COLLECTED REPRINTS - OF - Hedical Communications - BY - WILLIAM SYDNEY THAYER, M. D. Series II. 1899-1904 BALTIMORE, MD. 190$. CONTENTS. XXXI. Remarks on Dr. MacCallum's Paper on the Haematozcan Infection of Birds.* Johns Hopkins Hosp. Bull., Balt., 1898, ix, 18. XXXII. Alfredo Antunes Kanthack. Johns Hopkins Hosp. Bull., Balt., 1899, x, 47. XXXIII. A Second Case of Gonorrhoeal Septicaemia and Ulcerative Endo- carditis with Observations upon the Cardiac Complications of Gon- orrhoea. W. S. Thayer and Jesse William Lazear. J Exper. M., N. K, 1899, iv, 81. XXXIV. Malaria. Maryland Med. J Balt., 1899, xli, 79. XXXV. Malarial Fever; Typhoid Fever; Pneumonia. Progressive Medicine, 1899,1, 281-345; 381-393. XXXVL Remarks on Dr. Cushing's Paper on Laparotomy for Intestinal Perforation in Typhoid Fever. Johns Hopkins Hosp. Bull., Balt., 1899, x, 71. XXXV11. Remarks on Dr. Futcher's Paper on A New Method of Straining Malarial Parasities. \ Johns Hopkins Hosp. Bull., 1899, x, 71. XXXVIII. Recent Investigations upon Malaria. Maryland Med J. Balt., 1899, xli, 335. XXXXIX. Remarks on Dr. Craig's Paper on A Case of Combined Ty- phoid and Quartan Malarial Fever. . Johns Hopkins Hosp. Bull., Balt., 1899, x, 214' * These remarks should have appeared in series No. 1 ^X^^Recent Investigations concerning the Haematozoa of Malaria. Med, Reg., Richmond, 1899, Hi, 243 XL1. Remarks on Dr. Ewing's Paper on a Form of Conjugation of the Malarial Parasite. Johns Hopkins Hosp. Bull., Balt., 1900, xi, 94- XL11. On Recent Advances in Our Knowledge concerning the Aetiology of Malarial Fever. Tr. Cong. Am. Phys. J Surg., N. Haven, 1900, v, 50; also (incomplete') Phila M. J., 1900, v, 1046. aLIH. Observations on the Blood in Typhoid Fever. * J. Bost. Soc. M. Sc., 1900, v, 23. LIV. Obituary : Jesse William Lazear. Johns Hopkins Hosp. Bull., Balt., 1900, xi, 290. XLV. Observations on the Blood in Typhoid Fever. Johns Hopkins Hosp. Rep. Balt., 1900, viii, 487. XLV1. Discussion of Dr. McrCae's Remarks upon Cases of Pernicious Anaemia with Involvement of the Spinal Cord. Johns Hopkins Hosp. Bull., Balt., 1901, xii, 262- /XLV1I. Observations on the Frequency and Diagnosis of the Flint Mur- mur in Aortic Insufficiency. Tr. Ass. Am. Physicia'ns, 1901, xvi.393; also, Am J M Sc, Phila., 15901, cxxii, 538. XLV!Il On the Occurrence of Strongyloideslntestinalis in the United States. J. Exper. M., N. K, 1901, v,75. XL1X. Remarks on Dr. Yates'Paper on A Fatal Case of Enteritis with Anemia caused by Uncinaria Duodenalis. John Hopkins Hosp. Bull., Balto., 1901 xii, 372. L. A Case of Aestivo-Autumnal Fever with Unusally Few Parasites in the Peripheral Circulation. Johns Hopkins Hosp. Bull., Balt., 1902, xiii, 59. LI. Remarks on the Diagnosis of Pancreatic Disease. Am. Med., Phila , 1902, Hi 341. z Lil. Laennec. Maryland Med. J, Balt., 1902, xlv, 104. LUI. Remarks on Typhoid Fever. St. Paul M. J., St. Paul, Minn , 1902, iv, 239. LIV. Notes on A Case of Acute Haemmorrhagic Polymyositis. Boston M. d? -S'. J, 1902, cxlvii, 313. LV. On the Teaching of Physical Diagnosis. Boston, M. c£ S. J., 1902, cxlvii, 689. LV1. On Arteritis and Arterial Thrombosis in Typhoid Fever. N. Y. State J. M , N. Y., 1903, Hi, 21. ! LVII. Observations on the Teaching of Clinical Medicine. J. Am. M. Xss., Chicago, 1903, xli, 1. LVII1. Bichat. Johns Hopkins Hosp. Bull., Balt., 1903, xiv, 197. LIX. Preliminary Report of the Tuberculosis Commission of Mary land- s'3, Baltimore, 190). LX. Remarks on the Occasion of the Opening of the Tuberculosis Ex position in Baltimore on the twenty-fifth of January, t904. Maryland Med. J., Balt., 1904, xlvii, 33. LX1. Remarks on Dr. Steiner's paper on A Case of Typhoid Arteritis. S Johns Hopkins Hosp. Bull., Balt., 1904, xv, 60. LX11. On the Late Effects of Typhoid Fever on the Heart and Vessels. Am. J. M. Sc., Phila., 1901/., Ixxvii, 391. LXIIL Observations on Two Cases of Tuberculosus Pericarditis with Effusion. Johns Hopkins Hosp. Bull., Balt., 1904, xv, 149. LXIV. The Relation of Acute Infections to Arterio-Sclerosis. J. Am. Med. Chicago, 1904, xliii, 726. LX/ Analysis of Forty-two Cases of Venous Thrombosis occuring in the Course of Typhoid Fever. Tr. Ass. Am. Physicians, 1904, xix, 164- Also, Med. News, N. Y, 1904, Ixxxv. 637 LXVI. On the Cardiac and Vascular Complications and Sequels of Typhoid Fever. Mobile M. J S. J., 1904, v, 1. Also, Johns Hopkins Hosp. Bull., Balto., 1904. xv, 322. LXVI1. The Probelms of Internal Medicine. Science, 1904, n- s> 706, Also, Am. Med., Phila., 1904, viii, 915. LXVI11. Remarks on the Unveiling of the Tablet in Memory of Jesse William Lazear. Johns Hopkins Hosp. Bull., Balt, 1904, xv, 388- Dr. Thayer.-Dr. MacCallum's communication is most refreshing. For nearly 20 years the question of the nature of the flagellate bodies has been one of the most keenly studied points in connection with the malarial parasite, and that this important discovery should have come from our laboratory is an honor to the institution. Owing to my absence from America I have not seen the whole process as it takes place in birds, but a part of the pro- cess I have been able to follow out in man. The specimen was that which Dr. MacCallum has described, and the body which I observed was one which had just been penetrated by a free flagellum. This body was a large round form of the aestivo-autumnal parasite without evidence of any surround- ing corpuscle. It contained a central ring of pigment. About this body there were two flagella which, though actively motile, did not disturb or agitate the round body. On careful observation, however, it was easy to observe that the flagella were quite free from the organism. These flagella which were very active would draw away from the parasite and then attack it, butting their heads against its periphery, struggling around it, and apparently making every effort to penetrate into the interior. Now this parasite represented a form which we have been looking at quietly off and on for these last seven years, considering it to be a flagellate body which for some reason or other was not agitated by the surrounding filaments, as is ordinarily the case. And yet after being taught by Dr. MacCallum to observe the picture before us, how perfectly simple it was to realize that the organism was not really pos- sessed of motile filaments, but was a separate body attacked by free flagella. These observations are, as I said, most refreshing and encouraging, and may well lead us to hope for more. It is par- ticularly satisfactory to realize that Dr. MacCallum's dis- covery was not accidental, but was the result of intelligent and well-directed observations. It bids fair to be the most important contribution to our knowledge of the malarial parasite since the discovery by Golgi in 1885 of the ordinary cycle of development, u ALFREDO ANTUNES KANTHACK. (From The Johns Hopkins Hospital Bulletin, Nos- 9t-95, January-February, 1899.) (From The Johns Hopkins Hospital Bulletin, Noa- 94-95, January-February, 1899.) ALFREDO ANTUNES KANTHACK. Died at Cambridge, England, on the twenty-first of December, 1898, Alfredo Antunes Kanthack, M. A., M. D., F. R. C. P. (London), Fellow of King's College and Professor of Pathology in the University of Cambridge. This announcement is a cruel blow to those who have had the good fortune to know and work with this brilliant man. Born in Brazil in 1863, the son of the former British consul at Para, Kanthack received much of his early education in Ger- many. Studying in England at the University College in Liverpool and at London University, he obtained bis B. A. in 1884, his intermediate M. B. in 1885, and B. Sc. in 1886. Pursuing his studies at St. Bartholomew's Hospital, he received in 1887 the double qualification of M. R. 0. S. and L. R. C. P. In 1888 he obtained the F. R. C. S. as well as the M. B. and B. S. (London), with honors, receiving also the gold medal for obstetrics. The year 1889 Kanthack spent in work under Virchow in the pathological laboratory at Berlin, but he was compelled in 1890 to leave, in the midst of some important investigations, to serve as obstetrical assistant in St. Bartholo- mew's Hospital under Dr. Matthews Duncan. In the summer of 1890 he went to India as one of the com- missioners appointed by the Royal College of Physicians, the Royal College of Surgeofts and the Executive Committee of the National Leprosy Fund to inquire into various points with regard to leprosy in India. A large share of the voluminous report of the commission was his work. Returning from India he became the John Lucas Walker student at Cam- bridge, but in 1892 he went to Liverpool with the intention of practising medicine. Here he held the post of medical tutor and demonstrator of bacteriology at the Royal Infirmary. Later, however, he went to London as director of the patho- 2 logical laboratory, lecturer on pathology and bacteriology, and curator of the pathological museum at St. Bartholomew's Hospital. In 1896, during the illness of Professor Roy, he was appointed his deputy, and finally in the fall of 1897 he became professor of pathology at the University of Cambridge. In the same year he became an F. R. C. P., and was given the honorary degree of M. A. at Cambridge. In his school days Kanthack had planned to devote his life to classical studies, and it was a disappointment to him at first to be compelled to turn to what he feared must be a more practical career; but from the beginning his energy and ability brought him enthusiasm and success. In the labor- atory at Berlin he earned the admiration of all who knew him, and his early work in Virchow's Archiv on the pathology of the larynx* gained for him the recognition of many others. By no one was he more appreciated than by his great " Master " as he reverently called him, whose attitude toward his pupil was one of genuine affection. The feeling of his contemporaries cannot be better shown than by quoting in full the cordial letter of Prof. Langerhans, written at the time of his application for the professorship of pathology at Cambridge: "Herr Dr. med. Alf. A. Kanthack, zur Zeit in Cambridge, hatte vom Sommer 1889 bis August 1890 im Berliner patho- logischen Institut einen Arbeitsplatz in demjenigen Arbeits- saal inne, welcher fur vorgeschrittene, selbststiindige wissen- schaftliche Arbeiter bestimmt ist und fur welchen ich damals als zweiter Assistent von Rudolf Virchow meinem Chef gegen- iiber verantwortlich war. In dieser Eigenschaft bin ich damals taglich mit A. A. Kanthack zusammen thatig gewesen und *Beitrage zu der Histologie der Stimmbander mit specieller Beriicksichtigung des Vorkommens von Drusen und Papillen. Arch. f. path. Anat., etc., Berl., 1889, cxvii, 531-544; Studien uber die Histologie der Larynxschleimhaut-I. Die Schleimhaut des halbausgetragenen Foetus. Ibid, 1889, cxviii, 137-147; Zur His- tologie der Stimmbiinder : Erwiderung auf den vorstehenden Artikel des Herrn Prof. B. Fraenkel. Ibid, 376-381; Studien uber die Histologie der Larynxschleimhaut. Ibid, 1890, cxix, 326; cxx, 273. 3 bestiitige ich hierdurch, dass sich Alf. A. Kanthack durch sein urnfassendes Wissen, eiserne Energie, unermiidlichen Fleiss, durch seine grosse Wahrheitsliebe und strenge Selbst- kritik und durch seine feinen, liebenswiirdigen und gewin- nenden Umgangsformen die Achtung und Liebe aller, die mit ihm in Beriihrung kamen, gewonnen und dauernd erhalten hat." Kanthack had published a considerable number of valuable scientific communications, a few of the more important of which were, perhaps, the researches referred to concerning the larynx, his studies upon snake poison,* his various communi- cations with relation to leucocytosis, chemotaxis and immunity,f his studies on mycetoma,J his Jackson Prize Essay on the bacillus of tetanus, and his further contributions to the same subject with Dr. Connell,§ and his admirable article upon the general pathology of infection in the first volume of Clifford Allbutt's System of Medicine. He also published in 1894, in association with Dr. Rolleston, a " Manual of Practical Morbid Anatomy, being a handbook for the post-mortem room," and *The Nature of Cobra Poison. Journ. Physiol., Camb., 1892, xiii, 272-299. Reporton Snake Venom in its Prophylactic Relations with Poisons of the Same and of Other Sorts. Rep. Med. Off. Local Gov., Bd. (1895-6), Lond., 1897, 235-266. f Acute Leucocytosis Produced by Bacterial Products. Brit. Med. Journ., Lond., 1892, i, 1301-1303; Immunity, Phagocytosis and Chemotaxis. Brit. Med. Journ., Lond., 1892, ii, 985-989; (with Hardy) On the Characters and Behaviour of the Wandering (migrating) Cells of the Frog, especially in Relation to Micro- organisms. Proc. Roy. Soc. Lond., 1892, lii, 267-273, and Phil. Tr., Lond., 1895, clxxxviii, 279-318; (with Wesbrook) Report on Immunity Against Cholera : An experimental inquiry into the bearing on immunity of intracellular and metabolic bacterial pro- ducts. Brit. Med. Journ., Lond., 1893, ii, 572-575; (with Hardy) The Morphology and Distribution of the Wandering Cells of Mammalia. Journ. Physiol., Camb., 1894, xvii, 81-119. f Madura Disease (mycetoma) and Actinomycosis. Journ. Path, and Bact., Edinb. and Lond., 1892, i, 140-162. § The Flagella of the Tetanus Bacillus and Other Contributions to the Morphology of the Tetanus Bacillus. Journ. Path, and Bact., Edinb. and Lond., 1896-7, iv, 452, and Trans. Path. Soc. Lond., 1896-'97, xlviii, 271-279. 4 in 1895 with Dr. Drysdale, a " Course of Elementary Practical Bacteriology, including Bacteriological Analysis and Chem- istry." He superintended the observations upon the Tsetse fly disease for the Royal Society, and one of his last publications related to this subject.* Much of his work, however, through his modesty and gener- osity, remained unknown. Only his more intimate friends are aware of the fact that he was the first to succeed in cultivating the parasite of actinomycosis. Compelled in January, 1890, to leave Berlin in the midst of his experiments, he made all possible arrangements for the preservation of his cultures, but on his return, they had, unfortunately, 11 died out " and another observei* had anticipated him with the discovery. A large share of his energy was given to the help and instruction of others who will bear the warmest testimony to the true worth of their friend and teacher. His uncompromising honesty, his hatred of anything super- ficial or incomplete, combined with an active, keen, discrimi- nating mind, and it seemed, an almost unlimited power for work, were a source of admiration to all who knew him. His amazing energy and capability for work were, however, too much even for a fine athletic physique, and his friends had for some years before his death looked with anxiety upon the amount of labor which he crowded into the day. To the writer Kanthack always seemed the most brilliant of his contemporaries. His ideals were the highest; and never was a man truer to his ideals. An exacting and searching critic of his friends, he was a severer critic of himself. This amounted sometimes to self-depreciation; it was indeed, on such occa- sions, almost pathetic to note the apparent unconsciousness of his own superiority. And with his high ideals he was ever full of practical sug- gestion. He never tired of urging the necessity of a more general introduction of accurate and scientific methods into *Kanthack, A. A., H. E. Durham and W. F. H. Blandford : On Nagana or Tsetse Fly Disease. Proc. Roy. Soc., Vol. 64. 5 medicine. His last public address* was an earnest appeal for more systematic and thorough clinical study in hospitals and schools. His influence which was beginning to be generally felt in his own country, was destined to have a far wider sphere. The loss of such a man is hardly greater to his university and to his friends than to the world at large. Personally, Kanthack was the simplest and most lovable of men. In 1895 he married Lucie, the daughter of F. Henstock, Esq., of Liverpool. W. S. T. * The Science and Art of Medicine. The Mid-sessional Address delivered before the Abernethian Society on July 7, 1898. St. Bar- tholomew's Hospital Journal, August, 1898. COMPTES-RENDUS DU XII CONGRES INTERNATIONAL DE MEDECINE MOSCOU, 7 (19)-14 (26) AOUT 1897. EXTRAIT MEMOIRE Par MOSCOU. Societe de Plmprimerie „S. P. Yakovlew", Saltykovski pereoulok, 9. 1OOO. Dolega, Massage in dor Behandlung innerer Krankheiten. 359 Alagens, zur Besserung der Erschlaffung tier Haltapparate bei den ver- schiedenen Formen der Enteroptose. Von allgemeinen Wirkungen der Massage wird Gebrauch gemacht bei Diabetes, bei Ernahrungskuren, besonders der Weir-Mitchell'schen Kur; in der Behandlung der Obesitas, und nach neueren zuverlassigen Mitteilungen auch bei Herz-Oedemen (Zabludowsky) bettlageriger Kranken neben anderer zweckentsprechender Herz-Therapie. Ferner geben verschiedenartige Erkrankungsformen der Ilaut, z. B. beginnende Sklerodermie, hyperplastische Epidermis-Processe, z. B. Elephantiasis, ferner Prurigo etc., Indicationen fiir Anwendung der Massage im Sinne eines palliativen wie curativen Mittels. Mit Bezug auf die Neuropathologie ist Massage ein souveraines therapeutisches Mittel in der Behandlung der sogenannten Coordina- tions-Neurosen, und ebenso von teilweise -wesentlichem Nutzen bei coor- dinatorischen Stdrungen bestimmter Nervenkrankheiten, z. B. der Cho- rea und bei der Tabes. Allerdings ist zu betonen, dass der Lbwenanteil eines eventuellen Erfolges der in diesen Fallen glcichzeitig anzuwendenden Heilgymnastik zukommt. Genug der speciellen Beispiele. Ich glaube, dass es fiir den Arzt lohnt, ja, dass es fiir ihn unumganglich notwendig ist, die unter Umstanden so ausser- ordentlich dankbaren Methoden der Massage wie der Mecha- notherapie iiberhaupt, zu beherrschen. Gerade der Umstand, dass er eventuell in der Hausbehandlung wie klinischen Behandlung sehr dankbares Material fiir die Methode findet, muss ihn bestimmen, dieselbe zu kennen und zu kbnnen. Selbstverstiindlich ist, dass fiir eine Zahl von Fallen cine ganz be- sondere Technik in Betracht kommt und dass z. B. zur Durchfuhrung systematischer Bewegungskuren ein grbsserer Apparat notwendig ist und solcher nur in geeigneten Instituten gegeben sein kann. Trotzdem aber soil der Arzt auf keinen Fall die Methoden der Me- chanotherapie so vorwiegend, wie bisher, nur Specialisten oder gar den Handen kurpfuschender Laien belassen, wenn er auch vielleicht der Laien- hande nicht immer ganz entbehren kann. Staat und Universitat miissen dafiir sorgen, dass die Kennt- niss der Mechanothdrapie, wie der physikalischen Methoden iiberhaupt, Gemeingut der Aerzte wird, und dass gleichzeitig ein besser geschultes Laienpersonal in ganz eng gezogenen Grenzen heraus- gebildet wird, welches jederzeit nur unter arztlicher Controlle arbeiten darf. Die physiologischen Beobachtungen am Lebenden, wie sie die Metho- den der Alechanotherapie uns in die Hand geben, haben noch eine Fiille offen stehender Fragen zu erklaren und bieten ein reiches Feld fiir wissen- schaftliche Arbeit. 360 Section V: Maladies internes. Prof. Thayer (Baltimora). Gonorrhoeal Endocarditis and Septicaemia. The accumulating observations of recent years have demonstrated the fact, that pathogenesis of the different complications of gonorrhoea may vary materially in different instances. 1) That the complicating process may be of purely gonorrhoeal origin, has been shown particularly by the numerous cases of arthritis, occurring in connection with gonorrhoea, where the specific microorganism has been demonstrated microscopically and obtained in pure cultures from the affected joints. 2) That complications may be due to a mixed or secondary infection with other pyogenic organisms has long been known; the manner of development of such secondary processes has been well pictured by Finger in a recent article. 3) There is good reason to believe, that serious focal lesions may occur in gonorrhoea without the actual presence of either the gonococ- cus or other microorganism, lesions due solely to the presence of a circulating toxic substances. Definite proof of this hypothesis has not yet been advanced, but in view of complete absence of bacteria on microscopical examination as well as of the complete sterility of cul- tures taken from the affected regions in cases, for instance, of neuritis or myelitis secondary to gonorrhoea, as well as from analogy with other similar infectious processes, there is strong probability, that such lesions may occur. That a true gonorrhoeal septicaemia may exist, the occurrence of local foci of infection at remote points from the region originally affected-joints, tendon sheaths, etc.-would lead us to infer. Every- thing points to the blood as the means, by which the organisms are transferred to the distant points. Especially important, as proof of the possibility of the transmission of gonococci by means of the circulation, are the instances of ulcerative endocarditis, which have been reported in association with gonorrhoea, where the specific microorganism has been demonstrated in the lesions upon the valves. Such cases, as is well known, have been described by Martin1), Rothmund2), His3), Leyden-4), Gluzinski5), Win- terberg0), Fressel7), Finger, Ghon & Schlagenhaufer8), Dauber & Horst9), Zawadski & Bregman10), Michaelis11), Stengel12). x) „Rev. med. de la Suisse Romande", 1872, p. 308. 2) Endocarditis ulcerosa nach Gonorrhoee, Dissertation, Zurich, 1889. 3) „Deutsch. Med. Woch." 1892, p. 993. 4) „Deutsch. Med. Woch." 1893, p. 909. 3) „Quotet from Councilman, Tr. Assoc. Amer. Phys." 1893, VIII, 165. 6) Festschr. z. 25-Jahr. Jub. d. Vereins Deutscher Aerzte zu St.-Francisco, 1894, 40. 7) Inaug. Diss., Leipzig, 1894. 8) „Arch. f. Derinat. u. Syph." Bd. XXXIII, 1895, Heft. 1-3, p. 141. 9) „Deutsch. Arch. f. Klin. Med.", Bd. LVI, H. 5-6, 1896. 10) „Wiener Med. Woch.", Feb. 15. 1896. n) „Zeitschrift f. Klin. Med." XXIX, II. 5-6, 1896, p. 556. X2) „Univ. Med. Mag. Phil.", 1897, 426. , Thayer, Gonorrhoeal Endocarditis and Septicaemia. 361 In none of these instances, however, have the authors succeedet in obtaining the gonococcus in pure culture either from the affected valves of from the circulating blood. It was the good fortune of Dr. Blumer and the speaker to succeed for the first time in obtaining the gonococcus in pure culture during life from the circulating blood of a case of ulcerative endocarditis and thus to furnisch definite proof of the possibility of the existence of a gonor- rhoeal endocarditis and septicaemia. This case, which has already been reported *), I will briefly summarize. Case I. The patient was a woman 34 years of age, who entered the John's Ilopkin's Hospital on the 25th of April 1895. Iler family and personal history was negative, excepting, that for three months she had had rheumatism off and on in various of her joints. Since the beginning of her rheumatism she hat not been strong and had suffered somewhat from dyspnoea on exertion. A few days before entry into the hospital she had a severe chill and took to bed. On entrance she was found to have the signs of a well marked mitral stenosis. During the time, when she was in the hospital, there was an irregular temperature, associated with severe chills. There was a well marked leucocytosis. The urine showed a trace of albumen and an occasional cast. The patient grew rapidly amemic and feeble and died on the 16th of May. A diagnosis of ulcerative endocarditis, having been made during life, cultures tfere taken from the blood on several occasions. These cultures were made by Dr. Blumer according to the method of Sitt- mann, the blood being taken from the median basilic vein with a steril- ized syringe and mixed with melted agar, which was immediately plated. Large quantities of blood were used so that the medium contained, at least, one-third blood. The first culture taken on the fourth of May was negative, but upon the seventh and twelfth of May, the plates contain- ed very minute, white colonies, representing apparently a pure culture of small biscuit-shaped diplococci, which failed to grow on transmission to agar-agar, gelatine, potato, bouillon and litmus-milk. These organisms decolorized entirely when treated according to Gram's method, not an organism retaining the stain. The autopsy confirmed the diagnosis during life, revealing an extensive ulcerative endocarditis of the mitral valve. In the trombi, upon the valve, there were found large numbers of small oval diplococci, having all the morphological and tinctorial character- istics of gonococci. There were, unfortunately, at the time of autopsy no media suitable for the culture of gonococci, but cultures, taken upon agar-agar and ox's blood serum, from the heart's blood, valves, liver, spleen, lungs and kidneys, were totally negative; but a small quantity of the heart's blood was mixed with the agar. Inoculation of a mouse with a piece of thrombus from the valves was without result. The charac- teristic appearance and disposition of the cocci, their decolorization according to the method of Gram, their failure to develop upon ordinary media, and finally, Their growth on two occasions during life upon a medium essentially the same, as that recommended by Wertheim, x) „Arch. de Med. Experim. et d'Anatomie Pathol.", 1895, VII, 701. „The John's Ilopkin's Hospital Bulletin", As 61, 1896. 362 Section V: Maladies internes. leaves, it seems to us, little doubt, that this was a true gonorrhoeal infection. It is further interesting, that, post-mortem, similar organisms were f und in the vagina and uterus. Certain reviewers have been inclined to doubt the complete relia- bility of this observation. Thus, Fraenkel in the „Hygienische Rund- schau" asserts, that „Because during life, a gonorrhoeal affection was not discovered in the patient despite careful observation (while), mor- eover, cultures of the microorganism, 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 entirely see the justice of this observation. It is a well known fact among all gynaecologists, that gonorrhoeal af- fections in the female may often exist without being recognized by the ordinary methods of examination during life. As was stated in a pre- vious communication, we had not during life thought of the possibility of the case being one of gonorrhoeal infection, and the vaginal secre- tion was not examined, but after death characteristic gonococci answer- ing to all tinctorial and morphological characteristics, were found in both, the vagina and the uterus. Moreover, the medium, upon which the successful cultures were twice obtained during life, was a human blood agar, essentially similar to that of Wertheim. Upon this medium the organism grow; upon all ordinary media they failed to reappear. In the following case, however, there can exist, we believe, little doubt as to the true gonorrhoeal nature of the septiemmia and the endocarditis. Case II. J. K., aged 19; a native of Germany; was admitted to the John's Hopkin's Hospital on the 5th of February 1896 complaining of fever and weakness. His family history was negative. He had always been strong and well. There was no history of the ordinary diseases of childhood. He had never had rheumatism or scarlet fever. Drinks beer in moderation. Six months ago he contracted his first attack of gonorrhoea. Shortly after the onset of the gonorrhoea the patient began to complain of chilly sensations, fever and general weakness. Toward the end of No- vember he. began to have violent chills occurring daily, usually in the morning hours; these were followed by fever and profuse sweating. Under treatment the shaking chills disappeared, yet fever continued becoming, however, more irregular. He has grown progressively weak and pale and for two weeks there has been oedema of the feet and ankles. Physical examination. The patient is very dull and drowsy. He has a large well nourished man; lips, mucous membranes and skin extremely pale. The pulse is rather large, low tension. Lungs are clear throughout. Heart: Point of maximum impulse in the 4th space just inside the mamillary line; relative dulness begins in 3rd interspace; does not pass the sternum; practically no absolute dulness. The first sound at the apex booming and prolonged; there is no actual murmur; passing toward the base, there is a soft systolic souffle; the second pulmonic sound is a little sharper, than the second aortic. Thayer, Gonorrhoeal Endocarditis and Septicfemia. 363 The hepatic flatness is increased in extent, the lower border being felt 6,75 cm. below the costal margin in the mamillary line. The spleen reaches 9,5 cm. below the costal margin. There are slight ascites and moderate oedema of the feed and ankles. No tenderness or irregularities on any of the long bones. The left km e joint contains an excess of fluid, being distinctly swollen and fluctuating. There is no tenderness. Moderate enlargement of the inguinal glands; no further glandular enlargements. The blood contains no malarial parasites; no pigment; there is moderate poikilocytosis. Red blood corpuscles 2292000 Colorless „ 9000 Urine, reddish amber; acid; 1015; no sugar: albumen 0,1%; sediment considerable; whitish; microscopically, it shows numerous pus cells; usually separate, not in clumps; red blood corpuscles; small round cells about the size of leucocytes with single nuclei; numerous hyaline and granular casts with pus, epithelial cells and renal cells adherent; epithelial casts; pus casts. The patient remained in the hospital but nine days, during which time the temperature franged between 99.6 and 103.3. The urine was somewhat reduced in quantity, averaging a little under 1000 cc. and in the 24 hours. The specific gravity ranged between 1013 and 1015, while the amount of albumen and the sediment continued about, as noted above. The blood on 11. IL 96 showed: Red blood corpuscles 2283000. Colorless „ 14250. Haemoglobin 45%. Dried specimens stained according to Ehrlich's method showed slight variations in the size of the corpuscles; moderate poikilocytosis; a very few nucleated red corpuscles; no malarial parasites. Differential count of the leucocytes. Small mononuclear 4,8 Large „ and transitional . 2,6 Polymorphonuclear 92,6 Eosinophiles none. The direct sequence of the symptoms upon the gonorrhoea sug- gested to us the possibility, that we might be dealing with a gonor- rhoeal pyelonephritis and possibly a general infection and cultures were taken on two occasions by Dr. Lazear from the circulating blood by the same method adopted in the previous case. These cultures were without result in both instances. The patient was kept in bed, placed upon a milk diet, diuretics and iron. On the 14th, however, the patient left the hospital objecting to the strict regime. On the 9th of March he returned having lost ground. The patient was excessively pale and there was marked general oedema; pulse 108; temperature 101,8 F. 364 Section V: Maladies internes. Physical examination was otherwise much as in the previous note. The point of maximum cardiac impulse had, however, moved out- ward and downward into the 5th space and slightly outside the nipple, while the soft systolic murmur, which had not been noted on the former entry was now to be heard all over the cardiac area; loudest at the apex. The second sounds at the base were not loud and of normal relative intensity; no accentuation of the second pulmonic. The urethral discharge had almost disappeared. The anmmia had increased, the blood count showing on 10/3/96: Red blood corpuscles 1920000 Colorless „ 8500 Haemoglobin IS'/o- On 25/3/97: Red blood corpuscles 1896000 Colorless „ 18000 Haemoglobin 18°/0. The patient grew rapidly worse, the urine averaging but little over 600 cc. for the 24 hours, was almost suppressed during several days before his death. The albumen had increased up to nearly VaVo? while there were any fatty renal epithelial cells and numerous fatty, blood waxy and epithelial casts in addition to the elements previously described in the sediment. On the 23rd of March the patient, who was in a semi-comatose condition, developed a well marked to and fro pericardial friction murmur and on the patient died, comatose. Bacteriological examination during life. On the 22nd of March 1896, a culture was made by Dr. La- ze ar in the following manner: 2 de of blood were drawn from the median basilic vein by means of an hypodermic syringe, which had been steriliz- ed and every antiseptic precaution was used. The blood was mixed with 4 cc of nutrient agar and the mixture poured into a Petri dish and allowed to harden. It was kept in the thermostatt at 35 C. At the end of 24 hours no growth was visible. At the end of 48 hours there appeared numerous colonies half the size of a pin head, granular in appearance with somewhat irregular borders. These colonies were found to be made up of cocci, usually in pains. They were of biscuit or kidney shape, the flattened sides of the cocci being turned toward each other in the pairs. They stained well with the ordinary basic dyes and decolorized by Gram's method. Transplanted to human blood serum agar by a smear upon the surface, there developed a fair number of colonies similar to the above, and made up of diplococci having the same morphology and tinctorial reactions. Transplanted to ordinary agar there resulted a growth of a very few fine colonies made up of the same diplococci. On gelatine, ox's blood serum and bouillon there was no growth. At the end of ten days the cocci had all died out on the original plates. On March 24th and 25th plate cultures were made by the same method, and on each instance there wras an abundant growth, in pure culture, of diplococci identical with those of the first plates, and be- having in the same way toward stains and the various culture media. Thayer, Gonorrhoeal Endocarditis and Septicaemia. 365 On the basis of these positive culture experiments and the clinical history of the case, the patient was brought before the class on the 25th, of March, as an instance of gonorrhoeal septicaemia. The autopsy was performed on the evening of March 25th by Professor Flexner: Anatomical Diagnosis. Septicaemia gonorrhoica; gonorrhoea sub- acuta; endocarditis tricuspidalis ulcerativa et vegetativa subacuta go- norrhoica; tumor lienis subacuta; hyp^rmmia hepatis passiva chronica; nephritis haemorrhagica subacuta; nephritis glomerulorum; pleuritis et pericarditis fibrinosa et sero-purulenta gonorrhoica; infarctio pulmonis. It will be impossible here to enter into a lengthy description of the anatomical condition of the organs, which will bo more carefully described in another publication. The lesions of the tricuspid valve were most remarkable. They are admirably represented by the accompanying painting, which was made at the time of the autopsy by Mr. Max Broedel. The following is an extract from the autopsy report: The tricuspid valve is the seat of an extensive thrombus formation. The thrombus masses occupy the entire middle segment with the ex- ception of its base and to a lesser extent the two remaining segments. The thrombus attached to the middle segment is firmly united to the valve at a distance of 5 mm. from its attachment to the auriculo-ven- tricular ring and projects into the cavity of the ventricle. At the point, to which the thrombus is attached, the valve substance is destroyed. The thrombus mass presents an irregular convoluted appearance and for description may be sub-divided into three distinct portions. The, central portion, which is largest, measures 4.5 X 2 cm. and 4-5 mm. in thickness; it has, in general, a conical shape, its base at the valve, its apex projecting into the ventricle. To the left of this is a second mass 18 X 22 mm. in extent, almost quadrangular in form, but irregular in contour. The remaining mass to the right is about one-half the size of the last. This thrombus mass by its weight im- pinges on the endocardium of the ventricle, where there are small throm- bus masses, situated upon the endocardium and corresponding to the points of contact. Fully one-half of the cordae tendiniae of the left segment of the valve are ruptured and their free ends are covered with globular thrombi presenting a grape-like appearance. Small miliary vegetations exist on the papillary muscle, to which these are attached and on a moderator band, which extends from the papillary muscle to the mid-portion of the left segment of the valve. The right segment of the valve is the seat of two thrombus masses, which sit on the anterior surface and project into the auricle. They average about 10x12 mm. and 12x6 mm. Bacteriological Examination. Cover-slips were examined from the pleural and pericardial exudates and from the vegetations upon the heart valves. These preparations contained large numbers of cocci in pairs. The majority were found upon the surface from the heart valve, where they were excessively numerous. These cocci were in almost all instances included within polymorphonuclear leucocytes. Where they were found free, evidences of injured and broken leucocytes were not 366 Section V: Maladies internes. wanting. The form of the cocci was as a rale typically biscuit-shaped and at times, though rarely, two pairs lay side by side suggesting a tetrad arrangement. These cocci stained freadily in the usual aniline dyes, but were quickly and uniformly decolorized by Gram's method. A cover-glass from the spleen showed one pair of cocci; others were not found. From the kidney, pelvis of the kidney and urinary bladder cover-slips were negative. From the urethra, among a variety of bacilli, definite intra-cellular biscuit shaped diplococci decolorizing by Gram's method were found. Cultures. Cultures were made at the autopsy as follows: a) Upon Loeffler's blood serum prepared: I) from human blood; 2) from bullock's blood; 3) from dog's blood. b) Upon agar-agar. The cultures were made from the various local inflammatory exudates, from the heart's blood and from the organs. A few tubes in all of the human serum were on hand and these were used for the local exudates and blood. Upon those from the pericar- dium, tricuspid valve and heart's blood faint growths were obtained, which consisted in part of confluent minute colonies, in part of small, almost pointlike greyish white, slightly elevated colonies. Upon cover- slips these were found to be composed of diplococci readily decolorizing with Gram's stain and resembling in every way excepting, perhaps, for the vigor of growth the organisms isolated during life. Xo growths whatever were obtained upon the bullock's serum, dog's serum, or agar agar. Transplantations of the 48-hour old growths from the human serum upon the ordinary agar, swine liver agar (Livingood) and foetus agar (Flexner) were negative. As no human serum remained transplantations entirely fdled. We believe then, that in this instance we have been able to de- monstrate, beyond a doubt, the gonorrhoeal nature of the endocarditis as well as the actual existence of a gonorrhoeal septicaemia, by the discovery and reproduction of the gonococcus in pure culture from the circulating blood, during life and after death from the blood, from the affected cardiac valves and from the pleural and pericardial exudates. The complete absence of any other microorganism on microscopical examination, or in the various cultures either in the circulating blood during life, or in the blood, or organs after death can, we believe, leave little doubt, that the infection was purely gonorrhoeal in nature. In conclusion then, we believe: 1) That we have in these two instances an absolute proof of the existence of a true gonorrhoeal septicaemia. 2) The successful cultivation of the gonococci in these two cases from the circulating blood would justify us in the assertion, that in cer- tain instances the absolute diagnosis ot gonorrhoeal septicaemia may be made during the life of the patient. Discussion. Dr. Michaelis (Berlin): Gestatten Sie mir zu dem so interessanten Befunde des Herrn Thayer einige Worte. Ais im Jahre 1893 v. Leyden jenen ersten Fall von Endocarditis gonorrhoica verdffentlichte, bei dem ich mit der bakteriologischen Untersuchung betraut war und in dem Charles Sziklai, La therapeutique avec la pilocarpine. 367 es zum ersten Male gelang Gonokokken in Reincultur als die Erreger der Endocarditis nachzuweisen, begegnete dieser Befund teils zweifelndem Kopfschiitteln teils energischem Widersprusche. Seitdem sind die Gono- kokken als alleinige Erreger der Endocarditis gonorrhoica in mehr als einem Dutzend Calle gefunden worden, von uns selbst in 3 Fallen, und die Thatsache ist eine allgemein anerkannte geworden. Einzig und allein in jenen Fallen von ulcerbser Endocarditis nach Gonorrhoee findet man jene Diplokokken von Semmelform die in den Zellen liegen und sich nach Gram entfarben. Verlangte man friiher noch den Nach- weis der Cultur, so ist darauf zu verweisen, dass ein Aufgehen der Cultur nach langerem Liegen der Leiche ausgeschlossen erscheint. Der Versuch die Gonokokken intra vitam im Blute nachzuweisen, war mir bisher nicht gelungen und freue ich mich aufrichtig, dass dieser interes- sante Befund als eine weitere Bestatjgung von Herrn Thayer in seinem Faile erhoben werden konnte. Gestatten Sie mir noch einige Worte iiber die Haufigkeit des Vor- kommens der gonorrhoischen Septicaemie. Sowol Endocarditis wie beson- ders die gonorrhoischen Gelenkerkrankungen sind in ausserst zahlreichen Fallon beobachtet worden, und geht z. B. Kb nig (Berlin) rein praktisch soweit, circa 90% der chronischen Gelenkerkrankungen als gonorrhoische zu betrachten, obwol ihm der Nachweis der Gonokokken nur ausserst selten gelang. Wir selbst haben auf der v. Leyden'schen Klinik im letzten Jahre 5 Faile beobachtet und in alien Gonokokken nachgewiesen. In dem zuletzt beobachteten Faile handelte es sich sogar um eine multiple, fieberhafte Gelenkaffection, bei der in zwoi Gelenken Go- nokokken in ausserst roicher Menge gefunden wurden. Das mikroskopi- sche Bild war das typische des gonorrhoischen Eiters, die Cultur auf den specifischen Nahrbbden (Ascitesagar) bei jeder Function positiv. Doch mbehte ich noch einmal erwahnen, dass bei der gonorrhoischen Gelenkaffection wie bei der Endocarditis gonorrhoica das mikroskopische Bild allein geniigt. Wir haben auf der v. Leyden'schen Klinik in den letzten 6 Jahren mehr als 60 Faile von Endocarditis untersucht. Wir haben Streptokokken, Staphylokokken, Pneumokokken, Tuberkelbacillen gefunden. Jene typischen semmelformigen Diplokokken, die in den Zellen liegen und sich nach Gram entfarben, fanden wir nur in jenen 3 Fallen, die sich eben direkt an eine Gonorrhoee anschlossen. Dr. Charles Sziklai (Kis-Lomba, Hongrie). L'elargissement de Vindication de la therapeutique avec la pilocarpine. Messieurs! Je crois pouvoir presumer que la therapeutique propagee par moi depuis des annees ne vous soit pas entierement inconnue, vu que depuis 1892 j'en ai parle largement a plusieurs Congres (Kronstadt, Rome, Budapest), de meme que principalement a plusieurs reprises au journaux speciaux j'en ai chaleureusement recommande l'application. Je dois done dire d'avance que j'ai recommande d'abord la pilocar- pine en cas de croup du larynx, cas dans lesquels elle s'est prouvee d'un 368 Section V: Maladies internes. effet presque exclusivemont excellent. Du croup du larynx, j'avan^ai avec l'application de la pilocarpine an croup en general, c'est a dire aux maladies croupeuses de tous les organes qui en peuvent etre afffectes, et de meme cette medication s'est prouvee comme presque jamais de- trompant en cas de Bronchitis, Pneumonia, Nephritis, Cystitis, etc. etc.-crouposa, de sortc que la pilocarpine pent etre designee le re- mcde specifique du Croup dans la plus grande etendue du mot. Il y a deja longtemps que je ne me trouve pas seul avec cette opinion; mes compagnons d'armes, c'est A dire ceux de mes collogues lesquels j'ai etc assez heureux de gagner pour cette therapeutique, sent presque tous de la meme opinion, dont ils ont donne 1'expression en plusieurs publications relatives, d'autres en lettres directement ad- ressees a moi. Comme chaque innovation sur le terrain de therapeutique, mon traitement specifique des maladies' croupeuses etait aussi 1'objet de plusieurs discussions dans les journaux medicaux, et je peux constater avec satisfaction que les medecins pratiques, qui se sont occup^s serieu- semont de 1'examen de la methode speciale, etaient tous tout-a-fait contents du succes, en opposition aux cliniciens, dont jusqu'a present aucun n'avait le meme succes favorable, 1 equel nous, moi et mes col- laborateurs, declarons possible et lequel nous avons atteint en effet. Le mauvais succes des cliniciens, tant qu'il m'est connu par les publications relatives, trouve son explication et en meme temps sa fon- dation dans cette circonstance qu'aucun d'eux n'a imite ma methode strictement, et pour cette raison, les resultats ne peuvent, pour la plus grande partie, reclamer la reconnaissance de leur objectivite. L'objet de 1'examen de ma methode de traitement etait pour mes adversaires jusqu'a present exclusivement la pneumonie croupeuse, et c'est en effet etonnant que les cliniciens - car ce sont les seuls a nier les resultats excellents lesquels nous, moi et mes collaborateurs, decla- rons pour atteignables,-ne puissent pas atteindre le meme. Dr. Luzt1) (Tetetlen), un collegue tres erudit et ecrivain tres applique, en plus tres precautionneux au dosage de la pilocarpine, a present, selon son propre aveu, deja plus hardi, avait, malgre ses doses au comencement tres petites, au traitement de la pneumonie croupeuse, les resultats les plus satisfaisants; Dr. Kovacs2) (Isidve), Dr. Csevernyak 3) (Nags Karols) qui a applique la pilocarpine dans la pneumonie croupeuse en douze cas parallelement (c'est a dire de deux groupes-6 jeunes personnes et 6 personnes plus agees pneumoniques-1'une etait traitee avec et 1'autre sans la pilocarpine), Dr. Horovitz 4) (Arbe, Dalmatic), Dr. Soder- berg5) (Alma, Suede), et mon colfaborateur le plus recent, le Dr. Eber- son 6) (Tarnow)- sont tous des adherents enthousiastes de la thera- peutique avec la pilocarpine, et ils ont deja acquis jusqu'a present des merites incomparables en soutenant mes recherches a 1'elever a cette i) Voir „Gyagyaszat" 1895, 33. 2) „ „ 1896, 14. 3) „ „ 1896, 11. 4) „Medic. Wochenschrift" 1897, 9. 5) „Eira" 1897, Xe 5. 6) Voir „Aerztlicher Central-Anzeiger", Wien, N° 21 de l'annee courante. A SECOND CASE OF GONORRHCEAL SEPTIC/EMIA ULCERATIVE ENDOCARDITIS WITH OBSERVA- TIONS UPON THE CARDIAC COMPLI- CATIONS OF GONORRHCEA BY WILLIAM SYDNEY THAYER, M. D. AND JESSE WILLIAM LAZEAR, M. D. From THE JOURNAL OF EXPERIMENTAL MEDICINE Vol. IV, No. i, 1899 A SECOND CASE OE GONORRHOEAL SEPTICEMIA AND ULCERATIVE ENDOCARDITIS WITH OBSERVA- TIONS UPON THE CARDIAC COMPLI- CATIONS OF GONORRHOEA.* By WILLIAM SYDNEY THAYER, M. D., and JESSE WILLIAM LAZEAR. M. D. Plate I. Cardiac complications of gonorrhoea with or without coincident or preceding arthritis, wdiile not of frequent occurrence, are by no means so rare as has, even within recent years, been supposed. The litera- ture shows over a hundred cases in which a diagnosis of gonor- rhoeal endo-, peri- or myo-carditis has been made, and during the last several years considerable attention has been attracted to the subject by the accumulation of evidence demonstrating the fact that many of these complications are due to actual local infections with the gono- coccus. It was the good fortune of Blumer and one of the writers to observe a case of gonorrhoeal ulcerative endocarditis in 1895 and to succeed for the first time in obtaining the gonococcus in pure culture during life from the circulating blood; moreover organisms showing all the characteristics of gonococci were demonstrated in the lesions upon the affected valves, thus furnishing definite proof of the pos- sibility of the existence of a true gonorrhoeal septicaemia and endo- carditis. This case, which has already been reported,! it may be well to summarize: The patient, a woman 34 years of age, entered the Johns Hopkins Hospital, April 25, 1895. Her family and personal history were nega- * This case was reported at the Twelfth International Medical Congress at Moscow in August, 1897. Arch. de med. exper. et d'anat. pathol., 1895, vii, 701; also, The Johns Hopkins Hospital Bulletin, 1896, vii, 57. 82 Gonorrhoeal Septicaemia and Ulcerative Endocarditis five, excepting that for three months she had had rheumatism otf and on in various of her joints. From the beginning of her rheumatism she had complained of weakness and dyspnoea on exertion. A few days before her entry into the hospital she had a severe chill and took to bed. On entrance there were well-marked signs of mitral stenosis. During the period of her sojourn in the hospital there was irregular fever associated with severe chills. The blood showed throughout a well- marked leucocytosis; the urine contained a trace of albumin and the sediment contained occasional casts. The patient grew rapidly feeble and died May 1G. The diagnosis of ulcerative endocarditis having been made during life, cultures were taken from the blood on several occasions. These cultures were made by Dr. Blumer according to the method of Sittman. The blood, taken from the median basilic vein by a sterilized syringe, was mixed with melted agar which was immediately plated. Large quan- tities of blood were used, so that the medium contained at least one- third blood. The first culture, taken May 4, was negative, but in the cultures of May 7 and 12 the plates showed very minute white colonies representing a pure culture of small biscuit-shaped diplococci which failed to grow on transmission to agar-agar, gelatine, potato, bouillon or litmus-milk. These organisms were decolorized entirely by Gram's method. The autopsy confirmed the diagnosis made during life, revealing an extensive ulcerative and vegetative endocarditis of the mitral valve. In the thrombi upon the valve were found large numbers of diplococci having all the morphological and tinctorial characteristics of gonococci. At the time of autopsy there were unfortunately no media at hand suitable for the cultivation of gonococci, and implantations, made upon agar-agar and ox's blood serum, from the heart's blood, valves, liver, spleen, lungs and kidneys, were entirely without result; it should be stated that in these post-mortem cultures but a small quantity of the heart's blood was mixed with the agar. Inoculation of a mouse with a piece of thrombus from the valves was without result. The characteristic appeatance and disposition of the cocci, their decolorization according to the method of Gram, their failure to develop upon ordinary media, and finally their growth on two occa- sions during life upon a medium practically the same as that recom- mended by Wertheim, leaves, it seems to us, little doubt that this was a true gonococcal infection. Similar organisms were found after death in the vagina and uterus. William Sydney Thayer and Jesse William Lazear 83 Certain reviewers have been inclined to doubt the complete relia- bility of this observation. Thus, Fraenkel* asserts that " because during life a gonorrhoeal affection was not discovered in the patient despite careful search, and cultures of the observed microorganism were not made on human blood serum or Wertheim's serum agar, the observation cannot be considered as entirely free from criticism." We confess that we cannot see the justice of Fraenkel's observations. It is well known to gynaecologists that gonorrhoeal affections often exist in women without being recognized by the ordinary methods of exam- ination. As was stated in the previous communication, we had not thought during the life 'of the patient of the possibility of the case be- ing one of gonorrhoeal infection, and the vaginal secretion was not ex- amined. But after death characteristic gonococci, answering to all tinc- torial anol morphological characteristics, were found both in the vagina and the uterus. Moreover, the medium upon which the suc- cessful cultures were twice obtained during life-the mixture of blood fresh from the veins with melted agar-was essentially similar to the human blood-serum agar of AVertheim. Upon this medium the organism grew; upon all ordinary media it failed to reappear. Shortly after the publication of the foregoing case we observed a second instance of endocarditis and septicaemia of undoubtedly gon- orrhoeal nature. J. K., aged 19, a day laborer, unmarried, a native of Germany, was admitted to the Johns Hopkins Hospital on February 5, 1896, com- plaining of fever and weakness. Family history.-Father died with dropsy; mother, one brother and two sisters living and well; several brothers and sisters died in infancy. Personal history.-There is no history of the ordinary diseases of childhood. He has never had any severe infectious diseases; is sure that he has never had rheumatism or scarlet fever, stating that he has always been a healthy man. He drinks beer in moderation. Present illness.-The patient contracted gonorrhoea for the first time six months ago. Several weeks after the onset lie began to suffer from chilly sensations, fever and general weakness. Toward the end of November he began to have violent chills, occurring usually in the morning hours; these were followed by fever and profuse sweating. * H ygienische Rundschau, 1896, vi, 254. 84 Gonorrhoeal Septicaemia and Ulcerative Endocarditis Under treatment the shaking chills disappeared, but the fever continued, becoming, however, more irregular. He has grown progressively weak and pale, and for two weeks before entry there has been oedema of the feet and ankles. Physical examination.-The patient is very dull and drowsy. He is a large well-nourished man; lips, mucous membranes and skin extremely pale; pulse large, but of low tension, 108; respiration 30; T°, 103.4°. Lungs, clear throughout. Heart: Point of maximum impulse in the 4th space just inside the mamillary line. Relative dulness begins in the 3d interspace and is not increased to the right. Absolute cardiac dulness is obliterated by pulmonary resonance. On auscultation the first sound at the apex is booming and prolonged; there is no actual murmur. Passing toward the base a soft systolic murmur becomes audible; most marked in the pulmonic area. The second pulmonic sound is a little sharper than the second aortic. Liver: hepatic flatness begins at the 7th rib in the mamillary line, the lowTer border being palpable, 6.75 cm. below the costal margin. Spleen is greatly enlarged, flatness above beginning at the 7th rib, while the lower border is palpable 9.5 cm. below the costal margin. Abdomen: full, bulging a little in the flanks, tympanitic in the elevated, flat in the dependent parts; well- marked movable flatness. The left knee-joint contains an excess of fluid, being distinctly swollen and fluctuating. No redness or tender- ness. No tenderness or irregularities on any of the long bones. Mod- erate enlargement of the inguinal glands. Slight oedema of the feet and ankles. There is a thick, purulent urethral discharge showing char- acteristic gonococci. The blood contains no malarial parasites or pig- ment. There is a moderate poikilocytosis. Red blood corpuscles, 2,292,000; colorless corpuscles, 9,000. Urine: reddish amber; acid; 1015; no sugar; albumin, 0.1 per cent. Sediment: considerable; whitish; microscopically, numerous pus cells, usually separate, not in clumps; red blood corpuscles; small round cells about the size of leucocytes with single nuclei; numerous hyaline and granular casts with adherent pus and degenerated epithelial cells; epith- elial casts; pus casts. The patient remained in the hospital but nine days, during which time the temperature ranged between 99.6° and 103.3°. The urine was somewhat reduced in quantity, averaging a little under 1000 cc. in the 24 hours. The specific gravity ranged between 1013 and 1015, while the amount of albumin and the character of the sediment continued about as noted above. William Sydney Thayer and Jesse William Lazear 85 ll/ii/96. Examination of the blood: Red blood corpuscles, 2,283,000; colorless corpuscles, 14,250; haemoglobin, 45 per cent. Dried specimens prepared according to Ehrlich's method showed slight variations in the size of the corpuscles, moderate poikilocytosis; a few nucleated red cor- puscles, no malarial parasites. Differential count of leucocytes: small mononuclear leucocytes, 4.8 per cent; large mononuclear and transi- tional leucocytes, 2.6 per cent; polymorphonuclear neutrophilic leuco- cytes, 92.6 per cent; eosinophilic leucocytes, none. The direct sequence of the symptoms upon the gonorrhoea sug- gested to us the possibility that we might be dealing with a gonorrhoeal pyelo-nephritis and possibly with a general septicaemia, and cultures were taken on two occasions by Dr. Lazear from the circulating blood by the same method adopted in the previous case. These cultures were without result in both instances. The patient was kept in bed, placed upon a milk diet, diuretics and iron. On February 14 he left the hospital, objecting to the strict regime. March 9 the patient re-entered the hospital, having grown steadily worse. 10/iii/96. Physical examination.-The patient was extremely sallow, pale; tongue dry and fissured; pulse 108; moderate oedema of the de- pendent parts; slight puffiness of the face. The point of maximum cardiac impulse had moved outward and downward to a point in the 5th space slightly outside of the mamillary line, while a soft systolic murmur, which was not present on the former admission, was now to be heard all over the cardiac area, loudest at the apex. The second sounds at the base of the heart were not loud, but were of normal relative intensity; no accentuation of the second pulmonic sound. The urethral discharge had almost disappeared. The anaemia had increased, the blood count showing on 10/iii/'96: red blood corpuscles, 1,920,000; colorless corpuscles, 8500; haemoglobin, 18 per cent. The urine of the same date was of a pale but distinctly smoky color; acid; sugar absent; albumin 0.4 per cent. Sediment, abundant; micro- scopically, many pus cells scattered throughout the field, not arranged in clumps; many small round cells about the size of leucocytes with single nuclei; many red blood corpuscles, some "shadows," others crenated, others fairly well preserved. Numerous fatty degenerated epithelial cells, somewhat larger than pus cells; some small agglomera- tions of free yellow fat drops; occasional compound granular cells; casts 86 Gonorrhoeal Septicaemia and Ulcerative Endocarditis extremely abundant; hyaline, finely and coarsely granular with adherent pus and red blood cells; occasional fatty casts and blood casts; many epithelial and pus casts; occasional extremely large, slightly yellowish, typically refractive, waxy casts with broken ends; diazo-reaction absent. The patient grew rapidly worse; the anaemia increased, the blood on the day of death showing: red blood corpuscles, 1,896,000; colorless corpuscles, 18,000; haemoglobin, 18 per cent. The urine, averaging little over 600 cc. for the 24 hours, was almost suppressed during several days before death. The albumin increased up to nearly 0.5 per cent, while the number of fatty, blood, waxy, epith- elial and pus casts increased. On March 23 the paient became ex- tremely dull and drowsy. 23/iii/96. (Professor Osler.) " For the past few days the tempera- ture has been lower, not above 100° since the 19th; no change in the general condition. Pulse about 100; drops a beat occasionally; of low tension. Heart: apex beat is diffuse during expiration; well seen in the 5th space and a little outside the nipple line. Cardiac impulse is visible in the 4th space inside the nipple. A diastolic shock can be felt at the apex; both sounds are audible; no murmur. Over the entire praecordium there is a to-and-fro superficial pericardial friction murmur, the maxi- mum of which is at the 5th left cartilage; it is well heard at the ensi- form cartilage; not heard above the level of the 3d rib; no especial accentuation of the pulmonic second sound." On the 24th the patient developed a well-marked petechial eruption. 25/iii/96. (Dr. Thayer.) " The patient is lying on his right side; very drowsy and dull. Respirations 15 to the minute, rather deep and noisy; pulse 21 to the quarter: of low tension. Face puffy; pupils not contracted; general anasarca. Heart: diffuse heaving over the 4th and 5th interspaces just inside the nipple; the point of maximum cardiac impulse is not to be sharply differentiated; flatness does not pass the left sternal margin; begins at about the 4th space. At the apex the first sound is reduplicated and followed by a soft systolic murmur, while in connection with this there is a soft superficial to-and-fro rub. Over the body of the heart the sounds are considerably masked by this friction rub. The second pul- monic sound is, however, not accentuated. On the trunk and arms and occasionally on the legs are numerous small petechial spots, the largest scarcely larger than the head of a pin." On March 21 the patient began to suffer from diarrhoea,the movements William Sydney Thayer and Jesse William Lazear 87 becoming gradually more frequent and fluid. During the afternoon of the 25th the respiration became more stertorous; the patient lapsed into a condition of complete coma and died at 6.30 P. M. Bacteriological examination during life.