close relationship be- tween the origin of these two varieties of cells and forms suggestive evidence in favor of the view held by some observers, that the eosi- nophilic cells arise by some direct transformation from the ordinary polymorphonuclear neutrophilic elements. Brown suggests in an inter- esting manner, that some such change may in these instances have taken place in the areas of degenerated muscle. Here he was able to demonstrate an enormous percentage of eosinophilic elements among the wandering cells in the areas of degenerated muscle, a percentage dis- tinctly greater, than that present in the circulating blood upon the same date, or in the interfascicular vessels of the affected region. Brown also believes, that he has demonstrated in the affected areas of the muscles, transitional forms between the two varieties of cells, namely, polymorphonuclear elements possessing a granulation showing every stage between the small granules indefinitely staining with eosin, the ordinary neutrophilic granulation, to the well marked round or ovoid refractive deeply staining eosinophilic granules. Conclusions. 1° In two instances of trichinosis the circulating blood has been found to contain a larger percentage of eosinophilic cells, than has ever previously been demonstrated. 2° This increase in eosinophiles occurring in connection with a mo- derate or well marked leucocytosis always occurs at the expense of the polymorpho-nuclear neutrophilic elements, which are correspondingly diminished in number, the small and large mononuclear and transiti- onal forms being present in normal proportions in a percentage slightly below normal, not far from what one migth a leucocytosis of the exist- ing degree. 3° Whether these changes in the blood are characteristic of trich- inosis, or whether they are also to be found in extensive myositis from other causes remains to be shown. 4° The remarkable inverse proportion between the eosinophiles and Hermann v. Schrotter, Aetiologie der Caisson-Krankheit. 131 the neutrophiles in these instances as well as the changes observed by Brown in the histological study of the muscle, form suggestive evid- ence in favor of the view, that the increase in eosinophiles in these cas- es occurred by a direct transition from the polymorphonuclear neu- trophilic elements. Discussion. Prof. Ewald (Berlin) fragt an, ob der Vortragende eine directe Giftwirkung der Trichinose, resp. des trichinosen Gittes auf die weissen Elemente annimmt. Dr. Judson Daland (Penna): Importance of the observation, that Eosi- nophilic cells are enormously increased in number apparently at the expense of the polynuclear cells, which were correspondingly decreased in asso- ciation with a moderate leucocytosis, as a diagnostical sign of trichinosis. It is manifest from the symptoms of Case II, that the diagnosis of Trichin- osis would not have been made because of the atypical clinical picture presented and from the fact, that many of the crew suffered from malaria. It is to be hoped, that the number of observations upon the pre- sence of slight or moderate leucocytosis, in which the percentage of Eosinophiles is increased from 17-42% and more in Trichinosis rapidly increase so that this apparent diagnostic point be placed securely and safely in the possession of the Profession. Dr. Thayer (Baltimore): A positive explanation of the remarkable change in the blood, one can scarcely give, and I have wished here to insist only upon their diagnostic importance. In the more elaborate article of Mr. Brown, which will shortly appear, the subject will be discussed at greater lenght. Dr. Hermann v. Schrotter (Wien). Zur Aetiologie der sogenannten Caisson-Krankheit. Referent berichtet iiber gemeinsam mit Dr. Heller und Dr. Mager in Wien angestellte Untersuchungen iiber die Aetiologie der sogenannten Caisson-Krankheit und kommt zu dem' Schlusse, dass die Lahmungen und asphyktischen Erscheinungen denen die Arbeiter unterworfen sind, ihren Grund haben im Freiwerden von Blutgasen, der Hauptsache nach von N, der embolisch nach Ischaemisirung bestimmter Partieen des unte- ren Dorsalmarkes nekrotische Erweichung und Substanzverluste der weissen und grauen Substanz erzeugt. An der Hand von Tafeln wird der Gegenstand naher demonstrirt. Cinquieme Seance. kundi, le 11 (23) Aout, 9 h. du matin. Presidents: Prof. Rosenstein (Leide), Dr. v. Schroetter (Vienne), Prof. Bucquoi (Paris), Dr. Grawitz (Berlin), Prof. Gilbert (Paris), Prof. Charrin (Paris), Prof. Carmona y Valle (Mexico), Prof. Ribas y Per di go (Barcelone). Section V: Maladies internes. 132 Prof. Chauffard (Paris), Rapporteur. Formes cliniques des cirrhoses du foie. I. L'etude des formes cliniques des cirrhoses du foie, simplifiee d'abord il y a une vingtaine d'annees par les premiers travaux modernes con- sacres a la pathologic hepatique, et groupee autour de quelques types fondamentaux aussi nettement specifies par leurs lesions que par leurs symptomes, est devenue depuis singulierement plus complexe. L'analyse histologique et clinique, associee a 1'enquete etiologique, et controlee par les methodes de la pathologic experimentale, a peu a peu degage et individualise de nouvelles formes cliniques, elargi a tel point le cadre des cirrhoses, que la question est tout entiero a reprendre. Je vous demande la permission d'en aborder quelques-uns des points les plus generaux. L'analyse clinique des differents types de cirrhose du foie deman- derait, pour etre complete, que nous connussions, dans chaque cas par- ticulier, le processus anatomique, la pathogenic causale et revo- lution. Il faudrait pouvoir etablir la concordance de ces trois donnees, definir 1'ensemble des lois communes qui les regissent. Kous sommes encore bien eloignes de ce but, et notre ambition doit se borner a resumer aussi clairement que possible le bilan actuel de nos connaissances, a faire, pour les principales varietes de cirrhose du foie, le depart de ce que nous savons, de ce que nous presumons, et aussi de ce que nous ignorons. Il faut tout d'abord s'entendre sur la definition generale des cirrhoses du foie. Quel sens devons nous donner a ce terme? L'hyper- plasie conjonctive ne suffit pas a impliquer 1'existence d'une cirrhose, et 1'on pent admettre que trois conditions sont necessaires pour carac- teriser une cirrhose du foie q.' La proliferation interstitielle doit etre generalisee, totius hcpatis, predominante parfois en telle on telle region de 1'organe, mais toujours diffuse. Une sclerose peri-kystique, peri-calculeuse, ne constitue pas une cirrhose. Il taut que le tissu conjonctif neoforme soit du tissu fibreux et adul- te, riche en fibres clastiques, retractile souvent, et presque cicatriciel. Eufin, dans toute cirrhose du foie en evolution, le processus tend, a un moment donne, a ne pas roster purement interstitiel; la cellule hepatique entre en jeu, soit qu'elle arrive a compenser d'une fa^on plus on moins complete et durable les progres de la lesion sclereuse, soit qu'elle en subisse a son tour les effets nocifs. Tres nombreuses sont les cirrhoses hepatiques ainsi definies, et lour classification rationnelle doit tenir compte, a la fois, et des voies ana- tomiques vectrices de l'agent cirrhogene, et de la nature meme de cet agent; en d'autres termes, la classification doit etre anatomique et en meme temps etiologique. C'est a ce double titre que 1'on a dis- tingue des cirrhoses par voie vasculaire, biliaire ou capsulaire, et re- 1) A. Chauffard, in Traite de Medecine de Charcot, Bouchard et Brissaud, T. Ill, 1892, p. 821.. [Reprinted from Yale Medical Journal, January, 1898.] ON THE PARASITES OF MALARIAL FEVER.* By William Sydney Thayer, M.D., Associate Professor of Medicine in the Johns Hopkins University. Although the infectious nature of the malarial fevers has been suspected from the earliest times, as testified to by the varied and interesting hypotheses and theories as to its origin from that of Varro to those of Mitchell and Salisbury and Klebs and Tomassi Crudelli, the discovery of the specific parasite has been one of the more recent advances in the modern study of the infectious diseases. To-day, however, thanks to the discovery of Laveran, we know that malaria is a specific infectious disease. We further know that the causal agent, as pointed out by him, is a protozoan parasite of the class of the sporozoa, which inhabits the red corpuscles of the infected individual. Once entering the red corpuscle the parasite, by its growth, destroys its host, and, on reaching maturity, breaks up by a process of fission into a varying number of fresh young organ- isms, each one of which is, in turn, ready to attack a new red corpuscle and pursue again its cycle of existence. Within the bodies of these developing parasites the haemo- globin of the containing corpuscle is transformed into the dark brown pigment which has been recognized for many years as characteristic of malarial infections. The intracorpuscular development of the parasites accounts for the grave anaemia which has also so long been recognized as an important con- comitant of the disease. Following upon the work of Laveran in Algiers and Mar- chiafava and Celli in Rome, Golgi of Pavia made the discovery that, in the regularly intermittent forms of malaria, the para- sites exist together in enormous groups, all the members of which are approximately at the same stage of development; and, moreover, that the development of these groups of organisms bears a direct relation to the clinical symptoms of the case. It *An address delivered before the Yale Medical Alumni Association, Dec. Sth, 1897. 2 was shown by Golgi that the malarial paroxysm invariably coin- cides with or immediately follows the sporulation of one of these great groups of parasites. Golgi further noted the remarkable fact that distinct mor- phological and biological differences are to be made out between the organisms associated with the different types of fever. The parasite, for instance, of tertian fever, passing by for a moment its morphological characterisics, requires forty- eight hours to complete its cycle of development. Thus, in infection with a single group of parasites, sporulation occurs every other day, resulting in tertian paroxysms, while in infec- tions with the quartan parasite, whose cycle of existence lasts seventy-two hours the paroxysms occur every fourth day. The researches of Golgi have been confirmed by a large number of observers, and in addition both he and many others have distinguished a third type of organism which is associated with distinct clinical manifestations. This third parasite is believed to be associated with the more irregular types of mala- rial fever which are commoner in the tropical and more severely malarious districts-the "cestivo-azitumnal fevers" of the Italian observers, the "tropical malaria" of the Germans, the "Febris meridionalis" of Sacharov. Laveran, however, and some of his followers, persistently deny the justice of such a division, adhering to the view that the parasite is a single but polymorphous organism. Laveran does not deny that certain of these forms may be found more commonly in connection with certain types of fever, but that there is any definite relation between the types of organism and the types of fever, he is unconvinced. Shortly after coming to Baltimore in 1890 I became deeply interested in the question of the unity or multiplicity of the malarial parasites, and the results of the observations of several years were published by Dr. Hewetson and myself in the reports of the Johns Hopkins Hospital for 1895. Since that time we have accumulated a large number of observations which have tended in many ways to support, and in others to extend the conclu- sions reached in our earlier communication. During the seven years up to the first of January, 1897, we have had the good for- tune to observe over 2,000 cases of malarial fever; two or three hundred of these cases, occurring in the out-patient department, were so hastily and incompletely studied that they have been left out of consideration. However, 1,719 cases have been care- fully studied and tabulated. Our observations have led us to 3 distinguish three separate types of the parasite which are in turn associated with three distinct types of fever: i. The tertian parasite. 2. The quartan parasite. 3. The aestivo-autumnal parasite (Hamatozoon falciparum of Welch). We have never observed any indication of transitional forms between these different varieties of organisms, and our observa- tions would lead us to adhere to the view that these bodies represent three distinct species of parasites. 1. The tertian parasite. The tertian parasite is represented in the earliest stages by a small, pale, hyaline body which is possessed of active amoeboid movements. It lies clearly within the red corpuscle. It is so pale and its index of refraction is so like that of the including corpuscle that its outlines are often distinguished with considerable difficulty; but it may be readily detected by the trained eye even in the fresh unstained speci- men. As the parasite grows it accumulates fine yellowish brown pigment granules which may be seen to have a dancing motion, probably communicated to them by active undulations of the including protoplasm. These granules lie very frequently col- lected in groups at the extremities of the pseudopodia of the amoeboid parasite. As the organism grows the surrounding red corpuscle becomes expanded and decolorized. By the end of thirty-six hours the parasite has accumulated a large number of pigment granules which have also become somewhat coarser and darker, while the amoeboid movements of the body become much less active. Finally, at the period of complete development, the parasite has arrived at a size approaching that of a normal red corpuscle, while the pale expanded rim of the containing element is scarcely to be made out. The pigment granules then begin to collect in a small mass or clump at one point, usually about the middle of the organism; often they become apparently fused into a single distinct block. At the same time the protoplasm of the parasite which has begun to assume a slightly cloudy and more opaque appearance, begins to show evidence of a radial striation, while small glistening spots may be observed just within the periphery of the sphere, as well as often at different points in the interior of the parasite. Shortly after this, evidences of division of the parasite are to be made cut along the lines of these radial striations. Sometimes the division may take place into regular symmetrical leaflets, each stria extending from the periphery to the centre of the parasite. More commonly, however, there is an inner layer of segments 4 more or less irregularly arranged; so that, when separation is fully completed, we have a central pigment clump surrounded by a morula-like mass of small round hyaline bodies. These hyaline bodies represent complete young parasites, ready to attack a fresh corpuscle. The parasites in tertian fever exist in great groups, all of which are approximately at the same stage of development, and entire groups undergo sporulation within the course of a few hours. The result, then, in an infection with a single group of tertian parasites is sporulation every forty-eight hours; and with the sporulation of one of these groups of organisms occurs, inva- riably, the febrile paroxysm. The paroxysm follows, usually, within several hours after the observation of the first sporulating forms in the blood. 2. The quartan parasite resembles the tertian organism in many respects though it is readily distinguishable by the practiced eye. In the very earliest stages the organism is almost exactly similar in appearance to the tertian parasite, but soon differences are to be noted. It is less actively amoeboid, while the substance of the parasite is more refractive, its out- line more distinct. The pigment granules which begin early to appear are larger, darker, and more inclined to a peripheral arrangement. As the parasite grows, the red corpuscle instead of becoming decolorized and expanded, becomes rather dimin- ished in size, contracting, as it were, about the parasite, often assuming a somewhat * deeper, slightly brassy color. The amoeboid movements become lost earlier in the life history of the parasite and the full-grown form is somewhat smaller than that of the tertian organism. When the parasite has reached full growth which occurs in the course of about sixty-five hours after the paroxysm the pigment tends to collect in the centre flow- ing in toward the central point in more or less distinct radial lines, a point which, in our experience, is characteristic of the quartan organism. After the collection of the pigment the sporulation of the parasite takes place just as in the case of the tertian body, with the exception of the fact that here abso- lute symmetry is the rule, the parasite dividing into from six to twelve regularly arranged radial leaflets, resulting in a beautiful marguerite-like picture. The quartan parasites also exist in the blood in enormous groups, but the cycle of develop- ment of these organisms, as pointed out by Golgi, lasts approx- imately seventy-two hours, so that in infections with a single group sporulation and the paroxysms occur every fourth day. Very frequently, however, in both tertian and quartan infec- 5 tions more than"one group of parasites may be present; double tertian infections and double or triple quartan infections are extremely frequent. It is an interesting fact that when two- groups of the tertian parasite are present they segment, almost invariably, on successive days, causing a daily chill, while in case of double quartan infection chills occur on successive days with a day of intermission between, and, in triple quartan infections, quotidian fever, which from the chart alone, may be indistin- guishable from a double tertian infection. 3. The eestivo-autumnal parasite-haematozoon falciparum. This variety of organism is associated with fevers which differ distinctly in their clinical manifestations from the regularly intermittent tertian and quartan fevers. In some instances the paroxysms may, for a certain length of time, show marked regu- larity, occurring at intervals of from twenty-four to forty-eight hours more or less, but soon after the onset of the symptoms an irregularity usually becomes manifest and often the fever may pursue a continued course (the so-called remittent fever). This type of fever, as has been already mentioned, is rarely seen in the milder malarious districts. It is, however, common in Baltimore at the height of the malarial season and forms the majority of the cases occurring in the severely malarious districts. The parasite here begins, as in the other instances, as a small, amoeboid, hyaline body; it has, however, a marked tendency to take on a ring-like appearance. The body is not a true ring, but probably represents a bi-concave disc with a well marked central depression. It is also, in its earliest stages, distinctly smaller than the early forms of the tertian and quartan organ- isms. As it develops the pigment granules which are accu- mulated are scanty and extremely minute. The adult forms are materially smaller than those of the parasites of the regularly intermittent fevers, some organisms sporulating when scarcely more than a third the diameter of a red cell, though usually the diameter is approximately two-thirds that of the including element. The sporulating bodies resemble those of the tertian parasite. This organism, however, shows several distinct differences from the forms already described. The tertian and quartan parasites are found at all stages of development in the peripheral circulation, though, to be sure, in a case of the tertian organism the adult forms are found with greater frequency in the blood of the spleen. In the case of the aestivo-autumnal parasite, however, only the earlier stages are to 6 be made out in the circulating blood. These are the small hyaline bodies which may or may not possess a few very minute pigment granules. Occasionally, just before or during a par- oxysm, larger forms with a central pigment block are to be made out. Actual sporulating bodies we have observed in only three instances out of 633 cases of aestivo-autumnal fever. To properly study these latter stages of development it is necessary to aspi- rate the blood from the spleen, which is by no means a safe pro- cedure unless done with the utmost precaution. After a certain length of time, from five days to two weeks, there begin to appear in the circulation other bodies which are quite characteristic of this form of infection. These are large crescentic elements with sharp refractive outlines, containing a ring or clump of dark pigment granules arranged in the middle of the organism. These crescentic-shaped bodies may often be seen to change, under observation, into ovoid or round forms which are somewhat smaller than the normal red corpuscle. The round bodies in some instances lose their refractive charac- ter, and from them there develop, not infrequently, the flagel- late elements which were early described by Laveran. These flagellate forms which constitute one of the most inter- esting appearances to be made out in the malarial blood may develop from large full-grown parasites either in tertian or quartan fever, or from the above named round bodies in eestivo-autumnal infections. Their manner of origin is interes- ting. While observing such a body, at a period, usually of about ten to twenty minutes after the slide of blood has been made, the pigment may be seen to become excessively active. The entire parasite is shaken, the periphery showing protru- sions and undulations suggesting the efforts of some contained body to escape. And suddenly there appear from one to four or five delicate, actively motile filaments. These filaments are commonly of very regular size, measuring about twice the diam- eter of a red cell and usually showing at one extremity a slight clubbing. Sometimes one may observe bits of pigment on the extremity or along the course of a flagellum. Not infrequently the flagella may be seen to break away from the mother body and rush off alone across the field showing an active serpentine motion. Another characteristic in which the aestivo-autumnal parasite differs from the tertian and quartan organisms is in that it is not, as a rule, arranged in groups, each organism of which is. 7 at the same period of development. Though this would appear to be the case at the beginning of many infections, multiple generations rapidly develop, and often the arrangement of para- sites in definite groups is entirely lost. Sporulation thus occurs more or less continuously, or at periods rapidly succeeding one another, so that the result, not unnaturally, is an irregular or continued fever. It is very remarkable that while in tertian fever, for instance, infections with two groups of parasites segmenting on successive days and causing quotidian fever are very common, it is most unusual to find more than two groups present at the same time, or to find two groups segmenting within the same twenty- four hours. To be sure it is not infrequent, as Gotye has also noted, to find in a single or in a double tertian infection, organ- isms which, morphologically speaking, would appear to be some- what separated from the main group or groups present. It is, however, extremely rare to find a sufficient number of such parasites to constitute a generation large enough to produce febrile manifestations on its own account. This indeed would appear to constitute one of the main bio- logical differences between the parasites of the regularly inter- mittent fevers and those of aestivo-autumnal fever, where, as is well known, the tendency to the development of multiple groups would appear to be a striking feature. As has been pointed out by Antolisei and Bastianelli and Bignami, infections with the tertian parasite may give rise to irregular and even continued fever. This is, however, rare. Out of 931 cases of tertian infection we have observed but three instances of continued fever. Here, we have been led to believe that the parasite, as in aestivo-autumnal infections, was present in multiple groups, the segmentation occurring at intervals so frequent as to result in a practically continuous fever. The accompanying chart will show the relation of the different types of infection to the different times of the year: Jan. Feb. Mar. Api. May .Jun. Jul. Aug. Sept. Oct. Nov. Dec. Tot. Tertian, - - 12 12 28 51 76 68 131 161 153 168 54 17= 931 Quartan, - - 3 I o i 0 0 3 O 2 I 4 2= 17 ^Estivo-Autumnal, 5 I 2 5 2 3 37 99 I9I 203 63 22= 633 Combined, - - - o I I o 0 1 3 3 4 II 6 2= 32 Totals, - - - 20 15 3i 57 78 72 174 263 350 383 127 43=1613 Infections with the tertian parasite form the majority of all the cases of malarial fever observed in temperate climates. 