-March 22, 1896, cultures were made by Dr. Lazear in the following manner: 2 cc. of blood were drawn from the median basilic vein by a hypodermic syringe previously ster- ilized by boiling. The skin was, as far as possible, sterilized and every antiseptic precaution was used. The blood was mixed with 4 cc. of melted nutrient agar and the mixture poured into a Petri dish and allowed to harden. It was kept in a thermostat at 35° C. At the end of 24 hours no growth was visible. At the end of 48 hours there began to appear colonies half the size of a pin head, granular in appear- ance with somewhat irregular borders. These colonies were made up of cocci arranged usually in pairs. The cocci were of biscuit or kidney shape, their flattened sides being adjacent. They stained well with the ordinary basic dyes and decolorized by Gram's method. Transplanted upon human blood-serum agar by a smear upon the surface there devel- oped a fair number of colonies similar to the above, consisting of diplo- cocci having the same morphology and tinctorial characteristics. Trans- planted to ordinary agar there was a growth of a few fine colonies of the same diplococci. On gelatine, ox's blood serum and bouillon there was no growth. At the end of ten days the organisms had all died out upon the original plates. On March 24 and 25, plate cultures were made by the same method, and on each occasion there was an abundant growth, in pure culture, of diplococci identical with those obtained upon the first plates, behaving in the same manner with regard to stains and in their growth upon the various culture media. On the basis of these positive cultural experiments and the clinical history of the case, the patient was brought before the class on March 25 as an instance of general gonococcal septicaemia with endo- and peri- carditis. Autopsy, March 25, by Professor Flexner. Anatomical diagnosis.-Gonococcal septicaemia; subacute gonorrhoea; subacute ulcerative and vegetative, tricuspid endocarditis caused by the gonococcus; subacute splenic tumor; chronic passive congestion of the liver; subacute haemorrhagic and glomerular nephritis; acute sero-puru- lent pleurisy and pericarditis due to the gonococcus; pulmonary infarct. The following is a summary of the pathological record: On opening the abdomen nothing remarkable was to be made out 88 Gonorrhoeal Septicaemia and Ulcerative Endocarditis except the much enlarged spleen, adherent in its upper part to the diaphragm. Pleurae and lungs.-The right pleural cavity is free from adhesions and contains about 800 cc. of slightly turbid, yellowish fluid with large flakes of fibrin. On the pulmonary pleura there are small flakes of fibrin and beneath this are many punctiform ecchymoses. The left lung is bound down along its posterior border by firm adhesions. In the left pleural cavity are 550 cc. of fluid containing somewhat less fibrin than on the other side. There are less fibrin and fewer ecchymoses on the vis- ceral pleura than on the right side. In the middle of the left lower lobe at its inferior border there is a circumscribed, triangular area of infarction l|xl| cm. in extent; opaque, firm, of a brownish-yellow color. The surrounding tissue is congested. On section both lungs are of a light salmon-red color and oedematous. The bronchi are congested. The pulmonary arteries are free and prac- tically normal in appearance. The anterior edges of the lungs are em- physematous. Pericardium and heart.-The pericardial cavity contains about 300 cc. of turbid yellow fluid with fibrinous flakes. In the dependent por- tions the fluid is thick and puriform. The surface of the peri- and epicardium is congested, ecchymosed, and covered by a granular deposit. The weight of the heart and pericardium is 680 grammes. The right ventricle and auricle are dilated and contain fluid blood and partly decolorized clots. The endocardium of the right auricle is deli- cate, although near the obliterated foramen ovale beneath the endo- cardium are two or three slightly elevated minute opaque points. The tricuspid valve is the seat of an extensive thrombus, occupying the entire middle segment, with the exception of its base, and to a less extent the two remaining segments (see Plate I). The thrombus attached to the middle segment is firmly united to the valve at a dis- tance of 5 mm. from its attachment to the auriculo-ventricular ring and projects into the cavity of the ventricle. At the site of attachment of the thrombus the substance of the valve is destroyed. The thrombus presents an irregularly convoluted appearance, and for description may be divided into three distinct portions: The central portion, which is largest, measuring 4.5x2 cm. x4.5 mm. in thickness, has in general a conical shape with its base at the valve and its apex projecting into the ventricle. To the left of this is a second mass 18x22 mm. in extent, almost quadrangular in form but irregular in contour. The remaining mass to the right is about one-half the size of the last. This thrombus THE JOURNAL OF EXPERIMENTAL MEDICINE. VOL. IV. PLATE I William Sydney Thayer and Jesse William Lazear 89 mass is attached at certain points to the endocardium of the right ven- tricle. Fully one-half of the chord® tendine®' of the segment of the valve are ruptured and their free ends are covered with grape-like clusters of thrombi. Small miliary vegetations are on the papillary muscle to which these are attached and on a moderator band which extends from the papillary muscle to the mid-portion of the left seg- ment of the valve. The anterior surface of the right segment of the valve is the seat of two thrombus masses projecting into the auricle; they average about 12x10 and 12x6 mm. The pulmonary artery and valves are normal in appearance. The aortic and mitral valves and the endocardium of the left ventricle are entirely normal. In the lymphatics along the course of the vessels in the epicardium on the right side there are minute discoid nodules similar to those described in the endocardium of the auricle. The tricuspid orifice measures 16 cm.; length of the right ventricle 12.5 cm.; thickness 5-7 mm. The mitral valve measures 12 cm.; length of the left ventricle 8 cm.; thickness 15 mm. The cardiac muscle is pale and fairly firm. The spleen weighs 840 grammes; dimensions, 21x13x6 cm.; capsule wrinkled; on section the Malpighian bodies very prominent, the trabe- cul® visible; the pulp of an opaque grayish-red color, the consistence moderately firm. The liver weighs 2450 grammes, and is the seat of fairly well-marked chronic passive congestion. Kidneys.-The kidneys weigh together 670 grammes. Dimensions: right, 14x9.5x4; left 15x8x4. They are swollen, the capsule adherent in places; the surface mottled, of an opaque, grayish color with many punctiform h®morrhages. The cut surface appears swollen and cedema- tous. The stri® are obscure; the glomeruli visible, but pale. Numerous elongated hemorrhages-9 to 10 mm. long-are visible in the cortex. The pyramids are hyper®mic; the vessels of the mucous membrane of the pelvis are also somewhat congested and a few small h®morrhages are visible. The ureters are not enlarged; their mucous membrane shows the same condition as that of the renal pelvis. Bladder.-The vesical mucous membrane is pale, with the exception of the trigonum, where it is moderately congested. About the orifices of the ureters there are a few small h®morrhages. The neck of the bladder and the prostatic portion of the urethra are somewhat hy- per®mic. 90 Gonorrhoeal Septicaemia and [Ulcerative Endocarditis Gastro-intestinal tract.-The stomach and intestines show nothing noteworthy. Pancreas.-A number of small opaque areas of fat necrosis are to be made out in the fatty capsule of the pancreas. Teased preparations show in the necrotic areas groups of fat cells containing finely granular bodies. Treated under the microscope with concentrated sulphuric acid, gas bubbles may be seen to arise and soon fine crystals of calcium sulphate appear. Bacteriological examination.-('over-slips from the pleural and peri- cardial exudates and from the vegetations upon the heart valves showed large numbers of cocci in pairs. They were excessively numerous upon the surface of the tricuspid valve. These cocci were in almost all in- stances included within polymorphonuclear leucocytes which were numer- ous. The form of the cocci was, as a rule, typically biscuit-shaped, and at times, though rarely, two pairs lay side by side, suggesting a tetrad arrangement. The cocci stain readily in the usual aniline dyes, but are quickly and uniformly decolorized by Gram's method. A cover-glass specimen from the spleen showed one pair of cocci; others were not found. Cover-slips from the kidney, renal pelvis and urinary bladder were negative. In the urethra, among a variety of bacilli, definite intracellular biscuit-shaped diplococci which decolorize by Gram were found. Cultures.-Cultures were made at the autopsy from the various local exudates, the heart's blood and the organs as follows: (a) Upon Loeffler's blood serum, prepared; (1) from human blood; (2) from bullock's blood; (3) from dog's blood. (&) Upon agar-agar. Only a few tidies of the human serum were on hand and these were used for the local exudates and blood. Upon those from the pericardium, tricuspid valve and heart's blood delicate growths were obtained which consisted in part of confluent minute colonies, in part of small, almost point-like, grayish-white, slightly elevated colonies. Microscopically these colonies were composed of diplococci, readily decol- orizing by Gram, and resembling in every way, except perhaps in the feebleness of their growth, the organisms isolated during life. No growths whatever were obtained upon bullock's serum, dog's serum, or plain agar-agar. Transplantations from the 48-hour old growths from the human blood serum on to ordinary agar, swine-liver agar (Livingood), foetus agar (Flexner) were negative. As no human serum remained, trans- plantations entirely failed. William Sydney Thayer and Jesse William Lazear 91 Microscopical examination.-A histological study of the organs was made by Professor Flexner, to whom we are indebted for the following report: The description of the histological changes is confined to those of the kidneys, the liver, the spleen and the cardiac valves, these being the parts chiefly affected. The tissues were hardened in alcohol and Zenker's fluid, and the specimens stained by haematoxylin and eosin, Weigert's fibrin stain, and methylene-blue. Kidney.-Throughout the cortex there is a general increase of con- nective tissue, uniformly distributed and particularly well marked be- tween the tubules. This tissue is fibrillated, cedematous and not par- ticularly rich in cells. The chief lesions affect the glomeruli and the labyrinthine tubules. The least affected glomeruli completely fill the capsule of Bowman; the number of cells within the glomerular capil- laries is increased, this increase being due to an excess of polymorpho- nuclear leucocytes. The capillary walls are distinct, thicker than nor- mal, hyaline or slightly fibrillated in appearance. The more abnormal glomeruli show, in the first place, thrombosis of groups of capillaries by material presenting characters unmistakably indicative of fibrin. This material within the capillaries appears as a delicate network and may be limited to a single loop of a capillary or occupy a group of loops; it does not completely occlude the vessels. Outside of the capillary walls there is an increase in the number of cells within the glomerular space. These cells are partly of an epithelioid type, being doubtless derived from the capsular and glomerular epithelium, and partly leucocytes. Deposited within and intimately mixed with these cells a fibrinous material, which appears often as a crescentic band, dips down between the lobules of the glomeruli. It is in part distinctly fibrillated, in part dense and hyaline, and everywhere gives a sharp staining reaction for fibrin. Its association with the cells within the capsular space is of the most intimate character. In specimens stained with haematoxylin and eosin it takes a vivid red stain. In not a few situations there is evidence of a proliferation of cells clearly derived from the capsular epithelium, and, although less certainly marked, there is in our mind little doubt that a similar increase of cells is taking place within the capillaries themselves. As has been stated, leucocytes occur abundantly in the capsular spaces; these are derived from the glomerular capillaries and may be seen in the act of migration through the capillaries into the space. Of par- ticular interest is the passage of leucocytes from the capsular space through the capsule of Bowman into the interstitial tissue in which these 92 Gonorrhoeal Septicaemia and Ulcerative Endocarditis cells are increased. The uriniferous tubules contain also large numbers of polymorphonuclear leucocytes; in some places completely occluding the lumen of the tubes, forming definite leucocytic casts. The epith- elium, especially of the secreting tubules, is much degenerated, even necrotic, and in some places evidently proliferating, as is evidenced by multinucleated cells in certain of the tubules. The degeneration of the epithelium is partly fatty and granular, but largely of the hyaline variety, to which change can be attributed much cast material and definite casts occupying the tubules. Red blood corpuscles are rarely found within the tubules. The essential lesion is a sub-acute glomerular and intracapillary nephritis. Bacteria were not discovered in this organ. Spleen.-The connective tissue framework of the spleen is thickened. The new tissue is of a semi-fibrillated character. The blood-vessels of the pulp are diminished in size and apparently also in number. The splenic elements proper are also reduced in number, but there are scat- tered irregularly throughout the spleen in greatly increased number polymorphonuclear leucocytes, and within the venous sinuses groups of hyaline bodies and single hyaline bodies, globular in shape, varying in size from a red blood corpuscle to one of the largest white cells there present. The follicles are enlarged and very distinct, many of their cells being swollen and in process of division; they are infiltrated with polymorpho- nuclear leucocytes, the nuclei of many of which show the greatest irregu- larity in form. Nuclear fragments are scattered sparsely and irregu- larly throughout the spleen; for the most part they are not enclosed within other cells. Liver.-The connective tissue is not increased; the central veins are much dilated and the central portions of the lobules hyperaemic. This congestion varies in different lobules, being in some very marked, with corresponding atrophy of the liver cells. There is an interesting hyaline metamorphosis of some of the liver cells. Those peripherally placed in the congested areas show this change best, and in these the nuclei have become small, contracted and deeply staining. In parts of the liver distant from the congested areas the hepatic cells are swollen, fatty, and free from the hyaline change described, excepting where an occa- sional cell, more or less loosened from the rows of liver cells and per- haps lying in the capillary, is thus affected. There is a general increase in the number of leucocytes within the blood-vessels. Heart.-- Sections through the tricuspid valve include chiefly the thrombus, which consists of masses of blood platelets, of fibrin and of William Sydney Thayer and Jesse William Lazear 93 included leucocytes. No bacteria appear in sections stained by Gram's or Weigert's method. The pericardium shows, besides a superficial fibrinous exudate con- taining leucocytes, a considerable inflammatory infiltration of the sub- jacent fibrous tissue and a proliferation of the fixed tissue cells. The epithelial covering is in active proliferation. In some of the leucocytes in the pericardial exudate Dr. Lazear was able to demonstrate gonococci. A further study of the heart valves was made by Dr. Lazear: The tissues were hardened in alcohol and in Zenker's fluid, and embedded in celloidin and paraffin. For the bacteriological study they were stained with Loeffler's and Unna's methylene-blue, Ziehl-Neelsen carbolic fuchsin, Stirling's gentian violet and by Gram's method. For histo- logical study they were stained with haematoxylin and eosin and Weigert's fibrin stain. Tricuspid valve.-The connective-tissue structure of the valve shows areas of necrosis. In places the nuclei are merely swollen. There are also irregular areas extending throughout the valve in which the nuclei have entirely disappeared, leaving a homogeneous material which stains with eosin. Extending into the substance of the valve are numerous spaces filled with leucocytes, among which are a few large phagocytic cells, with large irregularly shaped nuclei and containing red blood cor- puscles. The vegetations are made up of granular masses of platelets sur- rounded by fibrin and a thick layer of leucocytes. Leucocytes are present also within the masses of platelets, either scattered or occupying spaces. Upon the surface of the valve and the vegetations is a layer composed of leucocytes and red blood corpuscles with strands of fibrin forming an irregular network through it. The same material occupies the inter- stices between the vegetations. Many of the leucocytes in this layer and in the more central portions contain micrococci with the typical biscuit shape and other morphological characters of gonococci and com- pletely decolorizing by Gram. Extracellular gonococci are present m the central portion of the thrombi but not in the superficial layers. At the line of junction of the central platelet mass and the leuco- cytic layer is a long line of globular bodies varying in size from that of a leucocyte to ten times this size. These bodies are made up of dense masses of gonococci. There can, it appears to us, be no doubt as to the nature of the organisms obtained in pure culture from the blood during life and 94 Gonorrhoeal Septicaemia and Ulcerative Endocarditis from the affected valves, heart's blood and pericardium after death. This case and that previously reported by Dr. Blumer and one of the authors (Thayer) are the first two recorded instances in which abso- lute proof of the gonococcal nature of the general infection has been obtained. The case presents several interesting and unique features. While the diagnosis of ulcerative endocarditis and gonorrhoeal septicaemia was made during life, the exact anatomical lesion-the remarkably extensive affection of the tricuspid valve-was not at this time sus- pected. Much of the thrombus upon the valve may have been of relatively recent formation, but older changes, probably of several months' duration, were clearly present. It is the first instance in which a pure tricuspid lesion has been found in a gonorrhoeal endo- carditis. It is not uninteresting that while the diagnosis was not made clinically, it was particularly noted that, in association with the systolic murmur, there was no accentuation of the second pulmonic sound, a fact which might well have excited our suspicion. The changes in the kidney are of especial interest. Clinically the case presented the features of a grave acute nephritis with anaemia, anasarca, ascites and finally uraemic coma. The urine showed, be- sides the large quantity of albumin, the blood casts and the epithelial cells, so large an amount of pus that a diagnosis of probable pyelitis or pyelo-nephritis was made. Especially interesting is the fact that during life casts consisting entirely of polymorphonuclear leucocytes were repeatedly observed. The absence of gross collections of pus in the kidney or in the pelvis was a surprise at the time of the autopsy. The microscopical examination of the kidney, however, revealed the source of this pus in the unquestioned evidence of the passage of numerous leucocytes directly through the capillaries of the glomeruli into the glomerular spaces and the urinary tubules. Tlie extensive thrombosis of the glomerular capillaries and the accumulations of fibrin in the glomerular spaces form a very remarkable picture. How this special localization of these changes in the kidney and the relative freedom of the liver from those degenerative processes so common in general septicaemia, viz. focal necroses, may be explained is rather William Sydney Thayer and Jesse William Lazear 95 an interesting question. May it perhaps be true that the renal changes were due to the direct deleterious action of the gonococci or their products in the process of elimination through the urine? That the gonococcus must be recognized as a true pyogenic organism capable of giving rise to the gravest local and general septic complications has been abundantly proven by recent observations. That cystitis, epididymitis, spermatocystitis, prostatitis and peri- urethral abscesses in man, metritis, vulvo-vaginitis, salpingitis, and peritonitis in woman, may owe their origin solely to the presence of the gonococcus has been clearly demonstrated. And further, sup- purative processes in remote parts are now known to be occasionally due to a pure gonorrhoeal infection. Horwitz and Lang* found the gonococcus in an ulcer upon the back of the hand, while its presence in joint fluids in cases of gonorrhoeal arthritis has been demonstrated by many observers. Within the past 15 months Dr. Young has ob- tained the gonococcus in pure culture in 7 instances of gonorrhoeal arthritis in the Johns Hopkins Hospital, demonstrating that the arthritis in a large proportion of instances represents a true local bacterial infection. The gonococcus has also been obtained in pure culture from a number of instances of tenosynovitis (Jacobi and Goldmann,f Blood- good and Young$), from subcutaneous abscesses (Lang and Paltauf§ and Horwitz||), from intramuscular abscesses (Bujwid*), from pleural effusions (Bordoni-Uffreduzzi**), from the circulating blood (Thayer and Blumer,ft Thayer and Lazear^), and recently by Young§§ from a case of general peritonitis following an acute gonorrhoeal * Wiener kiln. Wochenschr., 1893, vi, 59. t Beitrd'ge z. kiln. Chir., 1894, xii, 827. $ Unpublished observations in the Johns Hopkins Hospital § Arch. f. Derm. u. Syph., 1893, xxv, 330. || Wien. klin.. Woch., 1893, vi, 59. fl Centrib. f. Bakt., 1895, xviii, 435. ** Deutsche med. Woch., 1894, xx, 484. It Op. cit. Med. Record, N. Y., 1897, lii, 497, and present article. §§ Unpublished obscivation. 96 Gonorrhoeal Septicaemia and Ulcerative Endocarditis salpingitis. 1 hat in some instances, therefore, the gonococcus itself should be the cause of endocarditis, pericarditis, and myocarditis is by no means remarkable. Our own experience during the last several years, together with a study of the literature, indicates that the cardiac complications of gonorrhoea are more frequent than has generally been supposed. Endocarditis is by far the commonest of the cardiac complications of gonorrhoea. Gurvich* has collected 110 instances in 77 of which the cases are sufficiently well reported to allow of definite conclusions. From the more recent literature it is possible to add some ten or a dozen more cases to those of Gurvich. In the majority of these cases the cardiac complications have been preceded by an arthritis. In a considerable number of instances, however, joint symptoms have been entirely absent, while in several cases evidences of endo- or pericarditis have appeared before the development of joint manifestations. Pericarditis is a much less frequent complication. We have been able to collect but 17 positive cases in the literature. Myocardial changes have been demonstrated in the majority of the cases of acute ulcerative endocarditis of gonorrhoeal origin which have come to autopsy, the most satisfactorily studied instance being that of Councilman, where there was no affection of the endocardium. For a satisfactory study, however, of the cardiac complications of gonorrhoea one must turn to the cases which have been observed an- atomically as well as clinically. We have collected 32 instances of gonorrhoea with fatal cardiac complications where there were satisfac- tory pathological notes. Several of those included in other classifica- tions have been omitted because of insufficient data. Of these 32 cases 31 were instances of ulcerative endocarditis with or without marked pericardial or myocardial affection; one, that of Councilman, was an instance of peri- and myocarditis alone. Gonorrhoeal endocarditis.-These cases considered from a patho- logical standpoint may be divided into five classes: * Russk. arch, patol., klin. med. i. bakt., 1897, iii, 329 William Sydney Thayer and Jesse William Lazear 97 (1) The first class includes six cases, those of Bourdon,* Desnos,f Schedler,^: Draper,§ Fleury, || and His.^[ In these instances, although the history clearly shows the association of the process with gonorrhoea, no note is made with regard to bac- teriological examination. (2) The second class comprises ten cases, those of Martin,** Weckerle,ff Weichselbaum,^ Ely,§§ Wilms,|||| Golz,|f Keller,*** Zawadzki and Bregman,Babes and Sion,||^ and lastly an unpub- lished observation of our own, Case 32 of our series (p. 115). Here there existed mixed or secondary infections. In some instances organ- isms other than gonococci were obtained in pure culture; in others, strepto- and staphylococci were demonstrated microscopically. In several cases organisms morphologically similar to gonococci were found, while the actual sequence of the infection upon acute gonor- rheea is not to be doubted. (3) The third class includes four cases, those of Rothmund,§§§ His,|||||| IVinterberg^ll and Fressel.**** Here the infection was probably purely gonococcal. In all of these cases organisms showing the morphological and tinctorial characteristics of gonococci were * Gaz. d. Hop. Par., 1868, xli, 1. * L'Union med., 3s., 1878, xxv, 43; also, Gaz. d. Hop., 1877, 1, 1067. $ " Zur Casuistik der Herzaffectionen bei Tripper." Inaug.-Diss., Berlin, 1880. § Meddeal Bulletin, Phila., 1882, iv, 81. || Journ. de med. de Bordeaux, 1883-84, xiii, 65. V Berl. kiln. Woch., 1892, xxix, 993. ** Rev. med. de la Suisse Romande, 1882, ii, 308, 352. ft Munch, med. Woch., 1886, xxxiii, 563, 582, 608, 622, 636. Centralhl. f. Bakt., 1887, ii, 209. §§ Med. Record, xxxv, 1889, 287. Uli Munch. Med. Woch., 1893, xl, 745. flfl Ulcerbse Endocarditis der Klappen der Pulmonalarterie bei gonor- rhoischer Arthritis, Inaug.-Diss., Berlin, 1893. *** Deutsch. Arch. f. kiln. Med., 1896, Ivii, 387. ttf Wien. med. Woch., 1896, xlvi, 313, 351. JU Arch. d. Sc. Med. de Bucarest, 1896, i, 505. §§§ Endocarditis ulcerosa, Inaug.-Diss., Zurich, 1889. min °p-cit- flflfl Festschr. z. 25 Jahr. Jub. d. Vereins Deutscher Aerzte zu San Fran- cisco, 1894, 40. **** Inaug.-Diss., Leipzig, 1894. 98 Gonorrhoeal Septicaemia and Ulcerative Endocarditis demonstrated microscopically. Cultures, however, were not made. Other organisms were not found. (4) The fourth group comprises six cases, those of Leyden,* Finger, Ghon and Schlagenhaufer,f Hale White,$ Michaelis,§ Sten- gel || and Siegheim.T[ Here the proof of the purely gonococcal nature of the process is more nearly complete in that the observers made cultures upon ordinary media from the affected parts and from the circulating blood without obtaining positive results; while at the same time the microscopical demonstration from the affected regions of organisms showing all the morphological and tinctorial character- istics of gonococci would seem to form a fairly conclusive argument in favor of the existence of a pure infection by the gonococcus. (5) Lastly, there remain five cases, those of Thayer and Blumer,** Dauber and Borst,ff Thayer and Lazear,^ Rendu and Halle§§ and Lenharz,|||| in which the evidence of the purely gonococcal nature of the complication may be considered as definitely proven. In the first of these cases the gonococcus was obtained in pure culture twice during life and was found microscopically post-mortem in the affected regions. In the case of Dauber and Borst a pure culture was obtained after death from the heart's blood of organisms concerning the nature of which the reporters were in doubt. Most subsequent observers have, however, recognized them as gonococci. In the third instance, the writers were able to prove the purely gonorrhoeal nature of the affection by obtaining gonococci in pure culture three times during life from the circulating blood, while Dr. Flexner obtained similar results post mortem from the affected valves, heart's blood, and pericardium. * Deutsch. med. Woch., 1893, xix, 909. t Arch. f. Dermat. u. Syph., 1895, xxxiii, 141, 323. i Lancet, 1896, i, 533. § Zeitschr. f. klin. Med., 1896, xxix, 556. || Univ. Med. Mag., Phila., 1897, ix, 426. fl Zeitschr. f. klin. Med., 1898, xxxiv, 526. ** Op. cit. ft Deutsch. Arch. f. klin. Med., 1896, Ivi, 231. Med. Record, N. Y., 1897, lii, 497 (ease reported in this communication). §§ Bull, et mem. Soc. med. d. hop. de Par., 1897, 3. s., xiv, 1325. Uli Berl. klin. Woch., 1897, xxxiv, 1138. William Sydney Thayer and Jesse William Lazear 99 In the case of Rendu and Halle gonococci were obtained in pure culture from the endometrium during life and demonstrated micro- scopically in the phlegmon about the elbow. After death they were obtained in pure culture from the thrombus upon the affected valves. Finally the last link in the chain of evidence has been supplied by Lenharz, who, from a case of characteristic gonorrhoeal endocarditis, in which pure cultures were obtained from the thrombi on the aortic valves, introduced a piece of softened thrombus into the human urethra. A characteristic gonorrhoea, with gonococci in the dis- charge, appeared on the fourth day. Anatomical lesions.-As to the nature of the anatomical lesion there is little to say. Considering the 15 cases in which the pure gonococcal nature of the infection is probable, one finds that in all instances there were present the usual appearances of ulcerative endocarditis with ex- tensive polypoid ehrombi and more or less actual destruction of the valves, often with aneurism formation and perforation. The localiza- tion of the affection, however, presents several points of considerable interest. In ordinary chronic endocarditis it is well known how infre- quently the right heart alone is affected; thus, out of 300 autopsies on cases of endocarditis, Sperling found the lesions limited to the right heart in but 3 instances, or 1 per cent. Weckerle out of 846 autopsies on cases showing valvular cardiac lesions in Bollinger's laboratory found that the right heart alone was affected in 3.9 per cent of all cases. It has, however, been shown that in cases of ulcerative endocarditis the liability of the right side to infection is considerably greater. Thus, while in 802 benign cases from the Munich statistics the right heart alone was affected in 3.24 per cent, in 44 cases of ulcerative endocarditis the percentage of affections limited to the right side was nearly 16 per cent (15.91 per cent). In our 31 cases the lesions were as follows: Left heart: aortic 12 mitral 6 both 3 Right heart: pulmonary 7 tricuspid 1 21-67.7# 8-25.8# ,, Both s mitral, aortic, tricuspid 1 all four valves 1 2-6.4# 100 Gonorrhoeal Septicaemia and Ulcerative Endocarditis This surprisingly high percentage of right-sided cardiac affections in our cases is interesting and difficult to explain. Considering the ] 5 cases in which the pure gonococcal nature of the infection is prob- able, we have the following table: T i , Left heart: aortic 7 mitral 2 both 2 Right side : tricuspid 1 pulmonary .... 2 3-20^ Both sides : all four valves 1-6.6^. 11-73.3$ The remarkable high percentage of pure right-sided cardiac affec- tions in these cases, even as compared with the Munich tables, is an interesting point. To attempt to draw definite conclusions from so small a number of instances might well be fallacious, but the fact is none the less worthy of reflection. Indeed, why the right side of the heart should be so much more liable to disease in ulcerative endo- carditis is by no means perfectly clear. Another very interesting point is the fact that the aortic valves appear from our tables to be by far the most frequently affected. While this has been the case in those fatal instances which have come to autopsy, yet Gurvich's tables based upon 64 cases in which a diagnosis was made during life show appreciably different figures. His tables show: Mitral valve 31 Aortic 16 Mitral and aortic 13 Pulmonary 2 Mitral and tricuspid 2 Age.-The age of the patients in the fatal cases varied between 19 and 51, while taking the larger statistics of Gurvich we find records of one instance at the age of 64 and another at 10. The majority of cases occurred, as might be expected, in early adult life. Sex.-Of the 31 instances of fatal ulcerative endocarditis due to the gonococcus 23 were in men and 8 in women. Time of onset.-There appears to be nothing particularly character- istic with regard to the time of onset of these cases with relation to the attack of urethritis, some, as in the case of Prevost, coming on almost immediately after the onset, others some weeks or months later. Some of the cases occurred with the initial attack of gonor- rhoea, others in patients who had suffered once or twice before. William Sydney Thayer and Jesse William Lazear 101 Complicating arthritis.-Arthritis preceded the cardiac affection in the majority of instances, though in a considerable number the car- diac complication occurred without or before the development of joint symptoms. Symptoms.-The symptoms of gonorrhoeal endocarditis appear to differ in no essential way from those of endocarditis of other origin. While many instances are reported in which the cardiac manifestations were slight and transient, the proportion of cases of a malignant nature which have so far been recognized is unusually large. It is not im- probable, however, that this is due to the fact that the majority of milder cases escape notice. And it is well in this connection to remember how frequently the same is true in rheumatic cardiac affec- tions. In the fatal cases the symptoms are essentially similar to those in instances depending upon infection with other pyogenic organisms -an irregular intermittent or remittent fever, usually with severe rigors, profuse sweating and rapidly developing anaemia, albuminuria; in fact, the ordinary symptoms of a severe septicaemia. The duration of the attack in the 15 instances in which the pure gonococcal nature of the infection is probable, varied, as far as can be made out, from ten days to two months. The only exception to this rule was in our case, in which the symptoms of septicaemia lasted through a period of six months. From the consideration of these cases and of those others which were followed by recovery, it is rather difficult to see upon what Gurvich bases his conclusion that gonorrhoeal cardiac affections pursue a milder course than those depending upon the other pyogenic cocci. In a number of these instances the renal changes have been par- ticularly severe. In several the patient died with the general appear- ances of a grave nephritis as in our second case. These changes are possibly to be explained by the special exposure of the kidney through the elimination of the gonococcus or its products which, in these in- stances of general septicaemia, occurs in all probability through the urine. Pericarditis.-Pericarditis is a far less frequent occurrence than 102 Gonorrhoeal Septicaemia and Ulcerative Endocarditis endocarditis in gonorrhoeal infection. In 7 of the 32 fatal instances there is a note of a pericardial complication. The cases of Weckerle and Golz were mixed infections. In Councilman's case the pericar- dial cavity was enormously distended, containing 800 cc. of a haemor- rhagic exudate in which there were large masses of clot. Both sur- faces of the pericardium were covered with thick membranous masses containing haemorrhages. A few gonococci were found in the peri- cardium. In Winterberg's case it is noted that 20 ccm. of sero-puru- lent fluid were found in the pericardial sac. In our second case the pericardial cavity contained about 300 ccm. of turbid yellow fluid containing flakes of fibrin. In the dependent portions the fluid was thick and puriform. The surface of the peri- and epicardium was congested and contained small ecchymoses; it was covered by a granular deposit. Gonococci were obtained in pure cultures from the fibrin upon the surface of the pericardium. In Rendu's case it is noted that the pericardium contained 500 cc. of translucent fluid and that there were " pericardial lesions," nothing further. Cultures from the fluid were negative. Thus, it may be seen that anatomically nothing striking is to be made out from a consideration of these observations. The definite proof of the existence of a pure gonorrhoeal pericarditis is furnished by the positive result of our cultures in Case II. Myocarditis.-Grave myocardial changes, necroses with haemor- rhage, leucocytic infiltration, embolic abscesses have been described in a number of instances in association with fatal endocarditis. In Coun- cilman's case the areas of necrosis and suppuration were large and gonococci were found microscopically in the foci. CONCLUSIONS. (1) An acute gonorrhoeal urethritis may be the starting point for a grave general septicaemia with all its possible complications. (2) These infections may be mixed or secondary, due to the en- trance into the circulation of organisms other than the gonococcus, or they may be purely gonococcal in nature. (3) Endocarditis is an occasional complication of gonorrhoea. William Sydney Thayer and Jesse William Lazear 103 (4) This endocarditis may be transient, disappearing with but few apparent results, or it may leave the patient with a chronic valvular lesion, or it may pursue a rapidly fatal course with the symptoms of acute ulcerative endocarditis. (5) The endocarditis associated with gonorrhoea is commonly due to the direct action of the gonococcus, but may be the result of a secondary or mixed infection. (6) Pericarditis may also occur as a complication of gonorrhoea, but it is less frequent than endocarditis. It may, as in the case of the latter, be the result either of a pure gonococcal or of a mixed infec- tion. (7) Grave myocardial changes, necroses, purulent infiltration, em- bolic abscesses are common in the severe gonococcal septicaemias. (8) In instances of gonococcal septicaemia the diagnosis may, in some cases, be made during life by cultures taken from the circu- lating blood according to proper methods. 104 Gonorrhoeal Septicaemia and Ulcerative Endocarditis REPORTER. SEX. AGE. HISTORY. AUTOPSY. REMARKS. (1) Bourdon. Gaz. d. Hop., 1868, xli, 1. M 24 Gonorrhoea; one month later, arthritis; delirium; irregular chills; evidences of endocar- ditis. Ihemorrhagic areas in skin, becoming gangrenous; bed sores. Death 13 months after infection. Verrucous endocarditis of mitral and tricuspid valves with thrombi. Kidneys pale and fatty. (2) Desnos. L' Union Med. 3 s., 1878, xxv, 43. Also Gaz. d. Hop., 1877, L, 1867. M ? Gonorrhoea; bronchitis; ar- thritis; dyspnoea; palpitation; cardiac murmur; irregular fever. Death less than a month after onset of arthritis. The heart was normal on first examination. No history of any previous predisposing malady. Vegetative endocarditis aortic and mitral valves. of In the discussion of the case Fournier ac- knowledged its gon- orrhoeal origin. (3) Sehedler. "Zur Casuistik der Herzaffec- tionen nach Trip- per." Inaug. diss. Berlin, 1880. M 22 Gonorrhoea; epididymitis; arthritis and moderate fever, shortly after onset. 7 months later, irregularchills; evidences of aortic endocarditis with insufficiency. Death 5 weeks afte^onset of acute symptoms. Ulcerative endocarditis aortic valve. of Patient had had smallpox and a fever some time previously, which justifies one in asking whether the endocarditis may not have preexisted. At the autopsy the changes pointed to a recent affection. The reporter as well as Prof. Leyden have no doubt as to its gon- orrhoeal origin. (4) Draper. Medical Bulletin, Philadelphia, 1882, iv, 81. M 19 Chronic gonorrhoea for a year; arthritis; irregular fever, with chills; embolism in leg. Death 4 months after onset of arthritis. Ulcerative endocarditis mitral valve. Infarctions spleen and kidneys. of in William Sydney Thayer and Jesse William Lazear 105 REPORTER. SEX. AGE. HISTORY. AUTOPSY. REMARKS. (5) Martin. Rev. Med. de la Suisse Romande* 1882, ii, 308, 352* M 24 Previous history good. Lost appetite and began to feel ill 3-4 weeks before entrance in- to hospital. Chills; irregular fever; evidences of pyajmia; multiple arthritis; haematuria; right pleuro-pneumonia; sup- purative conjunctivitis; paro- titis. Death a month after beginning of symptoms. Gonorrhoea; suppurative pro- statitis; cystitis; suppurative inflammation of vesieulae sem- inales; multiple myocardial, abscesses. Ulcerative and veg- etative endocarditis of mitral valve. In the thrombi on valves were numerous cocci, some of which were exactly similar morphologically to Neisser's gonococci. The kidneys show- ed fatty degeneration with septic emboli. The case would ap- pear to be of gonor- rhoeal origin, whether or not a secondary infection occurred. (6) Fleury. Journ. de Med. de Bordeaux, 1883-'84, xiii, 65. M 27 Gonorrhoea; 3 months later disappearance of discharge; arthritis; thoracic pains; peri- carditis. Death 3 weeks after arthritis. No signs of cardiac disease on examination before this infection. Vegetative and ulcerative endocarditis of aortic valves with perforation. A certain amount of blood-stained fluid in the pericardium; a patch of false membrane just below the root of the aorta. - (7) Weckerle. Munch, med. Woch., 1886, xxxiii, 563, 582, 608, 622, 636. F 24 Gonorrhoea; inguinal aden- itis ; arthritis; 1 to 2 months after arthritis, signs of ulcera- tive endocarditis of pulmonary valve; chills; irregular fever; dry pleurisy. Death a month after onset. The urine, normal at first, showed a large quan- tity of albumin; sediment; red and white corpuscles: renal epithelium and casts. Sero-fibrinous pericarditis. Extensive ulcerative endocar- ditis of pulmonary valves. Numerous cocci in the thrombi on the valves, sometimes in chains, sometimes in groups. These organisms stain accord- ing to Gram. No particular search was made for gonococci. Kidneys large-subacute par- enchymatous nephritis. The author does not believe the endocar- ditis to have been gonococcal. The only portal of entry ap- pears to have been furnished by the gon- orrhoea. 106 Gonorrhoeal Septicaemia and Ulcerative Endocarditis REPORTER. SEX. AGE. HISTORY. AUTOPSY. REMARKS. (8) Weichselbaum Centralbl.f. Bakt., 1887, ii, 209. Also, Ziegler's Beitrage, 1889, iv, ' 125. M 21 Gonorrhoea for 3 weeks; high fever. Death on day of entry. Gonococci in urethral secre- tion. Acute splenic tumor. Ul- cerative aortic endocarditis. Gonococci in urethra. Only streptococci, morphologically and by culture, on the valves. W. believes that the gonorrhoea formed the portal of entry for the streptococcus. (9) Rothmund. "Endocarditis Ulcerosa." Dissertation, Zurich. 1889. M 51 Gonorrhoea; 8 or 9 weeks later epididymitis; poly-ar- thritis; heart sounds clear; moderate fever. 3 weeks later loud systolic murmur over mitral and tricuspid areas. 10 days later, high pitched diastolic murmur over aortic and pulmonary regions; deli- rium; jaundice. Death 5 weeks after arthritis. Urethritis; cystitis; right knee joint and left ankle con- tain sero-haemorrhagic fluid. Extensive ulcerative endocar- ditis of aortic valves. In the blood of the right heart and in the affected joints were found cocci having the form and grouping of gonococci. • (10) Ely. Med. Record, 1889, xxxv, 287. M 28 No history. Ill 3 days. Fever; delirium ; vomiting. 2 days after entry partial left hemiplegia and death. Gonorrhoea; old pericardial adhesions; fresh vegetative and ulcerative endocarditis of mit- ral valve. In thrombi on valve there were cocci and bacilli. In all embolic abscesses in liver, kidneys and in heart valves as well as in urethra, similar cocci staining by Gram and ar- ranged in clusters and chains, are seen. In urethral pus, gono- cocci decolorizing by Gram are also seen. The author believes the case to be one of secondary infection with pyogenic cocci. William Sydney Thayer and Jesse William Lazear 107 BEPOBTEB. SEX. AGE HISTOBY. AUTOPSY. BEMABKS. (11) His. Berl. klin. Woch., 1892, xxix, 993. M 19 Gonorrhoea; first attack, dis- appearing apparently in 3 weeks. 2 weeks later syncopal attack, followed by chills; haemorrhagic eruption; remit- tent fever; loud systolic mur- mur; signs of ulcerative andocarditis. Blood cultures from ear negative. General anaemia; ecchymoses of skin and serous mem- branes ; ulcerative aortic endo- carditis ; softened thrombus at cardiac apex. Acute interstitial myocarditis; septic emboli in spleen, kidneys and lungs. In the thrombi on the affected valve cocci resembling gono- cocci were found; these de- colorized when treated accord- ing to Gram. Unfortunately, the specimen had been previ- ously put in Muller's fluid. (12) His. Op. cit. M 19 Gonorrhoea; arthritis; a few days later irregular fever and chills, sometimes two a day. 4 months after onset of gonor- rhoea there were signs of ulcer- ative endocarditis; aortic sten- osis. Death 5X months after onset of gonorrhoea. Acute aortic endocarditis; partial aneurism at root of aorta with papillary thrombi; enlarged spleen with fresh in- farcts; subacute parenchymat- ous nephritis; slight hydro- thorax; hydropericardium. No bacteriological examination. Case observed by Wagner in 1879. Autopsy by Huber. (13) Leyden. Deutsch, med. Woeh., 1893, xix, 909. M 22 Chronic gonorrhoea; epididy- mitis ; arthritis of right knee; signs of ulcerative endo- carditis with aortic insuffici- ency ; irregular fever; chills. Death 6 to 7 weeks after onset of arthritis. Cultures from vein on ordinary media, negative. Acute myocarditis; ulcerative endocarditis of aortic and veg- etative endocarditis of mitral valves. Typical gonococci decolorizing by Gram in the thrombi on valves. Cultures on ordinary media negative. Doubtless a pure gon- orrhoeal endocarditis. 108 Gonorrhoeal Septicaemia and Ulcerative Endocarditis REPORTER. SEX. ' AGE. HISTORY. AUTOPSY. REMARKS. (14) Wilms. Munch, med. Woch.^ 1893, xl, 745. M 26 Gonorrhoea 6 months ago and again later; 3 weeks after sec- ond attack, chill, arthritis in knee; a week later signs of aortic insufficiency; high fever. Death 6 weeks after the second infection. Ulcerative endocarditis of aortic valve extending through into right auricle; suppurative myocarditis. Numerous cocci in thrombus, some separate, some arranged like gonococci and intracellular. They decol- orize almost immediately by Gram. In leucocytes in the sub-mucous tissue of urethra there were scanty diplococci, some resembling gonococci. The author does not believe the organisms were gonococci though the description is more than suggestive. (15) Golz. " Ulcerose Endo- carditis der Klap- pen der Pulmonal- pi arterie bei gonorrhoischer g Arthritis." Inaug.'Diss. Berlin, J1893. M 21 Gonorrhoea; right-sided bubo; 6 days later arthritis in right shoulder and left foot. Gono- cocci found in urethra. 2 weeks later chills; heart sounds clear; chills and fever continued, and 2 weeks later systolic mur- mur became audible; diastolic murmur in pulmonary area. 3 weeks later pericarditis and pleurisy with haemorrhagic ex- udate ; pulmonary embolism. Death 3)^ months after infec- tion and a little less than 3 months after apparent onset of endocarditis. Fibrinous pericarditis; in pericardium % litre of fairly clear fluid. Ulcerative endo- carditis of pulmonary valve and of wall of right auricle. No cultures. The specimen had been left for a considerable time in alcohol before a bac- teriological examination was made. Small cocci at times in groups and sometimes in chains were found. No characteristic gonococci. The organisms de- scribed by the author appear to have been staphylococci and streptococci. William Sydney Thayer and Jesse William Lazear 109 REPORTER. SEX. AGE. HISTORY. AUTOPSY. REMARKS. (16) Councilman. Am. Jour. Med. Sei., 1893, cvi, 540. M Gonorrhoea; 10 days later ar- thritis in various joints. Five weeks after infection pericar- ditis. Death suddenly 3 days later. Pericardium contained 800 cc. of haemorrhagic exudate in which there were large masses of clot. Both surfaces of peri- cardium covered with thick membranous masses, contain- ing haemorrhages. Suppurative myocarditis. Gonococci, char- acteristic morphologically, in suppurative foci in heart mus- cle, pericardium, urethra and joints; they decolorized by Gram. No cultures. (17) Fressel. Inaug. Diss. Leipsic, 1894. F 26 History imperfect. Severe symptoms came on a few days before death. Extreme weak- ness; emaciation ; orthopnoea; arthritis of left ankle. Ulcerative and polypoid en- docarditis of mitral and aortic valves. Kidneys practically normal. Cystitis; urethritis; vaginitis. The thrombi on valves showed organisms hav- ing microscopically the charac- teristics of the gonococcus ; some occupying cells; they de- colorized by Gram's method. No cultures. (18) Winterberg. Festschrift z. 25 Jahr. Jub. des Vereins Deutscher Aerzte zu San Francisco, 1894, 40. M 25 Gonorrhoea; 6 weeks later right epididymitis; double bu- bo ; arthritis of both elbows; dyspnoea; systolic and diastolic murmurs especially in aortic area. .Death after onset. Pleural effusion on both sides; 20 cc. sero-purulent fluid in pericardium; myocardial ab- scesses. Ulcerative endocar- ditis of aortic and pulmonary valves which were almost en- tirely destroyed. Endocarditis of mitral and tricuspid valves of a lesser extent. Amyloid kidneys. No cultures. Cover glass specimens from valves showed organisms answering morphologically and tinctori- ally to gonococci, decolorizing by the method of Gram. 110 Gonorrhoeal Septicaemia and Ulcerative Endocarditis REPORTER. SEX. AGE. HISTORY. AUTOPSY. REMARKS. (19) Thayer and Blumer. Arch, de Med. Exper., 1895, vii, 701, and Johns Hopkins Hospital Bull., 1896, vii, 57. F 34 Vague history of rheumatism 3 months ago; has been short of breath 3 or 4 years. About 3 months after "rheumatism," irregular fever and chills; signs of ulcerative endocarditis; mit- ral stenosis. Death 3 weeks after onset of fever. Cultures from median basilic vein 9 and 4 days before death showed pure growths of diplococci resembling in every way gon- ococci and decolorizing by Gram's method. The medium contained at least one-third blood (the syringe full of blood mixed with agar agar and plat- ed). Transplanted to ordinary media there was no growth. Ulcerative endocarditis of mitral valve. In the thrombi on valves and in vagina and uterus characteristic intracel- lular gonococci, decolorizing when treated according to Gram's method. Cultures made on agar agar and bullock's blood serum from all sources were negative. This is the first case in which gonococci were obtained in pure culture from the blood during life. (20) Finger, Ghon and Schlagenhauf er. Arch. f. Dermat. u. Sy ph., 1895, xxxiii, 141, 323. M 19 Chronic gonorrhoea for a year. Fresh attack in March, 1895. 6 months later arthritis in right knee; fever. Heart sounds clear; gonococci in urethral discharge; chills; 10 days later diastolic murmur over aorta, Death 9 days later. Myocarditis; ulcerative aortic endocarditis with perforation. Arthritis of right knee joint. Chronic urethritis; prostatic abscess; infarct of spleen; cloudy swelling of kidneys. Characteristic gonococci in urethra and in thrombi on valves, decolorizing by Gram. Cultures on ox's serum pep- tone agar were negative ex- cepting from urethra, from which an unidentified coccus was obtained. The authors believe the case to be purely gonorrhoeal, the gono- cocci having lost their vitality, possibly ow- ing to high tempera- ture before (and after, W. 8. T.,) death, and hence failing to grow. William Sydney Thayer and Jesse William Lazear 111 REPORTER. SEX. AGE. HISTORY. AUTOPSY. REMARKS. (21) Zawadzki and Bregman. Wien. med. Woch., 1896, xlvi. 313, 351. F 17 A month ago purulent vagi- nitis with staphylococcus and micrococcus tetragenus; chills and fever; 6 weeks after infec- tion, arthritis in hip not yield- ing to salicylates; 11 days later, serous pleurisy on right side, showing on culture, strepto- coccus pyogenes; staphylo- coccus albus; micrococcus tet- ragenus. 15 weeks after onset right hemiplegia and death. Verrucous mitral endocardi- tis ; embolism of right arteria fossae Sylvii. In the excrescen- ces on valves among other organ- isms were numerous character- istic gonococci. These were in part in groups in the interme- diate tissue, in partin the cells and in their neighborhood. They had the character and shape of gonococci and were decolorized when treated ac- cording to Gram. They were more numerous on the free border of the valves as were the other cocci. A mixed infection. Some question as to whether the organisms found were gonococci. (22) Dauber and Borst. Deutsch. Arch. f. kl. A fed., 1896, Ivi, 231. M 20 Gonorrhoea; tenosynovitis of left hand; inguinal buboes; periurethral abscesses. 2 weeks after onset, chill; irregular fever; heart's sounds clear. Pain in cervical vertebrae. 3 months after infection evi- dences of aortic insufficiency; septic nephritis. Gonococci gradually disappeared from urethral discharge, other bac- teria appearing. Cultures from blood, negative. Death. Ulcerative and vegetative endocarditis of aortic valve; suppurative myocarditis; acute nephritis; septic emboli and infarctions of kidney. In thrombi organisms showing all the characteristics of gono- cocci, decolorizing by Gram; also once in colorless corpus- cle in heart's blood. Cultures negative excepting one on hu- man blood serum agar on which there developed after 36 hours separate point-like, yellowish brown translucent colonies. On feeble magnification these appeared round, had a sharp clean-cut border, showed no outgrowths from their periph- eries or daughter colonies so characteristic of gonococci. Micro-organisms obtained from the culture were almostentirely diplococci, in part biscuit shaped, in part, round. While the authors doubt that these were gonococci, most will probably accept the case as positive. Vide Michaelis, Op. cit. and Thayer and Blumer. Johns Hopkins Hospital Bulletin, 1896, vii, 57. 112 Gonorrhoeal Septicaemia and Ulcerative Endocarditis REPORTER. SEX. AGE. HISTORY. AUTOPSY. REMARKS. (23) Michaelis. Zeitschr. f. kl. Med., 1896, xxix, 556. M 25 Gonorrhoea; 3 weeks later, arthritis; slight fever; no al- buminuria; 4 days later, sys- tolic murmur over aorta; dias- tolic sound not clear. Sudden death 10 days later. Gonococci in urethral discharge. Vegetative and ulcerative aortic endocarditis with per- foration. Pericardial and pleu- ral cavities showed abundant serous fluid with a few fibrin- ous flakes. Purulent cystitis. Characteristic gonococci in thrombi on valves, i. e. shape ; intracellular arrangement; de- colorization by Gram's method; failure to grow on attempts to cultivate on ordinary media. In all probability a pure gonococcal endo- carditis. (24) Keller. Deutsch. Arch. f. kl. Aled., 1896, Ivii, 387. M 25 Gonorrhoea; arthritis 4 weeks after; later pains in chest; chills; irregular intermittent fever; evidences of pulmonary endocarditis; pericarditis. Death 4 months after infection and 3 months after arthritis. Diagnosis: pulmonary stenosis and insufficiency. Increase in pericardial fluid which was made cloudy by the presence of fine flocculi. Vege- tative endocarditis of pulmon- ary valves and pulmonary ar- tery; myocarditis. Streptococci in cultures from pericardial fluid. In polypi on pulmonary valve streptococci were found; streptococci in kidneys. The author believes that this was a mixed infection through the urethra. (25) Hale White. Lancet, 1896, i, 533. M 19 Gonorrhoea; 3 weeks later, chills; irregular intermittent fever; anaemia; systolic and diastolic murmurs in pulmon- ary area; 5 weeks after infec- tion, acute nephritis; oedema. Two weeks later, death. Ulcerative and vegetative endocarditis of the pulmonary valve and artery. Acute ne- phritis; characteristic gono- cocci in vegetations on valves. These decolorized when treated by Gram's method. Cultures taken on agar, glycerine agar, broth and blood serum were without result. No cultures were made on serum agar. (These latter particulars were obtained in a personal commu- nication from Dr. Pakes.) The author remarks on the frequency of nephritis in ulcerative endocarditis, and be- lieves it to be a not uncommon cause of death. William Sydney Thayer and Jesse William Lazear 113 REPORTER. SEX. AGE. HISTORY. AUTOPSY. REMARKS. (26) Babes and Sion. Arch. d. Sc. Med. de Bucharest, 1896, i, 505. M ? August 5, gonorrhoea; 20 days later cystitis; epididy- mitis; purpura ; fever; chills; vomiting; splenic tumor. On September 2, aortic systolic murmur; albuminuria; diar- rlnea. Death October 14. lu blood during life Opresco saw cocci resembling gonococci and decolorizing by Gram; they were within leucocytes. Gangrene of skin over lower abdomen and genitalia; haem- orrhagic infarct of kidney; ulcerative aortic endocarditis. In the thrombi on valves or- ganisms similar to gonococci were found, decolorizing by Gram. On ordinary media saprophytes alone grew. No growths on beef blood serum agar. In spleen and kidney strepto- and staphylococci. They believe the case to have been gonor- ary streptococcus and rhoeal with a second- staphylococcus infec- tion. They seem to think that, the pus cocci having entered and caused a gen- eral septicaemia, the gonococci profiting by the diminished re- sistance of the organ- ism entered later and attacked the valves. (27) Stengel. Univ. Med. Mag., Phila., 1897, ix, 426. F 20 Had had valvular heart dis- ease, since rheumatism, at age of 7; gonorrhoea for a year (?); 6 days before entry into hos- pital diarrhoea; headache, vom- iting, tympanites; evidences of mitral stenosis; acute nephri- tis. Continued fever. Death after 32 days. Chronic endocarditis of mi- tral valve. Fresh ulcerative and vegetative endocarditis of mitral valve and part of auri- cle, particularly marked on an anomalous adventitious leaflet. Muco-purulent exudate in uterus and vagina. Cultures: Streptococcus from lungs and staphylococcus from right auricle and spleen ; endo- cardial vegetations negative. Characteristic gonococci were found in two thrombi on valves, mainly intracellular, decolorizing by Gram. No gonococci found in exudate in uterus or vagina. Deeper tis- sues not examined. 114 Gonorrhoeal Septicaemia and Ulcerative Endocarditis REPORTER. SEX. AGE. HISTORY. AUTOPSY. REMARKS. (28) Thayer and Lazear. Subject of present communication, read before XII International Congress in Moscow, 1897. Med. Record, 1897, lii, 497. M 19 Gonorrhoea 6 months before entry into hospital; several weeks later chill; 5 to 6 months later oedema of legs; subacute nephritis ; grave anaemia ; sys- tolic murmur; pericarditis. Death 1% months after infec- tion, about 6 months after onset of chills. Gonococci ob- tained three times during life from circulating blood. Diagnosis: gonorrhoeal sept- icaemia, endo- and pericarditis. Ulcerative and vegetative en- docarditis of tricuspid valve. Sero-purulent pleurisy and pericarditis; subacute haem- orrhagic and glomerular ne- phritis. Gonococci obtained microscopically and in pure culture on Loeffler's blood serum agar from heart's blood, pericardium and affected valves. All other cultures negative. This is the first case in which gonococci were obtained in pure culture before and after death from the blood, thus permitting a positive ante-mor- tem diagnosis of gon- orrhoeal septicaemia. (29) Rendu and Halle. Bull et. mem. Soc. med. de hop. de Par. 1897, 3 s.,xiv, 1325. F 30 Gonorrhoeal metritis; about 2 weeks later fever; night sweats; evidences of septicae- mia. Gonococcus isolated from uterine mucus. Phlegmon near elbow joint; intermittent fever; endo- and pericarditis about 5 weeks after onset of fever. Death 10 days later. In phleg- monous oedema at elbow gono- cocci " a l'6tat de purete " were found. Blood cultures negative. Vegetative endocarditis of aortic valve and of ascending aorta. Sero-fibrinous pericard- itis. Cultures from pleural and pericardial fluids negative. The bacteriological and histological examination of the aortic veg- etations showed the exclusive presence of gonococci. Were the gonococci obtained in pure cul- ture ? (30) Siegheim. Ztnchr. f. kl. Med. 1898, xxxiv, 526. F 20 Chills and fever and systolic murmur in tricuspid area in June; later, systolic murmur in mitral, and diastolic in aortic area; dyspnoea; irregular inter- mittent fever; chills. Death July 11. Cultures from blood on Kiefer's agar agar and pep- tone bouillon were negative. Ulcerative endocarditis of aortic valve; myocarditis; ne- phritis; purulent endometritis and cystitis. Cultures on Kief- er's agar from heart'sblood and vegetations negative. Micro- scopical examination of smear preparations from thrombi re- vealed organisms showing all the morphological and tinctori- al characteristics of gonococci. William Sydney Thayer and Jesse William Lazear' 115 REPORTER. SEX. AGE. HISTORY. AUTOPSY. REMARKS. (31) Lenharz. Berl. kl. Woch., 1897, xxxiv, 1138. F 19 Abundant vaginal discharge; symptoms of ulcerative endo- carditis of pulmonary valve. Death. Vegetative endocarditis of pulmonary valves. Character- istic gonococci in softened thrombi. These were obtained in pure culture. A piece of softened thrombus was intro- duced into the human urethra resulting in the development, after four days, of gonorrhoea with typical organisms. This case would ap- pear to remove all doubt as to the possi- bility of the existence of a true gonorrhoeal endocarditis. (32) Unpublished observation from the wards of Prof. Osler, Johns Hopkins Hospital. (Case observed by one of the authors- Thayer). M 38 Measles as a child; no other acute infectious diseases. En- tered hospital 20/vii/94. Has gonorrhoea with characteristic gonococci in discharge. For 3 weeks irregularly intermittent fever with chills. Physical examination: negative; heart sounds clear; apex impulse in 5th interspace, just inside mammillary line. Leucocytes 17,000 per cu. mm.; urine shows trace of albumin; no casts found. Irregular fever with severe rigors; left hospital unimproved on 2 / viii / 94. Urethral discharge and rigors stopped two weeks later; fever however continued. A few days after leaving hospital, stabbing pains in praecordial region, somewhat relieved by pressure over heart; dyspnoea. In latter part of October puf- finess of eyelids, frequency of (By Dr. Flexner.) Chronic and acute endocarditis (vege- tative and ulcerative) of the pulmonary valves ; deficiency of one segment; vegetation extending 3 cm. into the pul- monary artery; globular throm- bi in left ventricle; acute pneumonia; chronic diffuse ne- phritis. Coverslips from the thrombi on the affected valve show encapsulated dip- lococei; others biscuit shaped, resembling gonococci. On treatment by Gram's method some apparently decolorized, others did not. Characteristic gonococci in urethra. Cultures on ascitic fluid agar and Loeffler's blood serum from thrombi on affected valve, mitral valve, heart's blood, pleura, lung, kidney, spleen, liver and bladder all showed pneumococci. The clinical history suggests strongly that the original process was associated with the gonorrhoea, while the pneumococcus in- fection was a late sec- ondary event. The following note was made by Dr. Flexner : " Note.