8 Quartan fever is rare in Baltimore. We have observed but seventeen instances out of 1,613 cases. Of these, eight were single quartan infections; two were double quartan infections; seven were triple quartan infections. We have never observed continued fever in infections with the quartan parasite. The paroxysms in tertian and quartan fever average between ten and twelve hours in length, estimating the period of time elaps- ing while the temperature remains about ninety-nine. ^Estivo-autumnal fever is very frequent with us at the height of the malarial season; rare, however, in the early part of the year. Of 633 cases of aestivo-autumnal fever but eighteen occurred in the first half of the year and of these seven were imported from tropical regions, while most of the other cases were relapses from autumn infections, occurring in the first months of the year. In the second half year, however, the aestivo-autumnal infections amounted to nearly one-half of all the cases. In the months of September and October, that period at which malaria is most common in Baltimore, there were 394 cases of aestivo-autumnal fever to 339 of all other forms of infection. Adding to the aestivo-autumnal fevers fifteen cases of combined infections we have 409 cases of aestivo- autumnal fever against 324 cases of tertian and quartan fever. * * * The existence of these distinct types of parasites and their specificity have not only been proven by clinical observations; they have been controlled by a large series of careful inocula- tion experiments. These have shown that the introduction of fresh blood from an infected patient under the skin or into the veins of an healthy man will invariably produce the same type of disease with the same type of organism. These facts impress us as interesting and wonderful, but there is nothing new under the sun, and on consulting the liter- ature of malaria it is astonishing to find that they but confirm an hypothesis expressed more than sixty years ago by Rasori, who said, in a conversation with Bassi, "For many years I have held the opinion that the intermittent fevers are produced by parasites which bring about the paroxysm by the act of their reproduction which follows more or less rapidly according to their species. '' * * * But the recently acquired proofs of the accuracy of this hypothesis by no means clear up entirely the question of the eetiology of the malarial paroxysm. Why should the process of 9 sporulation cause fever? The question has been answered differently by different observers. The weight of evidence, however, tends to support the view that during the act of sporu- lation some toxic substance is produced-set free, probably, by the parasites themselves-which, entering into the general cir- culation, is the direct exciting cause of the febrile paroxysm. This idea is supported by the fact that the sweat and the urine during the malarial paroxysm show a markedly increased toxicity, while the clinical sequelae and the anatomical changes found after severe malarial infections go far in its support. Clinically, there exist a number of complications and sequels, such as albuminuria, nephritis, neuritis-entirely analogous to those which so commonly follow other severe general infections, changes which, in many instances, we know to be due to the presence of circulating toxic substances. The strongest sup- port of the theory of the toxic origin of the fever is afforded in the anatomical changes, especially the extensive focal necroses in various internal organs, as described by Guarnieri, Bignami, Barker, Monti, and others, changes which Flexner has recently shown to be pathognomonic of general intoxications. % * * Among the more interesting and disputed points in connection with the malarial parasite has been the question which has occupied a prominent position since the discovery of the organ- ism as to the nature of the flagellate bodies. Laveran has held from the beginning that the parasite represents a sort of cyst within which the flagella develop. The flagella, according to him, represent a certain phase in the evolution of the haema- tozoon. He has more than once hinted his belief that they represent an important stage in the history of the parasite. Most of the Italian observers, however, (Golgi, Antolisei, Grassi and Feletti, Marchiafava and Celli, Bignami and Bastian- elli), believe that they represent degenerate forms, basing their opinion upon the fact that they develop in tertian and quartan fever from the large, swollen parasites, which have, apparently, failed to sporulate, forms in which, beyond flagellation only degenerative changes have been seen; while in aestivo-autumnal fever they develop from the round bodies derived from crescents. But all evidence goes to show that these crescents are, while left within the organism, sterile elements. Experiment also has shown that crescents are incapable of transferring the infection. On the other hand, Danilevsky, who studied the closely sim- ilar haematozoa of birds, Dock, Mannaberg and Manson all agree 10 with Laveran in so far as they regard the flagella as active- phases in the life history of the organism. Mannaberg and Manson believe that they represent a form of the parasite capa- ble of preserving its existence outside of the human body. Sacharov advanced an ingenous hypothesis which has, until very recently, at least, commanded little attention. He believes that he has demonstrated that the flagella represent chromatic fila- ments of the nucleus which break loose from the organism. The argument of the Italian observers has much in it that is tempting and yet we have always felt with Laveran that the extraordinary activity of these forms, their singular regularity in shape and size, is hardly to be reconciled with the idea that they are products of fragmentation and degeneration. They impress one as preformed bodies. Within the last four months, however, an observation has been made which, in all probability, will clear up this long dis- puted question. And it is with considerable pride that I am able to say that this work has come from our clinic. Dr. W. A. McCallum in connection with Dr. Opie, undertook two years ago, the study of the parasites of the blood of birds, the great similarity of which to the malarial organisms has long been known. Opie was able to distinguish two separate varieties of parasites-varieties which had also previously been recognized by continental observers, and especially described by Labbe. These organisms grew within the blood corpuscles of the birds, and developed pigment exactly as do the malarial parasites in the blood of man. And in both forms of the parasite, flagella- tion of the organisms may be observed. In one type, that which has been termed by Labbe the "Halteridium Danilevskyi, " the flagellation occurs very rapidly after the preparation of the specimen, within a few minutes. And as many organisms are often seen in one field, a very large proportion of which develop flagella, the process is to be observed to a much greater advan- tage in birds than in man. Opie, in a very careful and satisfactory morphological study of the parasites, had already noted a previously undescribed dis- tinction between two forms of the Halteridium-forms which are found together in almost every specimen. In one of these the substances of the organism is completely clear and hyaline, while in the other the protoplasm has a somewhat granular appearance in which larger distinct hyaline points are to be made out. The staining reactions of these organisms are also different. The more granular forms take up basic dyes with 11 considerable avidity, the small clear points remaining unstained,, while the clearer hyaline bodies stain but faintly. Last summer, McCallum, continuing the studies of Opie, was able to confirm these observations and noted further the fact that the pigment is generally somewhat finer in the granular bodies. McCallum took upon himself especially the problem of the nature of the process of flagellation, and while studying one day the behavior of a granular and hyaline form lying close together in the same field of the microscope, he observed an interesting phenomenon. Several flagella breaking loose from the central, body, made their way directly to the granular non-motile form which they immediately surrounded, wriggling actively about it. Finally one of the flagella penetrated the granular sphere which appeared to put forth a process to meet it. The remain- ing flagella persisted in their attempts to enter but met with no success. Immediately after entrance of the flagellum the pigment of the young body became actively agitated. This was followed by a period of quiescence, after which the body changed into a fusiform element with the pigment at one end, and took upon itself a steady, sliding, forward motion. These elongated motile bodies had been repeatedly observed and described as pseudo-vermiculi by Danilevsky. Their significance is not known. They do not occur in human blood. This very remarkable phenomenon MacCallum was able to observe repeat- edly, and to demonstrate at the meeting of the British Associa- tion in Montreal last August. The conclusion is almost inevitable that this represents a process of fertilization. It is, as MacCallum points out, some- what analogous to the sexual process as it occurs in some lower plants under unfavorable conditions. "In spirogyra and oedogionus when their circumstances have become such that the ordinary reproduction by fission can no longer result in a success- ful preservation of life, a more resistent body is formed by the conjugation of the adjacent cells. But so long as the conditions of growth are favorable we may look in vain for this process.'' In various amoebae conjugation has been observed, though, as far as I know, the formation of spermatozoa has never been noted. Are we justified in a similar interpretation of the process occurring in the malarial parasites of human beings? It is too early to express an absolute opinion, but from recent observa- tions in the medical clinic at the Johns Hopkins Hospital, it is extremely probable that we can. Any one who has studied the 12 fresh blood in malarial infections has noted repeatedly that only a certain proportion of the round forms of the aestivo-autumnal parasite develop flagella. Many others, especially forms in which the pigment assumes a very regular ring-like appearance, remain unchanged. About a month ago Dr. MacCallum was able to observe the penetration of one of these round bodies by a free flagellum; I had the good fortune to see this form shortly after penetration. The round body was surrounded by two flagella which were wriggling about the parasite, bunting their heads against it, and making, apparently, every effort to enter. The picture was striking-almost convincing of itself. Dr. Pancoast and Dr. Mactier Warfield have also been able to see the process of penetration within a few days of the time of writing. Beyond the immediate agitation of the pigment granules after the entrance of the flagellum no further change has yet been observed in these fertilized (?) forms in the human blood. As has been before stated it is too early to draw definite con- clusions as to the entire significance of this important discov- ery. This much may be said: It is in every way probable that the flagella of the malarial parasite represent, as Laveran orig- inally held, important constituent parts of the organism; the view held by so many observers that the flagella are degenerate elements must be definitely abandoned; it is probable that the process of flagellation and penetration represent a sexual act, a process of fertilization which may well result in the development of more resistent forms of the organism, forms which under certain circumstances, possibly after escape into external condi- tions, may undergo changes rendering them capable of again infecting human beings. How might such an escape take place? In what form does the organism exist outside of the body? How does infection occur? These questions remain as yet unanswered. Certain observations by MacCallum suggest that in birds, the fertilized form may escape into the intestinal canal and thence reach the external medium. But the point needs further study. And indeed positive proof that flagella develop while the para- sites are in the circulation of the living animal has yet to be obtained. * * * In what form does the malarial parasite exist outside of the body and how does infection take place? It must be confessed that we are still sadly ignorant with regard to both these questions. 13 The subject has been admirably discussed in a paper by Dr. Norton of Washington and by Laveran in his most recent work. As to the form in which the parasite exists when it leaves the body, or, to speak more carefully, before it enters the body, for that it leaves the body we have no proof, we are absolutely ignorant. As to its manner of entry many views have been held. The most popular and ancient has been that infection takes place by the inhaled air. Hence indeed the name of the disease, which is but a joining of two Italian words, "mal'aria. " There are, it must be said, certain facts which speak in favor of this hypothesis. A second idea, long held, has been that infection may take place through the drinking water, while a third and, at present, very popular view is that the disease may be con- veyed by the bites of insects. The water-born theory of malaria must be said to rest upon an insufficient basis. A number of careful experiments have been made in relation to this question, all with negative results. Celli and Marino and Zeri administered water from the Pontine marshes, regions which are the seats of most pernicious malaria, by the mouth, by the rectum and as inhalations, and in none of these instances did fever develop, although the patients were subjected to this treatment in some instances for months. Grassi and Feletti fed healthy men upon dew collected from malarial regions as well as upon the fresh blood of infected individuals, blood which, as we have seen before, invariably conveys the infection when introduced hypodermically or intravenously; infection did not follow. They further failed to convey infection in birds by feeding birds of prey upon corpses of other birds dead or suffer- ing from avian malaria. Dr. Norton's interesting study has shown how unfounded are many of the statistics tending to prove this theory. In the absence of proof of the theory that malarial infection might take place through the gastro-intestinal tract one has commonly fallen back upon the idea that it must be conveyed by the inhaled air, and indeed there is considerable evidence in favor of this theory. Certain it is that simple exposure, especially to the night air in severely malarious regions is commonly followed by infection. There are also observations to the effect that malaria prevails especially upon that side of a swamp or stream toward which the prevailing winds blow; one has, however, 14 usually arrived at the assumption that this is the common mode of contagion by a process of exclusion. Of recent years there has been a strong tendency toward the idea that, in some instances, infection might occur through the agency of the bites of insects, more especially the mosquito. We possess abundant evidence that the disease is readily trans- ferable hypodermically. Moreover, the recently discovered fact that certain closely analogous protozoan infections of the blood may arise through the agency of insect bites has led one to regard this hypothesis with considerably greater favor. Especially the discovery that Texas fever, or as Celli has termed it, "Bovine malaria,'' is a disease caused by an haemacytozoon closely resem- bling that of malarial fever, an organism introduced into the infected animal through the agency of the cattle tick, is extremely suggestive. This discovery was the brilliant achieve- ment of Professor Theobald Smith of Boston. More recently also the interesting disease "Nagana'' has been shown by Bruce to be due to the presence of an animal parasite, a trypanosoma which is introduced by the bite of the Tsetse fly. Laveran, as has been said, has always favored the idea that malaria might arise from mosquito bites, and more recently Bignami has con- tributed an interesting plea in favor of this hypothesis. The districts in which malaria prevails, moist, hot, swampy, tropical regions are exactly those in which mosquitoes usually abound. In temperate climates malaria is most common during the latter summer and early fall, exactly the period at which mosquitoes are most numerous. In a malarious district the dan- gers of infection are generally greater by night than by day, at the very periods when mosquitoes are most numerous and active. A strong breeze is unfavorable to malarial infection, and during a strong breeze the mosquito is less dangerous. Furthermore, Bignami notes that in malarious districts the measures adopted by the inhabitants to protect themselves from infection are in great part such are also adopted to protect them from mosquito bites; namely, sleeping on upp ir stories of the house, closing of the windows. Again, he asserts that in certain very malarious districts, workmen who live in small conical huts with only one means of ventilation-an opening at the apex which serves as an outlet for the smoke of the small fire, are commonly free from malarial infections, while those about them may be almost without exception subject to the disease. Emin Pasha was so convinced of the danger of bites of mosquitoes that throughout his African travels he slept under a netting and never suffered from 15 the disease. These are interesting and suggestive arguments; positive evidence, however, of their justice we have yet to obtain. The role of the mosquito in malarial infections has also been discussed by Manson who believes that this insect forms the intermediate host of the malarial parasite and points out in his interesting papers a supposititious method by which the mos- quito might infect drinking water. But his ideas can be said to be little more than ingenious hypotheses; moreover, the possi- bility of infection through drinking water is, to say the least, very doubtful. * * * The diagnostic importance of the malarial parasite is in many ways parallel to that of the tubercle bacillus in pulmonary tuber- culosis and of the Klebs-Lceffler bacillus in diphtheria. The diagnosis of tuberculosis and diphtheria and malaria can be made in many instances without examining for the specific micro-organism, but on the other hand, how many, perhaps .fatal, mistakes may be avoided by the physician who examines his blood and sputa and takes cultures from suspicious throats. It may be urged that in malaria we have additional diagnostic assistance in the possession of a true specific. All malarial infec- tions it is true, yield to quinine; there is no evidence in litera- ture to the contrary; fevers which do not break within four days after the onset of the treatment are not uncomplicated malaria. In this connection it cannot be denied that in many cases in tropical districts the patient may be beyond help when first he comes under observation, though even here, perhaps, many might be saved by the intravenous administration of quinine according to the method of Baccelli. The anaemia and debility also following long continued or repeated malarial infections- chronic malarial cachexia-may be little influenced by the drug alone. But who would seek to deny that iodide of potassium is a specific in syphilis because, in some instances, a cerebral or hepatic lues may have reached a stage before the initiation of treatment, so advanced that the patient may die before the drug has had time to act? And who would be so unreasonable as to demand that iodide of potassium or mercury, in order to deserve the name "specific", must possess the power to restore degen- erated nervous tracts or regenerate destroyed liver substance? But the disappearance of the symptoms after quinine is only suggestive proof of the malarial character of the affection-more or less suggestive according to the nature of the case. 16 The discovery of the parasites in the blood is the- only diagnostic sign of malarial infection. Gentlemen: You may feel that all these facts are interesting, but of little practical importance in a community such as this, where, as a rule, the milder forms of malarial fever alone prevail. It is true that it will not frequently fall to the lot of a New England physician to save the life of a patient with pernicious malaria as a result of the happy discovery of the parasite, for pernicious malaria probably does not exist here. But while these capital cases do not occur, and while in some regions even the milder forms of the disease are uncommon, there is none the less considerable need of a clearer understanding of the manifestations of the malady. There is a grave and general misapprehension as to the nature and frequency of malarial fever throughout the Northern States. I have within a few years known a conscien- tious physician in a non-malarious district of a Northern State, to treat for several weeks a case of typhoid fever, who died from intestinal hemorrhage, with heroic doses of quinine, under the belief that it was an instance of continued malaria. Examina- tion of the blood would have cleared matters up instantly. A realization