- Had the gonococcus been pres- ent it is probable that it would have been so obscured by the uni- versal presence of the the Diploe.pneumoniae that it could not have been detected." 116 Gonorrhoeal Septicaemia and Ulcerative Endocarditis REPORTER. SEX. AGE. HISTORY. AUTOPSY. REMARKS. micturition, purpuric eruption on legs. Re-entered hospital 7/xi.- Physical examination: puffi- ness of face; pulse of high ten- sion. Heart; apex impulse in 5th space 2 cm. outside nip- ple; slight to-and-fro murmur over pulmonary orifice, so su- peificial that it was believed to •be pericardial; purpuric erup- tion on legs and thighs. Urine: trace of albumin ; sediment: hyaline, granular, pus casts and renal epithelial cells. Blood: 13/xi; red corpuscles, 3,920,- 000; colorless, 31,200; haem- oglobin, 46$. 14/xi; diastolic murmur, heard by Prof. Osler in pulmonary area. Irregular fever disappeared on the 18th and t° was subnormal after- wards, excepting on the 21st, 22nd and 23rd. The dyspnoea increased, pneumonia devel- oped, and on 26 / xi the patient died. The day before death the leucocytes were 78,000 per cu. mm. Cultures from the blood, made by Dr. Blumer on 17/xi, were nega- tive. [Reprinted from Maryland Medical Journal, February n, 1899.] • MALARIA. By William Sydney Thayer, M.D., Associate Professor of Medicine in tjje Johns flop- kins University. AN ADDRESS DELIVERED BEFORE THE MARYLAND PUBLIC HEALTH ASSOCIATION, AT EASTON, ON NOVEMBER 10, 1898. Mr. President, Ladies and Gen- tlemen-To deal with a subject as large as malaria in an hour's talk is rather a difficult problem, and I trust that you will pardon me for the necessary incom- pleteness of my remarks. It has, how- ever, seemed to me that it might be of interest to this association to hear a few words treating particularly of the nature of the disease and the relation of its man- ifestations to the parasites which have been shown to be the exciting cause. It may also interest you to learn a little con- cerning recent observations which have been made with regard to the manner in which the disease is acquired. That fevers, commonly associated with chills which show a marked tendency to- ward periodicity, are common in warm, swampy and marshy regions has been known for centuries, and with the intro- duction of quinine* in the seventeenth century it was discovered that a large class of these fevers responded immedi- ately to treatment by this drug. That the terrh "malaria" became applied to this affection is an interesting indication of the views held by old observers as to the manner of origin of the disease. The word "malaria" . represents the ,two Italian words "mal' aria," signifying bad air. But while the term was at one time limited to fevers which yielded to treat- ment by quinine, it has since been ap- plied in a general way to all sorts of fe- brile and non-febrile conditions, many of which have, in reality, nothing to do with the clearly-defined disease which we now know as malarial fever. To com- plain, as is so common, that we suffer from "malaria" when we are tired, or have headache, or are "run down" from over- work, is about as rational a.proceeding as if we were to say that we had smallpox or diphtheria or measles. Malaria is, in fact, a disease as sharply defined and as easy of diagnosis as any of these affec- tions. For many centuries, indeed from a pe- riod before the Christian era, malaria has been supposed to be due to some animal or vegetable poison which entered the body with the drinking water or the re- spired air. But it was not until 1880 that the existence of a parasite causing the disease was definitely proven. Lav- eran, a French army surgeon, at that time stationed in Algiers, discovered that the blood of patients suffering with malaria contained living organisms which devel- oped within and at the expense of the red corpuscles. He considered himself jus- tified in assuming that these parasites were the cause of the disease, because they were invariably present in patients suffering from the affection and never found in other individuals, and, further, because they disappeared rapidly and synchronously with the subsidence of the symptoms of the disease under treat- ment by quinine. F'ive years after this Golgi, in Italy, followed later by a num- ber of other observers, described the life history of these parasites within the cir- culation. Studies in Italy, America, Rus- sia and Germany since then have shown that there are three distinct varieties of the malarial organisms-one in which the parasite passes through its complete *The crude cinchona bark was then used. 2 cycle of development in about seventy- two hours, the quartan parasite; one in which the cycle of development lasts about forty-eight hours, the tertian par- asite, and one in which the cycle of de- velopment is more or less irregular, be- ing completed sometimes within twenty- four hours, in other instances extending over a period of forty-eight hours or even more. This parasite, which is associated with fevers which in temperate climates occur during the later summer and fall, has been called the estivo-autumnal or- ganism. These several types of parasites have certain morphological differences which are easily recognizable by the skilled microscopist. The tertian and quartan parasites in their youngest forms are represented by small, colorless, hyaline bodies, which lie within the red corpuscles. These bodies show active ameboid movements. ' As they increase in size they develop small, dark-brown pigment granules, which are often thrown into active motion by the undulations of the protoplasm of the par- asite. The pigment is developed appar- ently from the disintegrated substance of the red-blood corpuscle. Eventually, at the end of seventy-two or forty-eight hours, according to the variety of the parasite, the red corpuscle is entirely filled by the organism, which is now ripe for sporulation. The pigment then gath- ers into a small clump or block at one point, usually in the middle of the para- site, which breaks up into from six to twenty or thirty small, clear, hyaline bodies. These are more numerous in the tertian than in the quartan organism. The red corpuscle having been entirely destroyed, the clear hyaline segments, which apparently represent young para- sites, are set free in the circulation and are ready to attack other red-blood cor- puscles. Golgi first pointed out the re- markable fact that in infections with the tertian or quartan parasite the organisms are present in great groups, almost all the members of which are at approxi- mately the same stage of development. Thus in infections with one group of the tertian parasite sporulation of the entire generation occurs within a period of a few hotirs every other day; in infections with the quartan parasite within a few/ hours every fourth day. The estivo-au- tumnal parasite passes through a cycle of existence similar to that of these other organisms, with the exception of the im- portant difference that the tendency to- ward arrangement in groups is much less definite, the parasites frequently be- ing present in the blood in all stages of development. Not all mature parasites, however, un- dergo sporulation. Some are observed to break up and become disintegrated, while others show an interesting change, which has given rise to much speculation and inquiry. From full-grown bodies there develop suddenly a number of ac- tively-motile filaments, which thresh about among the surrounding blood cor- puscles and not infrequently break loose from the mother cell, rushing through the field with lively serpentine move- ments.. These filaments have been called flagella. What is their significance? Two main views have been held. On the one hand, they have been considered stages in a degenerative process; while, on the other hand, some observers have believed that they represent forms in the life his- tory of the parasite destined to preserve its existence under conditions other than those with which it meets within the hu- man body. This is a view which, from analogy with what we know of other par- asites, is not unreasonable. It is well known that some parasites, after having passed through their .ordinary intra-cor- poreal cycle of existence, develop forms which, while within the host which they then occupy, are sterile, but which are capable when, owing to the death of the host or from any other reason they reach another medium, of undergoing further development, representing, then, the first stages of a second extracorporeal cycle oi the organism. I mention these possibili- ties now, for I shall come back to the subject later on in connection with some recent studies. * * * Interesting as are these facts with re- gard to the constant presence of the par- asite in patients affected with malaria one might naturally ask further: (i) Where and how do these parasites exist outside of the human body? 3 (2) How do they obtain entrance into the body-in other words, how do we be- come infected with malaria? In answer'to the first question we can only say, "We do not know." Analogy, however, with what we know of other parasitic organisms justifies us in believ- ing that the form in which the parasites live outside of the human body is entirely different from that which they assume after they have entered. With regard to the second question, "How does infection take place?" there has been much speculation. Three main ideas have been held: (a) That infection occurs through drinking water. (b) Through the inhaled air. (c) Through the bites of insects. The theory that infection occurs through drinking water is old and time- honored, and yet not only is the positive proof wanting, but there is considerable evidence against this hypothesis. The diagnosis of malaria is often, unfortunate- ly even today, loosely made, and when we examine the evidence advanced in favor of the water-borne theory of the disease we find that much of what has passed for malaria is undoubtedly typhoid fever, which, as we all know, is only too fre- quently acquired in this matter. Furthermore, many experiments have been made which tend to throw discredit upon the water-borne theory of the dis- ease. Marchiafava and Celli, Mariotti, Ciarocchi and Zeri have all tested the question by the administration of water from the most malarious districts about Rome by the mouth, by the rectum and as a spray to individuals, who have volun- tarily subjected themselves to the expe- riments. But though the experiments were in some instances continued through long periods of time, in all cases the re- sult was absolutely negative. Grassi and Feletti administered dew collected from the most malarious districts, but without effect. They even went so far as to drink fresh blood from an infected individual- blood which, if introduced hypodemi- cally, will always cause a transference of the infection. After all this it is but rational to con- clude that it is unlikely that infection oc- curs through the normal gastro-intesti- nal tract. This does not mean that the parasites may not exist and develop in stagnant water, entering the system in other ways. Indeed, there is some reason to think that this may possibly occur. One of the oldest theories in connec- tion with the disease has been that infec- tion occurs through the inspired air, and while no positive proof can be advanced in its favor it is hard for most to com- pletely abandon this theory. Many in- stances of malaria occur when almost every other method of infection can be ruled out. Yet, as has been before said, evidence proving that infection occurs through the lungs is wholly wanting. Of late years there has been a strong tendency to return to an old idea, namely, that the infection in malaria may occur in many instances at least through the skin, the parasite being introduced by the bites of some suctorial insect. As a matter of fact a sufficient number of individuals have subjected themselves to the experiment to prove that the dis- ease may always be transferred from an infected individual to a healthy man by intravenous or hypodermic inoculation of blood. The same type of fever and the same variety of parasites are reproduced in the individual wrho is inoculated. But especially interesting is the fact that within a few years several diseases in lower animals which depend upon the presence of a parasite in the circu- lating blood have been shown to be transmitted by the bites of insects. Thus Professor Theobald Smith of Boston, at that time connected w7ith the Bureau of Animal Industry in Washington, showed that Texas fever in cattle is due to the presence in the blood corpuscles of a parasite closely similar to that of malaria, and this parasite is transferred by means of the cattle tick. A disease of animals in Africa, known as nag'ana, is due to the presence in the blood of a parasite, which is transmitted by the bite of the tsetse fly. In man suspicion has fallen upon the mosquito, and, indeed, there is much evi- dence which goes to suggest that the mosquito may play a part in transferring the malarial infection. In the first place, mosquitoes invariably exist in malarious 4 regions, and malarial fevers are more prevalent at those periods when the mos- quitoes are most abundant; they are es- pecially numerous in regions about swamps and marshes, where the dangers of infection are greatest. In a malarious district there is greater danger of infec- tion at about sundown and at night, but sunset and night are periods at which mosquitoes are highly active. The dangers of infection are greater near the ground than in elevated positions, but mosqui- toes are more numerous near the ground. The danger of infection is greater on quiet nights than in windy weather, but wind is particularly unfavorable to the mosquito. Emin Pasha was so convinced that the bite of the mosquito played an important part in the etiology of mala- rial fever in Africa that he always trav- eled with a mosquito net, and escaped the disease. Bignami further has noted that in certain parts of Italy workmen who live in conical huts with a hole at the top, through which the smoke of their little fire passes, are unusually free from the disease, while those about them may be almost universally affected. Of course, the presence of smoke is one of the surest protection against mosquitoes. Koch, who last year devoted some months in Africa to the study of malaria, was strongly impressed with the proba- bility of this hypothesis. He says: "The more I study this disease the more I in- cline toward the opinion that the latter" (transference of the infection by means of the mosquito) "is the main, probably the only" (method). Wherever one goes he finds tropical malaria and the mosquito present together. On the coast (in East Africa) there are several places which are free from the disease. One of these is the island Chole, which lies upon the southern extremity of the Island of Ma- fia. "This is the only place on the coast where I could sleep without a mosquito net. In the mountains malaria stops at exactly that point where no more mos- quitoes are to be found. Inland malaria diminishes together with the mosquitoes. At those times of the year when there are many mosquitoes malaria is more se- vere." The natives of Usambara moun - tain often acquire the disease when they descend to the lowlands. They believe it to be due to the bites of mosquitoes, and call the disease by the same name which they give to the mosquito-"Mbu." Koch is, however, especially impressed by the analogy with Texas fever and other diseases of animals in which the parasites exist exclusively in the blood. This is an interesting and seductive hy- pothesis. If we pursue it further we are immediately confronted with the ques- tion, how may the parasite enter the mos- quito, and how may the mosquito intro- duce it into the human being? There are many possibilities in this connection. Let us consider what occurs in some other parasitic diseases. In Texas fever it is not the adult tick which transfers the parasites from one animal to the other. The adult tick feeds upon the par- asites which infect the blood; the para- sites live in some form within the tick, are transmitted to its descendants, and it is only upon beirrg bitten by one of a new brood of ticks that infection is ac- quired. Another way in which insects may assist in transferring the disease is shown by the behavior of the mosquito and the filaria sanguinis hominis. This nematode has been shown by Manson to enter and live within the muscles of the mosquito. The mosquito, dying, very often infects water, which, if ingested by human beings, conveys the contagion. Manson some years ago advanced the hypothesis that the mosquito might form an intermediate host for the malarial par- asite as well as for the filaria,.and that if mosquitoes were to bite infected individ- uals the organisms might continue to live in some form within the body of the insect, and, being set free upon its death, contaminate drinking water. Beyond the fact that the development of flagellate bodies has been noted in blood contained within the stomach of the mosquito, and that Ross in India has noted, in several instances, curious pig- mented bodies in the stomach wall of some insects, which had been fed upon the blood of infected individuals, no con- firmation of this hypothesis has as yet been obtained from the examination of human blood. Recently, however, observers have 5 turned their attention toward the para- sites in the blood of birds. Birds are sub- ject to infection with several varieties of organisms which are very closely analo- gous to the malarial parasites of men, and inasmuch as experiments of various sort§, impossible with the human being, may be readily carried out with birds, this field has seemed a particularly hope- ful one for investigation. Two years ago two of our students, Opie and MacCallum, made some in- teresting studies upon the blood of birds, confirming the observations of several other foreign students and noting certain further, as yet, undescribed feat- ures, of the avian parasites. And last summer MacCallum was fortunate enough to discover what is partial proof at least of Manson's hypothesis with re- gard to the flagella. While studying a certain variety of parasite in birds' blood he noted that whenever flagellation oc- curred some of the filaments, breaking loose from the mother body, rushed across the field to other full-grown parasites, parasites which Dr. Opie had previously noted were apparently incapable of flagel- lation. Single flagella might be seen to penetrate these full-grown forms. Only one filament ever succeeded in entering, though sometimes bodies of this nature might be seen surrounded by three or four flagella, which would butt their heads against them and, apparently, en- deavor in every way to make entry. Shortly afterwards the body which had been penetrated changed its shape into a long pointed! element, the pigment gath- ering at one end; it then became motile, advancing steadily across the field, de- stroying with its sharp point any red cor- puscles which were in its way. These ele- ments had previously been described by Danilevsky under the name of "pseudo- vermicules." This remarkable process, which has been repeatedly observed, can, from analogy, scarcely be other than an act of fertilization. The discovery may be said to have definitely shown that the flagella are not degenerate bodies. The further fate of the pseudo-vermicules MacCallum was, however, unable to dis- cover. He is inclined to suspect that they may be forms capable of develop- ment under other conditions than those offered in the body of the bird. There are numerous analogies in natural his- tory which tend to support this view. Within the last year Ross in India has carried out some excessively interesting studies which bear directly upon the manner of infection. Ross noted that the process of flagellation might occur in avian parasites as well as in those of hu- man beings within the stomach of the mosquito. Furthermore, he noticed, when working with a particular variety of the mosquito fed upon birds in- fected with the proteosoma (a spe- cial variety of parasite), that a cer- tain length of time after feeding, curious, large, pigmented bodies began to appear in the walls of the mosquito's stomach. The pigment of these elements was clearly derived from that within the parasites which had been taken into the body of the mosquito. These structures, which appeared in crops after every feed- ing of the mosquito upon infected blood, were observed to increase gradually in size, until finally, at the end of six days, they reached a very considerable diame- ter, nearly ten times that of a red-blood corpuscle. At this time, according to Ross, they protrude from the walls of the stomach into the body cavity of the mosquito. In some full-grown forms a curious radial striation was noted. Later Ross found that in cases where the large elements had ruptured,the body cavity contained great numbers of small spindle-shaped, rather flattened struc- tures, which he was able to prove had es- caped at the time of rupture of the mo- ther body. To these filaments was due the striated appearance above noted. After their escape from the mother body they circulate in the insect's blood. Ross also discovered the presence of two glands in the thorax of the mosquito, which consist of a number of plump cells arranged about ducts which finally unite, forming a common trunk opening into the proboscis-salivary glands which probably convey the poison of the insect. In the cells of these glands great num- bers of the filamentous bodies become accumulated. Suspecting that it might be by means of these structures that the 6 infection was carried from mosquito to bird, he exposed healthy birds to the bites of insects which had been fed upon infected birds at a period such that the filamentous bodies must be present in the salivary glands. The experiment was brilliantly successful. Ross was able, in almost every instance, to produce an in- fection considerably more severe than was the case in birds where the source of the infection was unknown. Indeed, some of the birds died of the disease- an unusual result. If, then, Ross' observations are accu- rate we have at last the demonstration that a parasite closely similar to the ma- larial organism in man may have two cycles of existence-one within its warm- blooded human host, and one taking place within the body of the mosquito which serves as an intermediate host, be- ing capable later of actually transmitting the disease .from infected to non-in- fected individuals. And when we follow these observa- tions step by step we cannot fail to be led to believe that the first stage in the pro- cess is fecundation, as observed by Mac- Callum. Ross has not as yet reported the manner of entrance of the parasites into the stomach-wall of the mosquito, but when we remember the extraordinary behavior of the pseudo-vermicule which arises from the fecundated parasite-its sharp point and the manner in which it is capable of piercing and destroying every- thing in its way-it would seem almost more than probable that it is in this stage that penetration of the intestinal wall takes place. Not the least interesting point brought forth by these observations is the sug- gestion that a patient infected with ma- laria may be, through the help of the mosquito, a source of contagion to those about him. * * * I have already spoken of the fact that three distinct varieties of the malarial parasite have been described. It is inter- esting to note that these three varieties are each in turn associated with a definite type of fever. The quartan parasite, it will be remembered, has a cycle of ex- istence lasting about seventy-two hours, and further possesses the remarkable characteristic that it is present in the blood of infected individuals in great groups, all the members of which are ap- proximately at the same stage of devel- opment. Thus, in infections with a sin- gle group of organisms sporulation oc- curs at intervals of seventy-two hours or every fourth day. It has been shown that the paroxysm in malarial fever is always associated with the sporulation of a group of parasites, so that in such an in- fection the chill occurs every fourth day. There is reason to believe that the im- mediate cause of the paroxysm is some poisonous substance set free by the para- sites at the time of their sporulation. The tertian parasite, as has been said, has a cycle of existence lasting about forty-eight hours, and here, in infections with a single group, sporulation and the resulting paroxysm occurs every other day. The tertian parasite is the com- monest variety in these regions. But you may, perhaps, say that the commonest form of ague in Maryland is that in which chills occur daily. How are we to explain this? Very simply. In the great majority of instances two groups of the tertian parasite are present-one segmenting perhaps on Monday and Wed- nesday, the other on Tuesday and Thurs- day, the result being a chill daily. The same may and does occur in infections with the quartan parasite if three groups be present, while in some instances, in in- fections with two groups, chills may occur on two successive days, with a day of in- termission between. Rarely infections with multiple gener- ations of the tertian and quartan para- site occur, resulting in irregular fever. It is also, curiously enough, rare for two groups to segment upon the same day. The result of all this is that in infec- tions with either of these varieties of par- asites the symptoms are remarkably reg- ular and periodical. This is not the case in infections with the estivo-autumnal organism. Here the cycle of existence varies very much in different cases, oscillating all the way from twenty-four to forty-eight hours, or even more. In addition to this, the ten- dency to the arrangement of the para- 7 sites in groups is also much less marked. So that while regular paroxysms may oc- cur at intervals of twenty-four or thirty- six or forty-eight hours, the fever is often irregular or continuous. This is the form of parasite which is associated with the so-called remittent fevers which oc- cur at the height of the malarial season. * * * It may not be amiss to say a word be- fore closing with regard to the amena- bility of these different forms of fever to treatment. All types of malaria yield to treatment by quinine. One may meet with malignant infections so severe that death occurs within twenty-four or forty- eight hours, before quinine has had the proper time to act, or where the par- oxysms 'which have occurred have re- sulted in such injury to the human or- ganism that, despite the disappearance of the parasites, death may ultimately fol- low; but the infection always yields to quinine. Relapses, however, may and frequently do occur. There are many in- dividuals who treat themselves with a few doses of quinine at the time of their paroxysm, who have at more or less reg- ular intervals of one, two or three weeks recurrences of the infection. This may go on for months or years, resulting in very material-danger to the health and constitution of the individual. But the immediate attack will always yield rap- idly to quinine, and if treatment is prop- erly continued the danger of relapses is slight. It is perfectly safe to say that any fever in these regions which does not break after four days' treatment by qui- nine, properly^administered, is not sim- ple malaria. I have seen cases of malaria in which slight fever, strictly speaking, lasted longer than four davs. Occasionally in severe cases a slight ele- vation of temperature may last for some time after the infection has disappeared, but the marked manifestations are always broken within a few days. It is a fact that continuous fever, non-resistant to quinine, is not malaria, and observations with modern methods are showing us that the great majority of the cases which have been previously classed as malarial fevers, resistant to quinine, are really in- stances of typhoid fever. But I have already taken more of your time than I had intended to, and I will come to a few general conclusions: (i) Malarial fever is a specific infec- tious disease, due to parasites which ex- ist in the blood of the infected individual in great groups and give rise to par- oxyms at the periods of their sporula- tion. (2) There are three varieties of mala- rial parasite-one associated with quar- tan fever, one with tertian and one with paroxyms which occur usually about forty-eight hours apart, but occasionally at more frequent intervals, while often the fever is irregular or continued-the estivo-autumnal parasite. (3) Either of the first two varieties of parasite may also give rise to quotidian fever, owing to the presence of multiple groups of organisms undergoing sporu- lation on successive days. (4) The paroxyms in infections with the tertian and quartan parasites are usu- ally regularly periodical in their time of onset. In infections with the estivo-au- tumnal organism they are often irregular and associated with continued fever. (5) We do not know how the parasites live outside of the body or how infection takes place. (6) Experiments tend to show that it is improbable that infection occurs through the gastro-intestinal tract. It is possible, though not proven, that it may occur through the respiratory apparatus or through the skin, being introduced by the bites of insects, especially the mosquito. By analogy with the course of events in similar infections in birds it is highly probable that the mosquito may play the part not only of an intermediate host of the malarial parasite, but also of a direct transmitter of the infection from one in- dividual to another.* (7) Quinine, properly administered, is a true specific against the disease. (8) Relapses may occur after weeks or months, but they are in turn amenable to treatment. ♦Since the delivery of this address, studies hy Grassi, Bignami and Bastianelli in Ita'v with the parasites of human beings have entirely con filmed the observations of Ross on the narasites of Urds. The entire extra- corporeal cycl- of existence of one of the human malarial parasites has been followed within the intestinal wall and salivary gland of the mosquito, and infection by means of the bites of such mosquitoes has been produced. INFECTIOUS DISEASES, INCLUDING CROUPOUS PNEUMONIA. By WILLIAM SYDNEY THAYER, M.D. MALARIAL FEVER. Etiology and Manner of Infection. During the last year interest- ing observations have been made bearing upon the etiology and manner of infection in the malarial fevers. Indeed there is reason to hope that in the near future the problem of the extra-corporeal existence of the malarial parasite and its manner of entrance into the body will be solved. Since the discovery in recent years of the fact that Texas fever and Nagana, or the Tsetse-fly disease, are transferred by means of suc- torial insects, there has been a more or less general tendency among those particularly interested in the subject to return to the old idea that malarial fever may, in some instances at least, be transmitted by the bites of mosquitoes. Surgeon-Major Ross,1 of the Indian medical service, has, within the last year, published some remarkable observa- tions. Following the suggestions of Manson, who has, as is well known, repeatedly advanced the hypothesis that the flagella of the malarial para- site represent bodies intended to preserve the life of the organism outside of the human body, Ross studied the behavior of the parasites in the blood within the stomach of mosquitoes fed upon infected human beings. In the tissues of the stomach-wall of several mosquitoes which had fed upon patients suffering with sestivo-autumnal fever, peculiar oval pig- mented cells were found. The pigment was altogether like that in the malarial parasite, and these bodies were found only in several mosquitoes which had been fed upon the blood of malarial patients. Similar bodies were found on one occasion in the stomach of a gray mosquito which had been fed upon the blood of a patient with tertian malaria. Ross then proceeded to investigate the blood of birds, and succeeded in identifying the same varieties of parasites which had been previously described by 1 Report on the Cultivation of Proteosoma Labbe in Gray Mosquitoes. Calcutta, 1898. 281 282 INFECTIO US DISEASES. LabbS, Opie, MacCallum, and others. After feeding a particular variety of insect, which he termed the gray mosquito, upon the blood of birds containing mature proteosoma, Ross always found on the second day peculiar pigmented bodies embedded in the stomach-wall. The pigment contained in these elements appealed to be similar to that observed in the parasites previously present in the blood within the stomach. These bodies gradually grew until, on the sixth day or later, they reached a diameter of nearly 70 micromillimetres, the pigment in the mean-time disappearing. At this stage the bodies protruded from the wall of the stomach into the body cavity. There were two varieties of these elements, one more or less hyaline, the other vacuolated. They both contained a certain number of small glistening fat-like drops. Within some of these older bodies he noted a peculiar striated appearance, while within others there were ten or eleven curious black sausage-shaped structures. That the appearance of these bodies depended upon the ingestion of infected blood was apparently beyond doubt. No such elements were ever found in mosquitoes fed upon non-infected individuals, while in repeated experiments Ross was able to trace the appearance of fresh groups after feeding upon infected birds. He expresses his conviction in his first report that these studies go to prove Manson's theory that the mosquito is the intermediate host of the parasite. Manson,1 and later Ross,2 give a most interesting account of further experiments in this direction. Ross noted that in some instances the coccidia-like elements, which were protruding from the stomach-wall into the body cavity, ruptured, setting free great numbers of minute spindle-shaped, somewhat flattened bodies from 12 to 16/z in length by about 1/z in breadth. This rupture occurs apparently on the eighth or ninth day. He was able to satisfy himself that it was to the presence of these that the striated appearance of the ripe " coccidium " was due. By examining the blood of mosquitoes at a time when such rupture might reasonably be supposed to have occurred, great numbers of these filaments were found in the circulation. Further, Ross discovered a gland which has, apparently, heretofore escaped the notice of biologists. " This organ lies in the neck or ante- rior part of the thorax of the mosquito, and consists of a number of sepa- rate lobes. Each lobe is made up of numerous large cells clustered around a central duct and contained within a limiting membrane. The 1 The Mosquito and the Malarial Parasite. British Medical Journal, 1898, vol. ii. p. 849. 2 Preliminary Report on the Infection of Birds with Proteosoma by the Bites of Mos- quitoes. Nowgong, Assam, October 11, 1898. MALARIAL FEVER. 283 ducts of the several lobes ultimately unite and form a single main effluent. This runs up the under surface of the head in the middle line; enters the base of one of the stylets or lancets of the proboscis, namely, the cen- tral unpaired one, called the tongue or epipharynx ; traverses the whole length of it and opens at its extremity in such a manner that the secre- tion of the gland must be poured into the very bottom of the wound made by the piercing apparatus of the proboscis." In many of the clear plump cells composing these glands, in mosquitoes which had been fed upon malarial blood and preserved a sufficient length of time for the coccidia-like bodies to ripen, Ross found a great accumulation of the thread-like elements. Their appearance is similar to that presented by the groups of bacilli in the lepra cell. Suspecting that this organ represented a veneno-salivary gland, and that through its ducts the thread-like bodies, which he had come to believe might represent the infectious agent, might enter the bitten individual, Ross proceeded to interesting and apparently convincing experiments. Feeding mosquitoes on proteosoma-infected sparrows and keeping them more than a week until, as he knew from experience, the small rod- like bodies were present in the veneno-salivary glands, he allowed the insects to feed upon the blood of non-infected sparrows. The result of these experiments was most interesting. In 22 out of 28 birds, after an incubation period of from five to nine days, the sparrows developed an intense infection, considerably more severe than he had previously observed when the source of infection was unknown. Indeed, in the majority of instances, the birds died, an unusual result. In four weaver birds and in one of two crows a similar result was obtained. The function of the black "spores" is as yet unknown. While con- firmatory researches remain to be made, Ross's experiments seem to have been carefully carried out, and appear to show that in infections with a parasite very closely allied to those of human malaria, the mosquito may not only play the part of an intermediate host, but, further, be the direct conveyer of infection by means of its bite. If this be true with the proteosoma in birds, there is good reason to believe that similar conditions exist in connection with the malarial para- sites of human beings. It is interesting in this connection to note that Koch' expresses his conviction that this is an important and common means of infection. In his own words : " The more I study this disease, the more do I incline toward the opinion that the latter (method of infection), by means 1 Arbeiten aus dem Kaiserlichen Gesundheitsante, 1898, xiv. 299 ; also Keise-Berichte iiber Rinderpest, Bubonenpest in Indien nnd Afrika, Tsetseoder Surrakrankheit, Texas- fieber, tropische Malaria, Schwarzwasserfieber. Berlin, 1898. 284 INFECTIOUS DISEASES. of the mosquito, is the main, probably the only, one. Wherever one goes he finds a relationship of both place and time between the presence of tropical malaria and the mosquito. On the coast there are several regions which have the reputation of being free from malaria, among which is the island Chole, which lies at the southern extremity of the large island Mafia. I have visited this island, which was formerly used by Zanzibar Arabs as a health resort. It is the only place on the coast where I was able to sleep without a mosquito net. In the mountains malaria comes to an end just where the mosquitoes disappear. As one passes inland, malaria and the mosquitoes disappear together. At those times of the year when there are many mosquitoes malaria is more severe." One of the most interesting observations in this connection is that concerning the negroes of Usambara Mountain, who are frequently attacked by malarial fever when they come down to the lowlands. They call the malady 11 Mbu," and if one asks them how they have acquired the disease, they say that there were insects in the lowlands which are called by the same name as the disease, " Mbu "-that is, mosquito; that these had bitten them, and thus they have acquired the disease. In Nuttall's1 review of the subject, he states that Riibner has told him that this idea is popular in the southern Tyrol, while Lustig asserts that the same is true in Italy. Koch is particularly impressed, however, by the analogy between malaria and Texas fever, as well as other tropical diseases of men and beasts the parasites of which are found exclusively in the blood. In all of these diseases infection is conveyed by means of suctorial insects. While Ross has been making his brilliant studies in India the Italians have not been idle. Dionisi2 carefully examined the proboscides of mos- quitoes, but was unable to find any bodies resembling parasites either on the proboscis or in the drop of saliva often present. He then deter- mined the fact that mosquitoes do bite birds,3 provided any part is bared of feathers, and that in mosquitoes fed on infected birds the parasites rapidly become irrecognizable in the intestinal contents. He was unable to infect birds with mosquitoes from malarial regions. He notes, also, the interesting fact that the haematozoon infections in pigeons occur at 1 Hygienischen Rundschau, 1898, vol. viii. p. 1084. 2 Policlinico V.-M., 1898, 419. 3 Ross does not state at what points his birds are attacked by mosqui'oes. There is, however, nothing in his publications to suggest that any especial preparations need be taken to render the birds subject to attack. In this connection it may be interesting to note the observation of a friend of the reviewer that a pet canary was severely bitten about the legs and feet last summer. The legs were found to be much swollen and the bird appeared to be suffering. The cause of the condition was, however, not apparent until a mosquito was discovered in the act of biting. Protection by a netting was followed by speedy recovery. MALARIAL FEVER. 285 just the period of moulting, a fact tending to support the theory of mosquito infection. At the same time Grassi1 has made some important researches con- cerning the relation of different varieties of mosquitoes and gnats to malarial infection. As a result of a careful study of the different varie- ties of mosquitoes observed in malarious and non-malarious localities, he has discovered three species of insect which are constantly found in mala- rious regions and are absent in healthy localities. The association of these three mosquitoes with malaria is so surprisingly definite and con- stant that the author asserts " that after all the facts which have been stated, all the objections which could be made to the mosquito theory fall, and we may, on the other hand, assert that it explains all the phe- nomena of malaria. . . ." One of the varieties of mosquito, the Anopheles claviger, is, apparently, definitely associated, both in the localities in which it occurs and the time at which it bites, with tertian malaria, while the other two varieties, the Culex penicillaris and the Culex malarias, (a new species so named by Grassi), occur apparently, invariably, in the localities and at the times of year in which the aestivo-autumnal fevers predominate. The author states: "In conclusion, I am of the opinion that the Culex penicillaris and the Anopheles claviger, at least the Culex penicillaris, perhaps also the Culex malarias, behave in malaria as does the tick in Texas fever. One must bear in mind that very few paludal gnats and mosquitoes ('Zanzare e zanzarone palustri') can be infected with malarial parasites, and in fact the greater part of them bite domestic animals (oxen, horses, hogs, dogs, pigeons, hens) and healthy men. It may be, therefore, that a single bite of a paludal mosquito or gnat (' Zanzarone o di zanzere palustri') may cause malarial infection, just as it may be that a myriad of bites may fail to cause it." At the same time-independently of Grassi-Bignami2 had started experiments to test the possibility of infection by the bites of mosquitoes collected from malarious districts. First a patient was exposed for sev- eral days to the bites of mosquitoes gathered at Porto ; but as they were too scanty, he continued the experiment with two patients in a different manner. The mosquito larvae were collected from the same region, and were allowed to develop in a chamber in which the patients were after- ward exposed. The result was again negative. Later, hearing of Grassi's experiments, he obtained adult mosquitoes from Maccarese, a most malarious district, letting them loose in a room and allowing an individual to sleep in the same chamber, as a result of which he was frequently bitten. This patient was a young man who had never had 1 Policlinico, 1898, V.-M.,469. 2 Lancet, 1898, ii. 1461, 1541. 286 INFECTIOUS DISEASES. malaria in his life and had lived six years in the Santo Spirito Hospital where no autochthonous case of malaria had ever been known to develop. The patient slept in the room from September 26th until the last of October, though at various times there were but few mosquitoes present. On October 31st he had a slight elevation of ■ temperature ; on November 1st a chill, and afterward remittent fever up to the administration of quinine on November 3d. On the morning of November 3d characteristic sestivo-autumnal parasites were found in the blood. The author believes that infection from other sources than from mosquitoes can be absolutely ruled out. Specimens of the mosquitoes from each batch were saved and exam- ined by Grassi. All the mosquitoes examined from those hatched from larva; were found to be of the species Cider pipiens, and, according to Grassi, "It may be taken for granted that when experiments were made with the mosquitoes hatched from larvae collected in the Cam- pagna the insects obtained would be the Cider pipiens, because the larvae of this species are found in great swarms and, in consequence, are easy to collect; while larvae of the other species are found with greater difficulty and not in swarms. One cannot absolutely exclude the possi- bility that infection occurred in one of the earlier periods, but it is not probable." Specimens were sent to Grassi from every batch of the mosquitoes used in the last experiment, and among these he found the Cuter peni- ciUaris, the Culex malarice, and the Anopheles claviger; but this last only in one batch, and scanty in that. In other words, the mosquitoes to which the positive infection appeared to have been due were exactly those varieties which Grassi had found to be associated with eestivo-autumnal malaria. Bignami then discusses the question as to whether malaria is con- tracted by inoculation only. "So much is certain, viz., that inoculation is, up to the present, the only means for which experimented demonstration has been obtained. ... I believe it may be safely affirmed that all the facts known up to the present, regarding the biology of the parasites allied to those of malaria, favor the idea that infection is conveyed in only one way and introduced by only one method. ... To sum up, malaria is a disease which is contracted by inoculation-a fact of which we have now obtained the first experimental proof, since we have seen that an individual, who has never had malarial fever, by sleeping in a healthy place where no one had ever previously taken fever, may sicken of malaria of a grave type if bitten by certain species of the mosquito brought in the adult state from some distant locality of highly malarious character. Further, everything points to the conclusion that inoculation is the only mode by which infection is acquired, since air and MALARIAL FEVER. 287 water as carriers of infection may be excluded, and because arguments based on analogy all tend in the same direction. This much at any rate we can assert, namely, that inoculation is the only mechanism of infec- tion which has been demonstrated experimentally." Finally, Bastianelli, Bignami, and Grassi1 have made a most interest- ing report upon the cultivation of the malarial crescents of man in the Anopheles claviger. They assert that they have positively followed cer- tain phases of development of the semilunar bodies, in the wall of the middle intestine, of several specimens of the Anopheles claviger which had been fed on individuals suffering from aestivo-autumnal malaria. The most marked phases correspond to those described by Ross in his experiments with the proteosoma of birds (stage seen on the second and third day). They collected from a room in which four malarial patients, all probably suffering from aestivo-autumnal fever, were lying, six speci- mens of Culex pipiens, one Anopheles nigripes, four Anopheles claviger. In two of the last variety they found stages of further development corresponding to those of the fourth day found in the mosquitoes fed upon proteosoma by Ross. They believe that these mosquitoes are similar to Ross's dappled mosquito, in which he found stages of develop- ment similar to those of the proteosoma on the third day. Attempts to cultivate the parasites of owls and of pigeons in the Anopheles claviger were negative. They note that in Lentini, in Sicily, last October and November, when there was still danger of malaria, neither the Culex penicillaris nor the Culex malarue were to be found, but the Anopheles claviger was, on the other hand, extraordinarily abundant. And finally they note that they have obtained a characteristic double tertian malaria as a result of the bite of the Anopheles claviger (about 100 mosquitoes taken in the houses of Maccarese) in a man who was certainly not suffering from malaria and who lived in a non-malarious district. 'They have, moreover, confirmed the results of the preceding cultures and have obtained further stages of development of the crescents in the intestinal walls of the Anopheles claviger. " Moreover, in one individual of the same species, taken in a room inhabited by a man probably affected by aestivo-autumnal fever, there were found stages in which the process of sporulation was already advanced." If we may accept these experiments of Bignami et al., which, to say the least| are most suggestive, as positive proof of the inoculation theory of malaria, there remains yet the question as to how the infected 1 Reale Accademia dei Lincei. Estratto dal vol. vii., 2° sem, serie 5a, fasc. 11°. Seduta del 4 dieembre, 1898. 288 INFECTIOUS DISEASES. mosquito has acquired the malarial parasite. Does the mosquito form an intermediate host for the parasite in man, as Ross has appar- ently shown to be the case in birds, and as is suggested by the last- mentioned observations, or do the larvae possibly acquire the parasites outside of the human body, or, perhaps, may both of these conditions occur ? Not the least interesting feature of these observations, especially those of Ross, is the possibility which is suggested, that one individual infected with malaria may, through the intermediate action of mosqui- toes, prove to be a more or less direct source of contagion to those about him. Congenita i. Malaria. Bignami1 discusses the question of the possibility of the existence of congenital malaria. He reports a new case of a woman who, having had frequent attacks of malarial fever during pregnancy, died in a pernicious paroxysm. While the maternal blood and organs showed the usual changes, yet the organs and blood of the foetus were quite normal. In the absence of a single satisfactorily proven instance of the trans- mission of parasites from mother to foetus, he expresses his doubts as to the possibility of such an occurrence. Flagella of Malaria. Many important suggestions in connec- tion with human malaria are contained in the valuable papers of Opie2 and MacCallum.3 Of especial importance is the remarkable discovery of MacCallum, that in infections with the halteridium the flagella repre- sent sexual elements. Certain of the flagella, after breaking loose from the mother body, may be observed to penetrate other parasites which later take on the form described by Danilevsky as the pseudo-vermic- ulus. MacCallum's conclusion, that this represents a process of fertili- zation probably the first step in another cycle of existence of the parasite, seems most probable. In two instances a similar penetration has been observed in human beings in cases of aestivo-autumnal malaria. One of the most important results of this observation is that it would appear to settle the question as to the degenerate or non- degenerate nature of the flagella. The flagella are certainly not degen- erate elements. It is interesting in this connection that Bastianelli4 has just published the results of careful studies of the minute anatomy of the crescentic and flagellate forms. He has been able to prove the fact that crescents do contain chromatin substance. The flagella arise probably from the nucleus of the parasite, and generally contain a central filament of 1 Suppl. al Policlinico, 1898, vol. iv. 76 B. 2 Journal of Experimental Medicine, 1898, vol. iii. p. 80. 3 Ibid., pp. 103, 117. 4 Lancet, 1898, vol. ii. p. 1620. MALARIAL FEVER. 289 chromatin substance surrounded by a thin layer of protoplasm, prolonged to both extremities. Occasionally, where an isolated filament was found, it appeared as if the chromatin substance occupied the centre, while the two extremities consisted of protoplasm. Rarely filaments were found in which no evidence of chromatin substance could be made out. Bastianelli notes the fact that those who believe the flagellate bodies are not degenerate forms will hail this observation as a support for their theory. But he observes that it must not be considered irrec- oncilable with Bignami's oft-repeated opinion that the crescents from which these bodies develop are sterile elements .so long as they remain in the human body. Symptoms and Types of Fever. Solley and Carter1 have made a careful study of eighty-seven cases of malarial fever occurring in New York City during the season of 1897. Tertian fever, as might be expected, is by far the commonest form in New York. They met, how- ever, with several cases of sestivo-autumnal infection. No cases of quartan fever were studied. Of 85 cases of tertian fever, 55 were single and 30 double infections. In several instances infections with the tertian parasite treated with qui- nine became irregular, and the authors point with justice to the fact that this is a not uncommon cause of more or less irregular fever in cases of infection with the tertian organisms. Their investigations lead them to conclude that this is due to partial destruction of the parasites present in the blood and to a derangement of their regular grouping. Tn one instance irregular fever was noted from the primary presence of multiple groups of parasites. The two instances of sestivo-autumnal fever which came under observation appear to have been cases in which the cycle of the parasite lasted approximately forty-eight hours. Koch2 comes to the conclusion that sestivo-autumnal fever occurs, as a rule, in tertian paroxysms. Gautier3 has published a brief summary of his valuable work, O parazitie Laveran'a, which appeared in Moscow in 1896. He dis- tinguishes three distinct varieties of fever and as many separate forms of the parasite, the tertian, the quartan, and a third organism correspond- ing to the sestivo-autumnal parasite, which he calls the small two days' parasited In the sixty-two cases he failed to observe a quotidian form of sestivo-autumnal fever due to an organism whose cycle lasts twenty- four hours. Perhaps the most valuable part of Gautier's work consists 1 The Malarial Fevers of New York City. Medical and Surgical Report of the Pres- byterian Hospital in the City of New York, 1898, vol. iii. p. 89. 2 Op. cit. 3 Zeitschr. f. Hyg. und Infectionskrank., 1898, xxviii 439. 4 Gautier terms the quartan organism the "three-days' parasite," the tertian, the "two- days' parasite." 290 INFECTIOUS DISEASES. in a more careful study of the minute structure of the malarial parasite. Only part of the author's beautiful plates have been reproduced in the German publication. I have had the privilege of studying some of Gautier's own preparations, and can only state that, remarkable as are the reproductions, they fail to do justice to the originals. Zieman, in his excellent work,1 also distinguishes but three types of fever, and doubts the existence of more than one variety of the sestivo- autumnal parasite. In his own words : "At all events it is wisest, as we have already done, to include all the described small parasites for the present in a single group, though admitting variations in the length of the cycle of development from about twenty-four to forty-eight, pos- sibly as much as seventy-two hours. Cases with a cycle of develop- ment shorter than twenty-four hours I have not seen." Ue agrees with Gautier and the reviewer in believing the usual cycle of the aestivo- autumnal parasite to be about forty-eight hours. In view of the almost universal recognition of the existence of at least three types of the malarial parasite, the tertian, quartan, and the aestivo- autumnal or tropical organism, it is interesting to find that Laveran2 still holds to his doctrine of the unity of the malarial parasite. After dis- cussing the question as to the existence of a special parasite of tropical malarial fever, he concludes : "1. In patients who have contracted paludism in tropical countries, and who have had relapses after their return to Europe, there are to be found in the blood the same parasites as in those who have contracted the fever in temperate climates. " 2. There is no special parasite which causes the malarial fevers in tropical countries. " 3. The differences in appearance which have been described by some observers between the haematozoon of the tropical countries and that of our climates depends chiefly on the fact that the parasite, finding in trop- ical -countries a very favorable medium, has in newly infected subjects a more rapid evolution than in countries with a temperate climate. As soon as the conditions change the evolution of the parasite becomes normal." M. A. Brown has studied twenty-eight cases of malarial fever occur- ring in the Cincinnati Hospital. Two of these instances were combined infections, one with both quartan and tertian parasites, one with tertian and aestivo-autumnal. The author insists upon the rarity of malaria originating in Cincinnati. He is of the belief that the great majority of these cases arise elsewhere. 1 Ueber Malaria und andere Blutparasiten, etc. Jena, 1898. 2 Archives de Parasitologic. Paris, January, 1898, t. 44. MALARIAL FEVER. 291 Duggan' notes the difference between the aestivo-autumnal parasite as studied in West Africa and the ordinary tertian organism. Daubler2 was able to identify in East Africa two main varieties of parasites, the small (aestivo-autumnal organism) and the larger, more pig- mented forms, the tertian and quartan organisms. The aestivo-autumnal parasite has been found responsible for the greater part of the severe malaria contracted by our army in Cuba. Ewing, at Camp Wikoff,3 noted the fact that infections with more than two generations of parasites were rare. The cerebral type of malaria was common. He made the interesting observation, which has already been commented on by the Italian students, that after severe malaria the anaemia and prostration may become steadily worse, even after the disappearance of the organisms from the blood. Ewing usually found numerous crescents in the comatose cases, and he is of the opinion that the coma is probably referable to some embolic process. In a consider- able number of mild paroxysms with slight rise of temperature, associ- ated with restlessness or vomiting, young crescents were found in abun- dance, leading him to suspect that the presence of these organisms was responsible for the occurrence of many of the acute phenomena of malaria. Buckingham4 has studied 130 cases in the Boston City Hospital. He notes the fact that the absence of the chill in the paroxysm was rather the rule than the exception. Not infrequently comatose paroxysms, with fatal exit, were seen, the exacerbations occurring extremely suddenly. Dangerous paroxysms occurred in some instances after convalescence was apparently established. So frequent are relapses that the author states : " In private practice I should have it understood that if a man goes into the street unattended, within ten days of a severe manifestation of aestivo-autumnal malaria, he does it at his own risk. If he must go, it should be with an attendant prepared to inject quinine subcutaneously if necessary (!)." Maxwell5 reports two cases in which epileptiform convulsions occurred during the supposed malarial paroxysms. The fever and convulsions disappeared immediately under quinine. No blood examinations were recorded. Sequelae and Complications. Considerable literature has appeared during the past year upon the so-called " malarial haemoglobin uria " or haematuria. Koch6 studied sixteen cases of " black-water fever " in Ger- man East Africa, three of which, or 19 per cent., died. In two of these 1 British Medical Journal, 1898, i. 139. 2 Berlin, klin. Wochenschrift, 1898, xxv. 96, 123. 3 Medical Record, 1898, liv. 494. 4 Boston Medical and Surgical Journal, 1898, cxxxix. 433. 5 Medical News, 1898, Ixxiii. 338. 6 Op. cit. 292 INFECTIO US DISEASES. cases death occurred from obstruction of the urinary tubules by clotted hemoglobin. In the third case death occurred during the attack from the excessive destruction of blood-corpuscles. In only two of these cases was Koch able to find the malarial parasite. He found no other organisms. In two instances, one of sestivo-autumnal and one of tertian malaria, the paroxysms followed closely upon the administration of qui- nine, and the other fourteen cases, Koch believes, " must in all proba- bility be regarded as instances of quinine poisoning." He believes that there exists in these subjects an especial idiosyncrasy to quinine. Mala- ria, he thinks, was in most instances not responsible for the process, pig- ment having been absent from the liver and spleen in both cases which came to autopsy. It may be interesting to quote his own words: "Although I have met with no cases of black-water fever in which quinine poisoning is excluded, yet I should hesitate to go so far as to assert that every case of black-water fever is a quinine intoxication ; but that quinine poisoning plays a very important role in the etiology of black-water fever is, as a result of my investigations, no longer to be denied. One must, in the future, decide before everything else in cases of black-water fever whether it is or is not a quinine intoxication, and, if this is to be positively shut out, whether other substances introduced into the body in some way or other, in food or drink, may not have an action similar to that of quinine. It is, however, readily conceivable that a man in whom this remarkable idiosyncrasy against quinine has developed, might react, with hemoglobinuria, toward other substances which up to this time he has borne without ill effect. " Only when such possibilities have been entirely shut out is it reason- able to investigate the remaining, possibly very small, number of cases of black-water fever with regard to other etiological possibilities. More- over, it will also be very important to settle the question as to how the idiosyncrasy toward quinine arises in the tropics and whether it is not possible to remove this where it is present. It is probable, however, that this condition depends upon some appreciable changes in the consti- tution of the blood. In this connection it is certainly not an accident that black-water fever occurs almost only in men ; women and natives are only exceptionally affected by it. "If, however, it should be impossible to solve this riddle, this much is positive, that the treatment of black-water fever with quinine must absolutely cease, and that in patients with malaria who already have had an attack of black-water fever, quinine should be given with the greatest care, or, rather, should be replaced by other means." Koch does not lay stress in his communication on the fact which is universally insisted upon by others, namely, that these tropical hemo- globinurias are always or almost always preceded by repeated attacks of MALARIAL FEVER. 293 malaria. He appears to think that the injudicious use of quinine as a prophylactic measure may, of itself, account for many instances of black- water fever. Tsakyroglon1 reports two cases of fatal haemoglobinuria : one came on with the second, apparently malarial, paroxysm without any previous history of the disease, the other occurring, as usual, after repeated attacks. Both resulted fatally despite the use of quinine, and the author concludes that quinine plays no role in the pathogenesis or treatment of this disease. Woldert,2 in an article upon the use of quinine in malarial haemoglo- binuria, expresses his opinion that the drug has rarely any influence on the production of this symptom. Clarac4 notes, as do nearly all authors, that in almost all, if not in all cases the haemoglobinuric paroxysm is preceded by premonitory attacks of malarial fever. He has never seen haemoglobinuria last more than five days, and if there was not total anuria, the gravity of the attack was in direct relation to the extent of the haemoglobinuria, which in medium cases ends in three days. He has never seen intermittent haemoglobin- uria, and believes that this symptom may sometimes be due to quinine. He distinguishes three distinct types of haemoglobinuria : 1. Endemic haemoglobinuric fever. 2. Paroxysmal haemoglobinuria. 3. Quinine haemoglobinuria. The first and third of these forms are always preceded by malarial attacks, and he is inclined to believe that preceding malaria may dispose toward paroxysmal haemoglobinuria. He thinks, however, that it is unusual for actual acute malaria to be the. direct exciting cause of an haemoglobinuric attack, for haemoglobinuria in Dakar is especially fre- quent between December and April-that is, at a time when paludism has begun to disappear or has disappeared. It is not, he says, " la plus haute manifestation du paludisme," for if it were it should be more frequent at the time when the pernicious paroxysms are most common. He is inclined to believe that the season (cold) has a predisposing influ- ence. He has never seen haemoglobinuria in colored patients. In twenty-seven carefully studied cases he is positive of the important pre- disposing influence of malaria, but believes that this cannot explain all the cases. He acknowledges the possibility that the process may be due to a special variety of the parasite. Doering4 met with 40 cases of black-water fever out of 169 cases of malarial fever in Kamerun. 1 Allg. Wiener med. Ztg., xliii. 246. 2 Medical News, 1898, Ixxii. 547. 3 Ann. d'Hyg. et de M^d. col., 1898, i. 9. 4 Arbeiten aus dem Kaiserlichen Gesundheitsamte, 1898, xiv. 121. 294 INFECTIO US DISEASES. The chief condition favoring the development of black-water fever is a long residence in the tropics. In no case has he seen the disease occur inside of nine months. " Quinine in association with active malarial parasites has almost always been recognized as the important provocative cause of the outbreak of the disease. In several patients the blood had been already so much changed by residence in the tropics that, even with- out the presence of active plasmodia, quinine alone provoked a destruc- tion of the red blood-corpuscles. In one case a simple malarial fever without apparent cause (without quinine) developed spontaneously into a black-water fever. In a number of patients, fever of one day's dura- tion regularly occurring every three weeks, two weeks, or even every week, pointed to the imminent outbreak of black-water fever. In other cases the patients had been afebrile for six or even more months before the outbreak of the disease." He sums up as follows : " 1. Aly observations agree with those of A. Plehn : in the beginning of black-water fever typical malarial plasmodia are almost always found, which disappear within a short period of time. I was unable to dis- cover a special causal agent. 11 2. In a woman who used quinine prophylaxis every five days, black urine appeared for a month and a half, regularly, three or four hours after the taking of quinine, at first without, later with, an elevation of tem- perature. I was unable to find plasmodia despite the most careful exami- nation of the blood. " 3. In one case active plasmodia were still found in the blood on the fourth day after the outbreak of black-water fever. This was a case in which the action of quinine was excluded. It was, then, a black-water fever caused exclusively by the action of the plasmodia. Whether in such cases (black-water fever without quinine) it is judicious to adhere to treatment without quinine is a question for experience to settle. The quinine given by me1 was without influence on the course of the disease." All the cases were treated without quinine. Five of these patients died. The malarial parasites which are almost always present at the onset of the attack often rapidly disappear. " Through the destruction of the red blood-corpuscles in a paroxysm of black-water fever some substance is apparently set free in the blood which is capable of making the blood immune against malarial parasites for a certain length of time." This probably explains the fact that many cases after having recovered from such an attack remain free from malaria as much as six months or more. There are, however, cases in which relapses of uncomplicated malaria occur but a short period afterward. 1 This quinine was administered on the ninth day of illness, when the patient was almost moribund. MALARIAL FEVER. 295 The view that malarial haemoglobinuria may be due to a separate and distinct form of parasite is suggested by Manson in his Manual on Tropical Diseases, and also by Dr. Sambon.1 In most of this literature it is disappointing to find how unsatis- factory are the records of examinations of the blood. Any one who reads the communications upon malarial haemoglobinuria which appear annually, particularly if he has had the good fortune to read Bastia- nelli's2 admirable review of the subject, cannot fail to be impressed with the fact that haemoglobinuria may stand in very varying relations to malarial infection. A predisposition to haemoglobinuria may be acquired in various infections-typhoid fever, smallpox, yellow fever, and syphilis; that a similar predisposition may result from repeated malarial attacks is beyond question. It is also clearly demonstrated that many instances of haemoglobinuria, beginning with a sharp initial chill and fever, occur in patients who, although they have suffered from malaria, are at that time quite free from acute infection. There can be no doubt that some of these instances of haemoglobinuria occurring during or after a malarial attack, are actually provoked by quinine; such cases seem to be curiously common in certain, especially tropical, localities, and are very rare or unknown in other severely malarious districts and in most temperate regions. But it is equally certain that a large proportion of the so-called " malarial " haemoglobinurias have no relation whatever to the taking of quinine. What may be the direct exciting cause of many of these other instances of haemoglobinuria, all of which are too apt to be included under the one heading of "malarial," is a question. The reviewer is not impressed with the evidence in favor of the dependence of these outbreaks upon a special variety of parasite. In the present condition of the subject it would seem to be possible to summarize in a few words as follows : In certain severely malarious districts repeated infections result in the development of an individual predisposition toward haemoglobinuria. In some instances the attack seems to be provoked by the actual malarial paroxysm. More commonly the outbreak occurs without relation to the existence of the symptoms of the predisposing disease, and often after it has ceased to exist. The immediate provoking cause is often impos- sible to determine. In some instances, particularly in certain tropical regions, the ingestion of quinine may provoke the haemoglobinuric paroxysm. Ocular Changes. Bassfires3 describes two cases of retinal hemor- rhage in malarial fever, one of which was followed by a neuro-retinitis. He believes that the hemorrhage may be caused by : 1 Journal of Tropical Medicine, 1898, i. 70. 2 Annales de Medecine, 1896, ii. 847. 3 Arch, de Med. et de Pharm. milit., 1898, xxxi. 336. 296 INFECTIOUS DISEASES. 1. Embolism with pigment-bearing leucocytes or parasites. 2. Changes in the vascular walls due to anaemia. 3. Toxaemia. Mental Changes. Yanniris1 describes several cases of mania or melancholia, developing in degenerates after malarial attacks. 1 Ie believes that the malaria acted, in individuals predisposed to mental trouble, the part of an exciting cause. He cites, further, two instances in which symptoms of degeneracy followed paludism in individuals with a good family history, and he questions whether definite changes in the brain may not have been produced by the paludal infection. Renal Changes. Rem-Picci, in a valuable article,2 discusses the occurrence of albuminuria and renal changes in malaria. He distin- guishes two varieties of albuminuria, one a febrile albuminuria and one which occurs after the attack, during the post-malarial polyuria. The febrile albuminuria he found in 6 per cent, of the cases ; it is transitory and mild. That which is post-malarial and accompanies the usual polv- uria may last somewhat longer and be of greater intensity. There are, moreover, albuminurias which occur in the cachectic; these are also usually mild, but may be protracted for some time, disappearing, how- ever, with the improvement in the general condition of the patient. Malarial infection, however, may be associated not only with simple albuminuria, but with renal lesions indisputably dependent upon the disease. The kidney is not, according to Rem-Picci, particularly predisposed to injury in malaria, so that the occurrence of renal com- plications is rare. These occur more frequently in the fall than in the spring, and especially affect young individuals. They occur with the severe as well as with the mild forms of the disease, and are not more frequent in the former than in the latter. As a rule, the attack is subacute and accompanied by slight symptoms of a catarrhal, desquama- tive, tubular nephritis. Complete recovery occurs in the majority of instances ; but under some circumstances, either from a recurrence of the fever or from lack of proper hygienic methods, or owing to individual conditions, an apparently mild attack may be the point of origin of a permanent lesion. There occur also more severe acute nephritides, which may go on into a chronic form. All types of nephritis may be met with. There is apparently nothing specific in the nature of the renal changes, which appear to be of the same character as those in scarlet fever. (Edema is commonly present. The renal symptoms may occur during the febrile period or afterward. To the latter cases Rem-Picci has applied the term " post-malarial," 1 La Med. Orient, 1898, ii. 6. 2 Policlinic© V.-M., 1898, 197. MALARIAL FEVER. 297 inasmuch as he believes it useful to draw especial attention to the fact that, with the disappearance of malarial fever, the possibility of a subse- quent renal complication is to be borne in mind. It is a question of doubt whether the most chronic forms of contracted kidney may be primarily caused by malaria. Amyloid changes may be complicated with the malarial nephritis. Finally, there occur rare instances of acute anasarca in malaria without albuminuria. To these forms of malarial nephritis the changes in the kidney which occur in instances of hsemoglobinuria are indirectly related. The pathogenesis of these malarial nephritides is doubtless to be sought for in the elimination of toxic substances. The reviewer1 has also made a series of investigations upon the sub- ject of nephritis of malarial origin. 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 sestivo-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 apparently 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- 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 three 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 the sestivo-autumnal fever ; it is commonest during the height of the malarial season, in July, August, September, 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, and 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 Transactions of the Association of American Physicians, 1898, xiii. 339, and American Journal of the Medical Sciences, 1898, cxvi. 560, 646. 298 INFECTIOUS DISEASES. 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 aestivo-autumnal 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 2 per cent, of the cases treated in the wards of the Johns Hopkins Hospital, and in between 1 and 2 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 infections, 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. Abortion. Dock1 relates a case of abortion at three months, follow- ing an attack of double tertian malaria, which may possibly have been due to the high fever. There was no evidence of foetal or placental infection. Typhoid Fever. The campaign in Cuba, as well as the unhygienic condition of the camps in the South, has afforded an excellent oppor- tunity for the study of combined infections of typhoid and malarial fever, and in all probability we may expect valuable observations. Ewing,2 at Camp Wickoff, found the malarial parasites in the blood of five cases of typhoid fever in acute exacerbations occurring during con- valescence. From these observations he draws the following conclusions : 1. Mixed infection of typhoid and malarial fever undoubtedly exists. 2. When typhoid develops in a case of active malaria the malarial element nearly always becomes quiescent and has little or no effect on the course of typhoid fever. Malarial infection frequently outlasts the typhoid infection, and makes itself manifest during convalescence. In no undoubted case of typhoid fever, in which the diagnosis was con- firmed by autopsy, was the malarial organism found. Dr. Bark, in the discussion of this communication, states that from inquiry as to the experience of various hospitals in New York City he found that the malarial organisms had been found in the blood in from 1 to 5 per cent, of the typhoid cases in all but one hospital. 1 Philadelphia Medical Journal, 1898, i. 699. 2 See Typhoid Fever, p. 308. MALARIAL FEVER. 299 Kardamatis and Canellis1 discuss the continued malarial fevers and typhoid fever in Greece, and, though themselves offering no direct evi- dence, reach the conclusion that typhoid fever and malaria often occur simultaneously. There is no antagonism between the diseases, as was believed by Boudin. They recognize the fact that this association is a simple complication of diseases, and that there is no such disease entity as " typho-malarial fever." Nammack,2 in a clear article on the differential diagnosis and treat- ment of Cuban and camp fevers, states : " We found no reason to recog- nize a distinct type of continued fever which is neither malarial nor typhoid, or one which is a compound of both, the so-called typho-mala- rial fever." Several cases of mixed infection were found. "As a rule, in these cases of mixed infections the activity of the malarial plasmodium was shown early in the course of the typhoid diseases. In one very interesting case, however, . . . characteristic chills developed after convalescence from typhoid." " In every case of differential diagnosis between malarial fever and typhoid, the final decision was reached by examination of the blood, and in no case was it necessary to employ the therapeutic test of quinine." It is interesting to see that the observers who have adopted scientific methods of diagnosis unanimously repudiate the erroneous ideas which have been so long held, and are, alas, still held, with regard to the exist- ence of a special disease entity-" typho-malarial fever." The results of careful studies of combined typhoid and malarial infections, from the development of which such rare opportunities existed during the recent campaign, should shed much light upon the disputed question as to whether the complication of these two affections results in a particularly characteristic disease picture. Miscellaneous. Norton3 has contributed a valuable paper upon malaria as a causative factor in other diseases. In a careful study of the literature he demonstrates how recklessly maladies of every descrip- tion have been ascribed to malarial infection, and how few of these, after all, are positively proven to be truly malarial in nature. He reaches the following reasonable conclusions : " In making a short review of what has gone before there are several deductions which can be drawn : " First, and foremost, that malaria is not the cause of so many evils as are attributed to it; secondly, that its favorite seats of attack after the blood and blood-making organs are the gastro-intestinal and central ner- vous systems, and that other organs and systems are but rarely affected ; 1 Le Progres Medical, 1898, 3 s., vii. 195, 260, 276. 2 Medical Record, 1898, liv. 471. 3 American Journal of the Medical Sciences, 1898, cxv. 161. 300 INFECTIOUS DISEASES. thirdly, and not the least important, that the eases supposed to be malaria should, in the future, be more carefully studied, and that hereafter it should not be given as a cause of existing evils without sufficient and abundant proof. If the blood cannot be examined, then only a full history of the case should be accepted in which the fever, spleen, and effects of treatment are carefully noted." Bartolucci1 reports a case of pernicious malarial fever with pulmonary manifestations. The absence, however, of blood examinations renders the diagnosis inconclusive. Diagnosis. Methods of Staining. Ziemann2 deals at length with modifications of Romanovsky's valuable method of staining with eosin and methylene-blue, which are particularly fitted to bring out in a satis- factory manner the finer structure of the malarial parasites. It woidd be impossible in an article of this nature to go into the subject at length ; reference should be made to Ziemann's excellent work. Futcher3 has called attention to an extremely valuable method of using thionin as a stain for the malarial parasites. Upon a dried cover-glass specimen a little of a 1 per cent, solution of formalin in 90 per cent, alcohol is poured and allowed to remain for one-half to one minute. The specimen is dried between leaves of filter-paper; absolute alcohol is then poured over the glass, which is once more dried, and then stained for twenty to thirty seconds in Marchand's solution of phenol thionin, which is prepared as follows : Saturated solution of thionin in 50 per cent, alcohol .... 20 2 per cent, solution of ac. carbol 100 The solution must stand several days. The specimen is then washed in water, dried between filter-paper, and mounted in balsam. If the specimen has not been stained too long the corpuscles take a very slight greenish hue, while the parasites are of a deep violet color. The specimen should not be stained too long, as in pigmented parasites granules of pigment may be obscured by the depth of the color. This method is particularly valuable in that it brings out with great clearness the small, ring-shaped hyaline bodies of aestivo- autumnal fever with their chromatin dot. The chief value of this stain, however, is its readiness of application, which renders it particularly useful to the busy general practitioner. Enlarged Spleen. Koplik4 asserts that in children enlargement of the spleen is of little diagnostic value without corroborative examina- tion of the blood. Fairly severe cases of tertian malaria occur in chil- 1 Gaz. d. osp., 1898, xix. 1032. 2 Op. cit. 3 Remarks, as yet unpublished, at the Johns Hopkins Hospital Medical Society. 4 Medical Record, 1898, liii. 209. MALARIAL FEVER. 301 dren without enlargement of the spleen, and many cases in which the spleen is enlarged are not malarial. Treatment. Quinine. There is little new to be said with regard to the use of quinine in the ordinary manifestations of malaria. Van Marter1 denies its value excepting in the regularly intermittent forms, but he publishes no charts and quotes no cases to prove that con- tinued fevers in which he has failed to obtain good results are purely malarial in nature. He also asserts that it should never be used in hemoglobinuria. Row,2 of India, asserts that in the severe fevers of India he never has to give more than 15 grains of quinine at one dose. This he usually administers just when fever begins to subside. He then gives sulphate of quinine, gr. x to xv, and afterward gr. v every four, five, or six hours, often not more than four times a day, for a week at least, after which he continues quinine in 2-grain doses with Fowler's solution, gtt. iv to v, twice a day for a fortnight. Relapses rarely occur. Out of many cases he had but five or six, and in these instances the relapses rapidly yielded to quinine. Ten grains is his usual initial dose for an adult. Gilbert3 also testifies to the specific action of quinine. Ziemann4 recommends very highly the intramuscular injection of qui- nine. He inserts the quinine into the glutei, using as the usual dose bimuriate of quinine 0.5 (grs. vij) to 2 grammes (nt xxx) of water. The proportion of quinine to the fluid should be about 1:4. In higher proportion the injections are painful, while with this they are almost absolutely painless. The action is most prompt, and the author believes that it is the most satisfactory method of giving quinine. He has never seen any unpleasant results. Euchinin. Considerable attention has been paid during the last year to a new, tasteless product, euchinin, which is an ethyl carbonate of quinine. St. George Gray5 is enthusiastic over its action, asserting that, beside its great superiority over quinine in being tasteless, it reduces the tem- perature in smaller doses. It does, however, cause tinnitus aurium, deafness, and derangement of vision in more marked degree than the same dose of quinine. " Contrary to the statement of Professor von Noorden, that 15 grains of quinine are equal to 25 or 35 grains of euchinin as an antipyretic, 15 grains of euchinin are as efficacious as 20 to 30 grains of quinine sulphate." In doses of 12 to 15 grains it almost always causes buzzing in the ears, if not other symptoms of cin- 1 Texas Courier of Medicine, 1898, xv. 316. 2 New York Medical Journal, 1898, Ixvii. 94. 3 Journal of the American Medical Association, 1898, xxxi. 1162. 4 Loc. cit. 5 British Medical Journal, 1898, i. 551. 302 INFECTIOUS DISEASES. chonism. He has never given a larger dose than 15 grains. Unfortu- nately, he reports no blood examinations, but the cases in the West Indies which he studied were in all probability malaria. lie administers the drug as a simple powder placed dry upon the tongue. He concludes that: 1. Euchinin is as efficacious as quinine in malarial fever. 2. It causes cinchonism. 3. It is tasteless and, therefore, easily administered. This last point is a great advantage over quinine. Mori1 studied the effects of the drug in fourteen cases of various nature, and in twenty instances of malaria. Taken by the mouth in doses of 0.25 to 1. (gr. iijss to xv) it produces no disturbances in adults. In anaemic individualsand those in whom the stomach is a locus minoris resistentice a dose of 2. to 3. (gr. xxx to xlv) causes a sense of weight in the epigastrium, a slight pyrosis, nausea, eructations, vomiting, and loss of appetite if continued. It has apparently no influence on the intestine. Panegrossi found that elimination, which begins in half an hour, reaches its maximum in seven hours and is concluded in forty-eight hours. The nervous symptoms are like those following quinine, but shorter and less intense-i. e., heaviness in the head, deafness, buzzing and singing in the ears. He has never seen changes in vision. Doses of 3. (gr. xlv) in healthy adults result in a slight increase in the frequency of the heart- beat and an increase in the quantity of urine. In twenty cases of malaria the results of his treatment were satisfactory. He usually gave a gramme at a dose, six, four, and two hours before expected attacks, and then con- tinued the administration of the drug for five or six days following, reducing the daily dose gradually to 0.5. Under these circumstances the subjective symptoms were slight and never resulted in characteristic cin- chonism. Ringing in the ears was the most common symptom. The more severe symptoms mentioned above sometimes occurred in feeble individuals with gastro-intestinal trouble : pyrosis, weight in the stomach, nausea, eructations, and vomiting may occur. These, however, diminish under continuation of the treatment. His best results were obtained in children, in the treatment of which he believes the drug to be especially valuable. Sukhomlin2 tested the value of euchinin in eleven instances of malarial intermittent fever. A distinct antimalarial action was noted ; but given in doses equal to the ordinary doses of quinine the effect was not as good, the results being obtained considerably more slowly. The author notes the possibility that larger doses might have had a materially better effect. 1 La Sett Med. d. speriment, Firenze, 1898, lii. 306. 2 Ejened. journ. "Pract. med." St. Petersburg, 1898, v. 297. MALARIAL FEVER. 303 Zangri and Peratoner,1 from observations in Tomaselli's clinic, con- clude that enchinin is of great efficacy in malarial fevers, being equal to the best preparations of quinine known at present. In some cases in which quinine had not promptly stopped the fever, enchinin was efficacious in accomplishing this result. The observers insist that as much as 6 grammes must always be given before the com- plete disappearance of the fever. Single doses were apparently below 1 gramme. In no case were there disturbances of any sort, gastric or other. With the larger doses the patients complained of a slight buzzing in the ears. The new drug will occupy an important place in therapy if future experience shows that it may be borne in cases of quinine intoxication. Lewkowicz2 used enchinin in sixteen cases, six of which were tertian, four malignant malarial fever, and six quartan ague. The drug acted promptly and without failure in all cases. Large doses of the drug, 1. (gr. xv), twice in the day, are well borne through a long time, while by small doses administered through a long period complete cure is to be obtained in young individuals. The author observed in the parasites the characteristic alterations which occur after the use of quinine. He administered the drug in capsules ; it may be given to children in differ- ent substances-water, milk, coffee, etc. He observed unpleasant phe- nomena (buzzing in the ears and the symptoms characteristic of quinine intoxication) only twice, and then when large doses were used corre- sponding to about 2.5 for an adult. Goniev3 reports concerning six months' observations on the efficacy of enchinin in various diseases. These observations were made on one hun- dred patients in his private practice in Tiflis, patients suffering with diseases for which ordinarily he would have given quinine. He is con- vinced that enchinin acts very well in those diseases in which the use of quinine is indicated, and in addition it has the advantage of being more easily taken by the patient, owing to the absence of any bitter taste. In children vomiting is much more rare after enchinin than after qui- nine. The curative action of enchinin " was exactly as positive as that of quinine in all cases of malarial fevers." He considers the prepara- tion of particular value when dealing with children. To obtain its full action it is necessary to give it in larger doses than quinine, inasmuch as its action is weaker. Thus, in malarial fevers, he gave to adults up to 15 grains at a dose, four hours before the attack ; to children of four or five years of age, up to 5 grains in the twenty-four hours (in place of 3 grains of quinine), thus regulating his doses according to age. The dose of euchinin should be somewhat less than twice the dose of quinine. Thirty of the one hundred patients with whom he used quinine had 1 Riforma Medica, 1898, xiv. iii. 62. 2 Wien. klin. Wochenschrift, 1898, xi. 922. 3 Vrach, 1898, xix. 776. 304 INFECTIOUS DISEASES. malarial fever. Several of these had the usual symptoms which follow quinine-roaring in the ears, itching, and slight vertigo, with very large doses. The reviewer has seen good results from its use in two eases. These reports justify a more general test of this new drug. It will be unquestionably a material addition to medicine if the preparation proves to be as efficacious, while free from unpleasant taste, as quinine. Phenocoll, Analgin, etc. All observations go to show that these drugs have but little real antimalarial action. Lewkowicz, as well as Ziemann,1 sharply emphasize their relative inefficiency. Chinopirin. Laveran and Gessard have advised the following mix- ture for hypodermic injections in malaria : Hydrochlorate of quinine ......... 3. Antipyrine ............ 2. Distilled water ........... 6. Antipyrine appears to increase the solubility of quinine, and according to Santesson, a new, easily soluble combination of quinine and antipyrine results, to which he has given the name of chinopirin. Doses, however, of 0.5 (gr. viij) of quinine with 0.3 (gr. ivss) of antipyrine have been followed by unpleasant symptoms. Introduced hypodermatically doses twice as large may be used. Lewkowicz used the substance hypoder- matically in four instances with good results, giving a boy eight and a half years of age two injections of 1 c.c. of the mixture. The seat of injection may often be painful for some little time afterward, but the effects are excellent. Myrrh. Jeffrey2 states that he has been in the habit, in the treat- ment of malaria, of adding small quantities of myrrh to quinine, believ- ing that the efficaciousness of the latter drug is materially increased. He adds 1 grain of myrrh to 1 grain of quinine in capsules. Ergot. Jacobi3 asserts that in chronic malaria with enlarged spleen ergot is a valuable therapeutic agent. Treatment of Sequelae and Complications. Nephritis. In the treatment of nephritis of malarial origin, both Rem-Picci and the reviewer insist upon the necessity of treatment with quinine whenever active mala- ria exists. Quinine removes the malarial infection, which is the cause of the complication, and recovery, as a rule, follows. Further treatment should be directed toward the nephritis as such, which differs in no way from any other toxic nephritis. Anaemia. Brown4 believes, as a result of his experience, that arsenic has little effect in post-malarial amemia if not accompanied by iron. 1 Loe. cit. 2 Medical Record, 1898, liv. 268. 3 Medical News, 1898, Ixxiii. 513. 4 Loc. cit. MALARIAL FEVER. 305 Splenomegaly. Laccetti,1 discussing the treatment of post-malarial splenomegaly, asserts that simple congestive splenomegaly is influenced by quinine and the " ordinary vaso-constrictors (arsenic, strychnine, ergo- tine, hydrotherapeutics, electricity)." In cases of chronic splenic enlarge- ment with marked interstitial changes, however, especially where the spleen is movable and causes distressing symptoms, one must resort to splenectomy. Laccetti relates a case in which, six days after splenectomy, there occurred intermittent fever, which disappeared after the administration of quinine. After the operation there was pain in the diaphyses of the long bones, which the author believes to have been caused by the vica- rious activity of the marrow. Hemoglobinuria. As might be expected from the fact that under the heading of " malarial hsemoglobinuria " several different conditions are considered, the opinions of different authors as to its treatment vary materially. Koch2 protests against the employment of quinine in black-water fever, asserting that its injudicious use as'a prophylactic is, in most instances, responsible for the outbreak of the disease. Van Marter3 likewise insists upon the danger of the use of the drug. Tsakyroglon4 asserts that quinine plays no role in the pathogenesis and treatment of this disease (black-water fever). Woldert5 doubts the existence of quinine hsemoglobinuria, and insists upon the use of quinine. Denman6 asserts that malarial luematuria is most apt to occur in cases of malaria which have been neglected or not properly treated in the beginning, never as a result of quinine, but because quinine has not been given at the time when it, and it alone, could have arrested the process of the malarial infection. He has studied nineteen cases. " Unless the case shows a damaged state of the blood and kidneys sufficient to cause uraemia, I administer quinine and push it to cinchonism as rapidly as I can, to insure cutting off the next chill, no matter how much blood may be passing by the kidneys." In addition he usually gives calomel, strych- nine, nitroglycerin, and sometimes pilocarpin. Murdock7 makes some very sensible observations which may well account for many of the reports of the negative value of quinine. He recognizes the fact that the predisposing cause of the so-called malarial hsematurias is malaria, but he believes that in nearly all the cases malaria has ceased to exist, and, therefore, plays no part, or at least a minor part, 1 Giorn. internal, della sc. med., 1898, fasc. i. 2 Loc. cit. 3 Loc. cit. 4 Loc. cit. 5 Loc. cit. s Texas Medical Journal, 1898, xxiii. 501. 7 Journal of the Mississippi Medical Association, Biloxi, 1898-9, ii. 144. 306 INFECTIOUS DISEASES. in the condition present when hsematuria makes its appearance. In the treatment of his cases, all of which have been of this nature, he gives, in the beginning, calomel, gr. x to xv, and turpentine, gtt. x. After the calomel has acted well he gives tincture of chloride of iron, gtt. x to xx, every four hours. When the urine loses its dark color and begins to become more or less red, he stops the turpentine and gives fluid extract of ergot and acetate of potassium or spirit of nitre, and on convales- cence he gives arsenic and strychnine. Clarae,1 speaking with regard to the treatment of haemoglobin uric fever in Dakar, in Africa, recognizes the fact that few of the haemo- globinurias occur during the active malarial attack, though in most this has been the predisposing cause. He continues, " Quinine, even in strong doses, is useful at the time of the paroxysms which precede the haemoglobinuria, and is always taken by the patient. Medication seems to us useless when the temperature has fallen ; on the contrary, if fever persists one should pursue the elevations of temperature by moderate but sufficient doses of quinine, administered as far as possible hypodermat- ically, to arrest the destructive action of the haemotozoon and to prevent succeeding attacks. We have been able to make out that the recrudes- cences of fever or the augmentation of the temperature resulted almost always in a diminution in the number of red corpuscles, an observation agreeing with the researches of Kelsch and Kiener." The salts of qui- nine are contraindicated when there is anuria. He is inclined to believe that 4. (5j) to 6. (5jss) of chloroform in twenty-four hours, taken in the form of chloroform-water, has a certain value. The other treatment is symptomatic. Doering2 does not use quinine in the treatment of his haemoglobinurias. As has been mentioned before, he notes the fact that in some instances the attack of black-water fever itself seems to produce a spontaneous disappearance of the malarial parasites and of the symptoms of the disease. But if the relapses of malaria occur shortly afterward, without black- water fever, it is absolutely necessary to treat these with quinine. Small doses are often sufficient. "As a result of my experience I cannot lay enough stress upon the warning not to attempt to allow these malarial attacks, coming on shortly after a recovery from an attack of black-water fever, to heal without quinine. I would rather risk-if plasmodia are found-bringing on another attack of black-water fever by quinine than to allow the patient to die without having given him quinine. " Many an individual who would yet have happily escaped the dangers of the Kamerun climate has fallen a prey to an uncomplicated malarial attack as a result of his refusal of quinine, for fear of a fresh attack of black-water fever." 1 Loc. cit. 2 Loc. cit. MALARIAL FEVER. 307 In those eases where the attack comes on without the influence of quinine, parasites remaining in the blood, the question as to the advisa- bility of the administration of quinine remains for experience to settle. The reviewer cannot resist adding a few words, largely a repetition of what he has previously printed upon this subject. It is inconceivable that intelligent physicians should give such diametrically opposite reports as to the efficacy of quinine, and its possible deleterious effects, as are constantly received from different parts of the world, if they are dealing with exactly the same condition. Scientific observation of cases and the use of the microscope in diagnosis have shown that malaria frequently plays only a predisposing part toward this condition ; that when present it is absolutely necessary that steps should be taken to remove the infec- tion, and when not present there is no earthly reason for giving quinine, while the fact that in certain regions quinine may act as an exciting cause of hsemoglobinuria should be enough to make us cautious in our use of the drug where it is not necessary. In a word : (1) if the haemo- globinuric attack has come on without quinine, and there are active para- sites in the blood, quinine must certainly be administered. (2) If under the same circumstances parasites are absent, quinine is uncalled for. (3) If there is reason to believe that the attack has been precipitated by quinine, the drug should certainly be stopped, unless evidences of a very severe infection continue. The quinine already given, together with the destructive action of the attack, will probably be enough in most cases to overcome the infection. To properly treat " malarial hemoglobinu- ria" the microscope is indispensable. Koch puts it as follows: "For this reason alone, but especially in order to establish an early and sure diagnosis, the microscope is absolutely indispensable to the physician in the tropics, if he has much to do with malaria, and that is probably always the case. A physician who faces malaria without a microscope and without thorough practice in the detection of malarial parasites will always fight in the dark." Prophylaxis. Koch1 found that quinine, 0.5 (gr. viij), taken every other day, was sufficient in most instances to ward off attacks of fever; he believes that 0.5 (gr. viij) every fifth day, as advised by Plehn, is scarcely sufficient. As a purely prophylactic means, he hesitates to advise more, inasmuch as " larger doses of quinine are ill-borne through a long period of time." Doering,2 in Kamerun, used quinine, 0.5 (gr. viij), every fifth day, as advised by Plehn. His results were not quite as favorable with regard to ordinary malarial attacks as were Plehn's, although he feels that as yet his observations have not been sufficient to arrive at a positive conclusion. 1 Loc. cit. 2 Arbeiten aus dem Kaiserlichen Gesundheitsamte, 1898, xiv. 121. 308 INFECTIOUS DISEASES. He is, however, particularly impressed with the favorable influence which quinine prophylaxis, regularly carried out, lias upon the development of black-water fever. This, he thinks, is due not only to the warding off of repeated malarial attacks, the predisposing influence of which is gen- erally recognized, but to the fact that, " if one accustoms the blood regu- larly during the afebrile period to quinine, then the irritation which quinine exercises upon the red blood-corpuscles during the fever is appre- ciably less, and the quinine is much less likely to produce a destruction of the red blood-corpuscles than when the blood has not become regu- larly accustomed to the drug. Therefore, it would seem wise to use quinine prophylaxis wherever one has to remain for a considerable length of time in the tropics, even when the danger of black-water fever is not suggested by regular, continually recurring fever. " The predisposition to black-water fever is not dispelled by a long sojourn in Europe; therefore, whoever returns for a second time to Kamerun, should institute quinine prophylaxis as soon as he steps upon African ground." TYPHOID FEVER. Etiology and Manner of Infection. The Effects of Typhoid "Toxin" on Animals. Lepine and Lyonnet1 have studied the effect upon dogs of injections of typhoid "toxin" prepared by heating a cul- ture of the bacillus at 58° C. They arrive at the following conclusions : 1. There are rather marked individual differences in dogs in relation to their resistance to the action of typhoid toxin. The fatal dose by kilogramme varies from a minimum to four to five times that amount, " du simple au quintuple." 2. Removal of the spleen, if it be done immediately before injection of the toxin, appears to exercise no appreciable influence. 3. If this organ be artificially heated, a proceeding which increases its vitality, one may bring about the survival of dogs intoxicated by a dose of the toxin which would otherwise be surely fatal. 4. Generally, when new dogs succumb rapidly to an injection of toxin, their temperature becomes very little elevated, or even falls ; on the con- trary, if they resist, there is a rapid and often a considerable elevation of temperature. 5. With regard to the leucocytes, it may be said that if the dog succumb rapidly to infection with typhoid toxin, his colorless corpuscles undergo a marked diminution ; on the contrary, if he succumb slowly, his leuco- cytes do not diminish at all, but increase slightly ; if he resist they increase either a few hours after the injection or on the following day. 1 Revue de Medecine, 1898, xviii. 854. TYPHOID FEVER. 309 Rodet1 noted that filtered cultures of the typhoid organism resulted in local and general troubles very similar to those produced by cultures killed by heat. They differ only in that they do not produce suppura- tion. The soluble products favor the infective action of bacilli. The filtered cultures are, moreover, possessed of an immunizing power and of an agglutinative property. The Role of Contagion. Annequin2 takes up the question of the contagiousness of typhoid fever. The strongest argument in favor of con- tagion appears to him to be its frequency among the nurses in military hospitals. Inasmuch as they are not exposed to the various injurious influences which elsewhere may come into play-water, food, etc.-their disease may be ascribed exclusively to contagion. The morbidity from typhoid fever in the French army is about 1.07 per cent., while that of the nurses in the garrison hospitals amounts to 9 per cent., and, indeed, in the epidemic of 1882 it was as high as 23 per cent. The statistics of other armies give similar figures. Annequin has also studied contagion among the patients, and believes that it occurs chiefly by direct contact with the affected individual and everything that he soils. The hands and clothing of those who surround him may also convey the contagion. The air may assist either directly through the respiratory passages or by depositing substances on articles of food or drink. With the nurses the chief danger is probably negligence in cleanliness and antisepsis, mainly neglecting to wash their hands before eating. With patients the most frequent cause of contagion is promiscuous use of utensils, respiration of dust, and contact with the personnel of the hospital who are handling typhoid patients. The conclusions, though rather sweeping, are none the less interesting : "1. It is necessary to isolate typhoid patients, or at least not to place them in a ward containing young people who have not previously had typhoid fever. " 2. One should, if possible, employ as nurses individuals who have already had typhoid fever. In a family one should remove young people. " 3. Everything which has been in contact with the patient and could have been soiled by his excreta should be rigorously disinfected. The linen of the patient should not be thrown upon the floor but put in a metal box. "4. The chamber should be oiled, its floor impermeable, so that it may be cleaned with a cloth damp with antiseptic solution, to avoid the formation of dust. " 5. The nurses should wear in the room special linen clothes, which they should remove when they go out. They should take care not to 1 La presse medicale, 1898, Ann. vi. t. i. 247. 2 Lyon med., 1898, Ixxxvii. 181. 310 INFECTIOUS DISEASES. sit upon the bed nor drink and eat in the siek-room. The hands should be kept perfectly clean. " 6. If the patients with typhoid fever are isolated in special rooms these should be large and well aired ; every patient should have two beds. " 7. The bringing together of patients in a single room does not aggra- vate their condition, a conclusion arrived at in Grenoble from 1891 to 1897. The patients enjoy repose and silence, of which they have so much need. The organization of the service and the administration of the baths are more easy, and if the dangers of contagion are increased for the nurses, they are diminished for the other patients." Antonin1 has studied a severe epidemic of typhoid fever which occurred among the civil and military inhabitants of Bucharest. Out of 300 pupils in the military school, 26 were affected, with 3 deaths ; while out of 132 soldiers but 2 suffered. This disproportion is well explained by the grouping of the pupils in one part of the building, notwithstanding the fact that the hygienic conditions in other respects were better than those endured by the soldiers. Inasmuch as the pupils and soldiers drank the same water, which after the development of the epidemic was boiled, the origin of the disease from water may be ruled out. Indeed, there are no facts in relation to the epidemic which suggest that this was the case. Typhoid had never before occurred in the school, and arose on this occasion only after the pupils came, disappearing when they left. The most interesting point is that the greater number of cases was observed in two dormitories, where the disease began almost at the same time with one pupil in each dormitory. Here the crowding was such that the beds touched one another, and propagation took place from bed to bed with the greatest regularity. Of the first two cases one came from a city infected with typhoid, and the other from Bucharest, where the epidemic among the population had preceded that in the army. The author considers that these observations suggest prophylactic rules which should be observed in schools and barracks, and in general in all places where people are crowded together. Knowing that the danger of con- tagion is greater in dormitories, it is important to put the beds as far apart as possible ; to isolate immediately every suspected case; to avoid all immediate contact, and to carry out the disinfection of the bed- clothes and the room in which the first case has developed. Raw Oysters as a Cause of Infection. Du Camp, Sabatier, and Petit2 discuss the relation of the ingestion of oysters to the etiology of typhoid fever. They recognize the fact that some epidemics have appar- ently owed their origin to oysters, but their researches carried on at the Zoological Station at Cette, have shown : 1 Spitalul, Bucuresci, 1898, xviii. 7. 2 La presse m&L, 1898, vi. t. i. 240. TYPHOID FEVER. 311 il 1. That oysters from the beds of Cette contain neither the bacillus coli nor the typhoid bacillus, but common species frequently found in the water. " 2. That oysters placed for a month at the opening of a drain con- tain neither the colon bacillus nor the typhoid bacillus, but only bacteria of green fluorescence. " 3. That oysters inoculated directly either with the bacillus coli com- munis or with Eberth's bacillus, in liquid or solid cultures, and left in the beds, contain at the end of a few days neither the colon bacillus nor the typhoid bacillus. These organisms disappear either because the salt water forms an unfavorable medium for their growth or because the oysters exercise with regard to them some manner of vital defence." They believe that infection through the ingestion of oysters should not hold the place which it now occupies as one of the demonstrated etiological conditions in typhoid fever. Carrazzi1 also concludes that the idea that typhoid fever may be con- veyed by means of raw oysters is entirely without foundation. This observation, however, provokes an answer from Bordoni-Uffreduzzi,2 in which he quotes the observations of Klein, Foote, Cann, Broadbent, Pasquier, Chantemesse, and Levis, all of which tend to show that typhoid organisms may not only gain entrance into the oyster, but remain living for some weeks. He insists that the danger from eating raw oysters is by no means over-estimated. In connection with this subject it may not be out of place to refer to the fact that the most clearly proven epidemic of typhoid due to raw oysters in this country, that occurring at Wesleyan University, Hartford, Connecticut,3 was due to oysters infected not in their own habitat, but as the result of being placed in contaminated fresh water that they might swell and assume a more appetizing appearance. Infection Through Salads. The interesting suggestion is made, in La Riforma Medica,i that plants used as salad may serve to convey the infectious agents. This is especially possible in view of the fact that different species of herbs used as salad are often raised in manure, for which human feces are sometimes used. Lettuce is washed by gardeners in any sort of dirty water. And yet a more important manner in which such herbs may become infected is in the process of bleaching, for which manure is often used. If contaminated in this manner it is easy to see that it would be almost absolutely impossible to remove infectious agents by washing alone. Laveran5 has published several cases of typhoid fever 1 Giorn. di agricolt, mod., 1898, No. 25. 2 Riforma Medica, 1898, xiv. t. iii. 383. 3 New York Medical Record, 1894, xlvi. 743. 4 1898, xiv. t. ii. 287. 5 The reviewer has been unable to find the original article. 312 INF ECT IO US I) ISE A SES. occurring in a body of troops, among officers who lived in barracks, while those living outside were unaffected. The water used in the barracks was of excellent quality and beyond suspicion. Typhoid bacilli, as well as eggs of taenia, were found in the herbs used for salad. Contaminated Water-supply. That an infected water-supply is a very common cause of epidemics of typhoid fever needs no further proof, but two epidemics recently studied by Pfeiffer1 are such interest- ing examples of explosive outbreaks of the disease definitely traceable to this source, that they are well worth quoting briefly : The first, occurring in 1895 in Lueneburg, was restricted almost entirely to families supplied by a particular water company. This com- pany furnished unfiltered water from the river flowing through the city. For ten days, owing to changes in the water-works, the supply was drawn from a point in the middle of the city only 200 metres below the outlet of one of the main sewers, and less than 100 metres below a house where there was a case of typhoid fever whose excreta were being thrown, unsterilized, into the river. This criminal act of the water com- pany was followed, as might have been expected, by an explosive epi- demic. The second epidemic, which was due to an infected well, is even more interesting. Here it was demonstrated that out of about three hundred people exposed to the infection, nearly one-third contracted the disease. Komine and Closson2 also report an interesting epidemic of typhoid fever where, out of 225 men, 61 were seized with the disease and 12 died. All those taken sick had been drinking water out of a well which was shown chemically to contain an undue proportion of both free and albuminoid ammonia. No case existed outside of those drinking the suspicious well water. Such an epidemic as the first of those reported by Pfeiffer ought to strike home to those of us who live, as most of us do in this country, in cities where the water-supply is unfiltered and taken from sources in many ways open to contamination. In almost all of our large cities hundreds of valuable lives are sacrificed yearly because of our neglect to provide proper methods of filtration for our water-supply. It is a sad commentary on our nineteenth century " civilization " that when this danger is realized and when the means of escaping it are perfectly within our power, our hands are often tied by the dishonesty-and this is a mild word-of our city officials and legislators. Typhoid Fever Due to a Para-colon Bacillus.3 Gwyn reports a case of great interest which the reviewer had the good fortune to 1 Klin. Jahrbuch, 1898, xvii. 159. 2 Philadelphia Medical Journal, 1898, ii. 1030. 3 Bulletin Johns Hopkins Hospital, 1898, ix. 54. TYPHOID FEVER. 313 observe. This was clinically a typical instance of typhoid fever with rose spots, palpable spleen, diarrhoea, abdominal pain, and later, intestinal hemorrhage. The patient finally recovered. There was a diazo reaction in the urine. Blood cultures taken at the height of the attack revealed a small, actively motile bacillus, suggesting the B. typho- sus. u It decolorized fairly well by Gram, grew on agar as a gray-blue, moist, raised film, clouded bouillon, giving no scum on the surface and no precipitate. Milk was only faintly acidified, resuming its original tint in the course of ten or twelve days. Potato showed a brown-yellow, moist layer of growth. There was no liquefaction of gelatin; slight stab and surface growth. Plates of gelatin and of gelatin diluted with bouillon gave some circumscribed blue-gray colonies, about J mm. in diameter; the microscope showed light-brown, regularly outlined, granular colonies, with no nucleus. The fermentation reactions showed fermentation of glucose, slight in saccharose, kevulose, and mannite, but none in lactose. Sugar-free bouillon in tubes, to which 3 per cent, of various sugars was added, was used. There was no production of indol. By van Ermen- gen's flagellar stain, from two to four flagella could be made out. No peritrichal arrangement as in the bacillus typhosus was seen. " The serum reactions were as follows : The patient's serum at differ- ent dates during his illness gave a rapid, complete agglutination in low dilutions, and showed reaction in dilutions up to 1 to 150 to 1 to 200, the highest being at date of discharge. On December 18th, two months after date of culture, there still remains a slight reaction. " The same serum was without action on the bacillus typhosus in any dilution above 1 to 1 or 1 to 5. " Two varieties of colon were agglutinated by the patient's serum as high as 1 to 50 and 1 to 60, but two normal sera agglutinated the same organisms in dilutions running from 1 to 60 to 1 to 100. " Typhoid sera of agglutinative strength, ranging from 1 to 300 to 1 to 1100, were without effect on the bacillus in dilutions over 1 to 1 and 1 to 5. One typhoid serum, strength 1 to 900, with bacillus typho- sus, gave an incomplete reaction as high as 1 to 30. Several of these sera had little or no effect even in dilution 1 to 1. One normal serum affected the bacillus rapidly at 1 to 1, failing at 1 to 5. A typhoid bacillus was affected similarly; a colon was agglutinated as high as f to 220 ; another normal serum had little or no effect at 1 to 1, while rapidly and completely agglutinating the colon organisms." The cultural properties of this bacillus were almost precisely similar to those of Widal's1 para-colon bacillus, an organism which he considers to stand, as it were, half-way between the typhoid organism and the 1 Semaine med., August, 1897. 314 INFECTIOUS DISEASES. colon group. The only difference was in the fermentation of sac- charose. As Gwyn remarks, however, the fermentation of saccharose is a variable characteristic in the colon family and may not occur with every member, so that this slight difference in fermentative quality may, perhaps, be a feature of the para-colon family as well. The serum of this patient never gave Widal's reaction with typhoid cul- tures, not even a month after his discharge from the hospital. Though Gwyn speaks with much caution of the conclusions which are to be drawn as to the nature of the case, it would appear to the reviewer that there is every probability that the symptoms-clinically those of typhoid fever-were due to infection with this organism ; and the symptoms justify us in assuming that intestinal lesions with ulcera- tion existed. Out of 265 cases of typhoid fever Gwyn found the serum reaction in every case excepting here and in two doubtful infections. If this be true, the fact that an organism failing to react to typhoid serum and showing cultural differences, even though slight, from the B. typhosus may produce clinically and, inferentially, anatomically, typical typhoid fever is a discovery of no small importance. It would be a matter of great interest to know whether others of the occasional instances of absence of Widal reaction may not be due to similar conditions. Laryngeal Manifestations. Schulz1 has succeeded in demon- strating the specificity of the typhoid lesions in the larynx. In small swollen lymph nodules on the laryngeal surface of the epiglottis, in a fatal case of typhoid, he found, in the connective tissue between the infiltrated areas and the cartilage, staphylococci and short, rather plump, rodlets. The infiltration of the lymph follicles in the larynx was at the same stage as that in the intestine. Several of these lymph nodules were excised after being washed in distilled water, cut in two, and put in bouillon in the thermostat. From the bouillon they were transferred to agar-agar. From others smear preparations were made from the surface of the section onto agar. Both staphylococcus aureus and albus were obtained, and also a thin moist layer which proved to consist of motile rodlets. On some agar tubes only this whitish-gray layer was found. The rodlets grew well in bouillon, making it cloudy throughout; they gave no reaction for indol. They neither curdled nor soured milk, nor did they ferment grape-sugar bouillon. Fresh bouillon cultures, when treated with the serum of a patient with typhoid fever diluted fifty times, gave a typical Widal reaction. Symptoms and Types. Griffith2 treats of typhoid fever in infancy 1 Berl. klin. Wochenschrift, 1898, xxxv. 748. 