of the fact that malarial fever resistent to qtiinine does not exist either in the North or in the South would have prevented such a misapprehension. The intermittent fever of early tuberculosis here, as else- where, is often confounded with malaria, and the frequency with which the term is still applied to a variety of nervous manifesta- tions which are common in the North, as everywhere, is noto- rious. I remember well, for instance, the ideas with which I entered into practice with regard to the frequency of supraorbi- tal neuralgia of malarial origin. In the study of over 2,00a cases of malaria during somewhat over seven years, it has never fallen to my lot to see even a single case of this nature. One instance of supraorbital neuralgia I have observed in a case of post-malarial cachexia where the patient suffered also from an in- flamed lachrymal duct. The parasites had long since disappeared from her blood. A variety, also, of ocular phenomena are still, without a shadow of foundation, referred to this disease. The term malaria has, in times past, served as a cloak to cover our ignorance. It cannot be denied that we have made good use of it. Laveran, by his discovery, has rendered this much affected garment unfit for further application. Let us be thankful that he has delivered us from temptation! A THIRD CASE OF TRICHINOSIS WITH REMARKABLE INCREASE IN THE EOSINOPHILIC CELLS. BY W. S. THAYER, M.D., OF BALTIMORE, MD. THE PHILADELPHIA MEDICAL JOURNAL, [Reprinted from The Philadelphia Medical Journal, April 9,1898.] A THIRD CASE OF TRICHINOSIS WITH REMARKABLE INCREASE IN THE EOSINOPHILIC CELLS. By W. S. THAYER, M.D. Associate Professor of Medicine at the Johns Hopkins University, Baltimore, Md. The patient, a man 47 years of age, was admitted to the Johns Hopkins Hospital on December 21, 1897, complaining of headache, pain in the side, chilly sensations and swelling of the feet. His family history was unimportant. Mumps at 21 was followed by orchitis, and diphtheria at 26 left some " throat-paralysis "; he had acute rheumatism seven years ago, being confined to bed six weeks. He denies ven- ereal disease. He is a moderate drinker of alcholic stimu- lants. His work, that of a dairyman, allows him but little time for sleep. He was under treatment in the hospital in July and August for typhoid fever. Five weeks ago the patient began to suffer from cough, frequent headaches, and weakness, together with occasional chilly sensations, and pain in the left side. For five weeks on rising (at 3 a.m.) he has had a severe coughing-spell last- ing from 15 minutes to half an hour, during which he expec- torates about a tablespoonful of greenish mucoid substance. This is often associated with vomiting. During the rest of the day he is free from cough. He has had an almost con- stant frontal headache. Five days ago the man began to have diarrhoea with four or five movements daily; these are thin, of a greenish color, preceded by severe griping abdom- inal pains. Two or three days after the onset of the diarrhoea the patient noticed pain and numbness in the legs, feet and arms. The skin over these parts felt tight and cold. At the same time he noticed a feeling of stiff- ness in his knees, elbows and wrists. The extremities were also somewhat swollen. His employer called his attention to the fact that his eyelids were puffy. He kept at work until yesterday, but owing to weakness and pain he had to be assisted on his way to the hospital. There is no urinary disturbance. The patient says he has recently eaten a great deal of fried sausage. These sausages were made from his own hogs, one of which when killed was not well. The animal, according to the statement of the patient, was healthy looking, but on Thanksgiving Day " it did not seem to want to eat or move about," lying as if it were paralyzed. The patient states that the hog was immediately slaughtered with a number of 2 others for fear that it might die of itself and therefore be unfit to eat(!). There was no selection of the meat, the sausage being made from the mixed result of the entire kill- ing. There was no disease among the other hogs, and, so far as he knows, no illness among the other individuals who ate of the sausages. On physical examination the patient was found to be a large, well-nourished man; the lips and mucous membranes were of good color; the conjunctivae were suffused ; the eyelids puffy. The thorax and abdomen were quite negative on physical examination; neither the spleen nor liver were palpable. There was distinct puffiness and oedema of the arms and hands and feet, the skin being tense and the mus- cles markedly tender. There was a curious mottled cyanosis of the extremities which was not marked upon the face. The examination of the blood showed red blood-corpuscles 7,406,000; colorless corpuscles 34,000; haemoglobin 102%. The examination of the fresh specimen showed a surpris- ing increase in the eosinophilic cells, the differential count showing: Small mononuclear leukocytes, 1.5% +; large mononuclears, 4.7% + ; polymorphonuclear neutrophiles, 48.2% + ; eosinophiles, 45.4%+. The urine was normal in color, acid, 1025, no albumen, no sugar; there was a slight sediment. The diazo-reaction was not present. The tem- perature, which on entry was 99.2°, rose to 102.4° at night, and on the 22d ranged between 100.3° and 103°. On December 22d the following note was made by Pro- fessor Osler: The face and eyelids are puffy, the face suf- fused and red, the tongue clean, the arms and hands much suffused-the latter being cyanotic; they are closed with difficulty as they are so stiff. The feet and arms are considerably swollen, particularly over the backs and wrists where they are puffy. The swelling of the arms is actually in the muscles, which are sore; there is distinct soreness over the biceps; no distinct soreness exists over the muscles of the trunk. The feet are livid, the legs stiff and cold, the muscles of the calves are not particularly swollen, not very tender. On December 23d the temperature was 100.2°, the legs not swollen; the right hand was more congested than the left, but not cyanotic. No extreme sensitiveness existed over the muscles, but there was still some tenderness over the fore- arms. There was no special soreness of the pectorals, and none of the abdomen or thigh-muscles. There were 17,000 leukocytes per cu. mm. The urine was normal. A diagnosis of trichinosis having been made, the patient was given ol. ricini, 30 c.c., and the stools were carefully examined for trichinae. On December 23d no trichinae, however, were found in the dejecta, though lumbricoid's eggs were present in consider- able numbers. A large piece of muscle was removed from the right calf, 3 and in several bits of the fresh specimen no trichinae were seen. On December 24th, the temperature had fallen somewhat; the patient seemed better in every way; the tenderness was less; there was but little puffiness of the forearms or stiffness of the muscles of the neck. Three of the six stools dur- ing the last 24 hours were carefully examined and noth- ing abnormal was found excepting the ascaris eggs. From this time on the patient steadily improved, the temperature becoming quite normal by the 30th of the month, and sub- normal after January 2d. On the 16th he left the hospital, feeling perfectly well. The blood on the 27th showed 4,700,000 red blood-corpus- cles ; 15,320 leukocytes per cu. mm. The differential count showed: Small mononuclears, 5.6%; large mononuclears, 4.0%; polymorphonuclear neutrophiles, 45.4% ; eosinophiles, 45%. January 3, 1898. The blood-count shows: Red corpuscles, 4,300,000; colorless corpuscles, 12,000. The differential count was: Small mononuclears, 4.6%; large mononuclears, 4.2%; polymorphonuclear neutrophiles, 42.2 %; eosinophiles, 49.0 %. On January 4th, examination of the hardened specimens of the muscle taken from the leg showed a marked acute myo- stis with a moderate number of young, unencapsulated trichinae. January 10, 1898. The blood-count showed: Red cor- puscles 4,546,000; colorless corpuscles, 6,800; haemoglobin, 68%. The differential count was : Small mononuclears, 5.8%; large mononuclears, 18.2%; polymorphonuclears, 25.2%; eosi- nophiles, 50.5%. On January 16, 1898, there were 4,380,000 red blood-cor- puscles per cu. mm.; 8,000 leukocytes; haemoglobin, 86%, The differential count was: Small mononuclears, 2.3%; large mononuclears, 16.9%; polymorphonuclear neutrophiles. 32.3% ; eosinophiles, 48.3%. The urine was normal throughout excepting for the fact that on January 3d a faint trace of albumen and one hyaline cast were seen. The patient felt and appeared to be perfectly well, and at his own request was discharged on January 16th. At the 12th International Medical Congress in Mos- cow I communicated two observations of cases of trichi- nosis in which the circulating blood showed a remark- able increase in the eosinophilic cells, and pointed out the possible diagnostic importance of this discovery. The first of these instances has already been reported by Dr. Brown.1 The occurrence of this third case 1 In the Bulletin of the Johns Hopkins Hospital for April, 1897. 4 would seem to justify our conclusions, and warrant, perhaps, a brief repetition of the histories of the two previous cases. Case I.-The patient, a man 26 years of age, was admitted to the hospital March 3, 1896. His family and personal history were negative. For six weeks he had had general severe mus- cular pains, tenderness, and weakness, and irregular remittent fever. Physical examination was negative. Examination of the blood on March 6th showed: red blood-corpuscles, 4,232,000; leukocytes, 16,500. A differential count of the leukocytes stained according to Ehrlich's method with a triple stain of acid fuchsin, methylene green and orange G showed: Small mononuclear leukocytes, 5%; large mono- nuclear and transitional forms, 7%; polymorphonuclear neu- trophiles, 50%; eosinophiles, 38%. A piece of muscle removed from the right biceps showed numerous trichinae, living and active, with evidences of a marked interstitial myositis. The temperature became nor- mal by March 18th, and the patient left the hospital well, on May 13th. Throughout his stay in the hospital, examina- tions of the blood made by Dr. Brown showed from 13,000 to 35,000 leukocytes, the percentage of eosinophilic cells vary- ing from 8% on March 22d to 68.2% on April 23d. Case II.-A man 29 years of age, a sailor, was admitted to the Johns Hopkins Hospital, March 15, 1897. His family and personal history was negative. For ten days he had had loss of appetite and general muscular weakness, headache, and pain in the calves of the legs and back. Five days ago mdema of the eyes and face appeared, with slight diarrhoea, and intermittent fever with shaking chills. Physical exami- nation showed nothing remarkable excepting a palpable spleen. The urine was of normal color; acid, 1018, with a slight trace of albumen; there was no diazo-reaction; sediment slight; no casts were seen. The red blood-corpuscles numbered 5,000,000 ; the colorless, 13,000. The differential count of the leukocytes showed: Small mononuclear leukocytes, 11%; large mononuclear leukocytes, 5% ; polymorphonuclear neu- trophil es, 41 %; eosinophiles, 44 %. No parasites were found in the stools. Examination of a piece of muscle removed from the calf of the leg showed young embryos of the trichina spiralis, as yet unencapsulated. There was a marked acute myositis. The patient left the hospital well on May 18th. The num- ber of leukocytes, counted with great care by Dr. Brown, varied between 6000, on April 23d and 13,000 on April 15th and on May 13th. The percentage of eosinophiles varied between 14% on April 29th and 44%on the day of entry. Thus in three instances of acute trichinosis followed, 5 by recovery, in all of which the diagnosis was con- firmed by the discovery of living trichinae in bits of muscle removed intra vitam, we have found an enormous absolute and relative increase of the eosinophilic cells in the circulating blood. This extremely high percent- age of eosinophiles led us, in a second instance, to sus- pect the nature of the case when the history alone would have been quite insufficient to justify a diagnosis. The careful studies of Dr. Brown in the first two cases have demonstrated the fact that in all these cases the polymorphonuclear neutrophiles were pres- ent in a reduced percentage, the reduction from what normally might have been expected corresponding closely to the number of eosinophiles present. The small and large mononuclear elements were present in proportions just such as might have been expected with the degree of leukocytosis present. In all three instances there was a well-marked leukocytosis during the acute symptoms. A more extensive consideration of the changes in the blood and muscles will shortly be published by Dr. Brown in the Journal of Experi- mental Medicine. In conclusion, it is believed that we are justified in asserting: 1. That the blood in trichinosis shows a leukocytosis, the differential count revealing an enormous increase in eosinophilic cells, an increase occurring always at the expense of the polymorphonuclear neutrophiles. 2. This great increase in the percentage of the eosi- nophilic cells forms a very important symptom, if not a diagnostic sign of trichinosis. The Philadelphia Medical Journal 1420 CHESTNUT ST., PHILADELPHIA A WEEKLY JOURNAL WITH A MINIMUM CIRCULATION OF 10,000 COPIES $3.00 Per Annum This, one of the largest of American Weekly Medical Journals, contains more literature of value to practitioners than oth- ers, and at about one-half the usual price. Short, crisp editorials. All the very latest literature of the world abstracted and classified. Original articles from the leaders of American Medicine. Secret Pharmaceutical preparations are not advertised. ON NEPHRITIS OF MALARIAL ORIGIN. BY WILLIAM SYDNEY THAYER, M.D., ASSOCIATE-PROFESSOR OF MEDICINE IN THE JOHNS HOPKINS UNIVERSITY, BALTIMORE, MD. From the Transactions of the ASSOCIATION OF AMERICAN PHYSICIANS. 1898. ON NEPHRITIS OF MALARIAL ORIGIN. By WILLIAM SYDNEY THAYER, M.D., OF BALTIMORE. The fact that albuminuria may occur in the course of malarial fever as well as during other acute infections is well known. Martin-Solon1 estimated that it was to be found in a quarter of all cases. Laveran,2 however, believes that this is a high percentage for the simple non- pernicious fevers. Joseph Jones3 refers to its occasional occurrence, but says : " In several hundred examinations of the urine of the different forms of malarial fever in the Marine Hospital at Savannah, Georgia, albumin was found in only one case, which was complicated with typhoid fever. This fact is important in its bearing upon typhoid and yellow fever." Anders,4 in 1780 cases collected from the records of various hospitals in Philadelphia, noted only eighteen instances in which albuminuria (" marked ") was found. Hertz5 asserts that " it is no very uncommon thing to find albumin present in considerable quantities." . . . " Albumin is to be found in the urine either only on the fever days or during the intermission as well (fibrinous tube-casts have also been observed), and disappears on recovery." Atkinson6 studied the urine in seventy-six cases of intermittent and remittent fever, in which albuminuria occurred five times; in a second series, however, occurring during the late summer and fall of 1883, forty-five in number, albuminuria was noted in six instances. Kelsch and Kiener7 assert that in ordinary malarial fevers " the pres- ence of albumin is not rare in paroxysms of a certain intensity, but it is particularly common in relapses in old sufferers, where the kidney is 1 Gaz. M4d. de Paris, 1848, iii. s., t. iii. Annde, xix. 618. 2 Traite du Paludisme, 1898, 8°, Paris. 3 Medical and Surgical Memoirs, vol. ii. p. 772. 4 Journal of the Amer. Med. Asso., 1895, vol. xxiv. p. 916. 3 Ziemssen's Cyclopaedia, American edition, vol. ii. p. 641. 6 Amer. Journ. Med. Sciences, 1884, vol. Ixxxviii. p. 149. 7 Maladies des pays chauds, p. 144. 2 THAYER, already altered." They say that in the more severe bilious and gas- tric fevers (page 453) " albumin is frequent enough but inconsider- able and transient; it may be intermittent and disappear with the paroxysm, or it may continue during the intermission." Despite the relative frequency with which some observers have noted albumin in the urine of malarial patients, its presence or ab- sence has been used as a point in the differential diagnosis between certain forms of severe malaria and yellow fever, in which latter affection the early appearance of albumin is the rule. McLean, in Reynolds' System of Medicine, says: " Albuminous urine is almost invariable in yellow fever-only occasional in remittent." Again, of the urine in remittent fever, he says: " It seldom contains albumin . . . albuminous urine is the rule in yellow fever, a rare excep- tion in remittent." Ascoli,1 Dubujadoux,2 and others have noted the existence of pepto- nuria in association with the malarial paroxysm. The occurrence of acute nephritis in connection with malaria has also been recognized for many years: Ch^nouard,3 Hertz,4 Sol- datov,5 Dewalsche,6 Verhaeghe,7 Schmid,8 Pepper,9 Busey,10 McLean,11 Da Costa,12 Wood,13 Rosenheim,14 Atkinson,15 Bermann,16 Stefano- wicz,17 Dods,18 and many others noting this condition. Throughout the Southern States, as testified to particularly by the admirable records of Joseph Jones,19 the condition is not very infre- quent. The grave and often fatal acute nephritis following hmmo- globinuric attacks is well known. These cases have been well studied by Bastinelli20 and Kelsch and Ki6ner,21 who have described at length the changes in the kidneys following acute malaria. They be- lieve that severe acute, diffuse, or glomerulo-nephritides may directly 1 Lav. d. Cong d. Med. Int., 1892, Milano, 1893, vol. v. p 350. 2 Arch, de Med.et Pharm., Paris, 1892, p. 437. 3 Rec. des travaux de la Soc. M6d. du Depart. d'Indre-et-Loire, 2s, 1845, p. 101. « Op. cit. 6 St. Pet. Med. Woch., 1878, iii. 345. 6 Arch. Beiges de Med. Mil., 1859, xxiii. 20. 7 Ibid., 1860, xxvi. 31. 8 Deutsche Klinik, 1852, 442. 9 Amer. Journ. Med. Sci., 1866, li. 405, 408. Ibid., 1873, Ixv. 123. 17 Op. cit. 72 Med. Record, N. Y., 1880, xvii. 54. 73 Ibid., 1888, xxxiii. 320. !•* Deutsch, med. Woch., 1886, xii. 752. 76 Op. cit. 78 Internat. klin. Rundschau, Wien, 1894, viii. 1844. 77 Wien klin. Woch., 1893, vi. 365. 78 Edinb. Med. Journ., 1888, xxxiii. ii. 1890. 79 Op. cit. 20 Ann. di Med. Navale, Anno ii. 1896. 27 " Maladies des pays chauds," 8vo, Paris, 1889, and Arch, de Phys. norm, et path., Paris, 1882, 2 8., ix. 278, 458. NEPHRITIS OF MALARIAL ORIGIN. 3 depend upon the malarial infection. They assert that nephritis occurs in more than half the fatal cases. " It develops in cases where the disease has a relatively long duration and has been marked by symp- toms of corpuscular dissolution, especially by haemoglobinuria, from •which we may conclude that it depends less upon the direct action of the malarial poison on the kidney than upon the irritation produced in the gland by the passage of the haemoglobin and its derivatives." Bignami,1 in his valuable studies upon the anatomical alterations in acute malarial infections, noted the fact that the kidneys were, as a rule, but little affected. The glomeruli were markedly pigmented, the pigment granules sometimes being within large colorless cells, some- times apparently within the endothelium of the glomerulus; at times, the most important lesions consisted of an exfoliation and degenera- tion of the epithelium lining the capsule; only in algid pernicious fever did he find glomeruli with very slight albuminous exudates. Sometimes, however, marked and extensive alterations of the paren- chyma were found, consisting of focal necrosis of the epithelium, especially those of the tubuli contorti. Barker,2 in four fatal cases of malaria, found in three instances that the kidneys showed but few changes, consisting of a slight pig- mentation of the glomeruli with albuminous exudates and casts, and a more or less swollen and degenerated condition of the epithelium of the convoluted tubules. A fourth instance was one of marked acute nephritis which was probably of malarial origin, although complicated later in its course by a streptococcus infection-Case II. of our series. In Anders'3 1780 cases there were but four instances of acute nephritis. The frequency of the occurrence of chronic nephritis as a result of malarial fever is a point about which different opinions have been held. Lenz4 and Rosenstein5 both believed malaria to be a frequent cause of chronic nephritis. Bartels6 was also a strong upholder of this idea. Herz7 likewise asserts that cases of acute nephritis in malaria may pass into a chronic diffuse process, a sequence which is recognized by many 1 Atti della R. acc. med. di Roma, 1890, Anno xvi., s. ii., v. 317. 2 Johns Hopkins Hospital Reports, 1895, v. 230. 3 Op. cit. 4 De diffusa nephritide chronica, preecipue respecto decursu morbi post intermittentem fehrim, 8°, Gry phi®, 1865. 5 Path. u. Therap. der Nierenkrankheiten, Berlin, 1870, 215. 6 Ziemssen's Cyclopaedia, Amer, edition, vol. xiv. p. 328. 7 Op. cit., p. 649. 4 THAYER, observers. McLean1 says : " I can confirm from personal observations Dr. Parke's remark that chronic Bright's disease is a consequence of ague. Many ' old Indians ' who have suffered from malarial fevers die of this disease." Kelsch and Kiener2 have described in detail the changes in chronic as well as in acute nephritis occurring in cases of old " febricitants." They describe two main varieties of kidney as met w'ith in chronic paludism : (1) the congested kidney; (2) the atrophic kidney. 1. The engorged kidneys are increased in size and weight and of firm consistency. The surface is smooth, the color deep red, the congestion being particularly marked in the pyramids. Owing to the extensive congestion of the vessels, interstitial hemorrhages or the escape of blood into the tubules may occur. There is a marked granular degeneration of the tubular epithelium, while desquamation is common. Hyaline casts may be found. 2. The atrophic kidneys are small, the surface is irregular, the capsule adherent, the consistency increased. The color is usually of a maroon or mahogany tinge, and often there is a blotchy appearance. Small cysts are common. Microscopically, alterations are to be found in the interstitial tissue as well as in the tubular epithelium. They note in conclusion3 that " malarial nephritides have but little that is characteristic about them. We may again, however, note: (1) The tendency toward hemorrhages in all forms and at all periods of the nephritis. (2) The frank character of the inflammation in contra- distinction to the partly steatotic, partly sclerotic forms which gout and alcoholism give rise to so frequently with us. (3) The rarity, perhaps the absence of amyloid degeneration, the ordinary expression of septicaemia of all sorts. Even in the cachexias the fatty and col- loid degenerations of the kidneys are of a subinflammatory character and give rise to hemorrhages. They are sharply distinguishable from the lesions of the senile kidney by the wholly secondary im- portance of the vascular changes, and notably by the absence of arte- rial atheroma." Bowland4 noted the frequency of chronic nephritis in the malarial 1 Reynolds' System of Medicine, vol. i. 2 Maladies des pays cbauds, 8vo, Paris, 1889, 744; Arch, de Phys. norm, et path., 1882, s. 2, t. lx. p. 278. 