2 Philadelphia Medical Journal, 1898, ii. 783. TYPHOID FEVER. 315 and childhood. A number of cases have recently been reported tend- ing to show that the disease is not, after all, very uncommon during the first two years of life. Griffith reports the case of a child, aged three months, who died of typhoid fever. During life it had suffered for six weeks from frequent vomiting and a troublesome, dry cough. The physical signs were indefinite. Fof a week the temperature was not above 100° ; after this it became elevated, the bowels looser, curdy, and green. There was a hacking cough. Death occurred eight days later. Three further cases are reported : one, fatal, at seven months; one at fourteen months, and one at nineteen months. According to Grif- fith, the symptoms are, as a rule, indefinite and uncharacteristic in onset; milder, and with a tendency to a shorter course and a disposi- tion for the nervous symptoms to overbalance the intestinal manifesta- tions. The disease begins more suddenly than in adults, so that " in the course of only a few days the attack is in full swing, and even the characteristic spots may be present." More commonly, though, the attack is slight and insidious. Children walk about with loss of appe- tite, perhaps headache and slight malaise. The physician only gradu- ally comes to realize that he is dealing with typhoid fever. The tem- perature tends to vary from its more typical course in adults; it may rise suddenly, and often runs a very irregular course, especially in infants. During the fastigium the temperature often remains high, with but little variation between the morning and evening elevations. The remittent type which is so frequent toward the end of typhoid in adults is often absent or greatly curtailed, the temperature falling per- haps by crisis. Abortive types are common, lasting sometimes not more than a week; the average duration is certainly shorter than in adults; roughly speaking, this may be estimated at from fourteen to twenty days. The nervous symptoms overbalance the intestinal mani- festations, and yet even they are insignificant in the majority of cases. Headache is common, but is often slight, and many children remain in the best of spirits throughout the attack. Often there is slight delir- ium, and in some instances screaming. Apathy is an important symp- tom, but subsultus and coma vigil are rare; nervous disturbances, sug- gesting meningitis, may occur, especially stiffness of the neck and a tendency towards opisthotonos. Herpes may occasionally be seen Griffith believes that the eruption is as frequent as in adults. Enlarge- ment of the spleen is always present. The tongue is less often dry than it is in adults. Vomiting is a frequent initial symptom, and is commoner later in the attack than with adults. The condition of the bowels varies, and appears to bear no relation to the severity of the disease. Diarrhoea was, in Griffith's cases, a symptom of little impor- tance. Hemorrhage is rare and generally slight-a fact due, he believes, 316 INFECTIOUS DISEASES. to the moderate development of the intestinal lesions. Perforation is also infrequent, but may oceur, Schofield having reported a possible case in a baby of twenty-one months. Nervous Manifestations. Guizzetti1 found severe changes in the sympathetic nervous system in ten cases of typhoid fever, the lesions being especially marked where fatal complications, such as peritonitis, hemorrhage, or broncho-pneumonia, were absent. He, therefore, believes that these changes may have tended to cause the fatal exit. In two cases which died of heart-failure he found a neuritis segmentria in the cardiac plexuses and small-celled infiltration in the intracardiac ganglia. In twenty-two patients dying from other diseases no such severe changes were to be found in the sympathetic nervous system. Monteux and Lop,2 during an epidemic of typhoid fever in Marseilles, observed two cases in which the symptoms suggested some affection of the pneumogastric nerve. There was dyspnoea coming on in paroxysms, tachycardia, hiccoughs, tympany in the region of the stomach, pain in this organ, spontaneous and on pressure, and also in the region of the pneumogastrics in the neck, and the pupils were unequal. There were no lesions in the heart or in the lungs capable of producing these phenomena ; the urine was free from albumin. Several observers have described such symptoms, especially Peter. The authors believe that symptoms rela- tive to the pneumogastric nerve should be recognized among the other nervous troubles occurring in typhoid fever. Perforation of the Appendix. Rolleston3 reports a case of perforation of the appendix in walking typhoid. The accident occurred twelve hours after the patient entered St. George's Hospital, and opera- tion was without avail. In fourteen out of sixty cases of typhoid fever observed at St. George's Hospital, changes were found in the appendix. In five there was tumefaction ; in seven ulceration ; in two perforation. Perforation occurred in eighteen of these sixty cases (11 per cent, of all perforations). This is the same percentage found by Nacke. Finney estimates it at about 5 per cent., and Fitz at about 8 per cent. Hemiplegia and Aphasia. Rolleston4 also reports an instance of left hemiplegia, with aphasia, coming on in a man, aged thirty years, on the twenty-fourth day of the disease. There were no convulsions at the onset. The patient gradually recovered. Hawkins has collected seven- teen cases of this nature, and believes that they are due to embolism and thrombosis. The absence of convulsions is contrary to the idea of throm- bosis, and suggests that the lesion was probably in the middle cerebral 1 Arch, per le sci. med., 1898, xxii. 65. 2 La presse medicale, 1898, Ann. vi. t. i. 254. 3 Lancet, 1898, i. 1401. 4 Brit'sh Medical Journal, 1898, i. 1201. TYPHOID FEVER. 317 artery. There was no sign of syphilis. Herringham records the case of a girl of nine years, with paralysis in the third week. Two years later weakness of the limbs on the right side and in other parts still ex- isted. Thromboses in small veins are, of course, not unusual in typhoid. Hawkins says that eight cases similar to those of Rolleston are reported in English literature, although others have been observed on the conti- nent, and lately Osler has reported one. Recovery is the rule. Only two autopsies have been made, in each of which there was found throm- bosis of the middle cerebral artery. In Duncan's case the heart was dilated, but otherwise healthy. Rolleston comments on the difficulty in distinguishing clinically between thrombosis of cerebral veins and cerebral arteries. An interesting note by Osler upon this subject will be found in the Journal of Nervous and Mental Disease for May, 1886, while the reviewer has reported two. instances in the Johns Hopkins Hospital Bulletin for April, 1896. Low Temperature. Rosenthal1 reports a case of typhoid in which, on the fourteenth day, the temperature fell to 95° F., remaining subnor- mal for four days, and afterward pursuing a fairly characteristic course. There was no evidence of hemorrhage. Relapses. Hunt2 observed relapses in twenty-eight out of seventy- one cases-a proportion of 40 per cent., which is exceptionally high. In two cases there was a double relapse and in one three. No cause for these relapses could be found. The mortality in these seventy-one cases was 7 per cent. There were fifteen instances of intercurrent relapse, and eleven occurring after the apyretic period, which varied between one and nineteen days, the average being eight days. The course of the fever in all cases resembled that of the ordinary attack. Only three of the twenty-eight relapses died, and in eight the duration did not exceed a fortnight. In no instance was the onset sudden, nor was the characteristic temperature-curve of Irvine observed. Symptoms differed from those of the primary attack only in being milder and appearing at an earlier date, the temperature reaching its maximum sooner and the rose-spots appearing from the third to the seventh day. The shortening and mollifying of the relapse, the author believes, is due to the partial immunity conveyed by the first attack. The relapses were more common in cases with diarrhoea. Typhoid Fever without Intestinal Lesions. Several very interesting communications have been made within the past year on the subject of typhoid fever without intestinal lesions. Nichols and Keenan3 have collected nine instances of sufficiently well-identified cases of this 1 Philadelphia Medical Journal, 1898, i. 120. 2 Practitioner, 1898, lx. 263. 3 Montreal Medical Journal, 1898, xxvii. 9. 318 INFECTIOUS DISEASES. nature. They call attention to the fact "that the time has gone by when we could regard typhoid as an infective process localized in the intestines, producing the general symptoms by the secondary action of its toxin; rather, have recent researches proved that the disease is an infective one, invading the organism through the lymphatics of the intestine and infecting the system as a whole, the intensity of the lesions being generally, but not invariably, directly proportional to their prox- imity to the point of inoculation ; the brunt of the disease hence may fall upon lymphoid tissue, parenchymatous organs, or, at times, the central nervous system." The intestinal tract, then, merely represents a point of departure of the typhoid bacillus, not the sole place of localization for its development. They report the case of a laborer, twenty-five years of age, who was admitted on June 28th to the out-patient department, stating that for about two months he had been suffering from severe headache, loss of appetite, and general weakness. He had been obliged to give up work several times. He was somnolent and mentally dull. There was high fever; the tongue was coated ; the abdomen distended, tense, and tender, showing faded rose-spots; the spleen was palpable ; the pulse was dicrotic; the bowels were constipated. The urine was free from albumin ; the blood, examined by Wyatt-Johnston, gave the serum reaction. For five days the patient was semi-comatose, after which low, muttering delirium and vomiting came on. After the first week there were involuntary evacuations; fever continued with some variations up to the time of death, which occurred on the 21st. On autopsy there was splenic tumor ; enlarged, soft, congested mesen- teric glands, especially in the ileocsecal region, " while the lowest three Peyer's patches of the ileum were slightly raised above the general sur- face, but showed no signs of inflammation." No focal necroses were recognizable in the liver. Both lungs showed areas of broncho-pneu- monia at the bases. Microscopically, great numbers of Jf. lanceolatus were found about the areas of broncho-pneumonia. The spleen, which was hyperplastic and congested, showed infarctions ; it contained clumps of B. typhi in the pulp. In the mesenteric glands typhoid bacilli were also found in characteristic clumps. Sections were made through one of Peyer's patches which presented the slight swelling. All that could be found was a proliferation of the lymphatic tissue in the submucosa which was very generally infiltrated with lymphoid elements. The patch was not congested, and there was no evidence of necrosis. After staining by Lbffler's method, in the deeper parts were found small clumps of bacilli resembling typhoid which decolorized by Gram's method. In the superficial part were numerous bacilli of various kinds, evidently intestinal bacteria, which stained by the Gram-Weigert method. TYPHOID FEVER. 319 Cultures made from the blood at autopsy were negative, the serum giving the typical Widal reaction. Cultures from the spleen and liver revealed typical typhoid bacilli; these were obtained from the spleen. They conclude that atypical typhoid may be " a very protean disease, its toxic power at one time being concentrated upon the mesenteric glands, at another upon the spleen, the liver and gall-bladder, the central nervous system, upon the kidneys, heart, or lungs, as the case may be." They bring up the question as to whether in some atypical cases the typhoid organism may not enter in some other manner than through the intestinal canal, possibly, for instance, through the lungs. In their own case, however, they are inclined to believe from the enlargement of the mesenteric glands that the point of origin was intestinal; the local intestinal lesions may have been more marked earlier in the course. An extremely interesting instance of the same nature is reported by Flexner and Harris.1 After summarizing the cases in the literature, and particularly emphasizing the remarkable contribution of Chiari and Kraus, who found seven out of nineteen cases between January and May, 1897, in which the anatomical lesions of the disease were wanting, the serum reaction having been positive, they relate the following case, which the reviewer had the opportunity of observing clinically : A man, sixty-eight years of age, was admitted to the hospital on October 28th, complaining of shortness of breath. He had been losing weight and strength for two months. During this time he had felt ill, though he was unaware that he had had any fever. Two weeks before entry, severe pain in the abdomen ; shortness of breath. Two days before entry he fell to the floor while undressing, and had been in bed since that time. There was high fever; respirations 44 to the minute ; loud friction rub in the right axilla. The spleen was not palpable; there was a leucocytosis of 18,000. No great change in the patient's condi- tion was noted on the following day. He died at 10 o'clock on the 30th. The autopsy, made on the day after death, showed thrombosis of the main branch of the pulmonary artery supplying the lower lobe of the right lung, gangrene of the lung, perforation of the pleura, pyo- pneumothorax. There was acute splenic tumor. The oesophagus, stomach, and intestine, excepting the appendix vermiform is, which was converted into a fibrous cord, were not remarkable. The mesen- teric glands showed nothing abnormal. Plate cultures upon agar-agar made from the right lung (gangrenous portion), left lung, liver, kidneys, and spleen showed pure cultures of the B. typhosus. An agar-agar plate from the heart's blood and a blood-serum tube from the cerebro-spinal fluid remained sterile. 1 Johns Hopkins Hospital Bulletin, 1897, viii. 259. 320 INFECTIO US DISEASES. These organisms gave a characteristic Widal reaction with serum from a case of typhoid fever. The authors believe that "the tests employed for the identification of the organisms isolated from the several viscera leave no doubt as to their nature, and the case, therefore, is properly to be regarded as one of typhoid infection without intestinal lesions or glandular enlargement; indeed, it would have been impossible to diagnose the case as typhoid fever in the absence of bacteriological examination." These two cases are of great interest. In the former the manifesta- tions were clinically those of typhoid fever, and, as the authors them- selves acknowledge, it may be that the intestinal lesions were previously more marked than at the time of the autopsy. In the latter the absence of any intestinal lesions whatever, as well as of enlargement of the mes- enteric glands, together with the entire failure of any symptoms during life which suggested the disease, make the observations of very unusual interest. Did infection in these cases take place through the gastro- intestinal tract? In the first this seems probable, but in the second one need well raise the question whether infection may not have entered through some other channel. Intestinal Symptoms. Osler1 calls attention to the fact that the severity of the symptoms of typhoid fever bears no relation to the extent or intensity of the intestinal lesions, and protests against the growing tendency to treat the disease as if it were localized in the small intestine. He summarizes the intestinal symptoms in ninety-nine cases, occurring in his wards during the year 1897. The absence of intestinal manifes- tations in this particular series of cases is doubtless rather unusual, but nevertheless the analysis " will show how slight the enteric symptoms may be." He distinguishes (a) symptoms of onset; (6) symptoms during the course; (c) symptoms during convalescence. In the first class pain in the bowels was complained of in twenty-three cases, and was rarely severe. In one instance attacks of pain in the right flank suggested a possible appendicitis. This has been observed before, a number of cases being on record in which the appendix has been removed on account of this suspicion. In forty cases there was looseness of the bowels or active diarrhoea; in twelve purgative medicine had been taken, but in other instances this may have been and probably was the case. Of the symptoms during the course of the disease, pain occurred in eleven instances; one patient had persistent pain during the first week ; one for a single day only, the twenty-seventh. In two cases the pain was so severe as to cause some uneasiness, in one having been possibly due to a 1 Philadelphia Medical Journal, 1898, i. 30. TYPHOID FEVER. 321 cholecystitis. Of the ninety-nine cases only twelve had diarrhoea while in the hospital, and " in not a single instance was it severe or protracted enough to recpiire treatment." In three of these twelve cases it was just after admission ; in two it was only for a single day. " This, of course, is an exceptional experience, and illustrates how variable typhoid fever may be." Slight distention of the abdomen was present in eight cases. In no instance was it severe or the cause of any uneasiness. " It (meteorism) is rarely present with constipation, and is usually an accompaniment of diarrhoea. When extreme there is no intestinal symptom, with the exception of perforation, of graver omen or more difficult to combat." This observation is one which physicians who are in the habit of treat- ing their cases by the Woodbridge method, or by other methods which interfere unnecessarily with the action of the bowels, would do well to bear in mind. Any one with a large clinical experience with typhoid fever cannot fail, the reviewer believes, to recognize its truth. Hemorrhage occurred in five instances. All recovered. It is inter- esting that out of these ninety-nine cases there was no instance of perforation. Of the intestinal features in convalescence constipation was the only annoying one met with. Osler notes that diarrhoea, though rare, is a distressing symptom in convalescence, and is usually due to persistence of ulceration in the large intestine. It may prove very intractable. Among these ninety-nine cases not a death occurred from intestinal complications. There were but four fatal cases ; one, a colored woman, died the day after laparotomy was performed for acute cholecystitis and peritonitis ; one died of asthenia in the fourth week of the disease, the day after admission ; one, the old man already referred to in the note of Flexner and Harris, died of pneumonia with pulmonary gan- grene and general typhoid infection without intestinal lesions; and one died with a " most profound involvement of the nervous sys- tem." Sequelae and Complications. Glossitis. M'Crae1 reports a case of glossitis occurring at the beginning of a relapse. The tongue was much swollen, protruding between the teeth. There was marked sali- vation. The condition cleared up in the course of six days. Cultures from the tongue were negative. Considerable relief followed hemor- rhage after the taking of the culture ; this suggests the value of inci- sions into the substance of the tongue in the treatment of such cases. Cholecystitis and Cholelithiasis. Cushing2 reports a case of typhoid cholecystitis in a woman, aged twenty-six years, who had 1 Johns Hopkins Hospital Bulletin, 1898, ix. 118. 2 Ibid., ix. 91. 322 INFECTIOUS DISEASES. never, so far as could be made out, suffered from any febrile disease beyond pneumonia ten years before. For three years she had had occa- sional attacks of vomiting after indiscretions in diet. She entered the hospital complaining of pain in the region of the gall-bladder of five days' duration. There was moderate fever. The gall-bladder was palpable and on operation was found to contain a small amount of brownish mucoid material and fifteen gallstones. Cover-slip preparations showed rod-shaped organisms with rounded ends. The organisms, both morpho- logically and on culture, presented the characteristics of the B. typhosus. The serum reactions were also positive. " The patient's blood serum produces a distinct and rapid agglutinative reaction of the original organism and of the control, both obtained from agar slants four days old. The blood serum from a case of typhoid fever in the medical wards produces a similar reaction with both organisms. Blood serum obtained from a healthy adult produces no clumping or loss of motility in either case." Acute cholecystitis as a complication of typhoid has been recognized by many observers, and the extreme frequency with which typhoid bacilli are found in the gall-bladder in artificial infections in animals as well as in human beings is well known. Flexner has found the organism in the gall-bladder in 50 per cent, of his cases at autopsy. That the local inflammation is often due to this infection has also been clearly shown. Welch, in 1890, called attention to the presence of micro-organisms in the centre of gallstones, and suggested that they might be the starting-point for the deposition of the biliary salts. Since this time observation has tended to show that in reality cholelith- iasis is in most instances due to infection. Gilbert and Fournier,1 as a result of their experimental researches, have divided biliary lithiasis into two great pathological groups : lithiasis due to the colon bacillus- by far the most common-and lithiasis due to typhoid. Indeed, condi- tions similar to cholelithiasis have actually been reproduced in guinea- pigs and rabbits. What are the steps in the process? Observation and experiment justify one in assuming with Cushing that: "(1) The bacilli during the course of typhoidal infection" (or, under other cir- cumstances, the B. roll communis') "quite constantly invade the gall- bladder ; (2) the organisms retain their vitality in this habitat for a long period; (3) in the course of time the bacilli are almost invariably found to be clumped in the bile, suggesting the occurrence of an intra- vesical agglutinative reaction; (4) these clumps presumably represent nuclei for the deposit of biliary salts, as micro-organisms may with regu- larity be demonstrated in the centres of recently formed stones ; (5) gall- 1 Compt.-Rend. Soc, de Biol., 1897, 936, TYPHOID FEVER. 323 stones being present in connection with the latent, long-lived infective agents, an inflammatory action of varying intensity may be provoked at any subsequent period." Cushing has collected six cases of post-typhoid cholecystitis associated with gallstones where, on operation, the B. typhosus has been isolated, as well as five similar cases occurring in the Johns Hopkins Hospital in which only the B. coll communis has been found. The most interesting feature of Cushing's own case is that there was absolutely no history of clinical typhoid fever-a fact rendering the case unique. Miller1 reports the case of a woman, aged thirty-seven years, who had two attacks of biliary colic seven years before, followed a month after by what was termed a " bilious fever," lasting about four weeks, and succeeded four or five weeks later by a relapse of a months' duration. Ever since this time she had had frequent attacks of biliary colic. There was tenderness over the gall-bladder; no tumor to be felt. On operation there were extensive adhesions about the gall-bladder. Gall- stones were found in the bladder and cystic duct, as had been suspected by Dr. Ramsay, as well as a small amount of bile and a milky fluid. A bacteriological examination of the fluid showed a pure culture of the B. typhosus. Gwyn found that the organism gave a typical Widal reac- tion. " An agar smear from the patient, L. P., agglutinated typically by serum of a typhoid patient. Serum of patient L. P. agglutinates a known typhoid organism rapidly at 1 : 100 dilution. Reaction is imme- diate and positive, more like that of an acute attack than of an attack several years ago." This is a most important observation. Knowing what we do of the etiology of gallstones, the question naturally arises, Was the general typhoid infection secondary to a local infection of the gall-bladder, or was the infection of the gall-bladder, perhaps originally with colon bacilli, a secondary infection with typhoid following ? That the former is not an unreasonable supposition is testified to by the previous case of Cushing, where a local infection of the gall-bladder was present with- out history of a previous general infection. The work of recent years has shown us that the B. typhosus, like the M. lanceolatus, may give rise to various local affections as well as to general septicaemia. Most of these local affections probably follow a primary, more or less characteristic typhoid fever. We know, how- ever, that a general typhoid septicaemia may exist without intestinal lesions, and it is by no means improbable that local typhoid infections in other parts may exist primarily. These may, perhaps, in some in- stances give rise subsequently to more general invasions. 1 Johns Hopkins Hospital Bulletin, 1898, ix. 95, 324 INFECTIOUS DISEASES. Hematuria. Guinon1 reports the ease of a boy, aged ten years, who had a simple purpura at the time of the onset of typhoid fever. The development of the symptoms of typhoid was marked by haematuria, which lasted four days. The disease was of a severe type. The roseola was marked, and fresh purpuric spots kept appearing. There was a large amount of albumin in the urine. Finally, on the twenty-first day, there appeared a general morbiliform exanthem, which may have been due to a secondary infection or to large doses of quinine (1.5 in four hours). The case ended in complete recovery without persistent albu- minuria. Atrophy of the Optic Nerve. Pauas2 reports a case of atrophy of the optic nerve following typhoid fever ; this originated, apparently, in an optic neuritis. The condition was unilateral and due, the author believes, to foci of cerebral inflammation. The reviewer has observed a similar instance. Neuritis. Poix and Gaillard3 report a case of neuritis of the brachial plexus. A man, aged twenty-two years, with mild typhoid fever, suf- fered from pain in his right upper extremity, which was followed by paresis with consecutive atrophy of the rhomboids, serrati, deltoids, supraspinatus and infraspinatus muscles. The supraspinous and infra- spinous fossae on the right side became excavated, and the patient could not raise his arm above the horizontal position. The condition was one of typical angel-wing scapula. There were no fibrillary twitchings. There was diminution in the tactile, thermic, and pain-sense in the supraspinous and infraspinous fossae ; no vasomotor or trophic troubles. There was reaction of degeneration in the atrophied muscles. All the muscles affected belonged to the group innervated by the collateral branches of the brachial plexus. The authors know of no other instance where a neuritis of this localization has followed typhoid fever. Malarial Fever. Combined infections of typhoid fever and malaria have been discussed in the article on malaria. Diagnosis. The Widal Reaction. Although the Widal reaction is now in general use in diagnosis, its significance is quite obscure. Widal considered it as merely a reaction on the part of the body to the infection. Courmont ascribes it to the arousing of the defensive forces of the animal organism, and gives it great weight in prognosis. Chan- temesse believed that the appearance of the specific reaction indicated the formation of antitoxin. Gruber saw in the strength of the reaction a correspondingly firm establishment of immunity. The theories of 1 Riforma Medica, 1898, Ann. xiv. t. ii. 33. 2 Rev. internal, de med. et de chir., 1898, ix. 181. 3 La presse medicale, 1898, Ann. vi. t. i. 215, TYPHOID FEVER. 325 Widal and Courmont are at present given most preference; of the sub- stance or substances producing the reaction but little more is known ; its presence in the serum rather than in the cellular elements of the blood, and in most, if not all, of the fluids of the body, has been demonstrated ; a close connection with fibrin, the albumins, and the globulins has been repeatedly shown. Numerous experiments have made it clear that the blood is the tissue which possesses, as a rule, the maximum agglutina- tive power. With the general adoption of serum diagnosis various modifications in the original procedures have been introduced. Johnston,1 of Mon- treal, has shown that dried preparations give accurate and reliable reac- tions. Although precise measurements of the serum's power may be made, ordinary requirements call for only an approximation thereto. Dried blood is in almost general use in board of health labora- tories. In hospital service, however, the obtaining of serum presents no difficulties and is the more serviceable method. It is now generally agreed that the usual time for a reaction to appear is between the fifth and tenth days of the disease. Cases reacting earlier than the fifth day are not often met with. In these early reactions the common uncer- tainty as to the time of onset of typhoid must be considered. Delayed appearance of the reaction is quite common. Bensaude, A chard, Stern, Kolle, Durham, and Gruber instance reactions first seen as late as from the fourteenth to the thirty-fifth days of the disease. Thoinot reports a case negative until its second relapse. Cases reacting as late as the twenty-second, twenty-sixth, thirty-fifth, and forty-second days are given by Gwyn in the Johns Hopkins cases. Unfortunately, several well-authenticated cases are now on record as never having given the specific reaction.2 Among these are instances in which the diagnosis has been substantiated by the cultivation of the bacillus typhosus from the spleen ami circulation. The reaction may appear suddenly within twenty-four hours, or may completely vanish in the same time. Varia- tions in the agglutinative power in the same case from time to time arc not unusual. The persistence of the power is most uncertain. Remaining, as a rule, well marked for three or four months after the illness, it may dis- appear early in convalescence.3 Positive reactions have been found after eight and twelve years. During the febrile state the agglutinative power tends gradually to 1 New York Medical Journal, October 31, 1896. 2 Widal et Sicard. Soc. med. d. hop., December 11, 1895. Artaud et Earjon. Presse med., 1898. Gwyn, 1. c. 3 Bensaude. These Paris, July, 1897, No. 631. 326 INFECTIO US DISEASES. rise, falling subsequently in convalescence. In a majority of cases the serum may be diluted two hundred to three hundred times, and yet react well. Reactions in dilution of 12 :15,000 are instanced by Widal and by Biberstein.1 On the other hand, some cases may never give positive results if diluted more than ten to twenty times. The power may bear no direct relation to the severity of the infection. Many observers believe with Widal that the reaction is merely one of infection. Others, especially Courmont, as mentioned previously, illus- trate their theory of the defensive significance with appropriate cases in which the temperature falls with the rise of the agglutinative power, instancing also examples of the absence of the reaction until late in the course of severe infections, and its occasional disappearance before death. The evidence supports Widal. Pfeiffer has shown that the solvent property of the serum of immunized animals upon typhoid bacilli, a property which has been proven to be closely connected with the immunizing substance, is distinct from the agglutinating power. The former may be present in high degree while the latter is absent.2 Most statistics show figures apparently more or less influenced by the opinions of the authors. In some reports completely positive results have been recorded in all cases. In the majority, however, a small percentage of non-reacting cases show that the test is not absolutely without defects. Widal, in 177 cases, gives one case (proved bacteriologically) with- out reaction. Courmont3 reports 257 cases, among which three very doubtful infections failed to react; Bensaude,4 eighty-five, all positive; Biberstein,5 101 cases, with one negative result; Kerr,6 169 cases, of which number four doubtful cases failed to show the reaction. Gwyn, in 265 Johns Hopkins cases, found one typical typhoid, and two doubtful infections which failed to react. Thompson,7 in 800 collected cases, mentions six as giving negative results, leaving a positive per- centage of 99.2. Cabot,8 from 300 collected cases, calculates that in over 95 per cent, the reaction was present at some time in the disease. There are innumerable reports of smaller collections of cases, many of which are, unfortunately, open to criticism, owing to the incompleteness of their observation. 1 Zeitschrift f. Hygiene, 1898, xxvii. 3. 2 Pfeiffer and Kolle. Centralblatt f. Bakt., 1896, xx. Nos. 4 and 5. Pfeiffer and Marx. Deutsche med. Woch., 1898, xxiv. 489. Ehrlich and Morgenroth. Berl. klin. Woch., 1899, No. 1. 3 These Lyon, July, 1897, No. 122; Presse m^dicale, January 5, 1898. 4 These Paris, July, 1897, No. 631. 5 Zeitschrift f. Hygiene, 1898, xxvii. 347. 6 Scottish Medical and Surgical Journal, 1898, ii. 5, 70. 7 Medical Record, 1897, lii. 826. 8 Clinical Examination of the Blood, 1898. TYPHOID FEVEE. 327 With regard to the specific nature of the reaction it may be said that but few of the instances in which positive results with sera of diseases other than typhoid have been obtained can be considered. Normal serum will in many cases give quite decided reactions even when diluted five to ten times, especially if allowed to act for one or two hours. The non-observance of this fact has clearly been responsible for numerous doubtful results. We require now that serum in such low dilution as 1 :10 or 1 : 20 shall have agglutinated the organisms firmly within half an hour. Out of 3000 cases not typhoid not more than a dozen have given positive reactions with proper technique, and even these might be excluded (Cabot). Apparently reliable agglutination of the bacillus typhosus has, how- ever, been obtained by Jez in a case of tubercular meningitis, by Van Ordt in one of ulcerative endocarditis, by Block in a case each of malaria and diabetes, and by Stern in several normal individuals. After the expectations aroused by Widal's announcement, the results of serum diagnosis have been somewhat disappointing; though present in an immense majority of cases, the appearance of the reaction is often too late to be of diagnostic service. Reliable instances of its absence in typical typhoid infections and of its occasional presence in other affec- tions have, unfortunately, caused much skepticism among the general medical profession. Rarely more than 50 per cent, of cases are found to give a reaction when first seen or admitted to hospital wards. Many feel that its appearance thus after the establishment of the disease gives it value more as a confirmatory than as a diagnostic test. It must, however, be admitted that a sign present in over 95 per cent, of cases demands more consideration than any of the uncertain indications pre- viously relied upon, and it may finally be said that the presence of a Widal reaction positive under all requirements is an absolute indication of a typhoid infection, although, unfortunately, such an infection is not excluded by the reaction's absence. Typhoid Fever in Childhood. Griffith, in his article previously referred to, believes that many cases of so-called simple continued fever in children are typhoid. Meningitis must be carefully excluded. In- fluenza may cause sonic trouble in diagnosis. Typhoid fever cannot be excluded in young children or infants (or anywhere else, W. S. T.) because we fail to find roseola or enlargement of the spleen. The Widal reaction is reliable proof. The occurrence of other cases in a household will, of course, help in the diagnosis. Treatment. Diet. Bushuyev1 (Bushuyeff) makes an interesting 1 Vrach, 1898, xix. 786, 898. 328 INFECTIOUS DISEASES. appeal for the more liberal feeding of patients with typhoid fever. In- asmuch as his communication is in Russian and inaccessible to most, it may be well to give here a careful summary of his results. The author enters at length into the literature concerning the diet in typhoid. He notes the fact that most of those who object to liberal feeding base their objection, not so much on the insufficiency of the digestive juices as on the danger of the production of hemorrhage or perforation; but the changes resulting in perforation rarely appear suddenly; they come on gradually. They are so distant from the stomach that by the time substances, even though hard to digest, reach these areas, they are so far changed that one can hardly imagine that they could actually injure the intestine. Wholly indigestible substances, such as fruit-seeds or skins, might injure the gut, but even they are, as a rule, so far rolled up in mucus or intestinal contents as to be harmless. In autopsies on cases of typhoid on the thirtieth day or later, in patients who had been liberally fed, the intestine was in the same condition as under ordinary typhoid diet. One never hears of perforation of a tuber- culous ulcer due to food. The cause of perforation is the nature of the ulcer and not the character of the food. Bushuyev knows of nothing to support the view held by some that injury to the intestinal walls by solid food might provoke a re-entrance of the bacilli and an increased frequency of relapses. (On the other hand, we know that the organism is present in very small numbers, or, indeed, absent from the intestinal tract. W. S. T.) In the year 1895-1896 the author arranged with his colleague, Dr. Sartsievicb, a skeptic with regard to the advisability of liberal feeding, to divide all patients who entered the hospital into two series, one of which should come under Bushuyev's care, one under that of Dr. Sartsie- vich. The patients of Dr. Sartsievicb received only milk, as much as two litres in the twenty-four hours, and one or two eggs, soft-boiled or in Stokes's mixture. On the other hand, Bushuyev's patients were allowed, usually, 715 grammes of white bread, 170-180 grammes of boiled meat, a cutlet, and soup. If possible, there was given in addition a small quantity of supplementary milk and egg. The patients of both departments were allowed tea, wine (32 to 64 c.c.), and water. The following table shows the result: Whole number of patients Bushuyev. . 80 Sartsievich. 74 Recovered; . 72 (90 per cent. ) 65 (87.8 per cent.) Average day of illness on entrance into hospital .... . 7.5 5.8 Average day on entrance to division . 8.4 8.3 Day on which recovery was complete . 49.5 55 Number of days spent in hospital . . 42 49.2 Days of fever in hospital . 18.9 22.3 TYPHOID FEVER. 329 Bushuyev. Sartsevich. Dismissed incapable of duty . . 6 (8.3 per cent.) 10 (15.4 per cent. Died; , 8 (10 per cent.) 9 (12.1 per cent. Average day of entrance to hospital . 8.5 5.8 Average day of entrance to division . 9.1 8.4 Day of death (average) . 28.6 26.7 Number of days between entry and death 20.1 19.4 The figures, though small, speak decidedly in favor of liberal feeding, especially inasmuch as the cases coming under Bushuyev's care entered the hospital at a later period of their illness. The author especially emphasizes the fact that, though his patients received a relatively liberal diet, yet the conditions of a military hos- pital rendered it impossible to give them anything like a proper regimen. (And this, be it noted, in a Russian military hospital in time of peace ! Our own commissary department may not form so remarkable an excep- tion.-Reviewer.) From the table of supplies open to him the author has devised the following plan for feeding typhoid patients, which he has carried out for two years : 7 a.m. Tea with a roll. 8 a.m. 400 c.c. of soft (liquid) oatmeal, barley, or wheat porridge, with butter. 9 a.m. One or two boiled eggs, soft or hard, as the patient desires. 10 to 11 a.m. A glass (200 to 220 c.c.) of milk with a roll, one- half a cutlet, and a bit of boiled meat (160 to 168 grammes). 12 to 12.30 p.m. A plate (220 c.c.) of chicken-soup or a bowl of ordinary soup, sometimes with a bit of chicken from the soup, and a small cup of kisel (a sort of sour jelly); rarely, a little preserved fruit. 3 p.m. Tea with a roll. 6 p.m. A cup of chicken or beef-soup; semolina pudding or milk ; a bit of chicken. 8 p.m. Milk with a roll. During the night. Coffee or tea, with milk, two to four times ; coffee with cognac. For dinner and supper the white bread may be replaced by black (with the crust), and the soup by a thick wheat gruel. Many patients prefer the boiled meat to cutlets, and the ordinary soldiers' soup to hos- pital soup and gruel. The milk is generally boiled; occasionally it is given in the form of junket. As beverages, the patients were allowed cold water, boiled or unboiled, cranberry juice, milk of almonds, small amounts of beer, kvass. The cranberry juice was particularly grateful to the patients. In addition, all patients receive one to three ounces of wine in the morning, and every two hours 16 c.c. of Stokes's mixture. Patients when quietly sleeping were not awakened either for food or medicine. 330 INFECTlO VS DISEASES. The author believes that had he had a greater variety of artieles of food he could have excited the appetites of the patients, so that in some instances they might have eaten more. As it was, some com- plained of an insufficiency of bread. He was also unable to give the patients as much milk as he wished. As a result of his experience, he says, " Not allowing myself to jump at rash conclusions, I will restrict myself to this alone, that the outcome and course of typhoid fever with a hospital diet as general as possible is not in the least worse than with a restricted diet." During the year 1897, under this diet, he lost 26 out of 318 patients, or 8.2 per cent. During the ten years, 1888 to 1897, the deaths from typhoid fever at the military hospital at Kiev varied between 10 and 19.3 per cent.; the mean for the ten years was 12.4 per cent.-358 deaths in 2887 patients. Thus in 1897, with a mixed diet, the death-rate was materi- ally less than for the ten years previously. Under this regimen the general condition of patients is incomparably better than when kept upon an exclusively fluid diet. The common com- plaints are scarcely ever heard. At breakfast, dinner, and supper the patients are uncommonly wide awake ; even those who are very ill sit up in bed, beg for food, and eat with much satisfaction ; only a few have to be fed by nurses. If one observe the patients at meal-times he wholly forgets that these individuals are seriously ill, with temperatures above 39° C. The military authorities are amazed on visiting a typhoid ward at the time of breakfast or dinner, " inasmuch as they see almost no typhoids." The observation of the late Prof. AI. T. Chudnovsky, that the typhoid state disappears under a full diet, is confirmed. This condition was seen chiefly in patients transferred from other wards where they had been on an exclusively liquid diet. During the first hours in the ward the patient lies in a motionless condition, failing to answer questions and refusing food. But if one succeed in some way or other in persuading him to eat a bit of meat, or cutlet, or an egg, he immediately begins to show some interest in the surroundings. In a few days, often within a day, no trace of the typhoid condition remains. Unfortunately, it is impossible to persuade all typhoid patients to eat, at least what is at one's disposal in a military hospital. Attempts at forced feeding cause vomiting. Every care should be directed toward stimulating the pa- tient's appetite and to avoid disgusting him by what is brought before him. It is a different matter when the patient enters in an unconscious condition ; then a liquid diet should be given-as much as he can take without vomiting. If it be impossible to feed him by the mouth, then he should be fed through the nose with a tube. TYPHOID FIVER. 331 " Appetite, when it may be excited, lasts usually to the end of the illness; its diminution or disappearance is a grave sign." The tongue and lips of the patients remained in a relatively good condition. There were no unpleasant gastric or intestinal symptoms. The bowels were often constipated ; pea-soup evacuations were met with only in cases fed mainly on milk and bouillon. " Intestinal hemorrhage in feeding with a solid diet is not in the least more frequent than on an exclusively liquid diet. In the parallel inves- tigation with Dr. Sartsievich there was not a single case of intestinal hemorrhage among my patients. In 1897, among 318 patients, there were four instances of hemorrhage-that is, 1.7 per cent.; while according to Homolle, it occurs in 4.65 per cent.; according to Barth, in 2 percent.; according to Griesinger, in 5.3 per cent.; according to Murchison, in 3.77 percent.; according to Liebermeister, in 7.3 percent.; according to Steelier, in 10 per cent. Of my four patients with hemorrhage, two died ; the other two recovered, notwithstanding the fact that in one of them the hemorrhage was abundant and protracted. It is interesting that of these four patients only one received a solid diet; two entered in so serious a condition that they had to be subjected to forced feeding-i. e., only a liquid diet; finally one, a military physician, was fed throughout the course of his febrile stage, which lasted six weeks, only upon bouillon, milk, coffee, and tea with milk, because he feared solid food. Thus the figures also show that the critics' fear of hemorrhage from solid diet is not supported. " Perforation in the last two years has occurred only once in 509 patients-that is, in 0.19 per cent.-while other authors estimate it at from 1.25 to 3.04 per cent. "General peritonitis (non-perforative) was met with twice. One patient was admitted with a beginning peritonitis, but in the other it arose in the hospital. As in the case of perforation, so the peritonitis in the second case arose at a time when the patient was already being forcibly fed-i. e., on liquid nourishment. "Otitis media and parotitis were rare, and no bed-sores occurred." The loss of weight was less than in patients fed on a more restricted diet. The general condition was so good that the patients preferred, as a rule, to walk to their tubs and to the closet. " Long before the end of the fever they get out of bed, and there is much difficulty in making them lie down. In summer they go out into the garden almost upon the first day of the afebrile condition. All that has been said relates not only to soldiers, but also to officers. With the-latter, by the way, it is always necessary to enter into considerable explanation to overcome the fear of a solid diet and the early period at which they are allowed to leave the bed. It is to be hoped that this fear may disappear quickly 332 INFECTIOUS DISEASES. also among physicians, and that they may all in the end learn the simple truth, that for the patient as for the healthy man that diet is best which pleases him most. It is not necessary to go to any trouble that the food may contain a certain quantity of albumin, of fat, and of carbohydrates, but that it shall be tastefully prepared and may excite the appetite. Every effort of the physician who has under his care severely ill patients should be directed toward the stimulating of the latter by the, so to speak, natural means, namely, food. In the absence of appetite one cannot hope for much success, even from forced feeding. But if one succeed in exciting the patient's desire for food the privileges and advantages of a mixed, liberal diet become quickly evident. W hoever once attempts to feed his typhoid patients will never repent it, and will not meet with as many severe forms of typhoid as are observed under a restricted diet; for instance, the so-called hemorrhagic forms seen by Dr. Sartsievich in two patients." While one cannot but feel that this is the article of an enthusiast, yet both the reasoning and the figures are such as to make us reflect. Is it not more than likely that many cases of typhoid fever suffer from too restricted a diet ? Bearing in mind the long course of fever through which the patient must pass, the dangers to which he is exposed not only from exhaustion and the accidents peculiar to typhoid fever, but espe- cially from the various secondary infections to which he is so easy a prey at the end of his long period of fever and fasting, our main object should be to keep up his general nourishment by every means in our power. Obviously, if a more liberal diet than that afforded by the purely liquid regimen could be assimilated, the patient's strength would hold out mate- rially better. In diphtheria or pneumonia or febrile tuberculosis do we not make every effort to induce the invalid to take as much as he can bear of a simple, easily absorbable, and nourishing diet? And yet in typhoid fever we are restrained by a vague fear that any departure from the customary regimen is, for some reason or other, dangerous. What ground have we for this fear ? The ordinary answer is the quota- tion of a case where, after a long course of fever, with a much restricted diet, some indiscretion has produced a sudden rise of temperature with alarming symptoms. An indiscretion in diet may produce such symp- toms in any condition of severe physical exhaustion, but the reviewer has never seen anything to suggest that this is more common in typhoid fever than in any other similar condition. And those observers who in recent years have intelligently adapted the diet to the patient have only good reports to make. Such observa- tions as those of Shattuck1 and Bushuyev are the best proofs that there 1 Journal of the American Medical Association, 1897, xxix. 51. TYPHOID FEVER. 333 is no special condition in typhoid fever which contraindicates rationally liberal feeding. Bearing in mind the frequency of intestinal lesions we should, of course, avoid substances which leave an undue residue, but that the general course of the case would improve, that convalescence would be quicker, that lives would actually be saved, if, as Shattuck says, we paid more attention to our treatment of the patient than to that of the disease as such, the writer is convinced. The amount and nature of the nourishment given to each case must, of course, depend largely upon individual circumstances-the mental con- dition of the patient, the appetite, the character of the dejecta, the abdominal manifestations. Every care must, of course, be taken not to disgust the patient, and to avoid the development of unpleasant gas- tric or intestinal symptoms, for, as has already been said, our main object should be to keep up the strength; but in most instances there is probably no reason why the diet in typhoid should differ essentially from that in any similar infection. One cannot do better than to quote from the excellent article of Dr. Shattuck : " I would not be understood as advocating an indiscriminate diet. My plea is simply for treating the patient rather than the disease; for feeding him with reference to his digestive power rather than solely or mainly with reference to his fever; for the view that the danger of acci- dents from the local intestinal ulceration is not increased by allowing him to partake of articles which leave no irritating residue, and which cautious trial shows are digested without disturbance or discomfort. At one end of the scale are the cases with such irritability or weakness of the stomach as to lead to the unfortunate term gastric fever, or those with pronounced diarrhoea and undigested food in the stools; at the other end are those more numerous cases with clean tongue and a desire for food. Between the two is every gradation. The life of the former may depend on the skill and ingenuity of the doctor, assisted by the intelligent devotion of the nurse. The comfort and the duration of dis- ability of all others may be materially modified for good by careful study and wise individualization of our cases. A long list of permis- sible articles from which selection can be made for different cases, and for the same case at different times under varying circumstances, can be given. That which I append makes no claim to completeness, but is meant merely to be suggestive and illustrative : "Typhoid Diet. 1. Milk, hot or cold, with or without salt, diluted with lime-water, soda-water, Apollinaris, Vichy; peptogenic and pep- tonized milk ; cream and water (/. e., less albumin), milk with white of egg, slip buttermilk, koumyss, matzoon, milk whey, milk with tea, coffee, cocoa. 334 INFECTIOUS DISEASES. " 2. Soups : beef, veal, chicken, tomato, potato, oyster, mutton, pea, bean, squash ; carefully strained and thickened with rice (powdered), arrowroot, flour, milk or cream, egg, barley. "3. Horlick's food, Mellins's food, malted milk, carnipeptone, bovin- ine, somatose. " 4. Beef-juice. " 5. Gruels : strained cornmeal, crackers, flour, barley-water, toast- water, albumin-water with lemon-juice. " 6. Ice-cream. " 7. Eggs, soft-boiled or raw, eggnog. " 8. Finely minced lean meat, scraped beef. The soft part of raw oysters. Soft crackers with milk or broth. Soft puddings without raisins. Soft toast without crust. Blanc mange, wine jelly, apple-sauce, and macaroni." The Cold-bath Treatment. Much has been written during the last year concerning the advantages and disadvantages of the cold-bath treatment. Eichberg1 protests against its use. He asserts that the advocates of the Brand treatment are entitled to the thanks of the profession for proving : 1. That constant supervision and nursing are of greater importance to the patient than medication. 2. That the temperature furnishes the most important guide in the symptomatic treatment, and that it must be taken regularly day and night during the entire course of the disease, in order that the indica- tions of treatment be promptly met. He believes that this is all that can be said for the Brand treatment, which he considers cruel, bar- barous, and dangerous. Eichberg treats his patients by rest in bed, ice-cap to the head, a diet of milk and albumin-water, small quantities of dilute hydrochloric acid, or 2 grains of quinine in chlorine-water three times a day ; 4 grains of acetanil id and a tablespoonful of whiskey are given whenever the tem- perature reaches 103° in the mouth or 102.5° in the axilla. This dose usually suffices to control the temperature for six hours. " In some cases it has been found to be a powerful depressant, and a dose of 2 grains suffices. In other cases where the effect was inconsiderable the dose has been increased, though never exceeding 6 grains at a single dose." The patient is not allowed solid food until his temperature has been normal for a week. The bowels are moved by simple enemata, but when more than two movements a day occur Hope's camphor mix- ture is used. The ice-cap is not removed from the head until the tem- perature has been normal for twenty-four hours. 1 Philadelphia Medical Journal, 1898, ii. 297. TYPHOID FEVER. 335 Insomnia is treated by 25 grains of chloralamide. His tables are based upon a hospital experience of six years, and his figures, he says, are somewhat more favorable than those from other departments of the hos- pital. The cases, however, unfortunately numbered only 136. There were 6.6 per cent, of deaths; the percentage of relapses was 7.3 ; of hemorrhage, 2.9 per cent. During the past five years the mortality in other services than his own has been 12.1 per cent. Griffith,1 in children, uses purely symptomatic treatment: rest in bed ; milk diet if possible ; no purgatives ; enemata. Careful judgment is to be employed in giving baths to children. Some do not bear the plunge at all well. This is particularly true of younger children. " Certainly there is, as a ride, no period in childhood when one should use water at as low a temperature as in the case of adults. At the Children's Hospital in Philadelphia it is our custom to employ the graduated bath, placing the children into the tub with water at a tem- perature of 95°, and cooling it down to 85°, or occasionally, with older children, to less than this. In nearly all cases this is quite as effica- cious as the cold bath, and much less likely to cause fright." Very frequently sponging answers every purpose. A tepid bath sometimes suffices. Children bear fever well. "We can, therefore, often afford to let the fever alone. If it is true of adults, it is still truer of chil- dren, that hydrotherapy is not to be used as an unalterable treatment, no matter what its effect, and merely because the temperature has reached a certain degree. If it is used according to any such method it is capable, particularly in children, of doing far more harm than good." Wilson2 publishes statistics of eight years' treatment of typhoid fever by cold bathing in the German Hospital. In the entire eight years there were 741 cases, with 55 deaths, 7.42 per cent., a percentage very close to that obtained by Osler in the Johns Hopkins Hospital. Wilson modifies the Brand treatment somewhat, giving, at the onset, calomel, sometimes in fractional doses, but more frequently in doses of 0.3 to 0.05, followed, if necessary, in the course of several hours by a mild saline. These purgatives may be repeated once or twice in cases which come in sufficiently early, but are never administered in patients enter- ing after the tenth day. Cold compresses, or ice-bags, are applied to the abdomen in all cases of tenderness or spontaneous pain and in hemorrhage. When tympan- ites is marked, turpentine stupes are applied, at intervals, in connection with the external use of cold. The cold-bath treatment is abandoned, as a rule, only on signs of peritonitis, hemorrhage, or perforation. The other treatment is symp- 1 Loc, cit. 2 Philadelphia Medical Journal, 1898, ii. 79. 336 INFECTIOUS DISEASES. tomatic. With defervescence dilute hydrochloric acid is given for a short time, and later, if there be persistent anaemia, some form of iron. The baths are ordered every three hours if the axillary temperature is 101.4°. As every now and then a patient asked for the bath when the temperature was below the regular limit, Wilson adopted the ride of giving one or two plunges a day during the defervescence, and a plunge every day or every second day for a short time after defervescence has been completed. Wilson believes that the success of this method is determined by the period at which it is instituted in any given case-the earlier the better. " When the patients are able to, they are allowed to walk to their baths." This practice, he believes, has some advantages. " Our experi- ence leads us to believe, however, that the development of somnolence, gastro-intestinal catarrh, and the intestinal paresis to which tympanites is due, is favored by the log-like, continued passive recumbency of the patient suffering from enteric fever. The muscular atrophy due to dis- use and the diminished activity of the lymph through the body cannot be disregarded in this connection. The vast majority of patients suffer- ing from enteric fever are adolescent and young individuals at the most active period of life. The disease develops with comparative rapidity, and is of long course. Have we not in the enforced continued repose been adding to the pathological process a secondary disturbance of nutri- tion due to disuse of function? Our experience in the last year justi- fies me in answering this question in the affirmative." Theoretically, it would appear to the reviewer that thorough and well- carried-out massage, such as should be given during the baths, ought to accomplish these results as well, and with less danger to the patient, than by allowing him to take exercise which, in many instances, cannot but be fatiguing. The value of properly carried out massage in all dis- eases in which it is necessary to keep the patient for a long period in bed is, we believe, not sufficiently recognized; even if recognized, such treatment is not often enough put into practice. F. E. Hare1 is a most enthusiastic supporter of the cold-bath treat- ment. It cannot be denied that his results have been good, and he has had exceptional advantages in carrying out his treatment. With a very large clinical material, his patients have been placed in special wards. The diet in ordinary cases consisted of milk and beef-tea-three pints of the former and one of the latter, as a rule, a day. Ice-water is allowed ab libitum. Alcohol is given symptomatically when indicated. He has devised an ingenious and excellent stretcher, upon which the patient is lifted from his bed directly into the bath, thus avoiding undue 1 The Cold Bath Treatment of Typhoid Fever. TYPHOID FEVER. 337 violence. On admission, if the patient has not reached the ninth day of the disease, some unirritating purgative, usually castor oil, is given. Calomel was given in some cases, but the author believes that it has its disadvantages, occasionally failing to act, and not infrequently causing unexpected irritation. The baths are ordinarily given at a temperature between 75° and 80° -i. e., at the temperature at which the water flows from the main. They are repeated every three hours when the temperature is 102.2° F. or above. The duration of the first bath is ten minutes; a half-hour after its termination the temperature of the patient is again taken by the rectum. If this has not fallen to 101° or lower, various modifications in the temperature and duration of the baths are introduced. "Care is always taken that the patient is not unnecessarily disturbed. To this end food, stimulants, medicines, etc., are given at intervals of three hours, or some multiple of this time, except in the cases to be afterward considered, where the baths are given more frequently." Frictions could not be- given, as a ride, owing to insufficiency of service. The author is particularly impressed with the good influence of cold baths on the respiratory complications. Statistics, he believes, show the fear of inducing pneumonia to be baseless. "That the danger does not exist is proved by the fact that pneumonia is precisely one of the complications that is rendered infrequent by systematic bathing." The good influence of bathing upon the nervous and psychical symptoms was,also marked. The relative infrequency of the accumulation of sordes on the lips and teeth was due, the author believes, to the stimulation afforded by the baths to the salivary secretion. The tendency toward diarrhoea, statistics also show, has been diminished. Hare discusses at length the dangers of perforation and hemorrhage. In 586 carefully studied cases before the bathing period 2.9 per cent, died from perforation and 1.88 per cent, from hemorrhage. Out of 1902 cases treated during the ten years by bathing, 2.9 per cent, died of perforation and 1.2 per cent, of hem- orrhage. In discussing perforation he notes particularly the infrequency of the onset in connection with bodily exertion. He considers carefully the influence of the treatment upon the duration of the disease and upon the occurrence of relapses. The bath treatment appears to have short- ened the average stay of the patients in the hospital about 4.8 days. With regard to relapses, the author is unable to draw any positive con- clusions. The influence of the treatment upon the mortality and prognosis has apparently been very striking : 1828 consecutive cases occurred between May 15,1882, and December 31, 1886. These cases were under expec- tant treatment-cold sponging and the occasional use of other refrigera- tive measures short of the cold bath. The death-rate was 14.8 per cent. 338 INFECTIOUS DISEASES. Out of 1902 cases treated during the following ten years by the bath treatment, the mortality was 7.5 per cent. The following tables show his results : Table I.-"Expectant Period." Year. No. of Cases. Deaths. Percentage Mortality. 1882 (from May 15) . . 147 25 17.0 1883. . 273 40 14.6 1884 .... . 575 89 15.5 1885 .... . 369 49 13.3 1886 .... . 464 68 14.6 Totals . . 1828 271 Average 14.8 per cent. Table II.-"Bath Period." Year. No. of Cases. Deaths. Percentage Mortality. 1887 . . 239 27 11.3 1888 . . 339 23 6.8 1889 . . 595 42 7.0 1890 . . 160 16 10.0 1891 . . 137 7 5.1 1892 . . 104 7 6.7 1893 . 50 2 4.0 1894 . 79 1 1.3 1895 . 69 8 11.6 1896 . . 130 10 7.7 Totals . . 1902 143 Average 7.5 per cent. He considers the various possibilities of error, showing conclusively that a change in the type of the disease is not to be thought of. The systematically carried out bath treatment shows its main effect, appar- ently, in reducing the number of deaths from thoracic complications or from exhaustion as such. He discusses in an interesting manner the effects of delayed admis- sion, reaching the conclusion that: " (1) Admission was practically with- out influence in increasing the danger of death from perforation or hem- orrhage. (2) The whole difference in mortality in faver of cases admitted early was due to the lessened mortality from causes mainly pyrexial in nature." The mortality was appreciably greater among the men than among the women-8.7 to 5.6 per cent. The author believes that the prog- nosis is 50 per cent, better under the cold-bath treatment than under expectancy. The baths are regulated according to the temperature of the patient. "The following definite rule of practice was finally adopted : The first bath is of a temperature of as near 70° F. as possible, and lasts ten minutes. Tn the event of an insufficient fall in the temperature, each succeeding bath is prolonged by five minutes until the desired result is attained. When the bath has reached a duration of thirty to forty TYPHOID FEVER. 339 minutes, and still fails to reduce the temperature sufficiently, then the temperature of the bath is reduced by 5° F. at a time by the addition of cold water down to 60° F. or even 57° . There are cases, however, in which even this will not suffice, and in them I have again gradually prolonged the duration of the bath to sixty minutes. ... In cases which presented unusual resistance to refrigeration the baths were steadily decreased in temperature and prolonged in duration until, as in the case cited, the patient remained for one hour in water below 60° F." Alco- hol administered before the bath was found to increase its effect. " In a few isolated cases of obstinate pyrexia, in which from nervousness or from some other indiosyncrasy of the patient it is not possible to push refrigerative measures to the extent mentioned, ... I have been in the habit of administering in addition antifebrin. ... It should never be given in doses exceeding 5 grains for an adult, and its use should be limited strictly to cases just described ; it should be regarded, in fact, as a pis-aller. Furthermore, its use should be limited in these cases to the period, usually but a few days, during which the temperature is obstinate, being discontinued immediately the temperature becomes man- ageable by the bath. Finally, it should not be given more than three times in the twenty-four hours; once is frequently enough." The fever in the early stages of the disease is more resistant to the baths; these, therefore, are continued longer. In old patients with weak hearts "vig- orous antipyresis is . . . contraindicated, as a rule; while tepid baths of apparently short duration are found to be both efficient and grateful to the patient." Neither diarrhoea nor meteorism calls for a cessation of bathing. Small quantities of the blood in the stools do not of necessity contraindicate bathing, but the baths are always stopped if the hemorrhage has been sufficient to affect the temperature. If the temperature rises after the hemorrhage, and there is no reappearance within three days, the baths are resumed. Unusually high temperature during this period is combated by antifebrin. On the other hand, H. A. Hare and Holder,1 from a comparison of large numbers of statistics from different sources, arrive at much less favorable conclusions with regard to the value of the bath treatment. They believe that the effect of improved sanitation has been to decrease the virulence of the infection. They protest vigorously against Wilson's method of allowing the milder cases to walk to their tubs, and depre- cate the use of baths in patients who are feeble. They emphasize Lie- bermeister's suspicion that the cold bath may increase the tendency to hemorrhage, but acknowledge that this does not appear to be proved by statistics. They believe that statistics prove the greater frequency of 1 Therapeutic Gazette, 1898, xxii. 153. 340 INFECTIOUS DISEASES. relapses with the cold-bath treatment. They assert that " the influence of the bath treatment on the duration of the disease seems to be to prolong it," though their statistics are not conclusive. They conclude that, taking everything into consideration, the cold bath is responsible for the saving, at most, of but 2.5 per cent. Protesting against the almost universal use of the bath, they urge its more judicious and symp- tomatic application and its modification to suit individual circumstances. " When we consider all the points in the cold-bath treatment, it is almost impossible to avoid the thought that it is a measure to which in a few years we will look back with the same distress with which we now regard venesection and other excesses." Out of 356 cases in Osler's wards only 299 were bathed, 11 showing that in Osler's view a fairly large proportion of cases are not suited to the bath." " No bath in typhoid is properly given if active rubbing of the body is not resorted to while the patient is in the bath." If there be constipation or moderate diarrhoea at the onset of the disease, they advise the administration of a "full dose of calomel in divided doses." Cold sponging is sufficient in most cases. "It is advisable not only to use friction in a light form, but to use moderately active massage, with the same objects in view as when the rest-cure is undertaken, for the proper treatment of typhoid is modified rest-cure. We are firmly con- vinced that by this means bed-sores, local congestions and effusions, oedematous swellings, peripheral nerve-pains, and muscular feebleness will be largely decreased; and Pospischl has shown that mechanical irritation of the skin is capable of increasing heat loss 95 per cent." H. A. Hare particularly advises the administration of " more nourishment than the average typhoid patient has usually had in the past. Almost any article easy of digestion should be allowed, as one or two or more lightly boiled eggs, cornstarch, arrowroot, etc. Stimulants should be used in carefully graduated doses whenever the circulation needs them, particularly alcohol. . . . Let the physician be a watchman constantly, and a therapeutist or hydrotherapeutist only as necessity arises." While the statistics of the past year only go to uphold the generally accepted view that the cold-bath treatment of typhoid fever is the best method which we yet possess, there is wisdom in the protestations of Hare and Holder against the injudicious use of this measure. The reviewer has had opportunity of following the cases treated in the Johns Hopkins Hospital almost from the beginning of the application of this method; and, both from his observations there and from the accumu- lating statistics, is convinced of its value and of the wisdom of its appli- cation in most cases. Possibly, however, harm has been done by too specific and dogmatic directions as to just when and how it should be TYPHOID FEVER. 341 used. The author doubts the necessity or wisdom of ever giving baths below 70° F., and is convinced, on the other hand, of the advisability in many instances of raising the temperature of the water considerably. With a nervous or intelligent patient the first bath should almost always be given at 80° or even as high as 90°, the temperature being gradually reduced. In many instances baths at 80° may answer well throughout the course of the disease. Undue excitement of the patient should be avoided in every possible way. Modifications in the length of the baths or in their frequency must, of course, be made symptomatically, and such modifications are often advisable. As stated above, the reviewer heartily concurs with the observations of H. A. Hare upon the value of judiciously applied massage, not only during but after the bath period. It ought not to be necessary to remind individuals who are fitted to practise medicine that no rule can be laid down for the treatment of any disease which is not open to many exceptions. The appreciation of the conditions calling for such exceptions must depend upon the judgment of the physician. If the practice of medicine could be regulated by rules, the function of the physician would be small. Antitoxic Treatment. Walger1 reports upon several cases of typhoid fever treated with specific human serum according to the method of Weisbecker. Four cases, all of which were apparently of extremely serious nature, were thus treated. All recovered more or less rapidly after the initiation of treatment, which occurred on the eigh- teenth day. The injection appeared to be followed by an appreciable change for the better in the patients' condition, the temperature reach- ing normal for a part of the day, at least by the second or third day, practical apyrexia being reached by the seventh day in the first case and the fifth day in the second. In the latter two cases the improve- ment in the general condition was marked. This was especially shown by the great improvement in the appetite. The author enters into some speculation as to what the effect of the injections may be upon the anatomical course of the disease, and mentions the fact that in all four cases the diazo reaction persisted some time after the injection, while in three instances a typical typhoid roseola developed. In the two latter cases a relapse occurred, during which, on account of its mild character, the serum was not used. Chantemesse2 has apparently succeeded in obtaining a "toxin" of high virulence, to which horses are especially sensitive. He has obtained this substance in comparatively pure form, and studied its effects upon animals. He has succeeded, after two years' careful work, in immu- nizing a horse, and has obtained a serum which has high antitoxic and 1 Centralbl. f. inn. Med., 1898, xix. 941. 2 La presse medicale, 1898, Ann. vi. t. i. 180. 342 INFECTIO US DISEASES. preventive properties in animals. " Armed by these experiences, I have been able to inject antitoxic serum in men suffering from typhoid fever. The value of this new method of treatment cannot be judged other than by the study of statistics and by numerous observations. In the mean- time I may say that the serum acts well in men suffering from typhoid fever, acting after the manner of an antitoxin, diminishing and sup- pressing the nervous phenomena, lowering the temperature, hastening recovery." Laparotomy for Intestinal Perforation. Cushing1 reports three cases of operation for intestinal perforation. One of these instances was fatal; in another recovery followed ; in the third operation no per- foration was found, and recovery followed. The first case is of especial interest in that three operations were performed, the second and third being demanded by the existence of intestinal obstruction. The author discusses the importance of leucocytosis as an evidence of perforation, and, while acknowledging that its presence points strongly toward the ex- istence of some inflammatory complication, recognizes the fact that after perforation with a general septic peritonitis the leucocytosis may in great part or completely disappear. The conclusions, with which the reviewer most heartily concurs, arc as follows : " When the diagnosis is made operation is indicated, whatever the condition of the patient. As Abba's case exemplifies, no case may be too late. A precocious exploration from an error in diagnosis is not followed by untoward consequences, such as must invariably be expected after a neglected and tardy one." Our present knowledge amply corroborates the statement of Mikulicz made at Magdeburg in 1884 : " If suspicious of a perforation one should not wait for an exact diagnosis and for peritonitis to reach a pronounced degree, but, on the contrary, one should immediately proceed to an exploratory operation, which in any case is free from danger." Prophylaxis. Pfeiffer and Marx2 make a most interesting communi- cation upon preventive inoculations against cholera and typhoid fever with preserved virus. Pfeiffer and Kolle published a method of immu- nizing men against typhoid fever, based upon the same principle which Haffkine has made use of in his anticholera injections, consisting of the subcutaneous inoculation of 2 milligrammes of an eighteen-hour agar culture of typhoid organisms. This is followed by a transient rise of temperature to about 38.5°, accompanied by moderate subjective symptoms of headache and loss of appetite. In ten days the blood shows a solvent power upon typhoid organisms-in other words, the characteristics of the serum of individuals who have recovered from 1 Jolins Hopkins Hospital Bulletin, 1898, ix. 257. 2 Deutsche_med. Wochenschrift, 1898, xxiv. 489. TYPHOID FEVER. 343 typhoid infection. They found by experiment on animals that by the addition of 0.5 per cent, carbolic acid, after sterilizing the dose for inoculation, the substance might be kept for at least a month and a half without suffering any diminution in its activity. They then pro- ceeded to experiment with human beings, using of a virus preserved for two months and a half a quantity equal to that given by Pfeiffer and Kolle. They gave in quantity 0.2 of their mixture, which corre- sponded approximately to the 0.002 of typhoid culture used by Pfeiffer and Kolle. After several hours the patients complained of headache and weakness, and the temperature rose to about 38°. One patient felt well on the following day; the two others complained of headache and had a temperature of 38° on the following day as well. About the point of injection there was a slight swelling and reddening as large as the palm of the hand. By the end of the second day all the patients felt well. The results were as good as those obtained by Pfeiffer and Kolle with fresh inoculations. None of these individuals had ever had typhoid before, and in none did the blood possess before treatment an agglutinating or solvent power. Even after the inoculations the agglu- tinating power was absent in one and relatively slight in the others. The solvent action, however, upon the typhoid bacilli in the peritoneum of guinea-pigs was extremely marked in all instances. It is particularly interesting that the serum which was most active in the animal body was the one which gave no agglutinative reaction outside. The agglutinating and solvent powers of immune serum are, as has been pointed out before, quite different. The solvent power, as has been shown in the most interesting manner in another connection,1 is that indicating the presence of the anti-body. The significance of the agglu- tinating power is as yet unknown. The practical importance of these observations of Pfeiffer cannot be over-estimated. There is good reason to believe that this method is capa- ble of giving a really satisfactory immunity, the duration of which is, however, uncertain. The method is simple and apparently safe, and it is not unreasonable to hope that by its application the dangers to physi- cians, nurses, and attendants in typhoid fever and cholera epidemics will be greatly lessened. Further confirmation of the value of the method and observations as to the duration of the immunity acquired are neces- sary before arriving at conclusions concerning the advisability of its use in conditions other than during actual epidemics. Wassermann2 has made some interesting experiments which go to support Ehrlich's " Seitenkettentheorie " of immunity. According to Ehrlich, many toxins on injection into the animal body enter into 1 Ehrlich and Morgenroth. Berl. klin. Wochenschrift, 1899, xxxvi. 2 Berl. klin. Wochenschrift, 1898, xxxv. 209. 344 INFECTIOUS DISEASES. intimate chemical union with the protoplasm of certain body-cells. The protoplasm of these cells possesses special groups of atoms (Seiten- ketten), which normally have a chemical affinity for substances which serve to keep up the nutrition of the cell. This same affinity may, however, exist between these atom groups and certain poisons, so that on entrance of such a poison into the circulation a chemical union rapidly occurs. Such a union would deprive the cell of its normal nutritive functions, and in the absence of some regenerative power the affected elements would of necessity perish. This regenerative power, however, exists and results, according to Weigert's1 law of overcompen- sation, in an overproduction of similar groups of atoms. The excess eventually break loose from their point of origin and circulate in the blood. These groups of atoms are now capable of immediately uniting with and binding any fresh toxin which may enter into the animal organism. Thus the poison is neutralized before it is capable of uniting with the fixed body-elements. Such free groups of atoms, then, repre- sent the antitoxin. Every antitoxin has a physiological analogue, and the process of antitoxin formation is but the exaggeration of a physio- logical process of regeneration. Proofs of the accuracy of this theory have been rapidly accumulating. An admirable summary of the subject may be found in the article on " Toxin und Toxoide," in Eulenburg's Real-Encyklopaedie der gesamm- ten Ileilkunde, by Morgenroth. This chemical union between toxins and elements of the fixed tissues of the body does not occur everywhere, but is restricted in different diseases to especial tissues. Thus Wassermann2 has demonstrated in a most interesting manner that in tetanus the union occurs especially with elements of the brain and cord ; indeed, an emulsion of brain and cord if stirred up outside of the body with tetano-toxin results in a chemical union which destroys the toxicity of the mixture. Brieger, Kitasato, and Wassermann3 have shown that artificial immu- nity may be acquired by inoculations of animals with typhoid organisms. Pfeiffer, Kolle/and Marx5 have since demonstrated that, as a result of subcutaneous inoculation of dead or living typhoid bacilli, a substance appears in the blood-serum of animals and human beings which has a destructive and solvent property upon typhoid bacilli, and the presence of this substance in the blood of animals results in immunity against infections with the B. typhosus. Wassermann and Takaki have now shown that a few days after inoc- 1 Verhandl. der Gesellschafte deutscher Naturforscher u. Aerate, 1896. 2 Berl. klin. Wochenschrift, 1898, xxxv. 4. 3 Zeitschr. f. Hyg. u. Infectionskrank., xii. 139. 4 Centralbl. f. Fakt. 1896, xx. Nos. 4 and 5. 5 Loe. cit. DIPHTHERIA. 345 illation with typhoid bacilli, before these immunizing bodies are present in the blood, their presence in large quantity may be demonstrated in the bone-marrow, the spleen, and the lymphatic tissues of the body. This would appear to be convincing evidence that there is a special relation between the toxic substance in typhoid fever and these tissues, and that the anti-bodies which convey immunity against typhoid infection arise from these special organs. The possible practical significance of these discoveries is easy to see ; indeed, Behring has already announced that Wernicke in his laboratory has succeeded in immunizing susceptible animals against anthrax by the means of substances derived from the spleen. The nature of these anti-bodies, which convey immunity in typhoid fever and similar conditions and produce the solvent action upon typhoid bacilli, has recently been discussed in a most interesting and convincing manner by Ehrlich and Morgenroth.1 DIPHTHERIA. Etiology and Manner of Infection. Fritz Franz2 notes that the Klebs-Loeffler bacillus may vary greatly in its characteristics; those held to distinguish the pseudo-diphtheria bacillus all lie within the region of variations which the true diphtheria bacillus can show. There are wide-spread saprophytes which can be distinguished from the true diph- theria bacillus only by pathogeneity. The question arises, Is pathogeneity sufficient ? C. Frankel says that vindence is too variable a quality to be used as a dividing line. The virulence of the diphtheria bacillus can be varied according to the kind of medium used. It can be completely destroyed. Experiments by Trumpp, working in Escherich's clinic, are interesting and important. Ue obtained a pseudo-diphtheria bacillus from pleuritic pus, 5 c.c. of a bouillon culture of which gave no reaction when injected into a guinea-pig. He inoculated a guinea-pig with a culture of this bacillus mixed with diphtheria toxin. Then he cultivated the bacillus on media, and inocu- lated it again mixed with diphtheria toxin. He repeated this process a number of times, and at length obtained a culture which was highly viru- lent. This would indicate that the diphtheria bacillus and the pseudo- diphtheria bacillus are really one organism. This bacillus being found in the mouths of half of all individuals examined, Schanz puts forward the view that the Klebs-Loeffler bacil- lus cannot be the cause of the formation of false membrane, but that, 1 Berl. klin. Wochenschrift, 1899, xxxvi. No. 1. 2 Deutsche med. Wochenschrift, vol. xxiv. p. 522. 346 INFECTIO US DISEASES. lodging in the membrane and growing there, it produces the toxin which gives the general symptoms. The presence of this organism makes the disease a dangerous one. Schanz holds that the xerosis bacillus and the pseudo-diphtheria bacillus are identical. Slawyk and Manicatide1 made a careful examination of many different stock cultures of diphtheria bacillus with the object of throwing light on the subject of the unity of the diphtheria bacillus. Of forty-two cultures considered diphtheria, thirty-eight proved to be true diphtheria. These showed a uniform growth on blood-serum, glycerin-agar, gelatin, and potato. On ordinary agar there was more variation in the appearance of the growth. All the cultures were alike virulent, and all were neutralized by diphtheria antitoxin. Their con- clusions thus favor the unity of the bacillus. At the International Congress of Hygiene and Dermography, held at Madrid in April, Loeffler2 declared that one can call diphtheria bacillus only such an organism as can produce a toxin which stands in specific relation to the Behring antitoxin, and that all morphological criteria, even the recent granule stain of Neisser, have no value in the recognition of the true diphtheria bacillus. Kraus, Spronck, and Dauler expressed their acquiescence in this view. Myerhof3 made a study of the morphology of the diphtheria bacillus, and comes to the conclusion that we are not yet in a position definitely to classify it either with the schizomycetes or the hyphomycetes. The bul- bous masses and branchings are found under too many conditions to be regarded as degenerative forms or anomalies. Louis Martin4 describes improvements in the methods for the produc- tion of toxin. A temporary acidity, which occurs in ordinary bouillon cultures of the bacillus diphtheria?, interferes with the production of toxin. This acidity is due to the presence of sugars in the meat and peptone used. Efforts have been made to prevent its development. Roux and Yersin propose aeration of the cultures. Park and Williams made a great step in advance by alkalinizing the bouillon. Spronck proposed using partially decomposed meat. Martin places the macer- ated meat in a thermostat at 35° C. for twenty hours. He makes the peptone by placing the minced stomachs of hogs in acidulated water and maintaining this at 50° C. for twelve hours. He heats the bouillon made from this to 70° C., alkalinizes according to Park and Williams, and sterilizes bv passing' through a Chamberland filter. This medium is free from sugar and no acid forms in it, and it is most favorable for 1 Zeitschrift f. Hygiene, xxix. 181. 2 Berliner klin. Wochenschrift, xxv. 367. 3 Archiv f. Hygiene, vol. xxxiii. p. 1. 4 Annales de I'Institut Pasteur, vol. xii. p. 26. Pages 347-380 missing PNEUMONIA. 381 caused by the pneumococcus, the meningeal lesions containing the diplococcus intracellularis. The erroneous belief that pneumonia is a frequent complication of epidemic cerebro-spinal meningitis is due to the frequency of pneumococcus meningitis as a complication of pneu- monia. Conjunctivitis, strabismus, nystagmus, and dilatation and inequality of the pupils are frequently noted. Councilman finds the eye lesions to be due to three causes : 1. Degeneration of the nerves of the eye due to their involvement in the exudation at the base of the brain. 2. Extension of inflammation from the meninges, which is direct and not metastatic, as held by ophthalmologists; a metastatic choroido-iritis occurs in other forms of meningitis where the meningitis itself is metas- tatic. 3. Most cases of keratitis are due to neuritis of the fifth nerve with destruction of the Gasserian ganglion and loss of sensation. The ear lesions are the most common complication of cerebro-spinal meningitis. Councilman found an involvement of the auditory nerve in all cases in which it was examined. There was sometimes a puru- lent exudation along the nerve-sheath with more or less complete destruction and infiltration of the nerve. Otitis media occurred in five cases, in three of which the pus was examined and found to contain diplococci. Where meningitis is secondary to ear disease, the organism present is either the pneumococcus or the streptococcus. Treatment. There is no effectual method of treatment. Counter- irritation to the spine, as Wentworth says, probably does nothing but increase the discomfort of the patient. The application of the ice-bag to the head is still employed, and hydrotherapy is of use in hyperpy- rexia. Morphine may be needed for the pain. Stimulation and feeding are of importance, especially in the chronic cases, the use of the stomach-tube being sometimes necessary. Recent researches have served to clear up the bacteriology of this disease, and have given us a certain method of diagnosis in lumbar puncture, and it is possible that further studies may lead to the produc- tion of a curative serum. PNEUMONIA. Etiology. Atmospheric Conditions. Brunner1 has made a study of the atmospheric and cosmic conditions in relation to the origin of croupous pneumonia. From a consideration of 2140 cases he concludes, among other things, that the chill usually occurs toward evening or in the morning; that the outbreak of the disease has often an undeniable relation to changes in the weather. It is favored, he thinks, when, after 1 Deutsche Arch. f. klin. Med., 1898, lx. 339. 382 INFECTIOUS DISEASES. a period of cold weather, with falling barometer and much moisture in the air, there follows a rise in temperature, south winds, and snow or rain. Aspiration Pneumonia. Stubenrath,1 as a result of experiments with animals upon the production of aspiration pneumonia, concludes that the pneumonia is dependent upon the mechanical influences of aspi- ration, occurring without regard to what fluid is used. Traumatic Pneumonia. Bloch2 reports a case of pneumonia fol- lowing a contusion of the chest, and concludes that trauma predisposes toward the disease by causing a mechanical injury to the lung. The pneumococci, which normally are inhabitants of the upper air-passages, And here a suitable nidus for development. Padoa3 comes to the same conclusion as to the mechanism of trauma in causing the disease. ' Symptoms. " Pneumonitis Metapleurica." Baccelli,4 in a lec- ture upon croupous pneumonia, calls attention to a variety of the disease occurring secondarily to a pleurisy; he has seen a number of instances of this condition, which he terms " pneumonitis metapleurica." During the first day the patient shows signs of an intense pleurisy. On the fourth or flfth day evidence begins to appear of an acute pulmonary oedema with grave symptoms-dyspnoea and serous sputum 'which be- comes slightly tinged with red and sometimes truly hemorrhagic though not viscous. The pneumonia pursues a rapid course, reaching a stage of gray hepatization early. All Baccelli's earlier patients died, but when he began to treat his cases from the beginning of the pleurisy with repeated wet cupping the mortality was materially less. An epidemic of this nature occurred under the same physician's observation some years ago, before accurate methods of bacteriological study were in vogue. The Urine. Pick5 makes an interesting note upon the urine in pneu- monia. He finds that from twenty-four to forty-eight hours after the critical defervescence the urine, which has previously been strongly acid, becomes neutral or even alkaline. This phenomenon, which was observed in 31 out of 38 cases, persists for one or two days; the urine then becomes acid. The condition, he believes, is due to the absorption of the exudate which contains large quantities of sodium salts. Jacob, of Berlin, in the discussion suggested that it might be explained by the sudden enormous destruction of leucocytes which occurs during the crisis. Hyperpyrexia. Ironside'' reports a case of pneumonia with hyper- 1 Ueber Aspirationspneumonie, insbesondere nach Eindringen von Ertrankungsflussig- keit u. ueber ihre gerichtsarztliche Bedeutung. Wurzburg, 1898. A. Stuber's Verlag. 2 Muench, med. Wochenschrift, 1898, No. 30. 8 La Riforma medica, 1898, Ann. xiv. t. iii. 473. 4 Ibid., xiv. t. ii. 233. 5 Verbandl. d. XVI. Cong. f. inn. Med., 1898, 507. 6 British Medical Journal, 1898, i. 1258. PNEUMONIA. 383 pyrexia in a man of twenty-eight years. The highest temperatures were 109.5° F. on the fourteenth day, and 109° F. on the seventh day. Traumatic Pneumonia. Padoa,1 in his above-mentioned study of traumatic pneumonia, concludes that there is nothing in the course of the disease which enables one to separate it from lobar pneumonia of the ordinary sort. Sudden Death. La Fournier2 discusses sudden death in pneumonia. This is commonest during the stage of gray hepatization; neither the seat nor the extent of the pneumonia, nor the gravity of the case seems to have any special influence upon the development of this distressing complication. Undue physical effort is the commonest cause. The mechanism is obscure. Apyretic Pneumonia. Guider,3 in a thesis upon apyretic pneumo- nia, concludes that the absence of fever is attributable to the exhaustion of the economy, to functional disturbance of the nervous system, and to the action of the infective agents. Streptococcus Infection. Denny4 discusses the character of pneu- monias in which there is an infection with streptococci. These infections are remarkable for their tendency to wander, the frequency of affection of the upper lobe, the atypical fever-curve and delayed resolution. It is important to examine the sputa, which will often reveal the strepto- coccus infection. Delirium. Maragliano,5 in a communication upon the delirium in acute pneumonia, concludes that it depends upon two factors : pneumonic infection, which determines the immediate outbreak of the delirium, and modifications in the organism of the patient, which act as predisposing conditions. Its prognostic significance is not great. The disease runs its course independently of the delirium, which may, however, be of grave import if it lasts long. As an example of this possibility he mentions the case of a woman of hysterical tendency whose delirium lasted about twelve days after defervescence, the patient dying finally of exhaustion. Absence of Leucocytosis. Stockton6 reports a case of lobar pneu- monia with two relapses occurring in a little girl. During the first relapse the leucocytes were only 4000 to the cubic millimetre. The case seems to the reviewer to be of particular interest in view of the infre- quency with which we find a subnormal number of leucocytes in pneu- monia with favorable issue. Pneumonia in Children. West7 would reserve the term broncho- 1 Loc. cit. 2 These de Paris, 1897-1898. 3 These de Paris, 1897. ' Boston Medical and Surgical Journal, 1898, cxxxviii. 341. 5 La Riforma medica, 1898, Ann. xiv. t. ii. 728. 6 Philadelphia Medical Journal, 1898, i. 1201. 7 British Medical Journal, 1898, i. 1375. 384 INFECTIOUS DISEASES. pneumonia exclusively for those inflammatory conditions of the lung which are of secondary nature, following previous disease of the air- passages-mainly streptococcus infections. Primary broncho-pneumo- nias in children are always anatomically croupous pneumonias and depend invariably on pneumococcus infection. The two forms differ markedly in their course. The pneumococcus inflammation is almost as frequent in children as in adults, but differs in its clinical manifestations. In adults one or more lobes are usually affected throughout. In children, on the other hand, there appear numerous disseminated localized foci. There is, however, no true pathogenic difference between lobar pneu- monia in the adult and primary lobular pneumonia in children. The clinical differences depend, possibly, upon the special characteristics of children's lungs and respiration (paralysis of the diaphragm, elastic thorax, difference in structure of the lungs). Favorable Influence of Pneumonia on Hemorrhagic Ten- dency. Openschowski1 reports a case of typhoid fever with obstinate hemorrhage from the mouth and tongue, which could not be stopped until, with the breaking out of pneumonia associated with leucocytosis, coagulation appeared spontaneously. The coagulability of the blood, he believes, was due to the increase in the leucocytes which came on in this instance with the pneumonia. An Atypical Endemic. Haedke2 reports an interesting endemic of pneumonia with peculiar symptoms. Four members of one family were attacked one after another. The disease began with prostration, dyspnoea, and cough without expectoration. Signs of lobar consolidation developed. The fever ran an irregular course. Three of the four cases were fatal. Streptococci were obtained from most of the organs and also a bacillus which apparently was the protons vulgaris. The last organism was highly pathogenic for mice. Vasomotor System. Van Santvoord3 studied the condition of the vasomotor system in acute pneumonia. Cardiac failure is, he believes, usually due to vasomotor paralysis. The popular idea that the pulse in pneumonia is of high tension is in many instances erroneous. He draws the important conclusion that vaso-dilators, such as nitro-glycerin, are rarely called for. Theoretically, digitalis ought to be of use. Statistics. Elsner,4 out of 150 cases, found that 80 per cent, showed the characteristic chill and ran a typical course ending in from six to eleven days. The right lung was involved in 60 per cent, of cases, the left in 24 per cent., and both in 16 per cent. In 12 apex pneumonias 1 Wien, therapeut. Woch., 1898, No. 1. 2 Deutsche med. Wochenschrift, 1898, xiv. 220. 3 Philadelphia Medical Journal, 1898, i. 753. 4 Medical News, 1898, Ixxii. 33. PNEUMONIA. 385 active delirium was not present. The initial chill was absent in only 14 per cent, of these cases in adults. In 3 cases of pneumonia in old persons the temperature never rose above 100.1°. In 4 instances active delir- ium occurred three to ten days after the crisis. In 3 instances there was sudden death. A leucocytosis was found in 22 out of 30 cases, while in cases examined within thirty-six hours of the crisis there was no further evidence of a leucocytosis. A. A. Smith1 discusses 60 cases of lobar pneumonia. In 2 instances there was complicating pleuritic effusion ; in none empyema. The total mortality was 28| per cent. There were nine patients over fifty years of age, of whom only two died; 5 out of 12 cases of apex pneumonia ended fatally. Albuminuria was present in all cases in which the urine was examined with the exception of four. Cold compresses made with a padded sheet were found useful in reducing the temperature and the rapidity of the pulse, and in quieting nervous symptoms. Their effect seemed to be as good when applied to the abdomen as when applied to the chest. Sequelae and Complications. Arthritis. Boix2 reports a case of purulent arthritis complicating a pleuro-pneumonia in influenza from which the pneumo-bacillus of Friedlander was isolated. lie quotes3 a similar case observed by Oswiecimski in the Now. Lek., 1896. Endocarditis. Findlay4 reports a case of pneumonia associated with acute tricuspid endocarditis from which the pneumococcus was isolated post mortem. No cardiac murmur was made out during life, although thrombi as large as one's thumb were found upon the valve curtains. Neuritis. Aldrich5 reports a case of pneumonia which was followed by neuritis of the brachial plexus, resulting in atrophy of the trapezius, spinati, deltoid, and supinator longus muscles. The pain in the shoulder, associated with the neuritis, was preceded by a severe attack of hiccough which came on during recovery and lasted for five days. The author believes that this was an instance of neuritis beginning in the phrenic nerve and ascending to the brachial plexus. He also reports an instance of parotitis. Acute Nephritis. Kleinmann6 reports a case of acute nephritis occurring with pneumonia, which cleared up gradually during convales- cence. Pneumococci were found in the urine at the height of the pro- cess. The author believes that the changes in the kidney were due to the direct action of the pneumococci upon the renal tissue, rather than to circulating toxic substances. 1 Medical News, 1898, Ixxiii. 26. 2 Arch. gen. de medecine, 1898, t. i. 605. 3 Ibid. p. 499. 4 Montreal Medical Journal, 1898, xxii. 350. 5 Medical News, Ixxiii. 590. 6 Inaug. Diss., Berlin, 1898. 386 INFECTIOUS DISEASES. Phlebitis. Da Costa1 discusses phlebitis consecutive to pneumonia. This may occur anywhere from the second to the fifteenth day after the crisis, or even later. The course is in every way like that of typhoid phlebitis. The prognosis is generally favorable., rarely, however, embolism and sudden death may occur. Meningitis. Aufrecht2 reports a case of pneumonia with cerebral symptoms and empyema, which was followed two months after recovery by fatal meningitis. Mediastinal Abscess. Broadbent3 reports a most interesting case of pneumonia in a boy of twelve years. There was no crisis ; high fever and delirium continued. Cough was so marked that chloroform had to be administered. A diagnosis of enlarged and suppurative bronchial glands was made, which was confirmed by the later course of the case. Rupture of a mediastinal abscess into a bronchus occurred ultimately, and recovery followed. Diagnosis. Bezangon and Griffon* have been able to obtain an agglu- tinative reaction upon pneumococci with the serum of individuals suffer- ing from pneumococcus infections. The reaction appeared at a period varying from the third to the sixth day of the affection. This may serve as a valuable help to diagnosis in doubtful infections. They believe, however, that owing to various different types of pneumococci it may not be present in all instances. Treatment. Pilocarpine. Rosenthal,5 after using pilocarpine in nine cases of pneumonia, comes to the conclusion that the drug is not only of no value, but, further, that it is sometimes actually harmful in its effects. Its use is, therefore, contraindicated. Diuretics. Reusner," believing that the critical sweat in pneumonia has a weakening effect on the organism, endeavored to obviate this by giving diuretics at the time of the crisis. He believes that by the use of caffeine with camphor or digitalis he has been able to diminish materially the sweating, the crisis occurring in association with marked diuresis. Use of Cold. Mays7 pleads for the more general use of cold, par- ticularly as local applications, in the treatment of pneumonia. Fussell8 finds that cold baths give great relief in marked hyperpy- rexia. The local application of cold is also of value in relieving pain. 1 Philadelphia Medical Journal, 1898, ii. 519. 2 Deutsche Arch. f. klin. Med., lix. 3 British Medical Journal, 1898, i. 605. 4 Congres de Med. int. de Montpellier, April 14, 1898. 5 Deutsche Arch. f. klin. Med., lix. 6 St. Pet. med. Wochenschrift, xxiii., N. F. xv., 1898, 14. 7 Philadelphia Medical Journal, 1898, i. 406. 8 Medical News, 1898, Ixxii. 292. PNEUMONIA. 387 Counter-irritation. Stengel,1 in cases of pneumonia with delayed resolution, advises counter-irritants, active pulmonary exercises, and men- tions the fact that there is some evidence to suggest that the production of aseptic abscesses resulting in a leucocytosis may exert a favorable influence on the condition. Bloodletting. Maragliano2 discusses bleeding in pneumonia. Livi- erato has shown that when there are limited foci of pneumonia, bleeding is followed by a diminution in the oxygen absorbed, but when the foci are extensive the oxygen absorbed and the arterial tension are consid- erably increased. Bleeding is particularly indicated in grave toxaemia and where there are mechanical disorders of the circulation owing to the consolidation. Toxaemia may be combated by digitalis, which antagonizes the bacterial poisons, and with De Renzi's (Pane's) serum, which neutralizes them ; but when the toxaemia is marked and these means are not at hand patients should be bled, and the amount of fluid in the circulation increased by intravenous salt injections. When the circulation is disturbed bleeding is also a good remedy, and one need not be hindered from doing this because the pulse is small and irregular; according to Niemeyer, it is just in these cases that it should be em- ployed. Bleeding, then, is an occasional and not a regular method of treatment. The quantity of blood taken at each bleeding should vary from one-fiftieth to one-tenth of the total amount. Treatment of Pneumonia in Children. A discussion upon the treatment of pneumonia in children was held before the New York Academy of Medicine, which is reported in full in the Medical News, 1898, Ixxxiii. 641-650. Only a few points can be touched upon here. Chapin points out the fact that the temperature is not always a true indication of the degree of poisoning in the child. The best means for treating the fever, when treatment of the fever is necessary, is by the external application of cold, by ice poultices, or by applying to the chest compresses which have been dipped in water at 75° to 90°. The treat- ment may be employed until the temperature falls to 102° or 103° and then discontinued until it rises again. Ue believes that the fear and prostration incident to the giving of cold baths contraindicate them. Holt makes an excellent communication in which he lays considerable stress upon the necessity of saving the child as far as possible from the worry excited by too much attention. His conclusions are as follows : " 1. No depleting measures are ever admissible. " 2. Hygienic treatment, including fresh air, proper feeding, and intel- ligent care, is of the utmost importance. "3. No unnecessary medication should be permitted. 1 Therapeutic Gazette, 3 s. xiv. 78. 2 La Riforma medica, 1898, xix. t. iv. 811. 388 INFECTIOUS DISEASES. " 4. Many annoying symptoms may be relieved by local treatment, such as the cough by inhalations, pain by counter-irritation, restlessness by the ice-cap or sponging. " 5. Stimulants should be deferred until demanded by the condition of the pulse. " 6. High temperature is much more safely and effectively controlled by the use of cold than by drugs. " 7. Greater caution is necessary in the use of powerful stimulants than is generally observed. " 8. Rest is quite as important as in other serious diseases." Koplik believes that baths may be more frequently used, but advises great care in their administration. Almost all of these observers lay particular stress on the necessity of good ventilation, a point which the reviewer would also insist upon. The manner in which patients with respiratory affections are still shut in close, ill-ventilated, overheated apartments should be combated by every intelligent physician. Carr, discussing the treatment of broncho-pneumonia complicating measles, lays stress also upon the same fact, advising that the patient be kept in a freely ventilated room, between 65° and 70°. In these cases he advises that the diet should be of about the same quantity as that given to a healthy child ; peptonized milk, beef juice, eggs, custards, jellies, etc., are the best foods. Baths from 85° to 90° are the best antipyretics. Baruch discusses the methods of giving baths and packs, and lays particular stress upon the necessity of employing vigorous friction throughout. Baths are not always necessary-" treat the child and not the disease." Antitoxic Treatment. The most interesting literature in connec- tion with pneumonia which has appeared during the last year is that relating to the treatment of the disease by antitoxic serum. Washburn obtained from an immunized pony an antipneumococcus serum which clinically has given results of a favorable but not positive nature. Pro- fessor Pane and De Renzi, of the Naples school, have prepared an anti- toxic scrum which they have recently put on the market. The work has been done at the Institute Sieroterapico in Naples. They have suc- ceeded in immunizing larger animals, and have found that the serum of these animals has preventive and curative properties. Pane1 has col- lected nine cases treated during December, 1897, by this method. All but one recovered. The serum used varied in amount from 10 to 110 c.c. In the one fatal case the injection was made on the fifth day, and then only 10 c.c. in twenty-four hours were used. In very grave cases with 1 La Riforma medica, 1898, Ann. xiv. t. i. 195. PNEUMONIA. 389 serious symptoms as late as the fifth day, the quantity of serum injected on the first occasion has been as high as from 120 to 150 c.c., either at once or in two parts. In very severe cases several intravenous injec- tions of 4 to 10 c.c. have been added. The result is always favorable. The injections are followed by a rapid amelioration of the general con- dition and a fall in temperature. No evidences of intolerance to the serum have ever been noted, even after doses as high as 120 c.c. in twenty-four hours. Pane believes that at first the pneumococcus is localized in the affected area, but that after a certain length of time it may pass into the general circulation. When a true pneumococcus septicaemia exists the chances for recovery, even under antitoxic treatment, are nil. As in the treat- ment of diphtheria, everything depends on the early initiation of the antitoxic treatment. One of these last nine cases which he reports was an influenza pneumonia. The good effect of treatment was due, he believed, to the fact that the majority of influenza pneumonias, as shown by Weichselbaum, Bouchard, Netter, Menetrier, Birch-Hirschfeld, and others, are due to pneumococcus infection. Maragliano, at a meeting of the Royal Academy of Medicine of Turin,1 reported his results in five cases treated by this serum, and testi- fied to the remarkable therapeutic efficacy of the preparation. Not that it totally arrests the course of the morbid process, but that it moderates it. In all cases there was a fall of temperature and an improvement in the general condition with a shortening of the course of the disease. He believes that the substance acts as an antitoxin. Caruso and Staginitta2 report two cases treated successfully by Pane's serum. They conclude : " (a) The injections of antipneumonic serum give no local reaction, and are as practicable as any other hypodermatic injection. " (6) The serum has shown no toxic property in its general action. " (c) The serum has none of those remote unpleasant consequences which are often manifested after the injections of antidiphtheritic serum -fever, morbiliform or scarlatiniform eruptions, arthritic swelling and pain, etc. " (d) In two cases reported the serum has shown an indisputable effi- cacy against pneumonia. " (e) Therefore, in every case of croupous pneumonia, one may resort to serotherapy. "(/) In a croupous pneumonia with grave prognosis, it is the duty of the physician to advise serotherapeutic treatment." Gamba, in the discussion of this communication at the Laucisian 1 La Riforma medica, Ann. xiv. t. i. 439. 2 Bull. d. soc. lane. d. osp. d. Roma, xviii., 1898, 235 and 340. 390 INFECTIOUS DISEASES. Society in Rome, stated that he also had under treatment two severe cases of pneumonia in which he had been using the serum-one a man of seventy-five years-and both were doing extremely well. He emphasizes the fact that the treatment should be begun as soon as the diagnosis is made, without waiting for the condition to become grave. Garofalo insists upon the necessity of careful observations of numerous cases in hospitals. At the conclusion of the discussion the society unani- mously adopted a resolution recommending the systematic experimental use of Pane's antipneumonic serum in the hospitals of Pome. Marone1 reports a severe case of pneumonia in an old man of seventy- two years. Nine c.c. of serum were injected on the fifth day and repeated on the following morning. In the evening again 8 c.c. were given. Ten c.c. were injected twice on the three following days. Though the symp- toms were extremely grave, recovery gradually occurred. The serum seemed to have a very stimulating and a distinctly antipyretic effect. He concludes : " 1. Pane's serum is an excellent antipyretic. " 2. It regulates the pulse. " 3. It produces sometimes a transient cardiac arhythmia. " 4. It does not affect the course' of the pneumonia. " 5. It is a stimulant rather than an antitoxin." He believes that the antipneumonic serotherapy should always be tried, inasmuch as it is the best method of cure which we now possess. At the Ninth Italian Congress of Internal Medicine in October, 1898,2 a most interesting discussion took place concerning Pane's antipneumonic serum. This observer has recently succeeded in obtaining a serum of great strength. He has obtained cultures of the pneumococcus which are active in an almost imperceptible quantity, a quantity so small that there is even a danger of not injecting any bacteria, and his serum possesses 1000 to 3000 immunizing units. He believes that there is but one species of pneumococcus. He reasserts the statement above mentioned, that at first in man, as in rabbits, the infection is local; at this time the sero- therapy is most useful. No serotherapy can save an individual when the pneumococcus has passed into the general circulation. In double pneumonia with jaundice and albuminuria the doses of the serum must be large, even up to 120 c.c. Sylvestrini and Aporti made from rabbits an antipneumococcus serum which, in quantities of 10 c.c., produced a favorable influence upon the temperature in pneumonia ; but after a certain amount of trial they aban- doned their experiments with men, because they could not succeed in producing any appreciable change in the course of the disease. 1 La Riforma medica, 1898, xiv. i. 583. 2 Ibid., Ann. xiv. t. iv. 246, and Lancet, 1898, ii. 1075. PNEUMONIA. 391 Baduel asserts that true septicaemia is the rule in pneumonia, having been found in 55 out of 57 cases in the clinic in Florence, not only in grave but also in mild cases. Pane has not observed any other striking effects after the use of the antipneumonic serum excepting the fall in temperature. In answer to a question of Sylvestrini, he stated that to treat properly some cases of pneumonia one had to use as much as 300 or 400 c.c. of serum, to obtain which from thirty to forty rabbits had to be made use of. In answer to Baduel, Pane stated that many researches, both by Belfanti and by others in Florence and Rome, have shown that as a rule the pneumococcus is not to be obtained from the circulating blood, even when as much as from 10 to 15 c.c. of blood are taken for the culture. Belfanti states that Pane's serum has a preventive influence if inocu- lated before the beginning of a septicaemia and has a marked aggluti- nating and bactericidal action. The toxic substances in pneumonia are very difficult to separate. Carbone has extracted a phlogogenic sub- stance from the bodies of pneumococci, while Zenoni has found an extremely powerful soluble poison, which is, however, very unstable. It produces marked haemolysis. Against this poison Pane's serum has no influence. His own antipneumococcic serum has not produced as good effects as Pane's, but he believes the statistics with regard to the use of the latter, while favorable, are as yet insufficient. Belfanti has also observed that when the pneumococci appear microscopically in the blood it is never possible to save the animal. Pane believes that in pneumonia the direct action of the pneumococci plays a part more important than a circulating toxic substance. Massalongo and Franchinin at the same session report upon the treat- ment of ten cases of pneumonia with Pane's serum ; all were at an advanced period of the disease, " old in years or in misery, fatigue and debauch," and almost all chronic alcoholics, cardiopaths, nephritics, or arthritics. After having compared these cases with others treated in the ordinary manner they conclude : " 1. By the use of Pane's antipneumonic serum in very grave cases of pneumonia, in arthritic, nephritic, cardiopathic, and alcoholic patients who were also advanced in years, we have obtained curative results superior to those reached by any therapeutic means which are yet avail- able. " 2. Pane's antipneumonic serum, contrary to curative methods in acute pneumonia which have been known up to the present time, appears to have a direct action on the evolution of the pneumonic process, hin- dering its diffusion and facilitating resolution." Cantieri likewise reports 17 cases treated with Pane's serum with a mortality of 10.5 per cent. He believes that one may rely upon this 392 INFECTIOUS DISEASES. remedy in croupous pneumonia to destroy the most dangerous element of the pneumonia, thus leaving the pneumonic process to run its course under " natural physiological conditions." Bozzolo has used Belfanti's serum without much effect, but acknowl- edges that his doses were small as compared with those which Pane has given. He advises the use of this method in a large number of non- selected cases. De Renzi believes that the efficacy of this method is beyond a doubt, and earnestly recommends its use. " The last drop of water may turn the scale, and the elimination of this small part of the infection may just save a patient." Maragliano has treated successfully five cases selected from among the gravest. He is impressed with the beneficial action of the serum upon the toxaemia. " The existence of the antitoxin once demonstrated, there is no doubt of the efficacy of the antipneumococcic serum." Fanoni1 has used the serum in one instance. In a severe case of pneu- monia of the right lobe 10 c.c. were administered on the fourth day, and two similar injections were repeated each day for three days more. "A few hours after the first injection the patient began to feel a little relief; the fever gradually diminished and on the ninth day entirely disap- peared." As a result of the above-mentioned observations it would seem to be highly desirable that a more general test of Pane's serum should be made. We should not expect a panacea, but the results which have been obtained justify us in hoping that before long we shall possess an antitoxin which will save many lives. Treatment by Serum from Convalescents. Weisbecker2 treated 26 cases of pneumonia with serum from convalescents-the same method which he has used in typhoid fever. Ten to 15 c.c. of serum were used. His results were extremely favorable, particularly when the injections were made soon after the onset. The most marked effect was upon the general condition of the patient (the pneumonic process in some instances, however, continued through its usual course), the toxic symptoms being much relieved, while the patient was relatively free from subjective symptoms. There were but two fatal cases : one, a man of seventy-eight years, who died of heart-failure, and one a woman of fifty-four years, with extreme emphysema. Weisbecker's communication upon this subject, as upon his own anti- toxic injections in typhoid fever and other infectious diseases, is interest- ing, but not wholly convincing. His cases are, as yet, too few to justify 1 New York Medical Journal, 1898, ixvii. 646. 2 Muench, med. Wochenschrift, 1898, xlv. 202, 238. YELLOW FEVER. 393 any positive conclusion as to the value of the method. There are many objections to the extensive inoculation of serum from one individual into another. The simplicity of the method, however, might recommend its application in selected cases in family endemics. Prophylaxis. Eyre and Washburn1 have made a number of obser- vations relative to pneumococcus infection and the immunization of ani- mals. They find that by growing pneumococci on a special medium (agar streaked with sterile rabbit's blood) the organisms retain their viru- lence long enough for experiments to be carried on carefully through a considerable length of time. They conclude as follows : " 1. The pneumococcus when cultivated upon the medium described will maintain a constant virulence for a long period. " 2. Rabbits and mice are very susceptible, and to an equal degree guinea-pigs are refractory; but marked individual variations in suscep- tibility are observed; fowls are absolutely immune. " 3. The virulence toward guinea-pigs can be increased by repeated passages through a series of these animals without any alteration occur- ring in the virulence toward mice. " 4. The normal sera of the rabbit, guinea-pig, and fowl in doses of 0.5 c.c. will not protect against ten times the fatal dose of a living culti- vation, but will protect against the minimal fatal dose. " 5. The antistreptococcic serum of the horse has no protective power. " 6. Antipneumococcic serum can be accurately standardized by using the method above described. " 7. The agglutinative power of a serum bears no relation to the pro- tective power, although the serum of the immune contains more aggluti- native substance than that of the normal rabbit. " 8. There is no definite relation between the protective power of a serum and its bactericidal properties as tested by plate cultivations." YELLOW FEVER. Etiology and Manner of Infection. In 1897 Sanarelli isolated the bacillus icteroides from the blood and tissues of seven out of thirteen cases of yellow fever. This organism resembles the bacillus X found by Sternberg, in 1890, in the intestinal contents of about one-half of the cases of yellow fever examined by him at autopsy. A discussion has been carried on between Sternberg and Sanarelli in the Centralblatt fur Bacteriologie as to the relationship between these two organisms. There are certain differences as to the motility and the production of gas, acid, and indol, and Sternberg now recognizes that they are not iden- 1 Journal of Pathology and Bacteriology, 1898, v. 13. 