3 Arch, de Phys. norm, et path., 1882, s. 2. t. ix. 494. 4 The British Guiana Medical Annual and Hospital Reports, Demerara, 1892, 41. NEPHRITIS OF MALARIAL ORIGIN. 5 regions of British Guiana. Laveran,1 in his treatise, states that " acute or chronic nephritis is a fairly common complication of palu- dism. The nephritis has sometimes the characters of an epithelial nephritis (the urine contains albumin in great quantity, anasarca occurs and becomes rapidly generalized), sometimes those of interstitial nephritis or of mixed nephritis; this last form is, I believe, the com- monest." Other observers have paid very little attention to malaria as a cause of chronic renal changes. Thus, it is not mentioned in Senator's2 work as an etiological factor in chronic nephritis. Anders,3 in 1780 cases of malaria, met with chronic nephritis in but one instance. Bignami,4 in his admirable studies on the pathological anatomy of chronic malarial infections, lays but little stress on the changes in the kidneys. Marchiafava and Bignami5 have described amyloid degeneration of the kidneys following long and repeated febrile attacks. These cases had been associated with clinical and anatomical manifestations of a severe chronic nephritis. Beside the affection of the vessels of small and medium size and of the glomeruli, the authors found a consider- able involvement of the walls of the renal tubules themselves. Rem Picci,6 of Rome, has recently published an interesting com- munication upon the renal lesions in malarial fever, which has come to the author's observation since the writing of this paper. He rec- ognizes the fact that a malarial infection may be the cause not only of simple albuminuria, but of extensive renal changes, although such cases are rare. Malarial nephritis occurs more commonly in the fall than in the spring, and is particularly common in young individuals. It occurs in both the severe and the mild forms of the disease, and is no more frequent, apparently, in the former than in the latter. The attack is usually mild and of favorable outcome, but it may be severe, and in some instances passes into a chronic form. The symp- toms of nephritis appear not only during the malarial attack, but sometimes develop after the disappearance of the symptoms of the 1 Op. cit., p. 213. 2 Die Erkrankungen der Nieren, Wien, 8vo, 1896. (Excerpt from Spec. Path. u. Therap., herausgegeben v. Nothnagel.) 3 Op. cit. 4 Boll. d. R. acc. Med. d. Roma, 1893, xix. 186. 5 Riforma Medica, 1891, Anno vii., vol. i. 571. 6 II Policlinico, vol. v-M., 1898,197. 6 THAYER, infection. These cases Rem Picci has termed "post-malarial." Amy- loid degeneration is occasionally met with. The exciting cause of malarial nephritis is believed by the author to be the irritation of the kidney due to the elimination of the toxic products of the in- fection. Thus, in summary, it may be seen that the association of albumi- nuria with malarial fever has been generally recognized, but its fre- quency variously estimated, the general tendency being toward the idea that, even in severe forms, it is not so common but that the early appearance of albuminuria may be regarded as a valuable point in the differential diagnosis between this disease and yellow fever. And while acute nephritis dependent upon malarial infection is well un- derstood to occur, there are no existing statistics tending to show its relative frequency as compared with nephritis in other acute infec- tions. The same may be said with regard to the more chronic renal changes. It has therefore seemed advisable to us to analyze our cases of malarial fever occurring during the last eight years, with a view to determining the following points : 1. The frequency of albuminuria in malarial fever as compared with other acute infections. 2. The frequency of acute nephritis in malarial fever. 3. The possible influence of malarial fever in the production of chronic renal changes. Albuminuria. During the past eight years 758 cases of malarial fever have been treated in the wards of the Johns Hopkins Hospital. In 691 of these cases there are records of examination of the urine. Albumin was present in 321 instances-46.4 per cent. There was no albumin in 370 instances-53.5 per cent. In the great majority of cases the albumin was present as a small trace. Casts of the urinary tubules were found in 121 cases-17.5 per cent. The proportion of cases in which albuminuria was present varied materially, as might have been expected, according to the type of fever. NEPHRITIS OF MALARIAL ORIGIN. 7 Table of 691 Cases in which an Examination of the Urine was Recorded. Tertian fever-344 cases : Albumin present in . . . 132 cases.-38.3 per cent. No albumin " 212 " 61.6 " Casts " . . . 40 " 11.6 " Quartan fever-8 cases : Albumin present in ... 4 cases.-50.0 per cent. No albumin " 4 " 50.0 " Casts " 3 11 37.5 " Regularly intermittent fevers (tertian and quartan)-352 cases : Albumin present in . . . 136 cases.-38.6 per cent. No albumin " 216 " 61.3 " Casts " . . . 43 " 12.2 " JEstivo-autumnal fever-283 cases: Albumin present in . . . 165 cases.-58.3 per cent. No albumin " 118 " 41.6 " Casts " . . . 70 " 24.7 " Combined infection (tertian and sestivo-autumnal)-26 cases : Albumin present in . . .11 cases.-42.3 per cent. No albumin " ... 15 " 57.6 " Casts " 7 " 26.9 " Cases of uncertain type-30 cases : Albumin present in ... 9 cases.-30.0 per cent. No albumin " ... 21 " 70.0 " Casts " 1 " 3.3 " It thus becomes evident that albuminuria has occurred in nearly one-half of all the cases of malarial fever treated in the hospital. In the regularly intermittent fevers, tertian and quartan, the proportion of cases of albuminuria was 38.6 per cent., while in the aestivo- autumnal infections, the majority of all cases, 58.3 per cent., showed albumin in the urine. The large percentage in aestivo-autumnal fever is not remarkable when one considers the many other clinical evi- dences of the greater malignancy of infections with the aestivo- autumnal parasite. Our statistics show, however, a rather strikingly large proportion of instances of albuminuria in all types. They can scarcely be com- pared to those of Anders, who has used the qualifying term "marked." 8 THAYER, The percentage is, however, five times as large as that of Atkinson,' who found albuminuria in 9 per cent, of 121 cases. Particularly conspicuous is the high percentage of albuminuria among the cases of mstivo-autumnal fever. It is in the more severe infections with this variety of parasites that the so-called remittent and pernicious fevers most commonly occur, and in these more severe attacks it would be but fair to assume that the percentage of cases showing albumin would be yet larger than that shown by our figures. And yet it is in just these cases that, at times, the question of a dif- ferential diagnosis between yellow fever and malarial fever is believed by some authors to hang upon the presence or absence of albumin in the urine. It may be interesting to compare the frequency with which we have found albumin in the urine of patients with malarial fever with our own statistics and those of others with relation to certain other of the acute infectious diseases. Typhoid Fever. Here we may use our own statistics. In 389 cases of typhoid fever from the statistics of Hewetson and Osler, albu- min was observed in 303 instances, or 78 per cent., and casts in 164, or 42.2 per cent.2 Scarlet Fever. The frequency of albuminuria in scarlet fever has been variously estimated. Miller,3 Patrick,4 Steiner,5 and Guebler,6 as well as Lecorch6 and Talamon,7 believe that albuminuria is practically always present during the febrile period of the disease. S6e8 estimated that it was present in more than one-half the cases ; Haidenheim in 80 per cent.9 Cadet de Gassicourt10 found albumin in 21 out of 65 cases, but believes these figures to be too high. Barthez and Sann6u believe it to be relatively rare, while Vogel12 found it in two instances out of 50 or 60 cases, and Thompson13 in 40 out of 112 instances. 1 Op. cit. 2 Hewetson: Johns Hopkins Hospital Reports, 1894, iv. 113. Osler: Johns Hopkins Hospital Reports, 1895, v. 281. s Lancet, 1849, il. 1, 57,113, 197, 281, 524, 685. 4 Cited by Guinon : Art. " Scarlatine," in Traite de Med., Charcot, Bouchard, Brissaud, 8vo, Paris, 1892, t. ii. 6 Compendium der Kinderkrankheiten, 3d ed., 8vo, Leipsic, 1878. 6 Diet. Encycl. des Sci. Med , Par., 1869, ii. 476. 7 Cited by Guinon : Op. cit. 8 Le Moniteur des Hop., 1858, 659. 9 Cited by Barthez and SannS. io France Med., Par., 1881, ii. 388, 400. u Traite clin. et prat, des maladies des enfants, 3d ed., Par., 1891,124. 12 Cited by Barthez and Sanne. is Med.-Chir. Transactions, 1887. NEPHRITIS OF MALARIAL ORIGIN. 9 The later albuminuria, that occurring during convalescence, was observed in 30 per cent, of the cases of Cadet de Gassicourt, and in 55 out of the 112 cases studied by Thompson. Caiger,1 in the London Fever Hospital, found albuminuria present in but 7.69 per cent, of 4015 cases; he asserts that the frequency of this condition is much less than is generally supposed. He omits, however, from his statistics those cases in which 11 but a faint and transient cloud of albumin was noted for less than three days." My friend, Dr. McCollom, has very kindly sent me the results of the examination of the urine in 100 cases of scarlet fever in the Boston City Hospital: | to | per cent, of albumin 4 cases, per cent, of albumin 1 case. Large trace " " 1 " Trace " " 4 cases. Slight trace " " 14 " Very slight trace of albumin 15 " Slightest possible trace of albumin . . 49 " No albumin 12 " 100 cases. Diphtheria. The frequency of albuminuria in diphtheria is also variously estimated. See2 believed it was present in one-third or a half of all cases. Maugin and Bergeron3 assert that it occurs in the majority of instances. Bouchut and Empis4 estimate its frequency at 66| per cent., as does also Ebert.5 Smith6 found it present in 24 out of 62 cases, or 38.7 per cent., but believes that the proportion is probably greater, inasmuch as albumin was often missed, owing to the transient character of the symptoms. Sanne7 found albumin in 224 out of 400 cases, or 54.5 per cent. By far the most satisfactory statistics are those of McCollom.8 Out of 623 cases of diphtheria albumin was present in 57.7 per cent. If we compare our statistics of malarial fever with those of typhoid 1 Article "Scarlet Fever," in "A System of Medicine," etc., edited by T. Clifford Allbutt. London, 1897, vol. ii. 151. 2 Op. cit. 3 Moniteur des Hopitaux, Par., 1858, vi. 1035,1043,1051, 1064. 4 Gaz. des Hop., 1858, 524. 5 Cited by Oertel, Ziemssen's Cyclopaedia, Amer, edition, i. 603. 6 Keating's Cyclopaedia of Diseases of Children, i. 626. 7 Traite de la diphtherie, 8°, Par., 1877, pp. 128 et seq. 8 Med. and Surg. Reports, Boston city Hospital, 9th series, Boston, 1898, p. 27. 10 THAYER, fever we find that malaria stands well behind the former affection in the frequency with which albuminuria is observed. The figures show : Percentage of cases of albuminuria in malarial fever .... 46.4 " * " typhoid fever . . . .78 " in which tube casts were found in malarial fever . 17.5 " " " " " typhoid fever . 42.2 This is not remarkable when one considers through how long a period the kidneys of a patient with typhoid fever are subjected to the influence of the toxic products of the infection, as well as to the continued high temperature. If, however, we compare the percentages in the more severe aestivo- autumnal fevers, the figures approach one another more closely : Percentage of cases of albuminuria in aestivo autumnal fever . . 58.3 " " " typhoid fever . . . .78 " " in which casts were found in aestivo-autumnal fever 24.7 '' " " " " typhoid fever . . 42.2 Scarlet Fever. From a consideration of the varying estimates above mentioned it would appear that albumin is in all probability present in at least one-half the cases of scarlet fever. McCollom's figures indicate a still higher percentage. It is, perhaps, possible that in a certain proportion of the 49 per cent, of cases where the " slightest possible trace of albumin " was found this minute quantity would have passed unobserved with ordinary routine methods of urine examination. It may, perhaps, be fair to compare Caiger's estimate, where those cases showing " a faint and transient cloud lasting less than three days " were omitted, with our cases in which casts were found. Such a table shows : Caiger's statistics of the frequency of albuminuria in scarlet fever, 7.69 per cent. Percentage of our cases of malarial fever in which albumin and casts were present, 17.5 per cent. Despite these figures, and especially in view of McCollom's table, there can be little doubt that albuminuria is considerably more fre- quent in scarlet fever than in malaria. Diphtheria. Assuming that McCollom's figures form a fair basis of comparison, we find: NEPHRITIS OF MALARIAL ORIGIN. 11 Percentage of cases of albuminuria in malarial fever .... 46.4 " " " diphtheria 57.3 And this slight discrepancy in favor of diphtheria disappears when we consider festivo-autumnal fever separately : Percentage of cases of albuminuria in sestivo-autumnal fever . . 58.3 " " " diphtheria 57.3 Albuminuria, then, is more common in such notoriously severe acute infections as typhoid fever, scarlet fever, and diphtheria than in malaria; the difference, however, is by no means great. While oc- curring in only 38.6 per cent, of the regularly intermittent fevers, the frequency of albuminuria in sestivo-autumnal fever is probably fully as great as in diphtheria, and by no means so very much less than in typhoid and scarlet fevers. Yellow Fever. While the occurrence of albumin in the urine in malarial fever cannot be compared in frequency with that observed in yellow fever, and while the amount, when present, is probably usually smaller, the fact that a majority of all instances of sestivo- autumnal fever in the climate of Baltimore, cases lasting but a short time and treated almost immediately by quinine, showed albuminuria, is strong presumptive evidence in favor of the idea that a considerably larger percentage of the severe pernicious cases which are most likely to be confounded with yellow fever must show this symptom. This would suggest caution in placing too great reliance upon the mere presence of albumin as evidence of the existence of yellow fever in a suspicious case. It may be asked whether our figures represent the condition in the first days of an sestivo-autumnal infection. I think it may fairly be asserted that they do. There were 96 cases of sestivo-autumnal fever in which the urine was examined within a week after the first symptoms of the infection. In the urine of these cases, albumin was present in 57, or 59.3 per cent., and casts were present in 28, or 29.1 per cent. Acute Nephritis. Among 1832 cases of malarial fever occurring in the Johns Hop- kins Hospital and Dispensary we have observed 26 instances of acute 12 THAYER, nephritis. In 3 of these instances there is room for possible doubt as to whether the nephritis may not have preceded the malarial infection, though in none is this believed to have been the case. There were: Instances of tertian fever 7 " sestivo-autumnal fever 16 " quartan fever 1 " combined infection (tertian and sestivo-autumnal) 1 uncertain type 1 Total 26 These were all typical cases of acute nephritis, the majority showr- ing oedema, while abundant albumin and numerous casts and usually blood-corpuscles and epithelium were found in the urine. In 14 instances the complication occurred in the first attack of malaria; in 11 the patient had suffered from one or more previous infections; in 1 there was no history obtainable. In 13 instances the complication ended in recovery (Cases III., IV., V., VII., IX., X., XI., XII., XIII., XVIII., XIX., XXII., XXIV.).1 In 4 instances the complication ended in death (Cases I., II., XV., XVI.). In 9 instances the result was doubtful (Cases VI., VIII., XIV., XVII., XX., XXL, XXIII., XXV., XXVI ). Fatal Cases. The four fatal cases include the three instances in which some doubt may be held as to the true malarial nature of the case (Cases II., XV., XVI.). In Case II. there was a history of oedema and bloody urine for several months, while regular chills had been noted but three weeks. The patient, however, had throughout this period been working in an extremely malarious district at the most dangerous time of the year. It is improbable that his malaria was acquired in December; far more likely that the infection occurred earlier in the season. He was a dull, stupid negro, and experience has shown us that a clear history of the time of onset of a malarial infection is often very difficult to obtain in such instances. In Case XV. the clinical observation was unsatisfactory. Death 1 In Cases III, IV., and V. there was still a trace of albumin present on discharge. In Cases XXII. and XXIV., dispensary patients, but one examination of the urine is recorded. In all instances, however, the general condition warranted the conclusion that the patients were on the road to definite recovery. NEPHRITIS OF MALARIAL ORIGIN. 13 occurred in coma, the breath having a urinous odor and the urine containing one-fourth per cent, of albumin; the illness apparently began sharply with a malarial infection two wreeks before. The record of the examination of the urinary sediment, however, was incomplete. Case XVI. was one of characteristic acute nephritis w'hich took on a chronic course, resulting fatally seven months after the onset. The patient had been living in a malarious district, and had had chills and fever for a month and a half before entry, associated with anasarca, ascites, and evidences of acute nephritis. CEdema of the feet, how- ever, was said to have been noticed for a month before the onset of the chills. In this case there is a history of scarlet fever (without dropsy) six years before. It is our belief, in view of the absence of other causes, that all three of these instances were true malarial nephritis. It is but fair, however, to point to the possibility that an- other view of the matter may be taken. In Cases XV. and XVI. autopsy was not permitted. Case I. was an instance of pernicious fever in which death was due to the acute infection rather than to the nephritis. In Cases I. and II. the anatomical changes have been excellently described by Dr. Barker. Histories of Four Fatal Cases. Case I. Pernicious malarial fever ; cestivo-autumnal infection ; acute nephritis; death ; autopsy.-No. 1769. J. B., male, aged thirty-four years, entered the hospital on September 10, 1890, complaining of fever, weakness, and headache. The patient has been sleeping on the ground in a very malarious district. For three days he has complained of great weakness and continuous vomit- ing. No further history is obtainable. Physical examination. The patient is very weak and tremulous; tongue coated ; thorax negative ; spleen palpable ; pulse 104 ; temperature 101°. Blood. JEstivo-autumnal parasites; hyaline amoeboid bodies in great numbers. Sept. 11. The temperature rose this evening to 102°. No great change in the condition. 12/4. The patient seems better to-day; vomiting is less frequent. Treatment. Quinine, 0.325 (gr. v) three times a day. On the 13th and 14th there was no vomiting, but the patient complained of great weakness. On the evening of the 15th the patient passed into a peculiar condition ; he became drowsy and dull, and was aroused only with great difficulty ; he was restless and uneasy, turning and tossing the clothes about; occasional vomiting. Throughout the night of the 15th the patient was restless and there was hiccough; the temperature, which had been nor- 14 THAYER, mal since the 12th, fell to a subnormal point; the voinitus during the night was tingeri with blood. On the morning of the 16th the patient was cathe- terized, 1500 c.c. of urine being obtained. The examination showed a specific gravity of 1010 ; a .moderate quantity of albumin. The sediment contained many casts, chiefly granular and hyaline, though partly epithelial casts were not uncommon. At 4 o'clock in the afternoon the temperature had fallen to 96°. The patient was very restless, cold, and dusky; growing steadily weaker and finally unconscious, he died at 8.45 P.M. Autopsy. (Dr. Councilman.) Diagnosis: Pernicious malaria; acute splenic tumor; malarial pigmentation of spleen and liver; hypostatic congestion of the lungs. . . . " The kidneys were large and swollen, surface mottled, capsules adherent in places. On section the consistency is firm, the Mal- pighian tufts are prominent and congested. The medullary rays are pale, and betweem them the lines of vessels are deeply reddened. No areas of opacity are visible. The cortex is distinctly, though slightly, pallid." . . . Microscopical examination by Dr. Barker :l " On microscopical examina- tion all the bloodvessels of the kidneys were found to be dilated, the veins of the pyramids being especially wide. There is irregular dilatation of the glomerular capillaries. Comparatively few parasites are present in the kid- neys, although some distinct forms are visible within the veins and capil- laries. A number of phagocytic cells can be seen, intravascular phagocytes and endothelial cells. The capsules of some of the glomeruli have undergone fibrous thickening. In places the capsular endothelium is proliferated. The endothelium of the convoluted tubules is swollen and granular, and there are numerous hyaline casts to be seen in the small collecting tubules. In the pyramids haemoglobin casts can be made out." In this instance the nephritis, as in most cases of typhoid fever, played but a small part in the clinical picture of the disease. Possi- bly, had the patient recovered from the acute infection, or had life been further prolonged, clinical evidence of the renal changes might have appeared. Case II. Malarial fever ; double tertian infection ; subacute nephritis ; death three and a half months after onset.-No. 5421. L. W., male, colored, aged twenty-three years; admitted January 9, 1893. Family and personal his- tory negative. Gonorrhoea nine years ago. Three months ago, while work- ing in a very malarious district, began to suffer from frequent micturition, general oedema, and bloody urine. For three weeks has had regular tertian chills. Physical examination. Marked general oedema; ascites ; no cardiac hyper- trophy ; pulse tension not increased ; spleen not palpable (distended abdomen). 1 Johns Hopkins Hospital Reports, 1895, v. 234. NEPHRITIS OF MALARIAL ORIGIN. 