394 INFECTIO US DISEASES. tical, but ho believes they are nearly related or varieties of the same species. He reports1 the observations of Reed, who found that the serum prepared by Sanarelli, by the repeated inoculation of horses with the toxins of bacillus icteroides, agglutinates bacillus X in a dilution of 1 to 150, and that the serum of a dog immunized to bacillus X aggluti- nates bacillus icteroides in a dilution of 1 to 300. A dog immunized to bacillus X received into a vein 25 c.c. of a recent culture of bacillus icteroides, and five days later 40 c.c. more. He was not seriously affected, although this organism is highly virulent to dogs. Reed2 injected cultures of bacillus X into the veins of dogs after the method of Sanarelli, producing vomiting and diarrhoea with bloody stools, which are the same symptoms as those produced by bacillus icteroides. Gau- thier3 found the bacillus icteroides in the blood of a yellow fever ease in quarantine at Marseilles. Wasdin4 found the bacillus icteroides in 42 per cent, of cases examined in Louisiana and in three cases at Havana. Many individuals not having yellow fever were examined, but in none was this bacillus found. Novy5 made a study of the bacillus icteroides and the bacillus de- scribed by Havelberg as the organism of yellow fever. He believes that neither is concerned in the etiology of the disease. Havelberg's bacillus proved to be a non-motile colon bacillus, resembling Emmer- ich's bacillus napolitanus. When injected into subcutaneous tissue of an animal a local abscess results, followed by recovery. He finds that the bacillus icteroides belongs to the typhoid group. Clinical and hygienic experience indicates that the real germ of yellow fever is prob- ably destroyed by cold, but Novy showed that the bacillus icteroides will grow after being frozen for three days at- 10° C. He showed that the blood of normal human beings and that of many animals will agglu- tinate the bacillus icteroides when used pure and in a dilution of 1 to 10, and only occasionally in higher dilutions. The Archinards and Woodson,6 however, found that the blood of yellow fever patients in a dilution of 1 to 40 agglutinated the bacillus icteroides in 70 per cent, of forty cases. The agglutination experiments, there- fore, on the whole strongly support the specificity of the bacillus icter- oides. The methods and reasoning of Sanarelli arc open to criticism in many respects. He found, when the toxins of bacillus icteroides were inoculated into the veins of dogs, that vomiting and diarrhoea resulted, that the organs showed fatty degeneration, and that there was a hemor- 1 Transactions of the Association of American Physicians, xiii. 61. 2 Journal American Medical Association, xxx. 233. 5 Revue d'Hygiene, xx. 884. 4 Public Health Reports, xiii. 1265. 5 Medical News, Ixiii. 326 and 360. 6 New Orleans Medical and Surgical Journal, 1. 455. Laparotomy for Intestinal Perforation in Typhoid Fever.- [See Bulletin for November Discussion, 1898.] Dr. Thayer.-I had the good fortune to observe the first case which Dr. Cushing has mentioned throughout the greater part of its course. I happened to walk into the ward on the night upon which the second operation was done and found the boy in a condition of profound collapse. This had come on very suddenly, Dr. Cushing having seen the child but a short time before. When I saw him he had been vomiting; the skin was cool; there was profuse sweating; the temper- ature had fallen several degrees; there was abdominal tender- ness ; the pulse was feeble and rapid ; the face was drawn ; the cheeks and eyes sunken. There could scarcely have been a more typical picture of acute peritonitis. And yet, when the abdomen was opened, there was not only no peritonitis, but there was not enough disturbance to suggest the existence of obstruction to any one present. Such a picture is an excellent demonstration of the difficulties which may stand in the way of a correct diagnosis in these cases. What Dr. Cushing has said of the leucocytes is, it seems to me, of considerable importance. I have no doubt that it is quite true that in an individual with distinct evidences of perforative peritonitis a normal or subnormal number of leucocytes is a very bad prognostic sign. I remember one or two instances of general streptococcus septicaemia where the leucocytes were normal or subnormal in number; one case in particular where there were but 3000 leucocytes to the cubic millimeter. As long ago as 1892, Werigo showed that after inoculating animals with cultures of pyogenic bacteria there occurs primarily a reduction in the number of leucocytes to the cubic millimeter. In the milder cases this initial fall is followed by a subsequent leucocytosis. In the particularly malignant and rapidly fatal cases, however, no subsequent rise in the number of leucocytes occurs. The same condition has been noted experimentally by various other observers. And I am inclined to believe that, as in pneumonia, so in other ma- lignant general infections, a subnormal number of leucocytes may be regarded as a bad symptom, and it is not at all impos- sible that in Case III the fall in the number of leucocytes following the direct evidence of perforation may well have been associated with the sudden onset of what proved to be a rapidly fatal streptococcic infection, the previous leucocytosis having been due to the moderate local peritonitis about deep ulcers. * Dr. Thayer.-It appears to me that the method of staining advised by Dr. Futcher is one which is of very considerable practical value. It is often impossible for the busy practitioner to examine the fresh specimen of blood, and most of the other methods of preparation are rather delicate proceedings, at least if one wishes to obtain really good specimens. A thoroughly satisfactory method which can be carried out almost inside of two minutes is a great advance. I should like to emphasize particularly its value in staining the aestivo-autumnal parasites. The hyaline bodies take up all dyes very feebly, and it is often extremely difficult for the unskilled eye to distinguish them. By Dr. Futcher's method of staining with thionin, however, a perfectly satisfactory specimen may instantly be obtained. I know of no method which brings out the aestivo-autumnal parasite so well.1 [Reprinted from Maryland Medical Journal, May 27, 1899.] RECENT INVESTIGATIONS UPON MALARIA. By W. S. Thayer, M.D. REPORT OF REMARKS AT THE JOHNS HOPKINS HOS- PITAL ON THE OCCASION OF THE CENTENNIAL MEETING OF THE MEDICAL AND CHIRURGICAL FACULTY OF MARYLAND. Dr. Thayer spoke in brief as follows: In the short time allotted to him he wished to say a few words especially upon recent work with regard to the manner of infection in malarial fever. Up to the last year our ideas as to the manner of infection in malaria have been mainly speculative. There have been three chief hypotheses: (i). That the disease was acquired through the gastro-intestinal tract. (2). That infection took place through the inhaled air. (3). That the poison might gain access to the body through the bites of insects. The solution of this problem has been greatly delayed by our ignorance as to the form in which the malarial parasites exist outside of the human body. Ex- periment and analysis of the evidence goes to show that there is little to support the view that the disease may be acquired through the gastro-intestinal tract. Ex- periments by Mariotti and Ciarocchi, . Marchiafava and Celli, Marino, Zeri, i Grassi and Feletti have shown that the administration of large quantities of water from highly malarious districts, by the mouth, by rectum and by inhalations, as well as the actual ingestion of blood containing living malarial parasites, is in- capable of causing infection. And while in the absence of our knowl- edge of the form in which the parasites exist outside of the body it is difficult to positively disprove the possibility that the disease may be acquired by inhalation, there is no thoroughly satisfactory evi- dence in its support. On the other hand, it has been known for many years that inoculation, subcu- taneous or intravenous, of the blood of an infected individual will transfer the disease. Some years ago Laveran ad- vanced an hypothesis that infection might take place through the bites of mosqui- toes. Since this expression of opinion several other similar diseases in animals, diseases due to hematozoa, have been shown to result from the bites of insects. Thus the parasite of Texas cattle fever, an organism in many ways similar to the malarial parasite, has been shown by Prof. Theobald Smith to be transmitted by the bites of the cattle tick (boophilus bovis), while the Tsetse fly disease, or Nagana, is introduced through the bites of the Tsetse fly. More recently Patrick Manson of Lon- don has been an ardent supporter of the idea that the mosquito might play an im- portant part in malarial infection. Dr. Thayer then reviewed briefly the ordinary intracorporeal cycle of the mala- rial parasite, calling attention to the fact that in all varieties of the parasite certain forms upon reaching maturity fail to spor- ulate, but in many instances after five, ten or fifteen minutes of observation undergo a process of flagellation which was early described by Laveran, the separate flag- ella breaking away often from the mother element, moving about rapidly in the blood with an active serpentine motion. There has been much dispute as to the significance of these elements. Laveran believed that they represented a very im- portant stage in the life-history of the 2 organism, while Dock first suggested that they might be bodies intended to preserve the life of the parasite outside of the human body. The Italian observers, as a rule, vigorously opposed these views, be- lieving that flagellation was a degenera- tive process. Manson, who had demonstrated the fact that the mosquito forms an interme- diate host for the filaria sanguinis hom- inis, ventured the hypothesis that this insect might play a similar part in connec- tion with malaria. Surgeon-Major Ron- ald Ross, acting upon the suggestion of Laveran, observed the development of flagellate bodies in the fresh blood within the stomach of the mosquito. This single observation was not remark- able, inasmuch as the same is often no- ticed when mature parasites are observed for a sufficient length of time outside of the human body. But afterwards, in carefully studying mosquitoes, he ob- served remarkably large pigmented struc- tures in the stomach wall of several in- sects which had previously bitten infected human beings. The pigment in these structures was so similar to that previ- ously contained in the malarial parasite that the observer was impressed with the possibility that these elements might rep- resent some extracorporeal stage in the life-history of the malarial organism. At this stage in Ross' researches the mala- rial season came to an end and he was obliged to continue his studies upon the parasites of birds, which, as is well known, are closely similar to those of human ma- laria. The results of these observations of Ross form the most important contri- bution to our knowledge of this subject that has been made since the discovery of the parasite by Laveran. If a certain variety of mosquito, the gray mosquito (culex pipiens), be fed upon birds infected with the proteosoma (Labbe), there ap- pear, two days after feeding, in the wall of the middle intestine of the insect, pig- mented bodies similar to those just de- scribed. These structures gradually in- crease in size until at the end of the sev- enth day they are as large as sixty micro- millimeters. They have a distinct capsule, and contain a granular material showing at first a few pigment granules, which afterwards disappear. On reaching ma- turity they protrude from the surface of the mosquito's intestine into the body cavity. Shortly after this period rupture occurs and a large number of small spin- dle-shaped trypanosome-like bodies es- cape which enter the circulation of the mosquito. Ross further discovered that many of these accumulate within the cells of the veneno-salivary gland of the mosquito. The outlets of this gland unite into a common duct, which de- scends to the extremity of the mosquito's proboscis. The discovery of these spin- dle-shaped bodies in the cells of the sali- vary gland instantly suggested to Ross a possible method by which infection might occur. And experiments showed that mosquitoes fed a proper length of time before upon infected birds were capable of transferring the disease to non-infected birds in almost every in- stance. Ross' admirable experiments conducted with the parasites of birds, the nature and behavior of which is so similar to those of the malarial parasites that they have by some individuals been considered to be the same organism, abundantly jus- tified the suspicion that similar condi- tions might exist with the parasites of human beings. At the same time, independently of Ross' work, Italian observers, Bignami, Grassi and Dionisi, had come to the con- clusion from careful study of the etiolog- ical conditions of the disease, that the theory of infection through the bites of mosquitoes was by far the most probable hypothesis in connection with malarial fever in man. Grassi had gone so far as to narrow down upon two particular varieties of mosquito, the anopheles clavi- gcr and the culcx penicillaris, as the prob- able varieties of mosquito which were capable of inoculating the disease. The ordinary house mosquito, the culcx pip- i^s, that in which Ross had been able to cultivate the parasites of birds, Grassi believed to be harmless. Bignami, in- deed, succeeded apparently in inoculating with malaria a human being who had voluntarily subjected himself to the ex- periment,by subjecting him to the bites of these suspicious varieties of mosquito. Ross communicated the results of his ex- 3 periments to the Italian observers, send- ing them specimens illustrative of the conditions observed, and during the months of November, December and January, Grassi, Bignami and Bastianelli succeeded in completely confirming all that Ross has found in birds upon the human being. They have shown that if examples of the anopheles clavigcr be placed upon an individual infected with malaria, in whose blood full-grown forms capable of flagellation exist, bodies al- most exactly similar to those described by Ross appear on the second day in the stomach wall of the insect, undergo sim- ilar processes of development and rup- ture, setting free the same small spindle- shaped bodies which accumulate in the cells of the salivary gland. The experi- ment has been rounded out to complete success in the case of the estivo-autumnal parasite. Three mosquitoes which ten days before had been allowed to bite an individual infected with estivo-autumnal malaria were placed upon a non-infected individual, the result being the develop- ment of a characteristic estivo-autumnal malaria. The three mosquitoes were killed after biting this individual, and full- grown bodies were found in the walls of the stomach, while the cells of the sali- vary gland were filled with the small spindle-shaped "sporozoids." The result of these observations has then been a positive demonstration of one method by which malarial infection may occur, namely, through the bites of mos- quitoes. Is this the only method? This is a question which, as yet, we cannot an- swer. From analogy with similar dis- eases, and from a careful study of the etiological conditions of malaria, the Italian observers are strongly inclined to believe that this is the case. ■ Are we to assume that the mosquito can acquire the parasite only by biting infected human beings? Is it not prob- able that there are other forms in which the parasite exists outside of the human body? These are questions which remain to be answered. It should be said that certain of the capsule-like bodies in the stomach wall of the mosquito do not give rise to these small spindle-shaped structures, but con- tain a smaller number of large brown spores (?), which there is some reason to believe may be more resistant forms of the parasite and may possibly be trans- ferred in some way to the mosquito larvae. An interesting point in connection with these discoveries is that it has com- pletely supported Laveran in his original view that the flagellation of the malarial parasite was an important \ ital process, and not, as others had supposed, degener- ative in nature. The first important ob- servations tending to support this view were, as is well known, made by MacCal- lum two years ago. MacCallum showed that in certain parasites of birds, as well as in the human being, the free flagella penetrate other full-grown forms of the parasite in such a manner that there can be little doubt that the process is one of fecundation. In the birds' parasite in which this process was first studied, the fecundated form changed into an active "pseudo-vermicule," described by Dani- levsky. This "pseudo-vermicule" has a sharp point and a steady forward motion, as observed under the field of the micro- scope, which enables it to penetrate into and destroy almost any object in its way. As soon as Ross discovered the pig- mented bodies in the stomach wall of the mosquito he assumed that the parasite gained entrance into the walls as a "pseudo-vermicule," the result of fecunda- tion, as described by MacCallum. The discovery of MacCallum, then, seems to fill the last link in the chain, inasmuch as it will be remembered that both Ross and the Italian observers insist that the pres- • ence in the blood of forms capable of flagellation is necessary to the develop- ment of the pigmented structures in the stomach wall. In connection with this work a few re- marks concerning the observations of Professor Koch, which have been ap- pearing during the last year, may not be out of place. Both in the reports of his studies in Africa and in a recent commu- nication in the Deutsche Medicinische IVochenschrift, in which he describes his studies in Italy, Koch has detailed obser- vations confirming much that has been 4 done by French, Italian, American and Russian and German observers. The publications have unfortunately appeared in such a form as to give most readers the impression that the observations are orig- inal discoveries. They have been so re- garded in many non-medical, and in some, particularly German, medical pub- lications. It is but fair to say that Pro- fessor Koch's observations, while entitled to all the attention which is, of course, due to their distinguished author, are solely confirmatory in nature; Koch has not as yet made a single original observation in this field. Everything which he has de- scribed has been previously worked out and reported by others, and it is unfor- tunate, as Dr. Nuttall has elswhere ob- served, that his publication should have taken such a form. Dr. Thayer:-I think the reports that are gradually com- ing in from various military hospitals with regard to the fre- quency of these combined infections are rather interesting. Early in the fall and summer the papers were full of statements that cases of combined malaria and typhoid were very frequent and it was said that ten or fifteen, perhaps even twenty per cent, of all the cases were of the combined type. As the accurate reports are received, it is surprising to me to find how few cases have occurred. The conditions that existed in the army camps, in Cuba and in the South, were the ideal conditions for malaria and typhoid to develop together. One would expect that a very considerable number of cases of combined infection should occur, but as a matter of fact such cases seem to have been relatively few. Dr. Norton noted the fact that many cases of typhoid fever at autopsy showed evidences of preceding malaria, but he did not remember, I think he said, a single instance where they were positively found in the hospital. I think we may say safely that the actual course of typhoid fever is very little influenced by the combined infection with malaria. When the two diseases occur at the same time the condition of things seems to be very much that shown in Dr. Craig's case, the malarial symptoms are simply imposed upon those of typhoid. They may aggravate the disease and make the patient feel worse, but they do not affect the course of the typhoid itself, and we must absolutely abandon the name typho-malarial as suggesting a combination of the two diseases. Dr. Thayer is not responsible for the spelling in this communication. Biepr-i nted from tn. I. Iki Mr&tm MEDIGflLfHEGISTER. ^1 issued *^8RT*<*onw < ST *• ft IB* PMaJir Mt Mm, flDebtcal College of Virginia C4iMd by B. C. LBV Y M. O •m * Umvi, ■. 0. Law* C. boeme, M. tx YA VLB O» OOBTUTV. OBIOINAL ABTtOLBB BBFOFTB OF CABBB BDlTOBlAk MiaCBLUANKOUB sEES'SS5^ s w«<iif.i '«y •• «» W«W Wa^WMCMMM OFFICB OF FVBLXOAnOB / <. BIU. FVIBTIB® CO.. Boa M3 ,l~~ Vk boftobial books BBOIOAA COLABOB OF ▼tBOTVIA FHm Bl ee» aaee» 6lB«to Cey, IS Mate. J U-rWHIHI-HwhlfMl In December', 1899. Recent Investigations Concerning the Hematozoa of Malaria. By WILLIAM SYDNEY THAYER, M. D., Baltimore, Md., Associate Professor of Medicine, Johns Hopkins University. Read at the Thirtieth Annual Meeting of the Medical Society of Virginia, Richmond, October 24-26, 1899. RECENT INVESTIGATIONS CONCERNING THE HEMATOZOA OF MALARIA.* By William Sydney Thayek, M. D., Baltimore, Md., Associate Professor of Medicine, Johns Hopkins University. Since the discovery of Laveran in 1880 we have known that the malarial fevers are due to specific parasites which live in the blood of the infected individual. And, thanks to Golgi, and Marchiafava and Celli, we know that the malarial paroxysm coincides with the sporulation of generations of parasites. In the regularly intermittent fevers where the parasites exist in great groups, all the members of which are approximately at the same stage of development, while the length of the cycle of exist- ence of the organisms is fairly constant, respectively about forty- eight or seventy-two hours, the paroxysms occur with remark- able regularity, each new group of parasites reaching maturity every third or fourth day. In the case of the estivo-autumnal parasite, however, the arrangement in groups is by no means as constant; sporulation of large collections of organisms may occur at irregular intervals, resulting often in irregular or more or less continued fever. In our climate the earlier fevers in the spring are more commonly regularly intermittent, the tertian organism being responsible for the great majority; while in the later summer and fall the more irregular fevers, resulting from infection with the estivo-autumnal parasite, predominate. The discovery of the organisms, and of their characteristics, has given us valuable knowledge of the nature of the disease, and has also furnished us with a means of diagnosis of the greatest importance. Until very recently, however, we have been entirely in the dark as to the form in which the parasites exist outside of the human body and as to their manner of entry into the or- ganism. The various arguments in favor of the theory that infection occurs through air and water are familiar. Each idea has had its supporters, but proof of the truth of either is wanting. Indeed, there are facts which speak strongly against the theorv that the * Read at the Thirtieth Annual Meeting of the Medical Society of Vir- ginia, Richmond, October 24-26, 1899. 2 THAYER: HEMATOZOA OF MALARIA. disease may be acquired through the gastro-intestinal canal. We have, at least, tolerably good evidence that the ingestion of large quantities of swamp water from most malarious districts whether taken by the mouth or by the rectum, the inhalation of the same water, and the ingestion of dew collected from malarious regions are incapable of producing malaria. On one occasion, indeed, fresh human blood containing malarial parasites was administered internally without any ill results.1 Experiment has, however, shown that hypodermic or intravenous inocula- tion of blood containing malarial parisites is almost always fol- lowed by the appearance of similar organisms in the blood of the person inoculated, and the reproduction of a similar type of the disease.2 I'he fact that malaria could be transferred by hypodermic inoculation caused observers to turn back to an idea which had been previously advanced, notably by King3 and Laveran/ that the disease might be introduced by the bites of insects, especially mosquitoes. In 1896 Bignami5 considered the evi- dence in favor of the mosquito theory to be stronger than that in support of any other idea. This theory is exhaustively considered in a recent communication by Dr. Nuttall.*' Malarial localities are almost invariably infested by these insects. The height of the malarial season corresponds to the time at which the mosquitoes are most frequent. There is abundant evidence that protection of the body, the closing of windows and doors by night, the use of mosquito nets, etc., are protection against the disease. Agglomerations of houses exclude malaria, and in the same way mosquitoes are stopped by barriers of this and other nature, such as walls, hedges, etc. Cultivation and drain- age, which remove the breeding places of mosquitoes, are well known to be valuable prophylactic measures against the disease. Sleeping out of doors at night, or exposure after sunset have long been known to be dangerous, but these are both proceedings which render one particularly liable to mosquito bites. Bignami (loc. cit.) has called attention to the fact that peasants in certain districts in Italy, who sleep in huts with a single opening above through which the smoke of the fire is carried away, are rarely affected by malaria, though those about them are commonly afflicted. Despite objections which have been made, it seems to be true that wherever one finds much malaria, there also mosquitoes may be found. THAYER: HEMATOZOA OF MALARIA. 3 Especially suggestive are the discoveries in connection with certain other diseases due to heniatozoa. I refer to the remark- able observations of Theobald Smith' with relation to Texas fever and those of Bruce86 in South Africa concerning tsetse fly disease. Smith, as is well known, showed that Texas fever is transferred from beast to beast by means of the bite of the cattle tick, while Bruce showed that the tsetse Hy disease, or nagana as it is called, is inoculated by the bite of this particular fly. The first experiments with relation to the role of mosquitoes which have yielded positive results w'ere begun by Ross in India at the suggestion of Manson, and these studies have already established facts of the greatest interest and importance. Ross9 while studying the blood in the stomach of the "dappled-winged" mosquito [anopheles pictus (?)] fed upon malarial subjects, noticed in several instances curious pigmented bodies in the wall of the insect's stomach; the pigment resembled strongly that which had been contained in the parasites present in the human blood. These elements, he immediately suggested, might be stages in an extracorporeal cycle of existence of the parasite. Owing to the season, however, Ross1" was compelled to continue his observations upon the parasites of birds, which, as is well khown, are closely similar to those of human beings. He found that in the " grey mosquito " (Culex pipiens) fed upon birds containing a certain variety of parasite (the Proteosoma Grassii) similar bodies appeared within forty-eight hours after feeding. They lay in the muscular coat of the mosquito's stomach and steadily increased in size until about the seventh day, at which time they had acquired a diameter of about 70 micromillimetres, protruding from the surface of the stomach into the coelom. At this period the bodies -were noticed to contain a number of radial striae coming out from different centres, the pigment having in great part disappeared. Pressure upon the slide caused these full-grown elements to rupture, numerous small spindle-shaped bodies escaping; these structures had apparently given rise to the striated appearance. On examining the blood of mosquitoes in which the bodies should have reached about this stage of development, similar spindle-shaped elements were found in the circulation; while later Ross discovered that at the same period the cells of the salivary or poison glands of the insect were crowded with these " germinal threads," as he called them. As the collecting duct of these glands extends to the extremity of the mosquito's 4 THAYER: HEMATOZOA OF MALARIA. proboscis, the possibility that these germinal threads might be the actual agents of infection, being introduced by the bite of the insect, immediately occurred to the experimenter. And, on exposing non-infected birds to the bites of such insects, a fresh infection with proteosomoa was almost invariably ob- tained.11 Hero then was direct proof of an extracorporeal cycle of ex- istence of a parasite closely analogous to the malarial parasite in man, and, more than this, proof that at the end of this cycle the bite of a mosquito is capable of transferring the disease from one individual to another. These observations have been wholly confirmed by Daniels12 and by Koch.13 * * * How does the parasite enter the wall of the mosquito's stomach and what form of the organism performs this act? For a long time it has been known that when the parasites of all three varieties of malarial fever, as well as those of birds, reach maturity, certain forms do not develop spores. These bodies either become disintegrated or undergo a process which is termed flagellation. In the latter event, several delicate, filamentous structures, endowed with active serpentine move- ments, burst from the mother body; many actually break loose and rush about under the field of the microscope. Laveran, who first observed this process, has always insisted that the flagella must play some important role in the history of the parasite. The majority of observers, however, were inclined during many years to consider them as degenerate forms. Two years ago MacCallum11 while studying a certain parasite of birds, the Halteridium of Labbe, more properly the "Lav- erania Danilevsky i," discovered that the flagella, after breaking loose, sought out other full-grown forms which showed slight, but distinct, morphologic differences from those undergoing flagellation, and penetrated into their interior. Only one flagel- lum was ever observed to succeed in entering a given parasite. Shortly after penetration the organism changed into a spear- shaped structure and assumed a slow, slightly vermicular, for- ward motion through the field of the microscope. The sharp point of this moving " pseudo-vermicule," as it has been called by Danilevsky, is capable of rupturing and destroying blood corpuscles in its course. These observations have since been confirmed by Marchoux15 and Koch (Joe. cit.} THAYER: HE MATO ZO A OF MALARIA. 5 The nature of the process and its relation to the rest of the cycle of the parasite, as well as analogy with other similar organ- isms, left little doubt in MacCallum's mind that the proceeding was one of fecundation. In other nearly related parasites a similar proceeding has been noted.16 The organism, then, possesses a cycle within one host which may be repeated indefinitely, the full-grown sporocytes giving rise to a number of young spores, each capable of entering again upon the same cycle of existence. But sooner or later other full-grown forms appear which are sexually differen- tiated {gametocytes). The male and female forms may be dis- tinguished from one another histologically. These are appa- rently incapable of further development while still within the circulation; they are forms destined to preserve the life of the organism under other conditions; and on entering into a new medium (on the microscopic slide, for instance, or in the stomach waH of the mosquito) they undergo characteristic changes. From the male gametocytes {microgametocytes, Bas- tianelli and Bignami17) flagella \microgametes, Ross,18 Bignami and Bastianelli {loc. cit.}] escape. These seek out the female gametocytes {macrogametes), which they enter, penetrate and fertilize. The fertilized macrogamete, or zygote, as it is called, undergoes definite morphologic changes, becoming the pseudo- vermicule. The pseudo-vermicule, with its sharp point and motil power, is doubtless the particular form which penetrates into the stomach wall of the mosquito. And Koch {loc. cit.) has shown that between the time of ingestion of the parasite- containing blood and the appearance of the sporozoa in the stomach walls, flagellation, fecundation and the development of pseudo-vermicules occur within the mosquito in the case of the Protesoma just as they had been observed upon the slide by MacCallum with the Laverania Danilevskyi. In the case of the parasites of birds, and, as will be later shown, in essentially the same manner with the human malarial parasite, the zygotes develop within the walls of the mosquito's stomach. The nucleus of the proteosoma zygote divides into a number of different parts and finally there arise great numbers of filamen- tous zygotoblasts, which, upon the rupture of the mother zygote accumulate in the salivary gland of the mosquito, and produce infection on the occasion of the bite. * * * While Ross was engaged in these investigations, the Italian 6 THAYER: HEMATOZOA OF MALARIA. observers were also active. Grassi19 from a study of the mos- quitoes in malarious and non-malarious districts, had narrowed down to three varieties, which, because of their almost in- variable association, both as regards time of year and locality, with malarial fever, seemed to bear some relation to paludism; while Bignami,2" having collected mosquitoes from malarious districts, had succeeded in inoculating a patient who had volun- tarily subjected himself to the experiment. This patient had lived for years in the Santo Spirito hospital, where the disease never occurs. Among three varieties of mosquitoes to the bites of which this patient had been subjected, Grassi found two of the forms which had aroused his suspicions. Bastianelli, Bignami and Grassi21 then carried out with human beings experiments similar to those of Ross upon birds. They found that if mosquitoes belonging to the genus anopheles were fed upon patients whose blood contained parasites at a stage in their cycle of existence when flagellation might occur, there appeared, in the stomach walls, bodies closely analogous to those observed by Ross in his experiments with birds, and in every way similar to the structures that he had found after feeding dappled- winged mosquitoes, which belonged to this genus, upon infected human beings. They have followed the complete cycle of tins extracorporeal phase in the existence of the estivo-autumnal parasite and of the tertain organism. Similar sporozoa appear in the stomach wall, developing, in their interior, spindle-shaped sporozoids. These escape, as in the case of the proteosoma, accumulate in the salivary glands, and, lastly, as the Italians have proved by several unassailable experiments, the mosquito at this stage is capable of inoculating the human subject. And, what is more, a single bite by an infected mosquito is sufficient. These observations have been confirmed by the British West African expedition.22 Strong evidence supporting the specificity of the three different varieties of parasites is also brought out by these observations. The type of organism always remains the same after the extra- corporeal stage in the mosquito, just as has been shown to be the case in direct inoculations from one individual to another. The fact that but one genus of mosquito appears to be capable of playing the part of intermediate host of the parasite-a genus which, acording to Grassi, is rarely found, excepting in malarious districts, answers immediately the objections to the mosquito theory based upon the frequent presence of mosquitoes in non- TEA YER: HEMA TOZOA OE MALARIA. 7 malarious regions. The ordinary house mosquitoes, which breed about sinks and sewers and closets, belong to the genus culex, none of which have, as yet, been found capable of harbouring the parasites. * s * We are at present endeavoring in Baltimore to control this Indian and Italian work. Mosquitoes collected from different Anopheles Cities This rough illustration, copied from the Brittish Medical Journal, 1899, II, 869, shows some of the gross differences between the genus of mosquito (anopheles) which has been found to be a host of the malarial parasite and the commoner, innocent variety (culex). The manner in which the mos- quitoes sit on the wall and the position of the hind legs are well shown. The markings on the wings of the anopheles in the plate are roughly sug- gestive of those in our a. punctipennis. The palpi are not represented in the plate. parts of the city and from a number of different swampy regions about the town all proved to be members of the genus culex, and repeated dissections of these mosquitoes, before and after feeding upon infected individuals, failed to reveal any evidence of an extracorporeal stage of the parasite. In the latter part of August, however, I visited the town of Steelton at Sparrows' Point, a notoriously malarious district, and, in making rounds with my friend, Dr. Eldred, in the houses of patients suffering from malaria, I was immediately struck by the fact that the pre- vailing type of mosquito was different from that which we had previously found. This mosquito belonged to the genus anoph- eles, and has been identified by Dr. Coquillett of the Agricul- 8 THAYER: HEMATOZOA OF MALARIA. tural Department, as the anopheles quadrimaculatus (Say). A mosquito of this type was also brought to me by an out-patient who had been suffering from malaria. In several of about thirty specimens of this insect, collected from the bed-room of a patient suffering with a severe attack of malarial fever, bodies were found in the stomach walls, in every way similar to the specimens of the Italian observers which I have recently had the pleasure of seeing in Rome. Mosquitoes of this species have been found in the houses and huts not only at Sparrows' Point, but also in other neighboring malarious districts. Dr. J. W. Lazear, who has been associated in these studies, has recently found another form of anopheles in some houses in one of the suburbs of Baltimore-the anopheles punctipennis. He has further discovered a breeding place of this insect in some small pools about a neighboring stone quarry. This anopheles presents, in gross, similarities with the European anopheles pictus and is not improbably somewhat analogous to the form upon which Ross made his original observations. The anopheles quadrimaculatus, which is apparently more common in these regions, presents, in gross, striking similarities with the anopheles claviger, which is apparently the most important agent in trans- ferring malarial infection in Italy. I take pleasure in showing you examples of these two species.* * Several gross differences between mosquitoes belonging to the genus anopheles and those belonging to the more common genus culex, may be readily recognized by the ordinary observer. The culex sits upon the wall, or ceiling, with its body approximately parallel to the surface to which he has attached himself. Only in some instances when the mosquito is sitting on the ceiling and the stomach is very full of blood, does the abdomen sag downwards slightly. The anopheles, on the other hand, hangs from the wall, or from the ceiling, with its abdomen protruding at an angle of perhaps forty-five degrees or sometimes even more. When attached to the ceiling it looks almost as if it were hanging by the proboscis. The hind legs of the culex, when in a position of rest, are usually lifted up over the back. The posterior pair of legs of the anopheles, which are longer than those of the culex, are never raised over the back. Just at the root of the proboscis of the culex two short processes, the palpi, are to be seen. On gross examination, these often look merely like a thick- ening at the origin of the proboscis In the anopheles, however, the palpi form two long processes, one on either side of the proboscis nearly equalling it in length, so that on gross inspection the insect appears to have three proboscides. The wings of the different varieties of culex are unspotted. The wings of most varieties of anopheles, on the other hand, show distinct markings. In the anopheles quadrimaculatus there are two small longitudi- nally arranged spots, and at the end of the wing two others placed side by side; while in the anopheles punctipennis along the anterior border of the During September Mr. Wooley on__twa occasions fed several examples of the anopheles quadrimaculatus upon patients suffer- ing with tertian malaria, and in two instances obtained charac- teristic bodies in the wall of the mosquito's stomach. One of these specimens may be seen under the microscope. During the month of September, while in Rome, I had the privilege, through the kindness of Dr. Bastianelli, of examining some of the interesting specimens which form the basis of his and Bignami's communications. These are in every way similar to those which we have obtained. We are at present conducting further experiments in Baltimore which I hope to report in a later communication. * * * Tn summary, then, what light have the observations of the last two years thrown upon the nature and manner of infection of malarial fever? (1.) A certain genus of mosquito (anopheles') appears to be constantly associated with malarial fever, prevailing in the same localities and at the time of the epidemics of the disease. (2.) The malarial parasites have been shown to have two cycles of existence, one in the human being and one in the stomach walls of the different members of this genus of mosquito. (3.) Mosquitoes of the genus anopheles, having fed upon an infected individual are capable, after a certain time, of spread- ing the disease by their bites. (4.) An improperly treated case of malaria, may he a source of danger to individuals in the neighborhood. * * * The fact that mosquitos may spread the disease is proved-but a host of further questions arise to be solved: Just what varieties of mosquitoes are capable of propagating the disease in this country? What part do mosquitoes play in our endemics and epi- demics of malaria? Is the mosquito the chief or only agent of infection? THAYER: HEMATOZOA OF MALARIA. 9 wings are three deep brown spots or lines, between the latter two of which the wing has a buffy color, so as to give a mottled or brindled appearance to the mosquito as his wings are at rest. From these differences, which are suggested in the accompanying figures, especially from the manner in which the mosquitoes sit upon the wall, the two genera may be readily distinguished. 10 THAYER: HEMATOZOA OF MALARIA. ('an the mosquito acquire the parasites from other sources than from man? These are but a few of many questions upon which I cannot even touch to-day. It may not be out of place, however, to say that observations in Italy by Celli and Delpino23 tend to suggest that the majority of cases of spring malaria in climates such as ours are relapses; that the epidemic of new cases, which begins about July and is closely coincident with the appearance of the anopheles, is largely dependent upon these mosquitoes.* Our observations in Baltimore agree with these and strongly suggest that the mosquito plays an equally important part with us. A hopeful feature in connection with this work is the possi- bility that, owing to the nature and limited extent of the breed- ing places of these dangerous mosquitoes, valuable prophylactic measures may be within our reach. But discussion of these questions would lead me far beyond my limit of time. I have endeavoured to lay before you a few observations establishing one main fact-a fact it seems to me of very considerable importance. After centuries of speculation, thanks to Ross, and to the Italian school, we at last know one manner by which malarial infection occurs. Considerable study remains to be done to determine the fre- quency and practical importance of this manner of infection- to devise means of prophylaxis-but there seems real reason to hope that Ross's discovery may give us more help toward con- trolling this scourge of warm climates than any advance since the introduction of quinine. BIBLIOGRAPHY. 1. Celli: Bull. d. Soc. Lane. d. Roma, 1886, vi., f. i., 39. Zeri: Bull. d. R. Ace. Med. d. Roma, 1889-'9O; xvi., 244. Marino: Riforma Mediea, 1890, vi., 1502. Grassi and Feletti: CentraTbl. f. Balt., 1891, ix.. 403; 429; 461. 2. Elting: Zeitschr. f. Klin. Med., 1898, xxxvi., H. 4. 5 and 6 (with full references to the literature'). 3. King: Popular Science Monthly, New 'York, 1883, xxiii., 644. 5. Bignami: Lancet, 1896, ii., 1363, 1441. 4. Laveran: Du Paludisme, etc., 8° Paris, 1891, 147. 6. Nuttall: Johns Hopkins Hospital Reports, 1899, viii., 1. *An admirable discussion of the question of mosquitoes and malaria is to be found in Professor Celli's recent work.24 THAYER: HEMATOZOA OF MALARIA 11 7. Smith and Kilbourne: Investigations into the Nature, Causation, and Prevention of Texas or Southern Cattle Fever. U. S. Dep't of Agriculture; Bureau of Animal Industry; Bull. No. 1, 8°, Washington, 1893. 8. Bruce: Further Report on the Tsetse Fly Disease or Nagana, etc., 8°, London, 1896. 9. Ross: British Med. Jour., 1897, ii., 1786. 10. Ross: Report on the Cultivation of Proteosoma, Labb6, in Grey, Mos- quitoes, 80 Calcutta, 1898. 11. (a) Manson: British Med. Journal, 1898, vol. ii., 849. (b) Ross: Preliminary Report on the Infection of Birds with the Proteosoma by the Bites of Mosquitoes. Nowgong. Assam, Oct. 11, 1898. < 12. Daniels: Proc. Royal Society, vol. Ixiv., 16, March, 1899. 13. Koch: Zeitschr. f. Hyg u. Infectionskrankh, 1899, xxxii. 14. MacCallum: Journal of Experimental Medicine, 1898, iii, 117. 15. Marchoux: Compt. rend. hebd. d. se. de la Soc. de Biol., Par., 1899, ser. x., vi., 199. 16. Simond: Annales de I' Inst. Pasteur, 1897, xi., 545. 17. Bastianelli and Bignami: Annali d'igiene s perimentale, 1899, ix., n. s., f„ 3, 272. 18. Ross: Nature, 1899, lx., 322. 19. Grassi: Policlinico, 1898, vM., 469. 20. Bignami: Lancet, 1898, ii., 1461; 1541. Also, Bull. d. R. Acc. Med. d. Roma, 189, 1898-'99, f. 1. 21. (a) Bastianelli, Bignami and Grassi: Atti. d. R. Accad. d. Lincei. cl. di sc. Jis., mat e nat., Homa, vii., 2° Sem , Serie 5a, fasc. 11° (4 Dec., 1898). (b) Grassi, Bignami and Bastianelli: Do. do. (22 Dec., 1898). (c) Grassi, Bignami and Bastianelli: Do., Vol. viii., 1° Sem., Serie 5a, Fasc. 3° (5 Feb. 1899). (d) Grassi, Bignami and Bastianelli: Do. Vol. viii., 1° Sem., Serie 5a, Fasc. 9° (7 May, 1899). (e) Bastianelli and Bignami: Bull. d. R. Acc. Med. di. Roma, xxv., Fasc. iii., 1898-'99, and Annali d'igiene sperimentale, 1899, lx., n. s., f. iii., 272. (f) Bastianelli and Bignami: Ann. d'igiene sperimentale, 1899, ix., n. s., f. iii., 245. (g) Grassi, Bignami and Bastianelli: Do. do., 258. (h) Bastianelli and Bagnami: Communicazione fatta al X Con- gresso d. " Soc. Itai. di. Med. Int." Seduta del 25 Ott , 1899. (Reprint.) 22. Brit. Med. Journ., 1899, ii., 675, 746, 869. 23 Celli and Delpino: Suppl. al Policlinico. Anno. 1899 24. Celli: La Malaria Secondo le Nuove Ricerche, Roma, 8°, 1899. Dr. Thayer.-We all, I am sure, feel grateful to Dr. Ewing for the very interesting communication which he has made. I regret extremely that Dr. Lazear is not here to take part in the discussion, inasmuch as he has for the past year been making careful studies in this line. Unfortunately, he has gone to Cuba, and his specimens and the paper which I had expected to have in time to read to-night have not been received. Dr. Ewing's interpretation of his interesting observations is extremely suggestive. I recognize many of the pictures which have been described, but I must confess that their pos- sible importance had escaped me. I have, without much thought, always assumed that the reason why twin parasites were relatively common in the early stages of development of the organism and so infrequent later on was that with the growth of the several contained organisms the red blood-cor- puscle was eventually ruptured, both parasites escaping and meeting the fate which apparently inevitably befalls extra- cellular bodies at this stage of development. But, after all, this is a pure hypothesis, and in view of Dr. Ewing's careful studies I should surely feel called upon to thoroughly restudy the question before venturing to dispute his conclusions. A rather interesting point in connection with this matter, if we are to regard the process as one of fusion, is that at a certain stage the structure of the organism might justify the term plasmodium, the biological inaccuracy of which as applied to the ordinary parasites has been so generally recognized. In connection with the possibility that this process might be a true conjugation, a rather inviting, though I fear improbable, explanation of its possible significance suggested itself to my mind. In the aestivo-autumnal parasite, for instance, beside the organisms pursuing the ordinary cycle of development, there soon appear other bodies morphologically distinct from these, the crescentic and ovoid forms. These forms, Mannaberg contends, are the result of conjugation of two elements belonging to the ordinary cycle. Only from the bodies belonging to the crescentic group do the sex-ripe forms (macrogametes and microgametocytes) develop. In a recent communication Bastianelli and Bignami assert that the sex-ripe forms in the tertian parasite likewise develop from elements morphologically distinguishable from those belonging to the ordinary cycle. What causes the differentiation of the crescent group in the aestivo-autumnal parasite and of the group destined to develop into sex-ripe forms in the tertian parasite? May it be that these sex-ripe forms in both instances develop only as a result of conjugation of two bodies, each of which alone would be capable of pursuing only the ordinary asexual cycle-that the process observed by Dr. Ewing is a necessary stage in the production of elements destined to develop into flagellate forms (microgametocytes) or macrogametes ? I am, however, unaware whether there is any analogy to justify such an hypothesis-and what is more important the fact that the crescents are formed as a result of conjugation is by no means settled. Indeed, we are inclined to believe, with the Italians', that this is not the case. / ON RECENT ADVANCES IN OUR KNOWLEDGE CONCERNING THE AETIOLOGY OF MALARIAL FEVER. BY WILLIAM SYDNEY THAYER, M.D. Associate Professor of Medicine in the Johns Hopkins University. [From Vol. V., Transactions of the Congress of American Physicians and Surgeons, 1900.} BACTERIOLOGY IN HEALTH AND DISEASE. ON RECENT ADVANCES IN OUR KNOWLEDGE CONCERNING THE AETIOLOGY OF MALARIAL FEVER. BY WILLIAM SYDNEY THAYER, M.D. Associate Professor of Medicine in the Johns Hopkins University. ON RECENT ADVANCES IN OUR KNOWLEDGE CONCERNING THE AETIOLOGY OF MALARIAL FEVER. BY WILLIAM SYDNEY THAYER, M.D. Associate Professor of Medicine in the Johns Hopkins University. Three years ago, at the time of the last session of this Congress, the form in which the malarial parasite lives outside of the human body, and its manner of entrance into the organism, were matters of speculation. The idea, especially insisted upon by Manson,1 that the crescentic forms of the aestivo-autumnal parasite might represent bodies "intended to carry on the life of the species out- side the human body," and the view expressed also by Dock2 and Mannaberg3 that the flagella, upon the functional importance of which their discoverer, Laveran, had always insisted, might represent the first stage in the life of the malarial parasite in an external medium-these were still matters of dispute. With regard to the manner of infection there existed three main theories. i. That the disease was acquired through the gastro-intestinal tract, especially by drinking water. 2. That the infectious agent entered through the inhaled air. 3. That inoculation occurred through the bites of insects. Suggestive evidence against the idea that the disease might be acquired through the gastro-intestinal tract had been furnished by the experiments of Celli, Marino, Zeri, Grassi and Feletti4; while a careful study of the literature, as well set forth by Norton,6 revealed the utter lack of evidence in support of the theory that malaria is a water-borne disease. With regard to the theory that the infectious agent entered through the respiratory tract, it could only be said that while certain general facts spoke in its favor, no positive evidence had ever been adduced in its support. That inoculation might occur through the bites of insects, and especially of the mosquito, had become an attractive hypothesis. This theory, to which Nott0 had referred in 1848, was first definitely put forward by King7 in 1883; it was again mentioned by Laveran8 in 1891 and 1895. The arguments in favor of the mosquito-theory, AETIOLOGY OF MALARIAL FEVER. 51 the strongest being the remarkable observations of Theobald Smith9, concerning Texas cattle fever, were well brought together in 1896 by Bignami.10 Experimental evidence, however, in support of this view was entirely lacking, despite the fact that Bignami (loc. cit.) and Dionisi had already attempted to produce the disease by exposing individuals to the bites of mosquitoes. * * * Manson, it will be remembered, was not, at this time, an advocate of the theory that the disease might be inoculated through the agency of mosquitoes. Assuming, as has been mentioned before, that the crescentic forms of the parasite might represent bodies intended to carry on the life of the species outside of the human body, he put forward the hypothesis that the mosquito might act as an inter- mediate host for the malarial organisms, as it does for the filaria sanguinis hominis; that after ingestion the parasites might enter into the tissues of the mosquito, living there, in some form, until set free again with the death of the insect. He was inclined to think that they might be reintroduced into the human being through the gastro-intestinal tract.11 * * * In the summer of 1897 MacCallum12 cleared up the much dis- puted question as to the nature of the flagellate bodies. His obser- vation that in the Laverania Danilevskyi* there exist sexually differ- entiated forms of the parasite, the flagella, representing the male elements, penetrating and fecundating the female forms, was the first real advance. This discovery not only demonstrated the nature of the flagellate bodies, but, from analogy with other biological pro- cesses, justified the inference that the resultant fecundated element might represent a form capable, perhaps, of development in a medium other than the blood of the animal in which it had arisen. In the meantime Ross,13 working in India at the suggestion of Manson, had noted the development of flagellate bodies within the stomach of mosquitoes which had been fed upon patients whose blood contained crescentic aestivo-autumnal parasites. Later Ross14 observed in the stomach walls of several of these mosquitoes, which * In the studies of Opie and MacCallum this parasite has been referred to as the Halteridium of Labb6, but, as Laveran has justly pointed out (Comptes rendus hebd. d. se de la Soc. de Biol., Par., 1899, s- xb T. i, 603), according to the rules of nomenclature, the specific name Laverania Danilevskyi, recom- mended previously by Grassi and Feletti, is the more proper term. 52 H have been since shown to belong to the genus anopheles, a number of round, refractive, encapsulated bodies containing granules of pigment quite similar to that previously contained in the crescentic parasites which had been ingested. These structures, unlike any which he had previously observed in the mosquito's stomach, he suspected to be stages of an extra-corporeal cycle in the life history of the malarial parasite. Owing to a dearth of material Ross15 was compelled to continue his experiments upon birds. He soon found that on the second day after feeding the "grey mosquito"* upon birds infected with the Proteosoma Grassii, similar bodies appeared in the muscular coat of the stomach wall. These bodies, at the beginning, measured about 7-8 micromillimeters in diameter, showed a well marked refrac- tive capsule, granular contents and a number of particles of pig- ment quite similar to those previously existing in the haematozoa. In repeated experiments Ross followed the gradual development of these structures, until, at the end of seven or eight days, their diame- ter measured nearly 70 micromillimeters. At this period they pro- jected from the external coat of the stomach into the coelom. # Soon afterwards the capsules ruptured, setting free a number of delicate spindle-shaped bodies, which were later found accumulated in great numbers in the large clear cells of the veneno-salivary glands. Feeding experiments proved that at this stage the mosqui- toes were capable of transmitting the parasite to non-infected birds. Early in the course of the work Ross and Manson assumed that the penetration of the stomach wall was accomplished by the motile pseudo-vermicules which MacCallum (loc. cit.) had shown to be the followers of fecundation in the Laverania Danilevskyi; and Koch10 has since observed the development of these pseudo-vermi- cules in proteosoma-conteirdng blood within the mosquito's stomach. Ross thus demonstrated the fact that the "grey mosquito" was not only capable of-playing the part of an intermediate host of the Proteosoma Grassii, but further might actually transmit the infection from one bird to another. These observations have since been confirmed by Daniels17 in India, and Koch (loc. cit.) in experi- ments made with the culex nemorosus in Italy. *This mosquito was at first thought by Grassi to be identical with the culex pipiens, but Giles, who (Journ. Trop. Med., Lond., 1899, ii, 62) has recently made a careful study of the mosquitoes which Ross employed in its investigations, asserts that it is similar to, if not identical with the culex fatigans described by Wiedemann. AETIOLOGY OF MALARIA-L FEVER. 53 Simultaneously with Ross's work, Grassi's18 interesting studies in Italy revealed the fact that several varieties of mosquitoes, namely the anopheles claviger, culex penicillaris, and the culex malariae, were almost invariably present in malarious localities, at the malarial season. This association was so constant that Grassi was led to believe that some definite relation must exist between the presence of some or all of these mosquitoes and the prevalence of malaria. Bignami,19 in the meantime, had succeeded in producing malarial infection by exposing a patient to the bites of mosquitoes collected from malarious localities; and Grassi showed that while only mem- bers of the genus culex had been employed in the early unsuccess- ful experiments, on this latter occasion, a number of specimens of anopheles claviger had been present. Grassi, Bastianelli, and Bignami20 then proceeded to feed speci- mens of a. claviger on infected human beings, and were soon able to demonstrate the various phases of the life of the human malarial parasites in the mosquito. Only members of the genus anopheles appear to serve as hosts for the human malarial parasite, but all species of this genus so far studied by them have proved themselves capable of harboring the organism.21 The Italian observers have followed the complete extra-corporeal cycle of all three species of the parasites. After entering the mosquito's stomach, flagellation and fecundation* occur, the fecun- dated bodies develop into pseudo-vermicztlesand about forty hours after feeding, there develop within the stomach walls, structures closely similar to those observed in the "grey mosquito" fed on proteosoma-ccmtaxnvag blood. These undergo a similar course of development, reaching maturity in about a week, rupturing and set- ting free great numbers of small spindle-shaped bodies which accu- mulate in the salivary gland of the insect. *The actual process of fecundation has never been observed in the mos- quito's stomach. MacCallum's observations of penetration in fresh blood on the slide is as yet the only one. That it must occur, however, is fairly clear. t That it is the pseudo-vermicule which enters into the stomach wall is shown by the structure of the earliest forms of the fecundated aestivo-autumnal bodies found by Grassi, Bastianelli and Bignami, and by us in our one successful feed- ing experiment with the aestivo-autumnal parasite, and especially, by more care- ful studies of the early changes occurring in the fecundated aestivo-autumnal parasite in the mosquito's stomach by Bastianelli and Bignami.20' 54 A sufficient number of inoculation experiments have proved that the bite of a single mosquito with infected salivary glands is capable of transmitting the disease. Observations by the British West Africa expedition22 and a few which we have had the good fortune to make in this country, have confirmed the beautiful studies of the Italian observers. The conditions in Baltimore appear to be essentially the same as those in Northern Italy. In the city we observe one main variety of mosquito, the culex pungens* while in the suburbs, we have found numerous examples of other culices, especially the c. taeniorhycus and the c. triseriatus. Repeated feeding experiments with differ- ent culices upon human beings and upon birds infected with Lave- rania Danilevskyi were without result. At Sparrows' Point, a most malarious district in the suburbs, and in a number of houses in the neighborhood, besides the ordinary culices, there were found great numbers of the anopheles quadri- maculatus Say. This anopheles, both in the markings upon its wings, and in its gross appearance, is very similar to the anopheles claviger. In several examples of this mosquito obtained from the room of a patient suffering with malaria, there were found, in the stomach wall, characteristic encapsulated, refractive, pigment-containing bodies, corresponding in every way to the extra-corporeal stages of the tertian parasite which I have since had the pleasure of observ- ing in Bastianelli's specimens. In two examples of the anopheles quadrimaculatus, fed upon a patient whose blood contained full- grown tertain parasites, Wooley, in our laboratory, has been able to obtain similar bodies. In one a. quadrimaculatus fed upon the blood of a patient containing crescentic bodies there were found in the stomach wall, about thirty hours after feeding, two lanceolate pig- mented bodies, in every way corresponding to the earliest stages of the extra-corporeal phase of the aestivo-autumnal parasite. The relation of the distribution of anopheles to the prevalence of malaria has not as yet been carefully studied in this country. In Baltimore we have obtained only culices from the city proper, where malaria is infrequent. From two houses on the outskirts, in each of * I am much indebted to Dr. L. O. Howard and Mr. D. W. Coquillet, of the Agricultural Department in Washington, for identifying the different mosquitoes which we have found, and for many kind suggestions. AETIOLOGY OF MALARIAL FEVER. 