15 Blood. The blood was not examined until after death; it then showed an extremely severe double tertian infection. Urine. Dark amber; clear ; acid; 1017 ; large amount of albumin. Sedi- ment ; hyaline, granular, and epithelial casts; many epithelial cells. There were daily febrile paroxysms, the nature of which was not appreciated during life. The urine ranged in quantity at first between 500 and 1000 c.c., dimin- ishing gradually before death. For the last three days it amounted to but 260 to 350 c.c. The patient became enormously cedematous, and grew more and more ansemic. He was dull and stupid, but restless and uneasy. On January 26, 1893, he died. The patient was treated throughout as a case of nephritis. A milk diet was ordered and frequent hot baths. Diuretin and digitalis were given internally. Autopsy. (Dr. Councilman.) "Anatomical diagnosis; Acute malarial fever ; double tertian infection; general streptococcus infection; subacute Bright's disease; malarial pigmentation of the organs; chronic passive congestion; general anasarca ; infarctions of kidneys; erysipelas." . . . "The Blood. Examined fresh from the peripheral veins and various internal organs showed enormous numbers of malarial parasites, most of them nearly full-grown; others only half-grown (tertian type), many of them enclosed within the protoplasm of large mononuclear leucocytes. . . ." " The kidneys together weigh 400 grammes. They are both alike in size and general appearance. On the surfaces of each a few small fresh infarctions with hemorrhagic margins are visible. The capsules strip off easily. The general color of the external surfaces of the kidneys beneath the capsules is yellowish-brown, marked by scattered opaque darker areas, and here and there by minute hemorrhages. The whole kidney has a rather soft, cedema- tous feel. On section, the cortex has a yellowish appearance and is rather translucent; pyramids reddened, contrasting sharply with the lighter-colored cortex. In some parts of the cortex the striae are well marked, in others they are less apparent or invisible. Average width of cortex 1 cm. A small amount of fluid exudes from the cortical substance on pressure. The glome- ruli are indistinct. . . . Frozen sections of the kidney show a very little fat in fine droplets in the glomeruli. The epithelial cells of the tubules in the labyrinth are much swollen and are filled with fine albuminous granules and hyaline droplets. Many of the tubules are dilated and are lined by low epithelium. Casts are numerous in sections, and in urine collected from the bladder. Coagulated albumin is visible in the capsular spaces, in frozen sec- tions made from a bit of kidney previously fixed in boiling water. The capsular epithelium is swollen and evidently proliferated. . . ." The kidneys were carefully studied by Dr. Barker d " The Kidney. An examination of many glomeruli shows considerable varia- tion in the size of the capsular spaces. While in some instances the glome- rulus almost completely fills out Bowman's capsule, the space being a mere 1 Johns Hopkins Hospital Reports, vol. v. p. 257. 16 THAYER, chink, in others the latter is equal in size to one-third of the whole capsule. The space is not always empty, but may contain coagulated albumin, red blood-corpuscles and shadows, or a few mononuclear cells (desquamated epi- thelium). The fibrous capsules are not thickened except occasionally, where an atrophied glomerulus is visible. Frequently just outside the capsule of Bowman a narrow clear space can be made out, and this may contain a few cells, chiefly polynuclear leucocytes, or even be crowded with them. In many of the capsules the capsular epithelium is evidently proliferated, the whole inside of the space being lined by nuclei with intensely staining chro- matin. The glomerular capillaries vary in their size and contents; some of them are empty, others are distended. Occasionally one is seen to be plugged with streptococci. The number of white corpuscles within the glomerular capillaries also varies ; they are very irregularly distributed ; in some glome- ruli scarcely any are present; in others, one, two, or more of the glomerular capillaries may be packed full of polynuclear leucocytes. In a section stained in methylene-blue a capillary is visible plugged at one point with streptococci and crowded throughout the rest of its extent with leucocytes, with polymorphous nuclei-reminding one forcibly of the appearance of the capillary glass tubes in an experiment in positive chemotaxis. On the other hand, masses of cocci may be seen with no neighboring leucocytic accumu- lation. The nuclei of the polynuclear leucocytes vary in appearance: some stain sharply, and take on the ordinary forms ; others stain less sharply, have a blurred look, and assume bizarre shapes. The protoplasm of the poly- nuclear leucocytes frequently contains granules or minute clumps of granules of malarial pigment, occasionally a well-formed parasite or short chains of cocci. There is some malarial pigment in the glomeruli contained within the protoplasm of mononuclear cells. The majority of the malarial parasites in the glomerular capillaries are outside nucleated cells. Here and there in specimens stained with aqueous magenta a giant spindle shaped nucleus is visible. The lumina of the convoluted tubules are for the most part wide, and are lined with rather low cubical epithelium. There are a few areas of dilated tubules in which the lining epithelium is flattened so as to resemble endothelium. The nuclei of the epithelial cells, as a rule, stain normally, although in some swollen cells they stain feebly, and in some tubules the nuclei are shrunken and the chromatin stains more intensely than normally. Many of the convoluted tubules and collecting tubules contain hyaline casts; and hyaline droplets are visible within the swollen lining epithelial cells. These droplets, both the finer and the coarser, and the upper portions of the hyaline casts, stain intensely in Weigert's fibrin stain. Occasionally desquamated epithelial cells and a few red blood-corpuscles and round yel- lowish striped urinary concrements are to be seen within the lumina of the tubes. The intertubular capillaries contain enormous numbers of streptococci (methylene-blue, Weigert's fibrin stain). Many of them are dilated and completely plugged with cocci, and sometimes chains of cocci are visible in NEPHRITIS OF MALARIAL ORIGIN. 17 narrow pericapillary spaces. As in the glomerular vessels, some of the inter- tubular capillaries are crowded with leucocytes. Some of the small veins in the cortex are actually thrombosed with masses of streptococci, large num- bers of malarial parasites, white corpuscles (some of which are necrotic), and pigment clumps. No bacteria other than streptococci are present anywhere in the kidney. In the interstitial tissue of the kidney there is a slight but evident in- crease in the number of the cells of the lymphoid type. There are small nodal masses of smaller and larger round cells, usually with but little peri- nuclear protoplasm, many of them with fragmented nuclei. These minute nodes may contain, besides lymphoid cells, single polynuclear leucocytes or epithelioid cells. Sections of the kidney treated with ferrocyanide of potassium and hydro- chloric acid show an almost entire absence of cells containing haemosiderin. Here and there, however, a little is visible within the protoplasm of the endothelium of the vessels. The infarcted areas of the kidney present the lesions ordinarily seen under these circumstances-anaemic necrosis and neighboring reaction. The whole of the necrotic areas-glomeruli, tubules, bloodvessels, interstitial tissue- refuses to stain in the ordinary nuclear dyes, and has an increased affinity for eosin. The only nuclei which stain are those of polynuclear leucocytes which have invaded the interstitial tissue everywhere, and are accumulated in large numbers at the margins of the infarcted areas, and in the neighbor- ing dilated bloodvessels. There is extensive nuclear fragmentation in these polynuclear leucocytes, and the most varied distortion-processes (abschnii- rungsvorgange) of their nuclei are visible. Many of the bloodvessels at the apices and in the peripheries of these infarctions are thrombosed with strep- tococci, enormous numbers of malarial organisms, over 100 of which were counted inside the lumen of one vessel, and white cells. Small bits of the kidney hardened in Flemming's stronger solution and stained with aqueous magenta yield very instructive sections. Fine fat droplets are visible in the glomeruli and in the epithelium lining the capsular spaces. The convoluted tubules are not extensively fatty; some are entirely free from fat droplets,, others show numerous smaller and larger droplets, especially at the proximal ends of the lining epithelial cells. Fine fat droplets are also visible in the protaplasm of some of the leucocytes in the vessels, and also in the smooth muscle fibres of the arteries. The desquamated epithelial cells within the lumina of the tubules contain numerous rather coarse fat droplets. The cells of the convoluted tubules in sections prepared in this way are seen to be finely granular, and the hyaline degeneration of the protoplasm is well shown. Many of them contain large vacuole-like spaces which sometimes displace the nuclei. In some of the tubes free red blood-corpuscles, poly- nuclear leucocytes, and malarial organisms are visible. The last named are sometimes free or lie on red blood-corpuscles; sometimes they are enclosed within cells. They are to be seen in both polynuclear and mononuclear cells 18 THAYER, within the lumen of the convoluted tubules. In one tubule, besides numerous red blood-corpuscles and shadows, four free well-formed malarial organisms and a mononuclear cell containing within its protoplasm five malarial organ- isms of the same stage of development can be made out. Pictures such as these were seen too often to be accounted for by technical accidents. Occa- sionally red corpuscles, malarial parasites, and white cells are visible within the glomerular capsular spaces. The time at which the streptococcus infection came on is not clear. Case XV. Malarial fever; tertian infection; nephritis; uraemia; coma; death ; no autopsy.-No. 17,406. P. J., female, aged fourteen years ; admitted September 26, 1896. The patient had chills and fever during six months last year. No history of other infectious diseases. Eleven days ago she began to suffer from pains in neck and legs, dyspnoea on exertion, fever, and cold sen- sations. Physical examination. The face has a pasty white color; lips pale ; tongue coated. The patient is very apathetic ; somewhat delirious ; spleen not pal- pable ; no oedema ; breath has a urinous odor. Blood. Extra-cellular tertian bodies. Leucocytosis of 21,000. Urine. Passed involuntarily, and lost. Temperature. Subnormal. On the 27th the patient became comatose. Urine. Catheterized specimen: pale yellow; opaque; 1008 ; albumin | per cent. The sediment contains considerable pus. No casts or blood to be seen. Despite hypodermatic injections of quinine and stimulation, the patient died comatose on the 27th. Autopsy was not allowred. This case is unsatisfactorily recorded. The author was absent at the time, but Dr. Camac, who saw the case, tells me that there is little doubt that the death was from uraemia. As to the causal influence of the malaria there must be some question. Case XVI. Malarial fever; cestivo-autumnal infection ; acute nephritis, be- coming chronic; death.-No. 17,621. I. A., female, aged fourteen years, entered October 17, 1896. Family history negative. The patient had measles and whooping-cough as a child ; scarlet fever six years ago. Has always been well and strong. She lives in a most malarious district. Two and a half months ago she began to notice slight oedema of feet and puffiness of eyes. A month and a half ago began to have chills and fever. At this time the s-welling increased considerably, involving the genitalia and abdomen, and becoming very troublesome. The urine was reduced in quantity and red. There was marked pallor. The chills disappeared under treatment; she had but seven or eight in all, and thinks she has quite recovered from the malaria. NEPHRITIS OF MALARIAL ORIGIN. 19 Physical examination. Marked pallor ; general oedema and ascites. Heart's apex in fourth space, eight cm. from median line. Second aortic sound markedly accentuated. Blood. Half-grown tertian parasites. Urine. Pale; acid; 1012; albumin one-half per cent.; sediment abundant; epithelial cells, small round, and larger flat; hyaline, finely and coarsely granular casts ; blood casts ; pus cells ; granular matter. Under quinine the parasites rapidly disappeared. The temperature was normal. The urine, however, was always reduced in quantity and the oedema never cleared up. The pulse throughout was of high tension; second aortic sound markedly accentuated. Uraemic symptoms-headache, vomiting, and eventually coma-existed for five months, death occurring on March 20th. The albumin at times was present in as large quantities as 0.7 per cent. The patient was kept for the greater part of the time on a milk-diet; various diuretics and iron were given internally; hot-water and hot-air baths, with pilocarpine hypodermically, were given with only temporary effect. No autopsy was permitted. Cases with uncertain result. In nine instances (Cases VI., VIII., XIV., XVII., XX., XXL, XXIII., XXV., and XXVI.) the final outcome of the nephritis is not perfectly clear, though in the majority recovery probably occurred. Cases XXIII., XXV., and XXVI. were observed in the dispensary, and were seen on but one occasion. Case VI. was an instance of mild acute hemorrhagic nephritis occur- ring in sestivo-autumnal fever. The patient left a week after admission, feeling perfectly well, the urine, however, containing at the time of discharge a trace of albumin, while the sediment showed occasional hyaline and granular casts and red blood-corpuscles. There was no cardiac hypertrophy, no increase in the blood tension ; never any oedema. Case XIV. was that of a man, aged forty-one years, who had suffered off and on for a month with daily chills and for ten days with oedema of the face and extremities. The urine showed the characteristics of a miltl acute hemorrhagic nephritis. Considerable improvement in the general condition occurred under quinine, but the patient had a carbuncle upon the back of the neck, and four days after entry left the hospital against advice, dreading an advised operation. In Cases XVII., XX., and XXI., especially in the two former, there is some possibility that the process may have become chronic. These cases will be considered later. 20 THAYER, General Analysis of 26 Cases of Acute Malarial Nephritis. Age: From 1-10 years 2 cases. " 10-20. " 4 " " 20-30 " 9 " " 30-40 " 6 " 11 40-50 " 5 " Total 26 cases. The figures in this table run practically parallel to those in our former statistics as to the relative frequency of malarial fever, with the exception of the slightly greater percentage of cases of nephritis between the ages of forty and fifty. The small percentage of cases under ten years of age is perhaps explained by the absence of a chil- dren's ward in the hospital. Sex: Of the 26 cases there were: Males, 17 (65.3 per cent.); females 9 (34.6 per cent.). Race: 20 of the 26 cases were in white patients (76.9 per cent.) and 6 in negroes (23 per cent.). These latter figures are striking. Of 1832 cases of malarial fever but 82 (4.4 per cent.) were in colored patients; and yet of these few patients 6 (7.3 per cent.) developed acute nephritis, against 20 (1.1 per cent.) in 1750 whites. These figures are quite in keeping with the clinical fact which we have learned to recognize, in this hospital at least-namely, that the colored race is more susceptible to renal disease than the white. Relation of the Time of Development of the Nephritis to the Season of the Year. Table Showing the Time of Development of 26 Cases. January . . . . 0 February . . . 0 March .... 1 April . . . . 1 May . 0 June . . . . 1 July 5 August .... 5 September .... 7 October .... 6 November .... 0 December .... 0-26. It would thus appear that nephritis is much commoner at the height of the malarial season ; rare in the early months of the year. Of these cases 11.5 per cent, only developed before July, while our statistics in NEPHRITIS OF MALARIAL ORIGIN. 21 1712 cases as to the time of onset of the symptoms of malarial infec- tion show that 17.1 per cent, develop during this period. The greater relative frequency of malarial nephritis in the second half year is clearly explained by its predominance in sestivo-autumnal fever. (Edema was present in 19 of the 26 cases. Blood was noted in the urine in 18 cases; it was absent in 7, while in 1 instance no note upon the sediment was made. An exact estimate as to the relative frequency of nephritis in malaria is difficult to make. If we take into consideration the entire 1832 cases, it must be remembered that the urine was examined in the out- patient department in rare instances only, when the attention of the physician was definitely called to the possibility of some renal com- plication. And it is quite possible that cases of true nephritis may, under these circumstances, have escaped observation. Among these 1832 instances of malarial fever there were 26 cases of acute nephritis, or 1.4 per cent. The following table will show the percentage of renal complications in the different types of fever : Regularly intermittent fevers (tertian and quartan) . . 1014 cases-nephritis, 8 cases, 0.78 per cent. 2Estivo-autumnal fever . . 676 " " 16 " 2.3 " Combined infections . . 36 " " 1 " 0.9 " A more accurate estimate of the frequency of nephritis in malaria is probably to be obtained by a study of the cases observed within the hospital-758 in number. The objection might be raised that these cases were, as a rule, somewhat more severe than those observed in the dispensary. But, inasmuch as all patients presenting themselves at the dispensary with malaria are recommended for admission, many of the mildest cases entering, this objection is probably not as im- portant as it might appear at first. It is probably safe to say that the figures obtained from the house-cases, while doubtless somewhat too high, are less out of the way than those obtained from a consider- ation of the total number. Among the 758 cases of malarial fever treated in the Johns Hop- kins Hospital there were 21 instances of acute nephritis of probably malarial origin, or, in other words, 2.7 per cent. In three of these instances there is room for some doubt as to whether, possibly, the 22 THAYER, infection may not have occurred after the beginning of the nephritis. Leaving out these possible doubtful cases, we are then left with a percentage of 2.3 of acute nephritis. The frequency of acute nephritis in aestivo-autumnal fever was, as might have been expected, far greater than in the regularly inter- mittent fevers. In 394 cases of tertian and quartan fever there were 6 instances of nephritis (1.5 per cent.), or, if we omit the 3 cases in which there is some doubt as to the etiology of the nephritis, 3 instances (0.7 per cent.). Among 296 cases of sesti vo-autumnal fever there were 14 instances of acute nephritis (4.7 per cent.). Out of 26 instances of combined infections there was 1 case of acute nephritis (3.5 per cent.). A comparison of these statistics with those of other observers in other acute infections is interesting. a. Typhoid Fever. Among 389 cases of typhoid fever we have had 14 instances of acute nephritis,1 or 3.6 per cent. In none of these cases, however, was oedema present, and in none of the fatal cases was death apparently due to the renal complication. Complete recovery occurred in all instances which did not die from other complications of typhoid fever. b. Scarlet Fever. The most satisfactory statistics are those of Caiger,2 who observed, among 4015 cases of scarlet fever in the London Fever Hospital, 3.31 per cent, of instances of acute nephritis, a percentage but little higher than that observed by us in all varieties of malaria-2.7 per cent. c. Diphtheria. In diphtheria the frequency of true acute nephritis is difficult to estimate. Trousseau3 observed dropsies in barely 5 per cent, of his cases ; Sann6,4 in 7 (3.1 per cent.) out of 224 instances in which albumin- uria was present, or in 1.7 per cent, of all his cases. In our cases of 1 The determination of what shall be called clinically " acute nephritis" is necessarily some- what arbitrary. Among our cases, in the absence of gross clinical evidence of renal disturb- ance, we have included only those where the urine showed a large quantity of albumin with numerous casts-or, if the albumin were not especially abundant, where the sediment showed, in addition to casts, blood and renal epithelium. We have, for this reason, omitted from our typhoid statistics some of the cases classed by Hewetson as nephritis. 2 Op. cit. 3 Quoted from Barthez and Sann6, op. cit., p. 457. 4 Traits de la diphthSrie, 8vo, Par., 1877. NEPHRITIS OF MALARIAL ORIGIN. 23 malaria, dropsy was present in 4.6 per cent, of the cases in which there was albuminuria, or in 1.9 per cent, of all our cases. From McCollom's valuable statistics nephritis would appear to be an unimportant complication of diphtheria. But 5.2 per cent, of 638 cases had over 0.1 per cent, albumin in the urine, while oedema was noticed in but 4 instances. " In the 71 autopsies, in no instance was the condition of the kidneys such as to have materially contributed to the fatal issue." It may then be seen that while albuminuria is more common in typhoid fever than in malaria, true acute nephritis, with general dropsy and other characteristic symptoms, is apparently of greater frequency in the latter affection. And while malarial fever cannot be said to exercise as deleterious an influence upon the kidneys as does scarlet fever, the percentage of acute nephritis among our cases of malaria is more than half as large as that of Caiger in scarlet fever. Considering the different types of malarial affection separately, these facts are more strikingly brought forth. The percentage of cases of acute nephritis in our 296 instances of sestivo-autumnal fever is higher than that in any of the above-mentioned infections. Table. Percentage of cases of nephritis in sestivo-autumnal fever . . .4.7 typhoid fever 3.6 " " scarlet fever (Caiger) . . . 3.5 In comparison to Sanne's estimate that 3.1 per cent, of the albu- minurias in diphtheria have dropsy, we have the fact that out of 165 cases of albuminuria in sestivo-autumnal fever 9, or 5.4 per cent., showed this symptom. In view of these figures it is difficult to escape the conclusion that malarial fever is one of the acute infections in which acute nephritis is comparatively common. This is especially true of sestivo-autumnal infections where its frequency, if not its severity, would, from our statistics, appear to be equal to that of scarlet fever, typhoid fever, or diphtheria. The important role which malarial fever plays in the etiology of acute nephritis in Baltimore is testified to by the fact that out of 112 instances of acute nephritis observed in the Johns Hopkins Hospital 21, or 18.7 per cent., were of malarial origin. All observers agree that there is a great difference in the malig- 24 THAYER, nancy of different infections, and our statistics would lead us to recog- nize the justice of this observation. Fifteen of our 26 instances of malarial fever occurred during the summer and fall of 1896, at a time when an unusually large amount of severe malarial fever prevailed. It is not improbable that the especial malignancy of this epidemic of 1896 may account for the rather strikingly high percentage of instances of nephritis which have come under our observation. Our statistics would lead us to assume that this complication is more frequent than it would appeal' to be in Rome from the observa- tions of Rem-Picci. Chronic Nephritis. What influence, if any, may malarial fever have upon the develop- ment of chronic nephritis ? In four instances of acute nephritis observed in the hospital there is some reason to believe that the process may have assumed a chronic course. The first (Case XVI.) has already been mentioned among the fatal cases (page 18). The patient died, after an illness lasting from six to seven months, with the symptoms of a chronic diffuse nephritis. An autopsy was not permitted. It will be remem- bered that there was some question in this case as to whether the ma- laria might not have been a secondary infection developing in a patient already suffering from nephritis. The time of onset of the trouble, the surroundings of the patient, the absence of other etiological ele- ments, make it highly probable that the malarial infection was the primary cause of the disease. Case XVII. Malarial fever ; double tertian infection ; chronic nephritis ; little improvement.-No. 17,836. A. T., female, colored, aged twenty-one years. Admitted November 10, 1896. Family and personal history good; no his- tory of other infectious diseases. The patient suffered in September with chills and fever, which disappeared after treatment with quinine for one week, when she believed that she had completely recovered from the infec- tion. For four weeks she has suffered with oedema of the back and legs, abdominal pain, headaches, cough, and dyspnoea. Two days ago had a chill. Physical examination. Marked pallor ; general oedema and ascites ; right hydrothorax. Heart. Apex in fifth space 12J cm. from the median line; no accentuation of the second aortic sound. Spleen not palpable. Blood. Tertian parasites. Urine. Smoky; 1025 ; acid ; albumin abundant, nearly 1 per cent. Sedi- ment abundant; leucocytes; vaginal epithelial cells; occasional decolorized NEPHRITIS OF MALARIAL ORIGIN. 25 red blood-corpuscles ; numerous hyaline and finely granular casts; some coarsely granular casts, many having small round cells adherent; occasional blood and epithelial casts. There were slight febrile paroxysms on the 10th and 11th. Under treat- ment with quinine the temperature became normal on the 13th, and remained so thereafter. The patient was placed on a milk diet, given diuretics (diuretin, bitartrate of potassium) and iron (Blaud's pills). Frequent hot baths, with and without the addition of pilocarpine hypodermatically, were given to induce sweating. The urine, reduced in amount for the first several days, was normal or slightly increased in quantity thereafter. The specific gravity varied between 1025 on entrance and 1008 on December 2d. For the three weeks before discharge it averaged about 1010. The blood disappeared from the urine by the 18th of November, but returned again on the 21st. On the 5th of De- cember the patient left against advice, still oedematous, the urine showing | per cent, albumin. In this instance the duration of the case (two and a half months); the per- sistence of the symptoms, and the continued large quantity of albumin, led us to believe that we were dealing with a chronic diffuse nephritis. Unfor- tunately, we have been unable to learn the subsequent history of the case. Case XX. Malarial fever ; oestivo-autumnal infection; acute hemorrhagic nephritis; recovery (?).-No. 20,905. C. B., colored, aged twenty years. Ad- mitted October 12, 1897. Family history negative. Measles, whooping- cough, and chicken-pox as a child. The patient has suffered for a month with daily and tertian chills. He has been taking quinine, and has had no chills for five days. Two weeks ago oedema of the legs and feet appeared, and a week later became general. The urine has been of a dark color. Physical examination. Pallor; general anasarca; point of maximum cardiac impulse in the fourth space 10 cm. from the median line; pulse of rather high tension ; spleen not palpable. Blood. 2Estivo-autumnal parasites, pigmented ovoid forms. Urine. Yellow; acid; 1017 ; albumin 0.4 per cent.; sediment; many uric- acid crystals; many granular, hyaline, and epithelial casts. There were slight daily febrile paroxysms from the 15th to the 20th, on which date treatment with quinine, 0.325 (gr. v) every four hours was begun ; the temperature reached normal by the 23d. The patient was given a milk diet and bitartrate of potassium as a diuretic. Later, iron in the form of Blaud's pills was given. On the 23d the urine suddenly became smoky, containing red blood-cor- puscles ; it was somewhat reduced in quantity from the 23d to the 30th, after which time it was steadily above the normal amount, sometimes passing 3000 c.c. The albumin gradually diminished in quantity. The oedema and ascites had disappeared by the 26th. There was no evidence of albuminuric reti- nitis. There was no cardiac hypertrophy, the point of maximum impulse being in the fifth space 8.8 cm. from the median line just before discharge. A slight trace of albumin, however, still remained present in the urine. 26 THAYER, On the 23d the patient left the hospital with a trace of albumin yet in the urine, and a few hyaline, granular, epithelial, and blood casts still present. The patient has been heard from repeatedly since his departure. He believes himself to be-well. A specimen of urine obtained several weeks ago (April 18, 1898) had a specific gravity of 1018. There was a very faint trace of albumin. Microscopically, a few red blood-corpuscles were found in a centrifugalized specimen as well as one or two coarsely granular casts. From the patient's letter there would appear to have been a moderate polyuria. Case XXI. Malarial fever ; cestivo-autumnal infection; acute hemorrhagic nephritis; recovery If).-No. 20,981. C. K., male, aged thirty-one years. Ad- mitted October 20, 1897. Family history negative. Had measles as a child and diphtheria (?) at thirteen. For twenty days the patient has had quotidian chills and fever, off and on, relieved at times by quinine. Two days ago the legs became oedematous, and there was dyspnoea on exertion. The urine was of a reddish color. Physical examination. Pallor; general anasarca; no cardiac hypertrophy; spleen not palpable. Blood. TEstivo-autumnal parasites ; hyaline amoeboid bodies. Urine. Reddish brown; smoky; 1015 ; acid; albumin 0.4 per cent.; sedi- ment abundant; numerous hyaline, epithelial, granular, and blood casts; red blood-corpuscles, normal and decolorized ; epithelial cells. There was irregular fever for forty-eight hours. Treatment with quinine was begun on the 21st, and the temperature was normal by the 23d. The patient was given a milk diet and bitartrate of potas- sium as a diuretic. Later, tr. ferri chloridi, 1 3 (n^xx) t. i. d., was also given. The oedema slowly disappeared, remaining absent after November 15th. The urine, only 700 c.c. in amount on October 21st, and 1290 on 22d, was afterward continually increased in quantity, the amount at times passing 2500 c.c. The albumin diminished rapidly, but was still present as a trace on discharge. No blood appeared in the sediment after December 24th. The pulse tension was rather high, and the second aortic sound was some- what accentuated, but no retinal changes were to be made out. The patient was discharged at his own request on January 24, 1898, feeling quite well. The urine on this date was clear, acid, 1010. There was a trace of albumin. The sediment still showed a few granular casts. In both of these instances there is some question as to whether or not the renal changes have assumed a chronic course. In Case XX. the presence of blood and an occasional cast in the urine six months after the onset of the affection, testifies to the gravity of the lesions produced by the acute infection while in Case XXI. the high blood tension and the persistence of albumin and casts were suspicious of a chronic change. Case XVII. represented, apparently, a true chronic malarial neph- ritis, and, in view of the literature above quoted, there can be but NEPHRITIS OF MALARIAL ORIGIN. 27 little doubt as to the existence of such cases. Although unable to present any further instances than these mentioned in support of such a view, it is, I think, safe to assume that any infection, the toxicity of which is sufficient to produce as large a percentage of serious acute nephritides as malarial fever, must play a certain part in the etiology of chronic renal changes. It may probably be considered as a generally recognized fact that scarlet fever, diphtheria, and typhoid fever result sometimes in changes in the kidneys which may lead secondarily to grave chronic nephritis. And such changes are generally supposed to be due to circulating toxic substances, produced either directly by the growth of the infectious organisms, as in diphtheria, or set free from the bodies of the dead bacteria, as in typhoid fever, or resulting secondarily from the action of such substances on the fluids and tissues of the body. The surprising frequency of acute nephritis in our cases of malarial fever would appear to be an indication of the extreme toxicity of the circulating poisons present, evidence of the existence of which has been previously brought forward in the grave changes noted by Guar- nieri,1 Bignami,2 Barker,3 Monti,4 and others in the spleen, liver, and brain. Does it not, perhaps, justify us in considering seriously whether, after all, repeated and chronic malarial infections may not play a greater part in the development of chronic renal changes than we have previously been in the habit of assuming ? Summary. In 758 cases of malarial fever treated in the wards of the Johns Hopkins Hospital albuminuria occurred in 46.4 per cent, and casts of the urinary tubules in 17.5 per cent. Albuminuria was much more frequent in aestivo-autumnal fever than in the regularly intermittent fevers, occurring in but 38.6 per cent, of the latter and in 58.3 per cent, of the former, while casts of the renal tubules were found in 12.2 per cent, of tertian and quartan infections and in 24.7 per cent, of the cases of aestivo-autumnal fever. The frequency of albuminuria in aestivo-autumnal fever is appar- ently equal to that in diphtheria, though less than in scarlet and typhoid fevers. Out of 1832 cases of malarial fever in the hospital and in the out- 1 Atti d. R. acc. med. di Roma, 1897, s. ii., iii., 247. 2 Ibid., Anno xvi., 1890, s. ii., v. 317. 3 Johns Hopkins Hospital Reports, 1895, v. 220. 4 Bull. d. Soc. med.-chir. d. Pavia, 1895. 28 THAYER, patient department there were 26 instances of nephritis of malarial origin, or 1.7 per cent. Of these, 13 recovered, 4 died, and in 9 the result was doubtful, 3 instances probably becoming chronic. In 3 of the fatal cases there "is possible doubt as to the malarial nature of the case. Nephritis occurs apparently in from 1 to 2 per cent, of all cases of malarial fever in the neighborhood of Baltimore. The complication is more frequent and severe in aestivo-autumnal fever; it is common- est during the height of the malarial season, in July, August, Sep- tember, and October; it is rare in the first half of the year. The relative frequency of malarial nephritis appears to be much greater in the negro than in the white race. There is nothing especially distinctive in the clinical characters of the disease. It shows the usual features of an acute toxic nephritis; the tendency is apparently toward a short course and a favorable issue. Severe fatal or chronic forms of the disease may, however, occur, two, possibly four, instances of chronic nephritis of malarial origin having come under our observation. Conclusions. 1. Albuminuria is a frequent occurrence in the malarial fevers of Baltimore, occurring in 46.4 per cent, of our cases. 2. It is considerably more frequent in restivo-autumal infections, occurring in 58.3 per cent, of these instances, against 38.6 per cent, in the regularly intermittent fevers. 3. Acute nephritis is a not unusual complication of malarial fever, having occurred in over two per cent, of the cases treated in the wards of the Johns Hopkins Hospital, and in between one and two per cent, of all cases seen at the institution. 4. The frequency of acute nephritis in aestivo-autumnal fever is much greater than in the regularly intermittent fevers, having been observed in 4.7 per cent, of the cases treated in our wards, and in 2.3 per cent, of all the cases seen. 5. The frequency of albuminuria and nephritis in malarial fever, while somewhat below that observed in the more severe acute infec- tions, such as typhoid fever, scarlet fever, and diphtheria, is yet considerable. 6. There is reason to believe that malarial infection, especially in the more tropical countries, may play an appreciable part in the etiology of chronic renal disease. NEPHRITIS OF MALARIAL ORIGIN. 29 Cases. Case I.- Vide page 13. Case II.- Vide page 14. Case III. xEstivo-autumnal malaria ; acute hemorrhagic nephritis; recovery. -No. 8126. L. S., aged thirty-one years, was admitted September 6, 1893. Family history negative ; had measles as a child. The patient lives in a very malarious district, and had chills and fever three years ago. A week before entry began to complain of cedema of the legs, dyspnoea, and cough with tenacious mucous expectoration. Physical examination. Marked pallor; moderate oedema of the legs ; fine moist rales at the bases of both lungs; no cardiac hypertrophy ; pulse of normal tension ; spleen palpable. Blood. 2Estivo-autumnal parasites ; hyaline amoeboid bodies and crescents. Urine. Dark reddish-brown; opaque; acid; 1021; much albumin. Sedi- ment : very numerous hyaline, granular, epithelial, and blood-casts; red blood-corpuscles, normal and decolorized ; leucocytes ; epithelial cells. There were paroxysms of fever on the afternoons of the 7th and 8th; the fever rapidly disappeared under quinine, which was begun upon the 8th. On the 9th and 10th the patient was given four doses of quin, et urese muriatis, 0.65 (gr. x), hypodermatically. The albumin, at first nearly j per cent., rapidly diminished to a faint trace on October 18th. No casts were to be found in the sediment after September 30th. The quantity of urine, at first diminished, was always above the normal after September 14th. On October 23d the patient was discharged, feeling perfectly well; the urine, however, still showed a faint trace of albumin. Beyond the quinine, which was admin- istered in doses of 0.325 (gr. v) every four hours from September 9th to 23d, and afterward in doses of 0.325 (gr. v) three times a day, the patient received no medicinal treatment. Case IV. Malarial fever; mixed cestivo-autumnal and tertian infection; acute nephritis; recovery (?).-No. 8302. J. J., aged thirty years, was admitted Octo- ber 2, 1893. Family history negative ; always healthy, except for an attack of malaria two years ago. For two weeks daily chills, headache, vomiting; for two days cedema of the hands and feet and vertigo Physical examination. Sallow color; marked pallor; moderate general oedema; arteries slightly thickened; no cardiac hypertrophy; no accentua- tion of second aortic sound ; spleen palpable. Blood. Mixed infection; sestivo-autumnal and tertian parasites, the former in excess. Urine. Reddish-amber; clear; acid ; 1022 ; distinct trace of albumin. Sedi- ment: granular and epithelial casts, many cylindroids, few leucocytes. There were paroxysms of fever on the 2d, 3d, and 4th. Treatment. Quinine 0.65 (gr. x) every four hours on the 2d, 3d, and 4th, and 0.325 three times a day from the 10th on. The temperature, which had shown daily elevations, was normal after October 4, 1893. October 6th. Urine: dark-yellow; acid; 1015; trace of 30 THAYER, albumin; many large epithelial and hyaline casts, some with blood adhe- rent; few red blood-corpuscles; few leucocytes. The patient was discharged, apparently well, on the 12th. There was no final note upon the urine. Case V. PEstivo-autumnal infection; acute hemorrhagic nephritis; possible exacerbation of a chronic nephritis; recovery (?).-No. 8558. F. L., male, aged thirty-eight years, was admitted November 4,1893. Family history negative ; measles as a child ; typhoid fever fourteen years ago ; smallpox eight months ago. Has had tertian chills off and on for four weeks, relieved occasionally by quinine. For two weeks there have been oedema of the feet and legs, dyspnoea, headache, frequent micturition, and ischuria. Physical examination. Pallor; marked oedema of the legs ; breath urinous ; heart slightly hypertrophied; apex impulse in the sixth space just outside the mamillary line ; second aortic sound accentuated; radial tension some- what increased ; artery not thickened; spleen palpable. Blood. JEstivo-autumnal parasites; hyaline, amoeboid bodies, and crescents. Urine. Smoky; acid; 1015; albumin, 0.4 per cent. Sediment: numerous hyaline and granular casts; epithelial casts; red blood-corpuscles; round epithelial cells ; few leucocytes. There was slight fever on November 4th and 5th, disappearing immediately under treatment with quinine 0.325 (gr. v) every four hours, which was dis- continued on the 15th. The patient was placed on a milk-diet and given fre- quent hot-air baths. For five days the quantity of urine varied between 500 and 1200 c.c., after this date being above the normal quantity. The albumin rapidly diminished in amount, the oedema at the same time disappearing. On the 18th a faint trace of albumin was present and a few granular casts; a few red blood-corpuscles were still to be found. On the 23d the patient was discharged, apparently well. Case VI. JEstivo-autumnal malarial fever; acute hemorrhagic nephritis; re- covery (f).-No. 13,578. J. T., aged twenty-one years, was admitted August 13,1895. Family history good ; no previous illness beyond an attack of chills and fever two years ago, lasting three weeks. For three weeks has had daily chills and pain in the head and abdomen. Physical examination. Marked pallor; no cardiac hypertrophy; no increase in pulse tension ; spleen palpable. Blood. yEstivo-autumnal parasites ; hyaline bodies and crescents. Urine. Smoky; acid; 1012; trace of albumin. Sediment: dark-brown, flocculent, showing microscopically blood and pus cells, and hyaline and granular casts with blood adherent. There were febrile paroxysms on the 13th and 14th, disappearing immedi- ately under quinine, which was begun on the 14th-0.65 (gr. x), two doses, and then 0.325 every four hours. The urine increased in quantity; the albu- min diminished, but was still present as a trace, with occasional hyaline, granular casts, and red blood-cells in the sediment on the day of discharge. On August 19th the patient, feeling perfectly well, left against advice. Beyond quinine, iron, in the form of Bland's pills, was the only medicinal treatment. NEPHRITIS OF MALARIAL ORIGIN. 31 Case Vil. Malarial fever ; cestivo-autumnal infection ; cachexia ; acute neph- ritis ; recovery.-No. 14,527. M. J. M., female, aged twenty-nine years. Ad- mitted November 18, 1895. Family history negative. Scarlet fever, with dropsy, seventeen years ago; syphilis two years ago; otherwise always well and strong. Chills and fever, her first attack, off and on for seven months; frequent headaches ; general debility. For three weeks moderate oedema of the face and legs. Physical examination. Marked anaemia (1,160,000 red corpuscles) and cachexia. Heart. Apex just outside nipple in fifth space; soft blowing mur- mur all over cardiac area, lost in the axilla; no increase in pulse tension ; spleen much enlarged. Blood. iEstivo-autumnal parasites; hyaline bodies, crescentic and ovoid forms. Urine. Cloudy ; acid ; 1006; decided trace of albumin ; heavy brownish precipitate. Microscopically, numerous pus cells and granular casts with epithelial cells adherent. There was irregular fever on the 18th and 19th, disappearing rapidly under quinine, 0.325 (gr. v) three times a day. The diet was restricted, and iron in the form of Blaud's pills was given. The urine was increased in quantity throughout, and showed always a trace of albumin with a sediment as above, excepting for the occasional presence of a few red blood-corpuscles. The oedema disappeared, and on December 10th the patient left the hos- pital against advice, feeling greatly improved. On January 27, 1896, patient returned complaining of severe nocturnal headaches which were of luetic origin, and disappeared in two weeks under iodide of potassium. The an(emia was much improved ; red blood-corpuscles 3,300,000. Urine. Somewhat increased in quantity; still contains about 0.5 per cent, of albumin. The sediment showed hyaline and granular casts with occa- sional epithelial cells adherent. The patient was again in the hospital in April, 1898, suffering from syphi- litic periostitis. The urine throughout was normal; excretion of solids and urea normal; no albumin; no polyuria. Case VIII. Malarial fever ; obstinate quartan infection ; acute nephritis ; re- covery If).-No. 16,720. R. M., aged twenty-two years, colored. Admitted July 19, 1896. Family history negative. Measles and whooping-cough as a child. Lived in a malarious district; has had chills and fever off and on for many years, more or less steadily for a year. For several months there has been frequent micturition, for four weeks oedema of feet and legs. Physical examination. Marked pallor; no cardiac hypertrophy; no in- creased pulse tension; spleen palpable. Blood. Triple quartan infection. Urine. Pale yellow; neutral; 1010; albumin abundant; sediment; few leucocytes and red blood-corpuscles; hyaline casts. The paroxysms, quartan in character, disappeared rapidly after quinine, 32 THAYER, 0.325 (gr. v), every four hours, which was begun on the 24th. The oedema rapidly diminished, and had entirely disappeared on discharge, excepting for a slight puffiness about the eyes. The urine throughout was increased. The albumin and casts rapidly diminished in quantity, but there was still a trace of the former on discharge. The patient left against advice on July 30th, considering himself well. Besides quinine, the only medicinal treatment was with iron in the form of Blaud's pills. Case IX. Malarial fever; cestivo-autumnal infection; acute hemorrhagic nephritis ; recovery.-No. 16,832. W. E., colored, male, aged forty-two years. Admitted July 30, 1896. Family history negative. Measles, mumps, and whooping-cough as a child; pneumonia twenty-four years ago. For nine days, weakness,nausea, exhaustion. Syncopal attack two days ago; ischuria; frequent micturition. Physical examination. Color good ; tongue coated ; no cardiac hypertrophy; apex impulse in the fifth space within the nipple line ; no increase in pulse tension ; spleen not palpable. Blood. yEstivo-autumnal parasites; hyaline, amoeboid, and ring-shaped forms. Urine. Deep red ; acid; 1030; marked trace of albumin; sediment, con- siderable ; pus and red blood-corpuscles ; hyaline and granular casts ; small, round epithelial cells. There were febrile paroxysms on the 30th and 31st, which disappeared immediately under quinine, 0.325 (gr. v), every four hours. The patient left the hospital apparently well on August 8th. There was no marked polyuria. Unfortunately, no further record was made of his urine. The patient was seen again on April 16, 1898. Has been perfectly well since discharge. Is convalescent from a mild attack of acute bronchitis. Heart's apex in sixth space 10 cm. from the median line, about in the mammillary line. Pulse tension not increased. Radial artery very slightly thickened. Urine, passed at 11 a.m. ; high color; acid; 10261; no albumin by nitric acid or heat. Sediment; numerous cylindroids; small round cells ; occasional red blood-corpuscles ; a few hyaline casts with an occasional degenerated cell adherent. Case X. Malarial fever ; cestivo-autumnal infection; acute hemorrhagic neph- ritis ; recovery.-No. 16,995. A. H., male, aged thirty-five years. Admitted August 13,1896. Family history negative. Measles, scarlet fever, and small- pox in childhood; renal colic nine years ago. Has complained for three days of severe headache, general exhaustion, and fever; has never had mala- rial fever previously. Physical examination. Patient has high fever ; is flushed ; tongue coated ; no cardiac hypertrophy; no increase in blood tension ; spleen palpable. Blood. JEstivo-autumnal parasites ; hyaline amoeboid bodies. Urine. Dark; smoky ; 1030; acid ; trace of albumin ; sediment slight. Microscopically, red blood-corpuscles, granular and hyaline casts. NEPHRITIS OF MALARIAL ORIGIN. 33 There was high continued fever from the 13th to the 16th, after which date the temperature was normal following treatment with quinine, 0.325 (gr. v), every four hours, which was begun on the morning of the 14th. The patient left on the 18th, feeling well. Unfortunately, no further note was made upon the urine. The patient has been seen on a number of occasions since that time. Has had no further attacks of malaria, and believes that he is in perfectly good health. A specimen of urine obtained in June, 1898, was quite normal. Case XI. Malarial fever ; astivo-autumnal infection: acute nephritis ; re- covery.-No. 17,000. J. P., female, colored, aged forty-four years. Admitted August 13,1896. Family history negative. Measles, mumps, and whooping- cough as a child. Has had several previous attacks of chills and fever. For about two weeks has complained of vomiting, headache, and at times slight delirium; ischuria. Physical examination. Large woman; tongue coated; no anasarca; fine rales at bases of the lungs; slight accentuation of second aortic sound; no apparent cardiac hypertrophy ; no increased pulse tension ; spleen not pal- pable. Blood. 2Estivo-autumnal parasites; amoeboid hyaline bodies and crescents. Urine. Amber; acid ; 1025; albumin 0.2 per cent. Sediment: pus and vaginal epithelium, hyaline and granular casts. There were febrile paroxysms on the 13th, 14th, and 15th, disappearing rapidly under quinine. The patient left the hospital on August 22d, at her own request, feeling perfectly well. Unfortunately, no final note was made upon the urine. The patient was communicated with by letter, and states on April 10,1898, that she is perfectly well. She has, however, had chills and fever since leaving the hospital. A specimen of urine obtained in May, 1898, was ab- solutely normal in character. Case XII. Malarial fever ; cestivo-autumnal infection; nephritis ; recovery.- No. 17,071. C. S., aged twenty-seven years; male. Admitted August 21, 1896. Family history negative. Has had no serious illness. The patient never suffered from malarial fever previously; he lives in a malarious dis- trict. Seven weeks ago began to suffer with swelling of the abdomen and legs, for which he took to bed. Since then the swelling has become general. Physical examination. Yellowish complexion ; marked pallor; no cardiac hypertrophy; slight accentuation of the second aortic sound; spleen palpable; marked oedema of the legs. Blood. TEstivo-autumnal parasites; numerous crescentic and ovoid forms. Urine. Light amber ; 1012 ; trace of albumin ; numerous hyaline and gran- ular casts with epithelium adherent; epithelial casts ; yellow granular casts, suggestive of a blood staining. There was moderate fever on admission, rapidly disappearing under quinine, 0.325 (gr. v), every four hours, which was begun on August 23d. The patient was placed on a milk diet and given bitartrate of potassium as a diuretic. 34 THAYER, The quantity of urine up to September 11th was above normal, averaging over 2000 c.c., the albumin diminishing in quantity. Occasional blood-cor- puscles were also seen in the sediment and upon the casts. On the 16th, without apparent cause, the urine fell to 600 c.c. There were pain and swelling of the left knee-joint. 17/A. Urine reddish; smoky; albumin 0.15 per cent. Sediment, numerous blood-corpuscles and an increased number of casts. From this date the urine steadily improved, the quantity being throughout supranormal. The patient improved progressively; the swelling and pain in the knee rapidly disappeared. Oct. 2181. Urine: 3000 c.c. ; pale; acid; 1010; no albumin ; sediment shows nothing abnormal. Patient discharged well. Case XIII. Malarial fever ; cestivo-autumnal infection; acute hemorrhagic nephritis ; recovery.-No. 17,250. M. S., female, aged ten years. Admitted September 9,1896. Family history negative. Has had measles. Lives in a malarial district, and has had chills before. One week ago she began to have fever, abdominal pain, and headache. There were two chills at the onset; these were followed by swelling of the abdomen and legs. Physical examination. Marked pallor; general oedema and ascites. No cardiac hypertrophy; blood tension not increased; spleen palpable. Blood. jEstivo-autumnal parasites ; crescentic forms. Urine. Smoky; acid; 1015 ; 0.2 per cent, albumin. Sediment, pus, hya- line, granular and blood casts ; red blood-corpuscles. There were febrile paroxysms on the 10th, 11th, and 12th, disappearing im- mediately after quinine, 0.26 (gr. iv), three times a day, on the 13th. The patient was given a milk diet, and bitartrate of potassium as a diuretic. The oedema slowly disappeared. It was last noted on the 29th of September. The urine, at first reduced in quantity, soon became increased above the normal amount; the albumin diminished to a slight trace. Oct. 24th. Urine pale; acid; 1012; albumin 0.1 per cent. Sediment, few granular and hyaline casts; several red blood-corpuscles. Oct. 25th. The patient was discharged to-day feeling perfectly well. See subsequent history, Case XVIII. Case XIV. Malarial fever; cestivo-autumnal' infection ; acute hemorrhagic nephritis; carbuncle; left the hospital improved.-No. 17,266. H. J. S., aged forty-one years. Admitted September 11, 1896. Family history good. Measles as a child ; syphilis eight years ago; malaria seven years ago. The patient has had daily chills off and on for a month, the last twelve days ago; this is his first attack. Ten days ago, after exposure, oedema of the face and extremities appeared. Afterward he began to suffer with pain in the neck. Physical examination. Marked pallor; general oedema; ascites ; no cardiac hypertrophy; carbuncle on the back of the neck ; heart sounds normal; arte- ries slightly thickened; spleen not palpable. Blood. JEstivo-autumnal parasites ; hyaline bodies ; presegmenting forms ; crescentic bodies. NEPHRITIS OF MALARIAL ORIGIN. 35 Urine. Dark red ; acid; 1017; albumin abundant. Sediment, heavy, brownish ; granular, epithelial, blood, and pus casts ; epithelial cells ; leuco- cytes ; red blood-corpuscles. There were slight evening elevations of the temperature on the 11th, 12th, and 13th. On the 14th the patient left the hospital against advice; opera- tion upon the carbuncle having been advised. The patient was much im- proved, the oedema having almost disappeared. Case XV.- Vide page 18. Case XVI.- Vide page 18. Case XVII.- Vide page 24. Case XVIII. Malarial fever; double tertian infection ; acute hemorrhagic nephritis ; recovery.-No. 19,288. M. 8., female, aged eleven years. Admitted April 27, 1897. The patient, who had suffered from a similar attack in Sep- tember, 1896 (Case XIII.), had been enjoying good health since her discharge from the hospital. Seventeen days ago she began to have tertian chills, which have continued since. There have been frequent attacks of nausea and vomiting and vertigo. Physical examination. Marked pallor ; face puffy ; heart and lungs nega- tive ; spleen palpable. Blood. Two groups of tertian parasites. Urine. Smoky ; acid ; 1015 ; trace of albumin. Sediment, moderate; small epithelial cells, hyaline and granular casts, one with a considerable quantity of fat; few leucocytes ; occasional red blood-corpuscles. Febrile paroxysms occurred on the 27th and 28th, disappearing after treatment by quinine, 0.13 (gr. ii), every four hours. The patient improved rapidly, the smokiness disappearing soon from the urine. The oedema of the eyes rapidly subsided. May 4th. Urine. Pale; acid; 1012; faint trace of albumin. Sediment, slight; epithelial cells ; few small hyaline casts. 5th. Patient, feeling perfectly well, leaves the hospital against advice. On May 17th the patient returned to the hospital, having had a chill two days before, after which she had taken quinine. The blood was free from parasites and no further chills occurred; the treatment was continued. Physical examination was negative. The urine was examined frequently during the next two weeks; it was always perfectly normal. The urea, estimated on one occasion, amounted to 0.028 per c.cm. On June 2, 1897, the patient was discharged, well. Case XIX. Malarial fever; cestivo-autumnal infection; acute hemorrhagic nephritis ; recovery (?).-No. 20,421. J. P., male, aged thirty-eight years, was admitted August 25, 1897. Family history good; no history of infectious diseases. The patient had chills as a child and again last year. For four weeks he has suffered from chills and fever off and on ; for three weeks there have been swelling of the legs and abdomen, drowsiness, ischuria, dyspnoea. Physical examination. Pallor; general oedema and ascites; double hydro- thorax ; no cardiac hypertrophy; pulse tension rather high; spleen not palpable. 36 THAYER, Blood. JEstivo-autumnal parasites; hyaline amoeboid bodies; crescentic forms. Urine. Deep amber; slightly turbid ; acid; 1020; albumin abundant. Sedi- ment, flocculent; hyaline casts, with epithelium, pus, and blood adherent; free blood and pus. There were febrile paroxysms on the 25th and 26th, the temperature remaining normal after the beginning of quinine-0.325 (gr. v) three times a day-on the 27th. The oedema and ascites rapidly disappeared. The urine was reduced in quantity on the 26th and 27th (880 and 560 c.c.). From this time on there was polyuria, amounting to 2200 c.c. on September 1st. The albumin steadily diminished in quantity. On September 2d the urine was of normal color; acid; 1015; no albumin ; microscopically, a few hyaline casts are still to be found in the sediment. The patient left the hospital, against advice, feeling perfectly well. Case XX.- Vide page 25. Case XXI.- Vide page 26. Case XXII. Malarial fever; type ?; acute nephritis; recovery^?).-L. S., male, colored, aged forty-three years, visited the out-patient department on March 27, 1895. Family history negative; measles and whooping-cough as a child; chills and fever in spring of 1894. For three weeks he has complained of cough and expectoration; for three days he has had chills and swelling of the legs; frequent micturition. Physical examination. Pallor; oedema of the legs; harsh breathing, with fine crackling rales at the apex of the right lung. Blood. Malarial parasites found; type not mentioned. "Urine. Albuminous ring quite marked with HNO3." Treatment. Quinine. April 10, 1895, feels better in every way. Case XXIII. Malarial fever; tertian infection; acute nephritis; result (?).- K. W., female, aged seventeen years, visited the out-patient department on July 31, 1896. Family history negative; has had measles, otherwise no serious illness. The patient has had chills previously. For ten days there have been daily paroxysms. Physical examination. Tongue coated; nasal and labial herpes; spleen palpable. Blood. Partially grown tertian parasites. August AAth. Chills have disappeared, but a week ago noticed oedema of the feet; scantiness of urine. The urine contained large amount of albumin ; hyaline and granular casts; numerous bladder and vaginal epithelial cells. Treatment. Milk diet, rest in bed, quinine. The patient did not report again. Case XXIV. Malarial fever; tertian infection; acute nephritis; recovery (?).- F. G., female, aged twenty-three years, visited the dispensary August 17, 1896. Family history negative; has had no serious illness. The patient has never had malarial fever; for a day or so, very severe headache. NEPHRITIS OF MALARIAL ORIGIN. 37 Physical examination. Marked pallor ; moderate oedema of the legs. Urine. Decided trace of albumin; epithelial cells; leucocytes; numerous coarsely and finely granular casts. August 22d. Returned to-day, complaining of having had three tertian chills, the last on Sunday ; severe headache. Blood. Tertian parasites ; half-grown forms. Under quinine the patient made a perfect recovery. Seen again March 17, 1897, feeling perfectly well. No further examinations of the urine were recorded. Case XXV. Malarial fever; cestivo-autumnal infection; acute hemorrhagic nephritis; result (?).-J. S., aged twenty-one years, visited the out-patient de- partment September 28, 1897. Family history negative; measles as a child. The patient had never suffered from malaria previously. Two weeks ago two chills; since then swelling of the face and legs came on, and he has com- plained of bad taste in the mouth. Physical examination. General oedema; no cardiac hypertrophy; spleen palpable. Blood. JEstivo-autumnal organisms ; nemerous crescents. Urine. Smoky, bloody; contains a large quantity of albumin. Treatment. Advised to enter hospital. The patient did not return. Case XXVI. Malarial fever; oestivo-autumnal infection; acute nephritis; ■arteriosclerosis.-J. M., aged forty years, visited the out-patient department October 20, 1896. Family history negative; always strong and well. For four weeks and a half the patient has had chills off and on, his first attack; headache, vertigo, and swelling of the feet for a week. Physical examination. Pallor; oedema of the legs; apex impulse under the sixth rib in mammillary line ; sounds clear; radial arteries thickened. Blood. 2Estivo-autumnal parasites; numerous crescentic bodies. " Urine has marked amount of albumin." The patient refused to enter the hospital and failed to report at the dis- pensary again. [Reprinted from The Philadelphia Medical Journal, November 5, 1898.] HYPERTROPHIC PULMONARY OSTEO ARTHROPATHY AND AKROMEGALY? By WILLIAM SYDNEY THAYER, M.D., of Baltimore, Md. Associate Professor of Medicine in the Johns Hopkins University. In an article in the New York Medical Journal, two years ago, I reported several instances of Marie's hyper- trophic pulmonary osteo-arthropathy in connection with one case of typical akromegaly, calling attention to the marked differences that exist between the clinical pic- tures presented by these two affections, which have, in certain instances, been confounded. It occurred to me that it might be of interest to demonstrate several radiographs of two of these old cases, one of osteo- arthropathy and another of akromegaly, and to speak briefly of one new instance of the former affection that has recently come under my observation. It may be well to summarize our three earlier in- stances of osteo-arthropathy. Case I.-A woman, 28 years of age, was admitted to the hospital on June 12, 1892, complaining of cough, pain in the region of the heart, and swelling of the legs. Her family and personal history were negative excepting that she had had cough, with considerable expectoration and shortness of breath, for 15 weeks. For 6 weeks the patient had noticed enlargement of the shins and ankles, associated with some tenderness and pain on walking. There were evidences of pleurisy with effusion on the right side. There was con- siderable thick, greenish muco-purulent expectoration, but no tubercle-bacilli were found. The urine contained a trace of albumin, but no casts were found in the sediment. There was nothing remarkable about the hands or arms of the pa- tient beyond marked clubbing of the fingers, with incurva- 1 Remarks made before the Philadelphia Neurological Society, February 28, 1198. 2 tion of the nails. The feet and legs, however, were much enlarged. The tibiae at the upper end were about normal in size; as one reached the lower third on each side there was great expansion, particularly on the right. At the level of the malleoli both tibiae were large and massive. The feet themselves were not so enormously enlarged. The patient remained in the hospital but 9 days and has not been heard from since. Fig. 1.-(a) Hand of Case IT and that of an individual 0.5 cm. taller. Case TI.-H. H. first came to the hospital on March 13, 1893, at the age of 20 years, complaining of cough and pain in the right side of his chest. His family and personal history were good. He showed evidences of right-sided pleurisy with effusion, which, on account of his fever and general condition, was believed to be purulent. The man was not seen again until March 18, 1898, when he returned, complaining of the same symptoms. Nine months before his entry he had noticed that his spine was becoming somewhat " crooked." For two months he had been unable to grasp objects well with his hands, and for several months he had had occasional pains in his knees and Fig. 1 .-(6) Hand of normal individual and that of Case II The two men were of exactly the same height. Fig 2.-Hand and arm of Case II (osteo-arthropathy) beside that of a woman with akromegaly. Fig. 3.-Foot of Case II and that of a normal individual. Fig. 4.-Legs of Case II (osteo-arthropathy). 3 tenderness over his shins. Within the List six months before entry he had noticed that it was impossible to lace his boots on account of the increasing size of his ankles and shins. He had also noticed an increase in the- size of his wrists. He presented, at this time, a markedly retracted right chest, with evidences of thickened pleura, while daily paroxysms of cough in the early morning, accompanied by profuse quantities of foul, sweet-smelling sputa, pointed to the ex- istence of bronchiectasis. He showed the same remark- able changes that he now presents in his arms and legs. The radius and ulna, the tibia and fibula, particularly in the lower half of their extent, were enormously thickened and broadened. The hand as a whole seemed extremely large, while the metacarpal bones were greatly thickened, the fingers clubbed, the nails large and incurved. The skin was everywhere normal. There were no changes in the face. Since then the patient has been under observation off and on. He has had transient swellings in various of his joints-knees, wrists, and ankles-which have been sluggish and practically painless, and he has also had, at times, well- marked tenderness over the enlarged areas in his arms and legs. There has, however, been no apparent increase in the symptoms during the past six months, and there has been no tenderness during that period. Case HI.-A. K., a man, 31 years of age, entered the hospital on September 27,1895, complaining of cough, weak- ness, pain in the right side of the chest, and enlargement and soreness of the bones of the wrists, hands, ankles, and feet. His family and personal history were good. Five years before, he had had an attack of pneumonia, followed by left-sided pleurisy, and later by what was apparently a pul- monary abscess, or, possibly, the rupture of an empyema into the lung. Two years later he had another attack, in which he expectorated a large quantity of foul-smelling pus, and since then, for the greater part of the time, the cough and expectoration had continued. For a year before entry there was stiffness in the knees, and nearly a year before, he began to notice an increase in size of his feet and ankles. Nine months previously the ends of his fingers and of his wrists began to enlarge. There was at first a dull pain in his wrists, which of late had not been present. He had lost much power in his hands and his weight had fallen in six months from 143 to 127 lbs. On physical examination there was evidence of thickened pleura in the right back, where there was well-marked dul- ness. The respiration was enfeebled in the dull area, with fine crackling rales in the axilla. Both knees were somewhat prominent and enlarged, the lower ends of the femora being apparently expanded; the upper ends of the tibiae appeared also to be somewhat enlarged. There was an excess of fluid in the right knee-joint. Both ankles were enlarged, as well as 4 the lower part of the tibia and fibula. The toes of both feet were elongated and clubbed. The lower ends of the radius and ulna were markedly enlarged and thickened, though there was no impairment of motion at the wrist-joint. There was marked clubbing of the finger-tips; the nails were large and incurved. The patient stayed in the hospital but a short time and has not been heard from since his discharge. All of these three patients, then, showed more or less painful enlargement of the long bones of the arms and legs, particularly toward their distal extremities; in- crease in size of the phalangeal, metacarpal, and meta- tarsal bones ; clubbing of the fingers and toes ; indolent and almost painless joint-effusions. In all, these symptoms were secondary to pulmonary affections; in two to empyema and bronchiectasis, in one to long- continued pleurisy and bronchitis, a picture clearly different to that presented by akromegaly. The accompanying radiographs will illustrate these points. In Figure 1 is represented the hand of a nor- mal man and that of Case II of osteoarthropathy. It is interesting to compare them with the photographs. The hand of the normal individual is not the same in the radiograph as in the photograph. It is, however, that of a man of exactly the same height as the patient. The extreme thickening of the metacarpal bones is a striking feature. The shafts are massive, so as to be nearly as broad as the lower epiphyses. All the phal- angeal bones are rather large, especially the first phalanges. Figure 2 shows the hands and forearms of the cases of akromegaly and osteo-arthropathy side by side. The general roughness and plumpness of the bones, and particularly the tendency toward tufting about the epiphyses and at the points of tendinous attachment, are to be noted in the case of akromegaly. But the picture is very different from that of the case of osteo- arthropathy, in which the changes are entirely restricted to the thickening of the shafts of the bones. The much Fig. 5.-Hand of a woman with akromegaly beside that of a normal woman of the same stature. 5 greater thickness of the soft parts in the akromegalic hand is also striking, particularly when it is remem- bered that this is the hand of a small woman, while the other is that of a large man. The enormous thickening and deformity of the shafts of the ulna and radius in the osteo-arthropathy are strikingly brought forth, the bones in the case of akromegaly being practically normal. In Figure 3 the massive enlargement of the first metatarsal bone in the patient with osteo-arthropathy is strikingly shown. In Figure 4 the colossal enlarge- ment of the lower parts of the tibia and fibula is to be seen. Figure 5 shows the hand of the case of akromegaly together with that of a normal woman of the same stature. In these radiographs, then, a distinct difference be- comes evident between the bone lesions in the akrome- galic hand and arm and those of osteo-arthropathy. The akromegalic hand shows a general plumpness of the bones, with an exaggeration of the normal irregu- larities in outline, and a tendency to roughness and irregularity about the epiphyses and points of muscular and tendinous attachment. In this, as in many other cases, there is also a rather well-marked lateral rough- ening and tufting of the ends of the terminal phalanges. In the case of osteo-arthropathy there is well-marked more or less general diaphyseal enlargement of the long bones, the smaller bones of the hands and the epiphyses being quite unaffected. In the present case this is especially marked in the lower parts of the dia- physes of the metacarpal bones. To what are these changes in osteo-arthropathy due? Among55 typical cases, excluding all doubtful instances, there were 20 autopsies. In 11 of these there were satis- factory notes as to the condition of the bones. In all instances there was an ossifying periostitis limited almost entirely to the diaphyses of the long bones of Fin. 6.-Case IV. Hypertrophic pulmonary osteo-arthropathy. 7 the hands, feet, arms, and legs. The process is most marked toward the distal extremities of these bones. The ribs are apparently unaffected. In one instance there was thickening of the skull. The bones in other regions appear to be uninfluenced. The periosteum is thickened; the new bone is, in some cases, laid on more or less regularly in layers, in other instances in a rough and warty manner. In many cases erosions of the joint-cartilages are found with an excess of fluid in the joints. The skin is practically unaffected. The clubbing of the fingers does not depend upon bony changes, the last phalanges having been always unaffected. The changes here are probably in the main vascular. Frey tag described a dilatation of the papil- lary processes, but no other cutaneous alteration. There were no scleroses of the corium nor of the subcutane- ous tissue. In none of our cases have we been able to make postmortem observations. A fourth case, however, which has recently come under our care, has afforded interesting evidence, from clinical observation and radio- graphs, as to the nature of the process. Case IV.-W. H. I)., a clerk, aged 27 years, was admitted to the Johns Hopkins Hospital on February 7, 1898, com- plaining of shortness of breath, pains in the back, and pain and swelling of the hands and feet. Family History.-His grandmother on the mother's side died of tuberculosis, while his father, at the age of 23, had hemoptysis and was told that he had pulmonary tuberculosis, but he recovered. His father, mother, one brother, and one sister are living and well. He has been married six years and has had three children. His wife is healthy. Personal History.-As a child, he had measles and mumps, and four years ago he had typhoid fever. There is no history of diphtheria, scarlet fever, rheumatism, malaria, or pneu- monia. The patient was rather feeble as a child, but since his twelfth year he has been strong and well. Nearly all his life he has had frequent attacks of cough; these came on "like heavy colds" and are more frequent during the winter. There has been a good deal of shortness of breath 8 in association with these attacks, but not much expectora- tion. The man denies venereal disease. He is a moderate eater and drinker. Present Hines*. -About six months ago, in August, 1897, the patient began to sutler from pain in the small of his back. This was rather sharp and recurred in attacks lasting a day or two at a time, with intervals of about a week. At times the pain was sufficiently severe to keep him awake at night; it was always aggravated by walking. The general condition remained good. On December 19th the patient noticed that his hands and feet were swollen, his attention being first drawn to the trouble by difficulty in lacing his boots and in putting on his clothes. On consulting a quack he was told that he was " suffering from kidney-trouble " and was given some medicine. The pains in the back, however, became more frequent and severe, and since then they have been continually present. Ten days later the patient began to suffer from slight cough, which soon became much more severe, recurring in paroxysms that usually came on once in the middle of the night and lasted two or three hours. During the remainder of the night and the day he suffered but little. There was abundant yellowish sputum. After ten days the cough and expectoration diminished, but they were still present to a certain extent. During this attack the patient had several outbreaks of sweating at night. A day or two before -the onset of the cough he noticed a stiffness in his knees on going up-stairs. This has grown gradually worse, and during the past two weeks there has been some actual tenderness. For a week the patient has noticed swelling of the knees. He thinks that his hands and feet have been gradually growing larger since he first noticed the condition, and during the past three weeks movements of the extremities have been painful. For two weeks he has been unable to close his fist. He believes that the clubbing of his fingers has always been present and he states that his father's fingers showed a similar con- dition. Ever since he first noticed the swelling of the hands and feet, they have been tender on pressure. He does not, however, think that thermal or tactile sensation is in any way impaired. There has also been loss of strength in the hands and legs, which he has observed especially during the past two weeks. Three weeks ago the patient first noticed soreness and stiffness at the right elbow. The joint is also sore to the touch and on motion. The pain in the back has gradually grown worse up to about a week ago, since which time it has been about the same. Three weeks ago the pains began to shoot around toward the abdomen, seeming to follow the course of the last ribs. These pains are especially marked at night. The constant pain in the back, which at first was Fig. 7.-Hands and arms of Cases II and IV and oi a normal individual. The shadows along the diaphyses of the long bones, particularly along the outside of the ulna in the arm of Case IV (on the left of the plate), represent, apparently, the fresh periosteal bone-formation. (The shadows about the lower extremity of the radius, well marked in the plates, are, unfortunately, rather unsatisfactorily shown in the reproduction.) 9 sharp, has now become " rather more of a soreness than a pain." During the past two weeks walking has become more painful. There has been no fever at any time except- ing last December. The patient gave up work on January 1st, and remained at home for about ten days. He then returned to work, but had to give up again after ten days. Two weeks ago he came to the dispensary, where he has been under treatment. The appetite is good ; there has been no nausea or vomit- ing. The bowels move regularly every other day. Since the middle of December there has been frequent micturition -two or three times at night. The patient has lost from 12 to 14 pounds in weight during the last two weeks. Physical Examination.-The patient is emaciated ; the lips and mucous membranes are of tolerably good color, though the face is pale. The tongue is clear at the edges and in the middle ; there is a dryish coat on the lobes. The respirations are 28; the pulse is 30 to the quarter, and of rather low tension. The thorax is long, the costal angle narrow. The right side is distinctly retracted, the shoulder being a little lower on this side than on the left. The retraction is more marked in the lower front and axilla than in the back. The expan- sion, nearly equal above, is considerably diminished in the lower right front. There is slight rounded kyphosis, taking- in the whole dorsal region, and a moderate scoliosis, with its convexity toward the left in the upper dorsal region. The right upper chest is perhaps a little more tympanitic than the left, the resonance extending to the seventh interspace in the right mammillary line and to the ninth rib in the mid-axilla. On auscultation the respiration in the right front is a little harsh and sometimes wavy, but otherwise clear. The respiration in the left front is clear and normal. In the right back there is slight but distinct dulness in the lower part, while the left side is clear. The respiratory murmur is somewhat enfeebled in the lower right back. There is well-marked phlebo-sclerosis, almost all the veins of the arms being thickened. A few small glands in the neck are to be felt; the epi- trochlears are just palpable. The inguinal glands are not particularly enlarged. The conformation of the jaws, teeth, and facial bones is perfectly normal; the skin over the face is natural. The hands and forearms present a remarkable appearance. The terminal phalanges are extremely clubbed; the skin is shiny and glossy; the nails are thin and incurved, hav- ing a parchment-like fluctuation about the roots-typical Hippocratic fingers. The skin of the fingers as a whole is tight and glossy. The fingers are tender upon pressure, while the metacarpal bones feel rather thick and massive, especially toward their distal extremities, and particularly the first metacarpal bones. The forearm shows remarkable 10 expansion in its lower part, both the radius and ulna being distinctly enlarged. On palpation of the left radins there appears to be a somewhat more marked node-like irregu- larity about the middle of the upper third. There is a dis- tinct fulness about the lower part of the legs, ankles, and feet, well marked at the level of the malleoli, while the metatarsal bones feel rather large. There is a curious puffy, somewhat edematous appearance about the hands and feet, though pressure (foes not produce pitting. The marks of the stock- ings, however, are left upon the skin. There are no nodes on the tibia1. The second phalanx on each foot looks some- what Hippocratic. The knees on each side show a well- marked excess of fluid, and the patella is floating. The epididymis is natural on both sides. When seen in the dispensary, the day before, the hands showed a most remarkable cyanotic mottled appearance. This was not present at the morning visit, but in the after- noon it returned. The blood showed, on February 8, 1898, 4,344,000 red cor- puscles, and 10,300 colorless corpuscles; hemoglobin, 70%. Urine: Amber; acid; specific gravity, 1026; albumin and sugar absent. The sediment was slight and contained a few epithelial cells and an occasional leukocyte. On February 12th no albumin was made out with the ordinary tests; an occasional hyaline and granular cast was, however, found in the sediment. The bmpei ature ranged between 97.1° and 102.7° for three days. During the last two days in the hospital the highest point reached was 100.5°. The patient was given tincture of mix vomica gtt. xx, three times a day, cod-liver-oil, and creosote. He left the hospital on February 12th. greatly improved. He re-entered the hospital on March 9th, the pains in the back and the general symptoms having returned. The cough, with scanty expec- toration, still occurs at night. The condition was practically the same as upon the former entry. On March 16, 1898, the following note was made: The clubbing of the fingers is very marked, but the cyanosis and puffiness of the hands are no longer evident. The ulna feels rather massive on both sides, as do also the metacarpal bones. The drawn, glazed, tight condition of the skin of the lingers has, however, entirely disappeared. The note is a little higher on percussion throughout the right side ; the expiration is somewhat prolonged. In the back, in the dull area, there is well-marked enfeeblement of the respiration. The voice-sounds are distinct; there are no adventitious sounds. The legs still show a rather marked enlargement of the lower part of the tibia and a moderate effusion into both angle-joints. The urine was negative throughout the patient's stay in the 11 hospital; the blood was about as on the former entry. The temperature was slightly elevated at night, often reaching about 100°, but never after the first two days going above 101°. After March IGth the patient received 10 grains of potassium iodid three times a day. He gained 6 pounds and left the hospital on April 12th, feeling much better, the acute swelling having apparently disappeared The following measurements were made, unfortunately after the more marked swelling had disappeared : Ma ch 30, 1897. Measurements. Height 173.5 cm. (68.25 in.) Weight, 115 pounds (in ward-clothes).. Upper Extremities. Right. Left. From tip of acromion to tip of middle finger 73.5 cm. 73.0 cm. From tip of olecranon to tip of styloid process of ulna 26.0 " 26.0 " Circumference of lower end of forearm, 1 cm. above tip of styloid process 17.0 " 17.0 " Circumference of midcarpal region 16.75 " 16.75 " Length of Metacarpal Bones. First metacarpal 5.25 " 5.25 " Second " 7.25 " 7.25 " Third " 7.0 " 7.0 " Fourth " 6.75 " 6.75 " Fifth " 6.0 " 6.0 " Circumference of broadest part of me- tacarpus t 23.0 " 22.0 " Length of fingers from base of phalanx to tip. Thumb 6.1 " 5.9 " Index finger 8.8 " 8.8 " Middle " 9.4 " 9.3 " Ring " 9.0 " 9.0 " Little " 6.9 " 6.7 " ('ircumference of fingers at base of second phalanx. Thumb 6.8 " 6.5 Index finger 6.5 " 6.3 " Middle " 7.3 " 7.1 " Ring " 7.1 " 6.9 " Little " 6.0 " 6.0 " Lower Extremities. Distance from tip of greater trochanter to level of sole of foot 82.0 " 81.5 " ('ircumference of knee at middle of patella 33.5 " 34.0 " 12 Length of tibia1 from articulation at knee to tip of internal malleolus 38.25 cm. 37.15 cm. Circumference of leg7 cm. below lower margin of patella 27.25 " 27.5 " Circumference of calf, widest part (14 cm. below patella) 27.50 " 27.75 " Circumference of leg, 8 cm. above tip of external malleolus 20.5 " 20.0 " Circumference of leg at level of external malleoli (foot at right angle to leg)... 26.0 " 25.75 " Circumference at instep, tape passing over tip of heel 33.5 " 34.0 " Length of foot 25.5 " 26.0 " Length of femur from tip of trochanter to articulation between femur and tibia 37.0 " 36.5 " Length of toes from metatarso- phalangeal joints to tips. Big toe 6.75 " 6.75 " Second toe 5.5 " 5.5 " Third " 5.0 " 5.0 " Fourth " 4.75 " 4.75 " Fifth " 4.25 " 4.25 " Circumference of terminal phalanx of great toe at thickest point 9.5 " 9.5 " Figure 6 shows a photograph of this patient taken upon his second entry. The attitude exaggerates, un- fortunately, the size of the hands and feet, but the relative enlargement about the forearms and legs is clearly brought out. Figure 7 shows a radiograph of the patient's hand and arm. Upon the same figure is shown a nor- mal arm of a small individual and that of Case II of osteo-arthropathy. On first glance the bones of Case IV appear relatively delicate and small; but on careful observation it will be noted that along the diaphyses of all the long bones of the hand and of both radius and ulna there is a well-marked more or less irregular shadow. This is most extensive about the lower parts of the shaft of the metacarpal bones, the radius, and the whole outer part of the ulna. In other words, it corresponds exactly to the areas of enlargement and tenderness evident upon physical examination. 13 This shadow clearly represents the periosteal new bone-formation. It is, so far as I know, the first in- stance in which the nature of the process has been clearly demonstrated during life. The clinical picture, then, in these cases of osteo- arthropathy is materially different from that in akro- megaly. This may, perhaps, be graphically illustrated by the following table of the more important symptoms of the two affections : Akromegaly. Subjective symptoms: headache; ocular distur- bances. General nervous manifestations; sw e a t i n g; polydipsia, etc. Predominance of facial changes. Changes mainly in the soft parts. Changes in the bones are generally the indication of an abnormal growth, and while inflammatory changes (peri- ostitis) may be present, they are rare and are usually limited to the points of mus- cular and tendinous attach- ment and the epiphyses, resulting in a general plump- ness of the bone, with an exaggeration of the normal irregularities. Fingers flat and expanded laterally; nails relatively small. Absence of joint-symptoms Onset without apparent cause. Changes in the peripheral nerves are common. Tumor or disease of the pituitary body usual; goiter frequent. OSTEO-A RTH ROPATH Y. Pain in joints and extremi- ties only. Absence of facial changes. Few changes in the soft parts. Characteristic periostitis, limited usually to the lower parts of the diaphyses of the long bones of the extremities, resulting in marked thicken- ing and deformity of the bone. Fingers clubbed; nails large and incurved. Presence of joint-s y m p- toms. Secondary to some chronic, usually pulmonary, affection. Changes in the peripheral nerves rare. Neither pituitary tumor nor goiter. The theories as to the cause of osteo-arthropathy are various and not wholly satisfactory. Bamberger speaks 14 guardedly with regard to it. He notes the frequency of chronic suppurative processes, and suggests the pos- sibility of the condition being due to the absorption of toxic substances from the putrefying bronchial or other secretions. Similar processes have been produced by feeding hens with phosphorus. Experiments with rectal injections of putrefying bronchial secretion in rabbits yield negative results. Marie expresses a simi- lar view more positively, and compares the process to gout, in which the changes are limited in a similar manner to certain definite parts of the osteofibrous system. Thorburn has suggested that the condition might be essentially tuberculous in nature, a slow' tuberculous periostitis and arthritis, and has proposed the name " tubercular polyarthritis." Massalongo, in a recent article, insists on the fre- quency of the occurrence of osteo-arthropathy without pulmonary involvement. He is impressed by the fre- quency with which such cases present a history of previous rheumatoid affections, and the common exist- ence of a family-history of rheumatism. He notes the fact, moreover, that in several instances sensory dis- turbances and muscular wasting have been noted, while in his own case, which, by the way, was second- ary to chronic bronchitis with bronchiectasis, he found a more or less extensive peripheral neuritis, the alterations being analogous to those found by Pitres and Vaillard, Klippel and himself in chronic articular rheumatism, namely, thickening of the neurolemma and of the intrafascicular connective tissue, with limited alterations in the axis-cylinders. He concludes that " hypertrophic pulmonary osteo-arthropathy does not then depend upon the alterations in the respiratory appa- ratus, nor in circulatory disturbances, but that it is the consequence of divers causes acting contemporaneously or alone, among which the arthritic diathesis plays the 15 principal role, the secondary localization of pathogenic microorganisms (infective arthritis and osteitis, infective pseudo-rheumatism), syphilis and other humoral dys- crasias, and alterations in the trophic spinal centers." Massalongo, it appears to me, goes out of his way to make light of the relationship between this clinical picture and chronic pulmonary disorders. In 43 of 55 typical cases of hypertrophic pulmonary osteo- arthropathy the affection was secondary to a pulmonary disorder. The symptoms followed : Pulmonary tuberculosis in 9 instances. Empyema " 9 " Pleurisy " 5 " Bronchitis with or without bron- chiectasis " 14 " Sarcoma of the lung " 2 " Abscess of the lung " 2 " Carcinoma of the pleura with effusion " 1 " Acute pneumonia " 1 " Total 43 The symptoms followed : Syphilis " 3 " Valvular heart disease " 3 " Chronic diarrhea " 2 " Spinal caries " 1 " Unknown causes " 3 " Total..... 12 / What the relation between the pulmonary affection and the periosteal and other changes may be is by no means clear. Thorburn's theory that the condition is tuberculous appears to have no foundation. On the whole the weight of evidence appears to me to be decidedly in favor of a modification of Marie's and Bamberger's theory of a toxic origin. The majority of the reported cases have followed conditions favorable to the retention of purulent secretions within the economy. 16 What these suppositious toxic substances may be and exactly how they may arise, and why they should be so much more frequently present with pulmonary af- fections than with suppuration elsewhere, are matters for speculation. It seems to me that we stand, with regard to secondary osteo-arthropathy, in a position somewhat analogous to that which we occupy, for instance, toward amyloid degenerations. Thus we know that amyloid degeneration follows commonly chronic suppuration, particularly of bone; but it is not infrequently found in instances of syphilis in which there has been rela- tively little suppuration, as well as in other cachexia due to malignant disease, or in chronic malarial ca- chexia, and lastly in a certain proportion of cases in which no distinct cause can be found. So, in like manner, we have learned that the secondary osteo- arthropathies are particularly frequent in connection with chronic suppurative processes in the lungs or pleurae; but they have also been found in several in- stances of syphilis, in 2 instances of chronic diarrhea, in 3 instances of valvular disease of the heart, and lastly, occasionally, unassociated with other organic disease. In each condition we are led to believe that the process owes its origin to some toxic substance arising within the economy. What this is we are at present entirely unable to say. There is little evidence, it seems to me, in favor of the idea that the condition may be due to primary or even secondary changes in the nervous system. The term, " Secondary hypertrophic osteo-arthropathy," suggested by Massalongo, is much better than that originally proposed by Marie, but it is a question whether it will be possible to abandon a term that has . come into such general use.