55 which malaria existed, specimens of the anopheles quadrimaculatus have been obtained. From Sparrows' Point and a number of houses in the neighborhood along the Eastern shore, a district in which malaria is prevalent, considerable numbers of a. quadrimaculatus have been found. On October 28th, I was enabled, through the courtesy of Dr. Lewis, to visit the town of Jackson, Northampton County, North Carolina. This is situated in the lower Roanoke region, near an excessively malarious district. The season was late, frosts having occurred, but in the houses in that part of the town in which the most serious malaria prevailed, we found only the anopheles-not a single culex. In one of these houses thirty or forty examples of the a. quadrimaculatus were found. In the swamps about the Roanoke we found several specimens of the c. posticatus and of the c. triseriatus and one anopheles punctipennis Say. Two days later I visited Newport News, Virginia, where a con- siderable amount of malaria had existed. The weather had been cold, and only in one house did I find anopheles quadrimaculatus. In this house, however, there were two convalescents from malarial fever. In New Orleans, in the first week in December, great numbers of the c. pungens were found in the city. In the swampy malarious regions about the lake beside c. pungens, c. consobrinus and c. fasciatus, numerous specimens of anopheles quadrimacxtlatus and c. crucians Wied, were found; these were, for the most part, hibernat- ing in barns and stables. In a pool, in a stone quarry just outside the city limits of Balti- more, Dr. Lazear discovered a breeding place of the a. punctipennis; and numerous examples were found hibernating in the cellar of a house in a similar locality. The malarial season, last year, was unusually mild, and our oppor- tunities for feeding experiments were poor. So far our only positive results have been those mentioned, all three having been obtained with the a. quadrimaculatus. Last September, however, I had the privilege of seeing the beautiful specimens of Drs. Bastianelli and Bignami, which are entirely convincing. The malarial parasites then possess, in common with the coccidia as shown by Simond, Schaudinn, Siedlecki and others, two cycles of development. The first, taking place entirely within the human 56 SBwLGZKKJDWGY - Ji KALTH AND DISETOE. x being, is asexual (Schizogonia23) ending in segmentation, the result- ant segments, merozoids, penetrating new corpuscles to undergo again a similar cycle of development. After a while, however, there develop sex-ripe forms, gametes, which may be distinguished mor- phologically, especially by their staining reactions. These elements are destined to pursue another cycle of existence in the body of the mosquito (sporogonia). After ingestion by the mosquito the male elements (microgametocytes) undergo flagellation, the flagella (microgametes) escaping and penetrating the female elements (macrogametes). These fecundated bodies undergo the changes above described, developing, at first, into the motile pseudo-vermi- cule or, as Liihe23 prefers to term it, ookinete. This penetrates the stomach wall of the mosquito and there becomes an oocyst (zygote, Ross24) in which there arise great numbers of sporoblasts (zygoto- blasts, Ross) which, escaping from the mother cyst, change directly, without encapsulation, into sporozoids which accumulate in the veneno-salivary gland of the insect, and with its bite, are introduced into the new host, giving rise thus to a fresh infection. The sporozoid which has developed in the oocyst, in the stomach wall of the mosquito, is then the equivalent of the merozoid resulting from the asexual segmentation of the full-grown parasite in the circula- tion. Either, on entering a red corpuscle may give rise to the asexual or sexual cycles. As a rule the first several generations after a fresh infection pursue, for the most part, the asexual cycle, sexual forms developing later. The time of appearance of the sex-ripe forms varies greatly in different cases and in different species of parasites. In some cases of tertian and aestivo-autumnal fever they appear relatively early. In quartan infections they are apparently particularly tardy in their development20 h It may then be considered as proven. i. That the malarial parasites possess a cycle of existence which is completed in the stomach wall of mosquitoes of the genus anopheles. 2. That members of the genus anopheles are capable of transmit- ting malaria from infected to non-infected individuals. Is this the only way in which malaria may be acquired? At the present moment it may be said that it is the only proven way; that from analogy with other similar diseases it is rather unlikely that there is more than one manner of infection; that up AETIOLOGY OF MALARIAL FEVER. 57 to the present time this theory explains most conditions associated with malarial infection25; that reports showing the protective efficacy of mosquito nets, even in the most malarious districts, are rapidly accumulating; that there is no serious evidence in support of any other theory. And yet, even if we accept the theory that the only manner in which malaria can be acquired is through the bites of mosquitoes, several questions arise. Experiments have as yet failed to show any evidence of a transmission of the infectious agent from mosqui- toes to their progeny. Can the mosquito acquire the infectious agent only from man? Would the mere removal of all cases of malaria from a given region eliminate all source of infection? The evidence which we now have tends to favor an affirmative reply to these questions. Are we then to assume that, in wild and sparsely populated tropi- cal regions, an intermediate part must always be played by man? This seems, at first, hard to believe. And yet it would be rash to express oneself too positively before careful investigations have been made with this point in view. It is often surprising to find how firmly baseless impressions become fixed upon our minds. Have we any positive proof that uninhabited, tropical, anopheles- containing regions, are dangerous to individuals free from infection on their arrival ? One cannot but remember, in connection with this, the statement sometimes made, that in tropical Africa, for instance, exploring parties may spend considerable periods of time in the uninhabited interior without illness, even though the regions may appear, from outward conditions, most unhealthy. It is only on returning to the sea coast, to districts where the surroundings might appear to be better, that outbreaks of malaria occur. This hitherto inexplicable fact becomes clear if we assume that, in the interior, though all conditions are present for a spread of the disease, the mosquitoes are uninfected and so, harmless; it is only on coming back to a settlement where malaria is endemic and the mosquitoes are infected, that the disease breaks out. The well known history of the epidemic of malaria in Reunion Island is interesting in this connection. Here, in a region which, from its climate and general character might have been expected to be malarious, the disease was unknown. In 1869, in connection with an immigration from India, malaria appeared as an epidemic, and since this time has remained endemic. 58 BAOTBIITOIJWT JIN HE ALTAIAN 1) WJjJAbJL.--. Studies by Celli and Delpino,26 by Grassi (Joe. cit.), and by Bas- tianelli and Bignami (loc. cit.), of epidemics in small communities, have shown that the vernal cases of malaria are almost all relapses; that during the month of June the anopheles begins to be active; that about a month after the beginning of the activity of the anopheles, the true epidemic of malaria begins, starting apparently in foci about individuals who have recently suffered from relapses of the disease. During the season in which the anopheles prevails the malarial epidemic flourishes only to subside again with the disappearance of the mosquitoes. There is then reason to believe that if, in any given region, (i) proper measures for treating the early relapses of malaria were adopted, and (2) efficient measures for destroying the dangerous mosquitoes in their larval stage could be carried out, the prevalence of malaria might be materially controlled. The importance to the community of insisting upon the proper treatment of all cases of malarial fever cannot be too strongly emphasized. An infected patient in a malarious district is a source of danger to those about him. Before we can attempt, however, to carry out intelligently meas- ures to destroy the mosquitoes, we must first further control the important work of Ross and the Italians; we must determine defi- nitely the dangerous species of mosquitoes in this country; we must study their distribution, their habits, their breeding-places. The valuable prophylactic hints which the recent discoveries have given us, have been well brought together and published by the Liverpool School of Tropical Medicine.27 It is much to be hoped that the results of the intelligent applica- tion of such and other measures may, in the near future, demonstrate the practical importance of the new knowledge which we are now gaining. Literature. 1 Manson : Brit. Med. Jour., 1894, ii, 1306. 2 Dock : Medical News, 1890, Ivii, 59. 3 Mannaberg : Die Malariaparasiten, Wien, 8vo, 1893. 4 Celli; Bull. d. Soc. Lane. d. Roma, 1886, vi, f. i, 39. Zeri : Bull. d. R. Ace. Med. d. Roma, 1889-90, xvi, 244. Marino : Riforma Medica, 1890, vi, 1502. Grassi and Feletti: Centralbl. f. Bakt., 1891, ix, 403, 429, 461. 6 Norton : The Johns Hopkins Hosp. Bull., i^"], viii, 35. 6 Nott: New Orleans Med. and Surg. Jour., 1848, iv, 563. AETIOLOGY OF MALARIAL FEVER. 59 1 King: Popular Science Monthly. New York, 1883, xxiii, 644. 8 Laveran: (a) Du paludisme et de son hfematozoaire. Paris, 1891, 8°, 147. (£) Bull, de I' acad. de med., 1895. (c) Rev. de Hygiene, 1896, xviii. 9 Smith and Kilbourne : Investigations into the Nature, Causation and Pre- vention of Texas or Southern Cattle Fever. U. S. Dep't of Agriculture ; Bureau of Animal Industry; Bull. No. I, 8vo, Washington, 1893. 10 Bignami: Lancet, 1896, ii, 1363, 1441. 11 Manson : Lancet, 1896, i, 751, 831. 12 MacCallum : Johns Hopkins Hosp. Bull., iZqt, viii, 236. 13 Ross: (a) Proc, of the So. Indian Branch of the Brit. Med. Assoc., December 17, 1895 (original not consulted). (b) Lancet, 1896, i, 751, 831. 14 Ross: (a) Brit. Med. Jour., 1897, ii, 1786. J) Brit. Med. Jour,, 1898, i, 550. 15 Manson : (a) Brit. Med. Jour., 1898, i, 1575. Ross : {b) " Report on the Cultivation of Proteosoma Labbe in Grey Mosquitoes," 4to, 21 pp., 9 plates, Calcutta, 1898 (Office of the Superintendent of Government Printing, India). Manson : (c) Brit. Med. Jour., 1898, vol. ii, 849. (^) Preliminary Report on the Infection of Birds with the Proteo- soma by the Bites of Mosquitoes. Nowgong. Assam, Oct. 11, 1898. 16 Koch : Zeitschr. f. Hyg. u. Lnfectionskrankh., 1899, xxxii, I. 11 Daniels : Proc. Royal Society, Ixiv, March 16, 1899. 18 Grassi: Policlinico, 1898, v. M, 469. 19 Bignami: Lancet, 1898, ii, 1461, 1541. Also, Bull. d. R. Acc. Med. d. Roma, 1898-99, f. 1. 20 (a) Bastianelli, Bignami and Grassi : Atti d. R. Accad. d. Lincei, cl. di sc. fis. mat. e nat., Roma, vii, 20 Sem., Serie 5a, Fasc. n°, (December 4, 1898). (^) Grassi, Bignami and Bastianelli: Do., (December 22, 1898). J) Grassi, Bignami and Bastianelli : Do., viii, i° Sem., Serie 5a, Fasc. 30, (February 5, 1899). (d) Grassi, Bignami and Bastianelli: Do. viii, i° Sem., Serie 5a, Fasc. 90, (May, 1899). (<?) Grassi: Rivista di Scienze Biologiche. Torino, 1899, i, 481. (/) Bastianelli and Bignami : Bull. d. R. Acc. Med. di Roma, xxv, Fasc. iii, 1898-99, and Annali d'igiene sperimentale, 1899, ix, n. s., f. iii, 272. (^Bastianelli and Bignami: Annali d'igiene sperimentale, 1899, ix, p. 5, f, iii, 245. Ji) Grassi, Bignami and Bastianelli: Do., 258. J) Bastianelli and Bignami : Communicazione fatta al X Congresso d. " Soc. Itai, di Med. Int." Seduta del 25 Ott, 1899. (Reprint.) 21 Grassi: Atti della R. Accad. dei Lincei, ann. ccxcvi, 1899, viii, f. 12. Also, Arch. Ltal. de Biol, 1899, xxxii, 435. 22 Brit. Aled. Jour., 1899, ii, 675, 746, 869. 23 Liihe : Centralbl. J. Bakt., 1900, xxvii, 436 (with full literature references to the recent work). 24 Ross : Nature, 1899, lx, 322. P nmr tit i i iih 1.1 11 A Klh may ASM 60 1 (a) Koch : Deutsch. Med. Woch., 1900, No. 5. (£) Koch : Deutsch. Med. Woch., 1900, Nos. 17 & 18. 1 (a) Celli and Delpino : Suppl. al Policlinico, 1899 ; also Centralbl. f, Bakt. 1899, xxvi, 480. (^) Celli and Delpino : Centralbl. f. Bakt. 1900, xxvii, 309. Instructions for the Prevention of Malarial Fever. (Liverpool School of Tropical Diseases.) Memoir (1), 8vo, Liverpool, 1899. For further references see : (a) Celli : La Malaria Secondo le Nuove Ricerche Roma, 1899, 8°, pp. 181. (b) Marchiafava and Bignami's article on Malaria in The Twentieth Century Practice of Medicine. (r) The complete summaries by Nuttall which have appeared during the past two years. (1) Centralbl. f. Bakt. 1899, xxvi, 140. (2) Centralbl. f. Bakt. 1900, xxvii, 193, 218, 260, 328. OBSERVATIONS ON THE BLOOD IN TYPHOID FEVER AN ANALYSIS OF THE EXAMINATIONS OF THE BLOOD IN TYPHOID FEVER MADE IN THE JOHNS HOPKINS HOSPITAL DURING ELEVEN' YEARS WILLIAM SYDNEY THAYER, M.D. Associate Professor of Medicine in the Johns Hopkins University Reprinted from The Journal of the Boston Society of Medical Sciences Volume v., pp. 23-30, October, 1900 BOSTON MASSACHUSETTS U.S.A. OBSERVATIONS ON THE BLOOD IN TYPHOID FEVER.1 AN ANALYSIS OF THE EXAMINATIONS OF THE BLOOD IN TYPHOID FEVER MADE IN THE JOHNS HOPKINS HOSPITAL DURING ELEVEN YEARS. William Sydney Thayer, M.D. (Associate Professor of Medicine in the Johns Hopkins University?) In connection with the third report upon typhoid fever it has been thought that it might be of interest to analyze the numerous examinations of the blood which have been made during the eleven years ending on the fifth of May, 1900. Since the opening of the hospital the blood of every case of typhoid fever has been examined microscopically. Careful counts of the corpuscles, however, have not been made in every instance, though for some years this procedure has been the rule. During this time a large number of examina- tions of the blood have been recorded. Doubtless a careful study of systematic observations in a more limited series of individual cases might give results of greater value than the analysis of a larger number of examinations of the blood made with less system in different cases. The records of so many observations have, however, been accumulating during the past eleven years that their classification and study seemed to be well worth undertaking. The subject has been considered under the following divi- sions : (1.) Analysis of the counts of the red blood corpuscles made during the course of typhoid fever and in the first weeks of convalescence. (2.) Analysis of the estimates of haemoglobin made dur- ing the course of typhoid fever and in the first weeks of con- valescence. 1 Excerpt from a communication to appear in The Johns Hopkins Hospital Reports, vol. viii. 2 (3.) Analysis of the counts of the colorless corpuscles made during the course of typhoid fever and in the first weeks of convalescence. (4.) Analysis of the differential counts of the leucocytes made in specimens prepared according to the methods of Ehrlich, during the course of typhoid fever and in the first weeks of convalescence. (5.) Analysis of the examinations of the blood made during various complications of typhoid fever. Methods. - The estimates of the corpuscles and haemo- globin were made by different house physicians, all of whom, however, were under the general supervision of the author or of Dr. Futcher or Dr. M'Crae. Many of the early esti- mates were made by the author himself. The red blood corpuscles were estimated by means of the Thoma-Zeiss counter. Toison's solution was used for dilu- tion. As a general rule the blood was diluted in the propor- tion of 1 :2oo, and a half of the entire field of the blood counter (200 squares) were counted. This was repeated several times, an average of the counts being taken. The colorless corpuscles were counted with the same instrument, Toison's solution generally being used. With a dilution of 1 :ioo or 200, the entire field was counted in at least four different drops, the average being taken. Some- times a per cent, solution of acetic acid was used with a dilution of I :ioo. In some instances the special mixer for white corpuscles was used, with an acetic acid solution of j per cent., the solu- tion being 1:20. The haemoglobin estimates were made with the Fleischl haemometer. The differential counts were made from dried cover-glass specimens stained with the triple stain of acid fuchsin, methy- lene green, and orange G. As most of the examinations were made in the ordinary ward routine, in a relatively small proportion was the number of corpuscles counted as great as would be demanded in a careful investigation. Generally at least 300 corpuscles were counted. None, with one excep- 3 tion, are included in the tables in which under 200 were recorded. In this case, where the estimate was made by a careful man, the averages of 195 elements were taken. A considerable number or counts of under 200 corpuscles were thrown out. The accumulation, however, of a sufficient number of esti- mates, based on a study of even as small a number as two or three hundred corpuscles each, cannot fail to give a more or less reliable average. In order to obtain a better general view of the fluctuations in the average number of the different elements of the blood during typhoid fever, all these observations have been tabu- lated according to the week of the disease in which they were made. Two tables have been prepared in every instance, one showing the averages of all the observations made in each week, and the other, which doubtless gives a fairer estimate of the true condition, upon a basis of one count a week for each case - that is, in every instance where more than one observation was made in a given week, the average of the counts was taken and recorded as a single estimate. In all, 265 estimates of the red blood corpuscles were made during the febrile period, and 80 during convalescence from typhoid fever; 160 estimates of haemoglobin during the febrile period, and 52 during convalescence; 832 estimates of the colorless corpuscles during the febrile period, and 85 during convalescence. There were 116 differential counts of the leucocytes during the febrile period which were suf- ficiently elaborate to justify conclusions, and 28 during con- valescence. A considerable number of superficial differential counts were thrown out. In addition to these a number of observations were made in the following complications of typhoid fever: haemorrhage from the bowels, perforation of the bowel, furunculosis, phle- bitis and thrombosis, pleurisy, pneumonia, severe bronchitis and broncho-pneumonia, periostitis, lymphadenitis, urethritis, cystitis, cholecystitis, parotitis, submaxillary abscess, otitis media, pulmonary tuberculosis, pregnancy, appendicular colic, peripheral neuritis, peri-rectal abscess, erythema multiforme, 4 purpura haemorrhagica, conjunctivitis, pericarditis, decubitus, convulsions, trichinosis (?). A consideration of these records justifies the following con- clusions : The Red Blood Corpuscles. (i.) A diminution in the number of red blood corpuscles becomes evident shortly after the onset of typhoid fever. (2.) This diminution increases gradually throughout the course of the disease. (3.) Our figures suggest that the fall in the number of red blood corpuscles may be somewhat accentuated during the fourth week of fever. (4.) The reduction in the number of the red blood cor- puscles is greatest at about the end of defervescence. (5.) In cases of short duration, the diminution may con- tinue into the first week of convalescence. (6.) In longer cases, with mild persistent fever, it is not uncommon for regeneration of the blood to begin well be- fore the end of defervescence. (7.) The average maximum loss of red blood corpuscles in typhoid fever is about 1,000,000 to the cubic millimetre. (8.) Considerable transient elevations in the number of red blood corpuscles per cubic millimetre may follow diar- rhoea, vomiting, or sweating. (9.) Sudden losses of a greater or less extent may be caused by haemorrhage from the bowels. (10.) Where the loss after haemorrhage is severe, a cer- tain amount of regeneration may occur during the course of the disease. In cases of long duration, however, a subse- quent fall may occur. The Hemoglobin. (1.) The percentage of haemoglobin pursues a course similar apparently to that of the red blood corpuscles. (2.) Study of individual cases suggests, however, that in instances where the anaemia has been appreciable the return to the normal point is, as in most secondary anaemias, more gradual than that of the red blood corpuscles. 5 The Colorless Corpuscles. (i.) The number of the colorless corpuscles in the per- ipheral circulation is subnormal throughout the course of typhoid fever. (2.) The diminution is progressive with the increase in the severity and duration of the disease. (3.) The average number of the leucocytes per cubic millimetre at the height of the disease is about 5,000. Much lower figures are, however, common. (4.) In cases with persistent fever there may be a tendency in the later weeks of the disease toward a slight elevation in the average number of leucocytes, as compared with that at the height of the infection. (5.) The normal limits of variation of the number of colorless corpuscles in different cases, and in the same case, are considerable. An increase to above 10,000 to the cubic millimetre, however, is usually an indication of some foreign influence (cold baths, inflammatory complications, haemor- rhage, etc.). (6.) Cold baths cause an immediate transient increase in the number of leucocytes in the peripheral circulation, an increase which may amount to three or four times the num- ber before the bath. (7.) The relative proportions of the different varieties of leucocytes one to another during typhoid fever show char- acteristic variations from the normal percentages - (a.) The percentage of small mononuclear leuco- cytes shows at first no great change, though it is dis- tinctly increased at the height and toward the latter part of the disease, as well as in the first weeks of con- valescence. (Z».) This increase is not, as a rule, in the typical lymphocytes, but in small forms with palely staining nuclei, and a relatively large amount of transparent or nearly transparent protoplasm. (r.) The relative percentage of the- large mononu- clear leucocytes increases progressively with the course 6 of the disease, the elevation continuing well into con- valescence. (zZ.) The increase of the largest varieties and of the transitional forms is, as a rule, not marked. (T.) The elements most increased in number are cells about the size of polymorphonuclear leucocytes with pale nuclei, often scarcely larger than those of lymphocytes, and transparent or palely staining pro- toplasm. (/.) The percentage of polymorphonuclear neutro- philes diminishes progressively throughout the course of the disease, the diminution keeping pace with the increase in large mononuclear forms. The average of eight counts for the fifth week was 61.7 per cent.; of those for the sixth week, 59.2 per cent. (^•.) The limits of variation in the percentage of the polymorphonuclear neutrophiles is considerable. Figures below 50 per cent, are not uncommon. (/z.) The relative proportion of eosinophilic cells in typhoid fever is diminished, the average throughout the course of the disease being under 1 per cent. (i.) With convalescence the percentage of eosino- philes increases, sometimes to a point rather above the normal average. (7.) In long-continued cases with persistent fever, where regeneration of the blood sets in before com- plete defervescence, the percentage of eosinophiles may increase to the normal average or above this, before the end of the febrile period. (£.) In the leucocytosis following cold baths, the relative proportions of the different varieties of color- less elements are unaffected. (8.) Inflammatory complications of typhoid fever are associated with an increase in the number of leucocytes similar to that occurring under ordinary circumstances. (9.) It is not impossible, though our observations are in- sufficient to justify a positive conclusion, that the increase, in complications occurring at the height of the disease and 7 during convalescence, is less than that observed with similar processes occurring under other conditions. (io.) The most extensive leucocytoses have been ob- served in connection with large abscesses, phlebitis, perito- nitis, pleurisy, pneumonia, periostitis, cystitis, cholecystitis. (11.) The extent of the leucocytosis depends, apparently, more upon the nature of the local lesion than upon the species of microorganism which may be its cause. (12.) In some cases in which the complication is asso- ciated with a particularly malignant infection, especially if the patient be already in a condition of prostration, the count of the leucocytes may not only fail to show any in- crease, but may even reveal a tendency toward a diminution in number. In other similar conditions a slight increase in the number of colorless elements may be followed by a subse- quent diminution. (13.) Hcemorrhage from the bowels maybe followed by an increase in the number of leucocytes which begins imme- diately after the haemorrhage, reaching its maximum in from twelve to twenty-four hours. Within a week, however, the number of leucocytes generally returns to about the normal average for the period of the disease. (14.) In some of our cases, however, haemorrhage had no appreciable influence on the number of colorless corpuscles in the peripheral circulation. (15.) Perforation of the bowel is usually followed, in a few hours, by an increase in the number of the leucocytes in the peripheral circulation. (16.) This elevation may be considerable (above 15,000) or slight (under 10,000), and appreciable only in com- parison with previous counts. (17.) In some instances a slight increase in the number of leucocytes succeeding the perforation may tend to diminish and disappear with the aggravation of the symptoms. It is not impossible that this diminution may be the rule. (18.) Not infrequently there is a complete absence of leucocytosis, and sometimes a diminution in the number of colorless corpuscles after a perforation. 8 (i9-) The absence or disappearance of a leucocytosis fol- lowing a perforation is an indication of the malignity of the infection or the prostration of the patient. (20.) The prospect of relief by surgical interference is best in those cases with a leucocytosis. (21.) A pre-perforative leucocytosis due to local perito- nitis about deep ulcers may occur. (22.) In the leucocytosis associated with the inflammatory complications of typhoid fever, especially if these occur late in the course of the disease or during the early weeks of con- valescence, the relative proportions of the different varieties of colorless corpuscles may show well-marked variations from the usual figures. (23.) These variations consist in a tendency toward the figures characteristic of typhoid fever - a diminution in the percentage of the polymorphonuclear neutrophiles, associated with an increase in that of the large mononuclear forms. The deviation from the figures characteristic of an ordinary leucocytosis may be so marked that with over 20,000 leu- cocytes to the cubic millimetre there may yet be under 70 per cent, of polymorphonuclear neutrophiles. Baltimore, September, 1900. Boston Society of Medical Sciences, October 16, 1900. OBITUARY: JESSE WILLIAM LAZEAR. Mr. President and Gentlemen: Before we proceed with the programme this evening, I should like to say a few words about our dear friend Lazear, whose sad death at Quemados, Cuba, on September 25, is so fresh in our minds. Lazear was born just outside of Balti- more thirty-four years ago. lie graduated at the Academic Department of the Johns Hopkins University in 1889, and three years later obtained the degree of M. D. from Columbia University, New York. After this he was an interne in the Bellevue Hospital for two years. After spending the greater part of the year in studying abroad, particularly in Paris, he returned in 1895 and became one of the medical staff of the Johns Hopkins Hospital. In the summer of 1896, Dr. Lazear was married and began the practice of medicine in Baltimore. At the same time, however, he was an assistant in clinical microscopy in the University, and in the laryngo- logical department in the Hospital dispensary. Last winter he obtained an appointment as assistant surgeon in the army with special laboratory duties, and was stationed in Havana. There he soon became interested in the study of yellow fever, and for several months he had been one of the commission appointed by the Surgeon-General, for the study of this dis- 1 Remarks made by Dr. W. S. Thayer, at the meeting of The Johns Hopkins Hospital Medical Society, Oct. 16, 1900. ease. He had been constantly exposed to infection, and finally, in the course of his duty, contracted his fatal illness. Dr. Lazear was a man of few words but keen perception. He was an extremely careful and thorough worker. He kept his own counsel, asked few questions and little help of his associates, but he was a man who, when he started an under- taking, had the ability and enthusiasm to keep quietly at work until he accomplished his end. It was through his ex- cellent work that we were able several years ago to make our first positive intra vitam diagnosis of septicaemia due to the diplococcus of Neisser. His valuable studies upon the in- ternal structure of the malarial parasite, which 1 had the pleasure of bringing before this society last winter, are re- membered by all. Personally, he was an exceptionally simple, high-minded and lovable man. He could not have failed to find in a short time a public position in which his unusual merits would have become more generally known. I should like to suggest to the Society the adoption of the following resolutions: " Whereas, On the 26th day of September, our beloved colleague and friend, Jesse William Lazear, lost his life in the discharge of his duty as a member of the United States Yellow Fever Commission; "And whereas, His exceptional ability in his profession. b>:s simplicity and modesty as a man, had greatly endeared him to all whose good fortune it was to know him; " Be it resolved, That we, his former colleagues and asso- ciates, do hereby express our profound sorrow at the loss, to the community of one whose future was unusually rich in promise, to ourselves, of a dear friend and fellow student; " And be it further resolved, That we express to his wife and family our warmest and most heartfelt sympathy." The resolutions were unanimously adopted. ' OBSERVATIONS ON THE BLOOD IN TYPHOID FEVER. AN ANALYSIS OF THE EXAMINATIONS OF THE BLOOD IN TYPHOID FEVER MADE IN THE JOHNS HOPKINS HOSPITAL DURING ELEVEN YEARS. BY WILLIAM SYDNEY THAYER, Associate Professor of Medicine in the fohns Hopkins University. (From the Medical Clinic of Prof. Osler.) From THE JOHNS HOPKINS HOSPITAL REPORTS, Vol. VIII, 1900. OBSERVATIONS ON THE BLOOD IN TYPHOID FEVER. AN ANALYSIS OF THE EXAMINATIONS OF THE BLOOD IN TYPHOID FEVER MADE IN THE JOHNS HOPKINS HOSPITAL DURING ELEVEN YEARS. BY WILLIAM SYDNEY THAYER, Associate Professor of Medicine in the Johns Hopkins University. (From the Medical Clinic of Prof. Osler.) PART I. The Blood in Uncomplicated Typhoid Fever, page Methods 489 Analysis of the counts of the red blood corpuscles made during the course of typhoid fever and in the first weeks of convalescence 490 Analysis of the estimates of haemoglobin made during the course of typhoid fever and in the first weeks of convalescence 494 Analysis of the counts of the colorless corpuscles made during the course of typhoid fever and in the first weeks of convalescence 497 Analysis of the differential counts of the leucocytes made in specimens pre- pared according to the methods of Ehrlich, during the course of typhoid fever and in the first weeks of convalescence 500 PART II. The Blood in Various Complications of Typhoid Fever. Haemorrhage from the bowels 508 Furunculosis 513 Phlebitis and thrombosis 514 Pleurisy 515 Pneumonia 518 Severe bronchitis and broncho-pneumonia 521 Periostitis 522 Lymphadenitis 523 Submaxillary abscess 523 Urethritis 524 Cystitis 525 Cholecystitis 525 Otitis Media 526 Parotitis \ 527 Pulmonary tuberculosis 527 Pregnancy 529 William Sydney Thayer. 488 PAGE Appendicular colic 529 Peripheral neuritis 529 Peri-rectal abscess 529 Erythema multiforme 530 Purpura haemorrhagica 530 Conjunctivitis 530 Pericarditis 531 Decubitus 531 Convulsions 531 Trichinosis (??) 531 Perforation 532 Cases of suspected perforation 541 General conclusions 543 PART I. The Blood in Uncomplicated Typhoid Fever. In connection with the third report on typhoid fever, it has been thought that it might be of interest to analyze the numerous examinations of the blood which have been made during the eleven years ending on the 5th of May, 1900. Since the opening of the hospital the blood of every case of typhoid fever has been exam- ined microscopically. Careful counts of the corpuscles, however, have not been made in every instance, though for some years this procedure has been the rule. During this time a large number of examinations of the blood have been recorded. Doubtless a careful study of systematic ob- servations in a more limited series of individual cases, might give results of greater value than the analysis of a larger number of examinations of the blood made with less system in many different cases. The records of so many observations have, however, been accumulated during the past eleven years, that their classification and study are well worth undertaking. 'The subject will be considered in the following divisions: (1) Analysis of the counts of the red blood corpuscles made dur- ing the course of typhoid fever and in the first weeks of convales- cence. (2) Analysis of the estimates of haemoglobin made during the course of typhoid fever and in the first weeks of convalescence. (3) Analysis of the counts of the colorless corpuscles made dur- ing the course of typhoid fever and in the first weeks of convales- cence. Observations on the Blood in Typhoid Fever. 489 (4) Analysis of the differential counts of the leucocytes made in specimens prepared according to the methods of Ehrlich, during the course of typhoid fever and in the first weeks of convalescence. Methods. The estimates of the corpuscles and haemoglobin were made by different house physicians, all of whom, however, were under the general supervision of the author or of Dr. Futcher or Dr. M'Crae. Many of the early estimates were made by the author himself. The red blood corpuscles were estimated by means of the Thoma-Zeiss counter. Toison's solution was used for dilution. As a general rule the blood was diluted in the proportion of 1: 200, while a half of the entire field of the blood counter (200 squares) were counted. This was repeated several times, an average of the counts being taken. The colorless corpuscles were counted with the same instrument, Toison's solution generally being used. With a dilution of 1: 100 or 200, the entire field was counted in at least four different drops, the average being taken. Sometimes a solution of acetic acid was used, with a dilution of 1: 100. In some instances the special mixer for white corpuscles was used, with an acetic acid solution of the dilution being 1: 20. The haemoglobin estimates were made with the Fleischl haemom- eter. The differential counts were made from dried cover-glass speci- mens stained with the triple stain of acid fuchsin, methylene green and orange G. As most of the examinations were made in the ordinary ward routine, in a relatively small proportion was the number of corpuscles counted as great as would be demanded in a careful investigation. Generally at least 300 corpuscles were counted. With one exception, no counts were included in the tables in which under 200 were recorded. In one recorded case, where the estimate was made by a careful man, the averages of only 195 elements were taken. A considerable number of counts of under 200 corpuscles were thrown out. The accumulation, however, of a sufficient number of estimates, based on a study of from two hundred to one thousand corpuscles each, cannot fail to give more or less reliable averages. 490 William Sydney Thayer. In order to obtain a better general view of the fluctuations in the average number of the different elements of the blood during typhoid fever, these observations have been tabulated according to the week of the disease in which they were made. Two tables have been prepared in every instance, one showing the averages of all the observations made in each week; and the other, which doubtless gives a fairer estimate of the true condition, upon a basis of one count a week for each case-that is, in every case where more than one observation was made in a given week, the average of these observations was taken and recorded as a single estimate. (1) Analysis of the counts of the red blood corpuscles made during the course of typhoid fever and in the first weeks of con- valescence. It has seemed best for purposes of comparison, to arrange the counts of the red blood corpuscles in groups according to the week of fever, and later to bring together those counts which were made after the temperature became normal, arranging these also by weeks according to the period after the first day of normal tem- perature. Two hundred and sixty-five estimates of the red blood corpuscles were made in uncomplicated cases of typhoid fever. Arranged according to the period of the disease the following table is obtained: TABLE I. Averages of the counts of the red blood corpuscles made during the course of typhoid fever. 1st week, 32 counts, 4913312 2d week, 86 counts, 4692428 3d week, 59 counts, 4429208 4th week, 36 counts, 4222236 5th week, 22 counts, 4118590 6th week, 7 counts, 4028428 7th week, 8 counts, 3309125 8th week, 7 counts, 3652285 9th week, 6 counts, 3509666 10th week, 1 count, 3920000 11th week, 1 count, 2109333 In a number of instances, however, several estimates were made in individual cases in one week; and inasmuch as, in some of these cases, the results showed a number relatively greater or less than the usual figures, it appeared that the accumulation of such counts ■might unfairly influence the general average for the week. It, therefore, seemed wise to make a second table, taking the aver- ages upon the basis of one count a week for each case-that is, I. CHART OF THE BLOOD IN TYPHOID FEVER. FEBRILE PERIOD, WEEKS. CONVALESCENCE, WEEKS. 1 23456789 xxx } 6,000,000 6,000,000 4,000,000 3,000,000 2,000,000 1,000,000 XXX 8,000 7,000 6,000 5,000 4,000 3,000 2,000 1,000 PLAIN LINE = RED CORPUSCLES. DOTTED LINE = HAEMOGLOBIN. BROKEN LINE = COLORLESS CORPUSCLES. Observations on the Blood in Typhoid Fever. 491 in every case where more than one count was made in a given week, the averages of these counts were taken and recorded as a single estimate. TABLE II. Counts of the red blood corpuscles, the weekly averages based upon one count per week in each case, the average being taken for the week in every case where multiple counts were made. 1st week, 32 counts, 4913312 2d week, 83 counts, 4706855 3d week, 54 counts, 4555814 4th week, 34 counts, 4187720 5th week, 22 counts, 4118590 6th week, 87 counts, 4028428 7th week, 8 counts, 3309125 8th week, 7 counts, 3652285 9th week, 6 counts, 3509666 10th week, 1 count, 3920000 11th week, 1 count, 2109333 The accompanying chart may bring the figures more into relief. On analyzing these counts, it will be noticed that in the first week, the number of red blood corpuscles is already somewhat below the normal. The record appears but slightly subnormal on the chart, where, as is generally the case, the average number of red blood corpuscles of the normal individual is estimated to be 5,000,000 per cu. mm. Our observations, however, would lead us to believe that these figures should probably be considerably higher-about 5,500,000. This diminution is probably in part due to the effect of the dis- ease itself, for most of the estimates were made toward the end of the first week of fever. It is, however, not impossible that while many patients are, when attacked, in apparently perfect health, yet a considerable proportion may be individuals predisposed to any infection on account of a previous debilitated condition, which, of itself, may well be associated with a greater or less degree of anaemia. From the first week, there is a gradual diminution in the number of corpuscles, slightly accentuated between the third and fourth weeks, until the seventh, when a more marked fall occurs, followed in the eighth week by a considerable rise. In the sixth, seventh and eighth weeks, however, only 7, 8 and 7 counts respectively, were made-far too small a number to justify positive conclusions. It may be noted, however, that excepting for this break in the seventh, the fall in the number of corpuscles is steady for the first nine weeks. After this period but two counts are recorded. 492 William Sydney Thayer. In these tables relapses have not been considered separately. The period between the end of the initial attack and the beginning of the relapse is generally too short to be associated with any es- sential improvement in the condition of the blood. In the few cases where long periods have intervened, it has happened that no blood counts were recorded. Our previous observations,1 and those of others/ tend to suggest that the lowest point in the percentage of red blood corpuscles is reached at about the end of defervescence, the return to normal being rather slow. While this is undoubtedly true in the majority of uncomplicated cases, yet in a considerable number, where defervescence is very slow, regeneration of the blood may set in well before the end of the febrile period. In cases where marked anaemia is present, this persistent fever may, indeed, be in great part that which is so com- monly associated with grave anaemia from any cause. The more gradual fall-leaving out of consideration the marked drop in the seventh week-after the record for the fourth week, may be due to the fact that in many of these instances the persisting fever was of this mild variety, the general condition of the patient being that of a convalescent. In this connection a table showing the behavior of the red blood corpuscles according to the week of convalescence, may be of inter- est. Eighty estimates of the red blood corpuscles were made during convalescence. Arranging these records according to the period after the last day of fever, the following table is obtained: Estimates of the red blood corpuscles during convalescence from typhoid fever, arranged according to the period after the last day of fever. TABLE III. 1st week, 32 counts, 4540000 2d week, 22 counts, 4637136 3d week, 15 counts, 4252733 4th week, 6 counts, 4391166 5th week, 2 counts, 5469000 6th week, 1 count, 4972000 7th week, 1 count, 3325000 9th week, 1 count, 4604000 'Thayer. Two Cases of Post-Typhoid Anaemia, &e. Johns Hopkins Hospital Reports, 1894, Vol. IV, p. 83. 'An interesting discussion of the whole subject, together with abundant refer- ences to literature, may be found in Tuerk's book (Klinische Untersuchungen ueber das Verhalten des Blutes bei acuten Infectionskrankheiten. 8°, Wien, 1898). Observations on the Blood in Typhoid Fever. 493 Reconstructing this table, the averages being taken upon a basis of one count a week for each case in every instance where multiple counts were made, one obtains the following figures: TABLE IV. Estimates of the red blood corpuscles during convalescence from typhoid fever, arranged according to the period after the last day of normal temperature, the averages being computed upon a basis of one count a week for each case. 1st week, 21 counts, 4546952 2d week, 20 counts, 4687850 3d week, 15 counts, 4252733 4th week, 6 counts, 4391166 5th week, 2 counts, 5469000 6th week, 1 count, 4972000 7th week, 1 count, 3325000 9th week, 1 count, 4604000 The small number of estimates must of necessity leave great possibilities for error. And after the second week, in addition to the fact that the estimates are but few, the results are vitiated by the fact that the cases remaining in the hospital at so late a period, were, for the most part, instances of severe fever of long duration, after which, as is shown by the first tables, a much greater degree of anaemia is reached. The figures in the first two weeks of convalescence, however, are interesting. As has been noted, the percentage of red blood corpuscles is generally found to reach the lowest point at about the end of defer- vescence, while the increase during convalescence is gradual. As the average duration of typhoid fever is probably about three weeks, we might, therefore, expect to find the figures in the first week of convalescence at a point somewhere between the record for the third and fourth weeks of the disease. But on comparing the record for the first week of convalescence in Table IV with those in Table II, we find that this is indeed the case, the figures, 4,546,952 lying between those of the third week of fever, 4,555,814, and those of the fourth, 4,187,720. We are then probably justified in drawing the conclusion that at the end of the ordinary uncomplicated case of typhoid fever of about three weeks' duration, there are about 4,500,000 red corpuscles to the cu. mm., the loss averaging, probably, about 1,000,000. The rate of increase during convalescence is, of course, impos- sible to estimate from a table of this sort. 494 William Sydney Thayer. While the figures in Table II, at least those for the first five weeks, give us, probably, a fair idea of the average number of red blood corpuscles present in uncomplicated cases, yet it must be borne in mind that great variations from this normal average may occur. The following table has been prepared to show the highest and lowest estimates by weeks. TABLE V. Table showing the highest and lowest counts of the red blood corpuscles arranged according to the week of fever. 1st week, highest, 6940000 lowest, 3400000 2d week, " 6604 000 " 2240000 3d week, " 6916000 " 2300000 4th week, " 5884000 " 1426000 5th week, " 6312000 " 1352000 6th week, " 4904000 " 2014000 7th week, " 4500000 " 1648666 8th week, " 4012000 " 2234000 9th week, " 4288000 " 2314000 Most observers who have studied the blood in typhoid fever call attention to the fact that great variations in the red blood counts may occur during the course of the disease, owing to actual condensation of the blood following profuse sweating, diar- rhoea or vomiting. Our observations would lead us to agree with these views. And yet, of all the high records, only one, that for the fifth week, appears to have been dependent upon such condi- tions. In that instance, however, the patient had. for some days, suffered from severe diarrhoea and frequent vomiting, which, doubtless, account in part for these unusually high figures as late as the fifth week of the disease. The low figures for the fourth, fifth, seventh and eighth weeks occurred in one of the two remarkable cases of post-typhoid anaemia previously reported by the author. Here, it may be seen, regen- eration of the blood began weeks before the temperature reached the normal point, the late fever being probably a sequel rather than a concomitant of the original typhoid infection. (2) Analysis of the estimates of hcemoglohin made during the course of typhoid fever and in the first weeks of convalescence. The haemoglobin has not been systematically estimated in our examinations of the blood during typhoid fever, only 160 records Observations on the Blood in Typhoid Fever. 495 having been made among the uncomplicated cases. A table, how- ever, based upon even so small a number of estimates may prove of interest. TABLE VI. Averages of the estimates of haemoglobin made during the course of typhoid fever. 1st week, 21 estimates, 76.1 % 2d week, 51 " 72.8 3d week, 34 " 66.2 4th week, 20 " 60.5 5th week, 20 " 57.8 6th week, 6 estimates, 62.1 % 7th week, 4 " 50.5 8th week, 3 " 56.9 9th week, 4 " 47.7 10th week, 2 " 66.5 Reconstructing this table on a basis of one estimate a week for each case we have: TABLE VII. Estimates of haemoglobin in typhoid fever, the weekly averages based upon one estimate a week in each case. 1st week, 21 estimates, 76.1 % 2d week, 50 " 72.7 3d week, 32 " 67.4 4th week, 20 " 60.5 5th week, 15 " 57.8 6th week, 6 estimates, 62.1 % 7th week, 4 " 50.5 8th week, 3 " 56.9 9th week, 4 " 47.7 10th week, 2 " 66.5 The course of the haemoglobin may also be better appreciated by consulting the chart. The discrepancy between the percentage of red blood corpuscles and haemoglobin, which is evident even at the onset, is, in part, probably, due to the fact that here, as in all secondary anaemias, a greater relative fall in haemoglobin is observed. It is, however, also partly due to the fact already pointed ou't, that the line indi- cating the normal average number of red blood corpuscles is mis- placed. On such a chart as this there is, normally, an apparent difference of at least 10^, 100^ of haemoglobin corresponding to 5,500,000 (110^) or more red blood corpuscles. When one considers the relatively small number of estimates of haemoglobin and the fact that, in many instances, they were made independently of the counts of the red blood corpuscles, it is re- markable how regularly the parallel to the curve of the percentage of red blood corpuscles is maintained. One is tempted to believe that the averages for the first five weeks give a fair idea of the true condition. After this, the small number of estimates renders the table of little value. 496 William Sydney Thayer. Only fifty-two estimates of haemoglobin were made during con- valescence and yet a table showing these may be of some interest. TABLE VIII. Estimates of haemoglobin during convalescence from typhoid fever, arranged by weeks according to the period after the last day of fever. 1st week, 22 estimates, 67.5 % 2d week, 19 " 68.9 3d week, 12 " 67.3 4th week, 3 " 58.3 5th week, 2 estimates, 68 % 7th week, 3 " 68 8th week, 1 estimate, 70 The relatively high percentage of haemoglobin in the first week of convalescence is contrary to what one might expect, and study of individual cases would lead one to believe that it is dependent upon an insufficient number of observations. There is little reason to believe that, in respect to the relation between the per- centage of red blood corpuscles and haemoglobin, the anaemia fol- lowing typhoid fever differs in any way from that after other acute diseases, where, with regeneration of the blood, the percentage of haemoglobin usually lags somewhat behind that of the red cor- puscles. The later estimates are so few that they are of little value. As in the case of the red blood corpuscles, the percentage of haemoglobin shows great variations in individual instances. The following table may give some idea of how extensive these variations may be: TABLE IX. Highest and lowest estimates of haemoglobin arranged according to the week of fever. 1st week, highest estimate 100 % lowest 50 % 2d " " " 90 " 40 3d " " " 88 " 25 4th " " " 85 " 24 5th " " " 86 " 27.5 6 th " " " 75 " 40 7th " " " 75 " 28 8th " " " 72 " 37.5 Of the high estimates, only one, that in the fifth week, appears to have been due to diarrhoea and vomiting. A glance at this table, however, explains the high record in Table VII for the sixth week. In the case of grave post-typhoid anaemia which furnished the lowest estimates for the fourth, fifth, Observations on the Blood in Typhoid Fever. 497 seventh and eighth weeks, no record was made in the sixth week, a fact quite sufficient to influence the general average where so few estimates were made. (3) Analysis of the counts of the colorless corpuscles made dur- ing the course of typhoid fever and in the first weeks of con- valescence. The analysis of the counts of the leucocytes is of special im- portance from a practical standpoint. 832 estimates of the color- less corpuscles were made in the uncomplicated cases. Indeed, a considerably larger number is recorded. Where, however, sev- eral counts were made in the course of one day, the average has been taken and entered as a single estimate. The following table shows these averages arranged according to the week of the disease: TABLE X. Averages of the counts of the leucocytes made during the course of typhoid fever. 1st week, 119 counts, 6442 2d week, 258 " 6251 3d week, 200 " 5528 4th week, 117 " 5431 5th week, 70 " 5510 6th week, 25 " 5690 7th week, 14 " 6132 8th week, 14 counts, 6614 9th week, 7 " 5057 10th week, 2 " 5000 11th week, 3 " 5333 12th week, 2 " 5000 13th week, 1 " 8000 In the case of the leucocytes it has been considered especially important to reconstruct the table on a basis of one count a week for each case. TABLE XI. The weekly average counts of the leucocytes, based upon one count per week in each case, the average being taken for the week in every case where multiple counts were made. 1st week, 100 counts, 6400 2d week, 206 " 6207 3d week, 150 " 5730 4th week, 95 " 5393 5th week, 58 " 5386 6th week, 19 " 5813 7th week, 13 " 6296 8th week, 12 counts, 6425 9th week, 7 " 5051 10th week, 2 " 5000 11th week, 3 " 5333 12th week, 2 " 5000 13th week, 1 count, 8000 Here, again, reference to the chart may make the significance of these figures clearer. 498 William Sydney Thayer. Estimating the normal number of colorless corpuscles at about 7500, one is struck by the fact that throughout the disease the figures are subnormal. Though this fact has been recognized for many years, yet the table gives us valuable information with re- gard to the extent of the reduction in the number of corpuscles, and its relation to the period of the fever. It will be noted that there is a gradual diminution in the number of colorless elements after the first week, the lowest point being reached in the fifth week. After this the counts are too few to be of any great value. After a temporary rise in the 6th, 7th and 8th weeks, a tendency to an even lower figure may, however, be noted. It would seem to be a general rule that the longer the disease lasts and the more pro- found the degree of the patient's prostration, the greater the dim- inution in the number of colorless corpuscles. Owing to the small number of estimates after the fifth week, it is perhaps hardly necessary to speculate as to the cause of the slight rise observed in the sixth, seventh and eighth weeks. It would, however, not be remarkable if, even with large numbers of estimates, the averages during these weeks should yet be slightly higher than those during the fourth and fifth, owing to the fact that at this period the pa- tient is especially open to a variety of secondary infections and intoxications which, without being appreciable with the ordinary methods of examination, might yet be quite sufficient to cause greater variations in the number of colorless corpuscles than are present in the earlier stages of the disease. In connection with the extent of the diminution in the number of leucocytes observed at the height of the disease, a diminution which is hardly as great as one might have expected from the general statements in literature, it is but fair to call attention to the fact that various transient influences may cause a degree of increase in the number of leucocytes, considerably greater than any possible decrease. Doubtless a large proportion of the un- usually high counts is, in reality, due to undiscovered complica- tions. It is then probably fair to assume that the extent of the diminution in most cases is somewhat greater than appears in our table. How great the variations may be in cases where there is no ap- parent complication, is shown by the following table: Observations on the Blood in Typhoid Fever. 499 TABLE XII. Table showing the highest and lowest counts of the leucocytes, arranged according to the week of fever. 1st week, highest 15000; lowest, 1600 2d week, " 18000; " 1000 3d week, " 13000; " 1000 4th week, " 10500; " 1700 5th week, " 10500; " 2334 6th week, highest 10000; lowest, 3250 7th week, " 11000; " 4000 8th week, " 9250; " 4000 9th week, " 9300; " 2000 While in some instances, the high records, such as that of 18,000 in the second week, which occurred in a case where subsequent counts were not unduly elevated, must have been due to unappre- ciated complications, others, as for instance, those in the first, sev- enth and ninth weeks, depended probably upon some idiosyncrasy of the patient. These counts were all made in the blood of one individual who, throughout the disease, without any apparent reason, showed a constantly large number of colorless elements. The hour at which the count showing 18,000 leucocytes was made, is not recorded, and it may well be that this was an instance in which the blood was counted just after a cold bath. All cases in which the counts were made at this period have been thrown out of consideration.1 Eighty-five counts of the leucocytes were made after the tem- perature was normal. These are included in the following table, arranged according to the period after the last day of fever: TABLE XIII. Estimates of the colorless corpuscles during convalescence from typhoid fever, arranged according to the period after the last day of fever. 1st week, 32 counts.. 6078 2d week, 24 " .. 6756 3d week, 16 " .. 6362 4th week, 6 " .. 7570 5th week, 3 counts. .11340 6th week, 2 " .. 6500 7th week, 1 " .. 5000 9th week, 1 " .. 9000 Rearranging this table again upon a basis of one count a week for each case, we have the following figures: 1 As a rule this period has been avoided in making the counts. The few esti- mates that have been made uphold the observations of the author, published in 1893. (Note on the Increase in the Number of Colorless Corpuscles in Typhoid Fever after Cold Baths.-Johns Hopkins Hospital Bulletin, 1893, iv, 37.) 500 William Sydney Thayer. TABLE XIV. Estimates of the colorless corpuscles during convalescence from typhoid fever, arranged according to the period after the last day of fever, the averages being taken upon a basis of one count a week for each case. 1st week, 26 counts, 5891 2d week, 23 " 6681 3d week, 16 " 6362 4th week, 6 " 7570 5th week, 3 counts, 11340 6th week, 2 " 6500 7th week, 1 count, 5000 9th week, 1 " 9000 While these estimates are far too few to give an accurate idea of the true curve of the leucocytes during convalescence, those made during the first weeks are yet of interest in that they show a decided tendency to approach the normal number. And it is also an interesting fact that if one takes the average of all the counts made after the second week, 29 in number, the figure 7180 is obtained-not far below what we have estimated to be the nor- mal number of leucocytes. One is justified in concluding from our figures, that the number of colorless corpuscles is subnormal throughout the course of ty- phoid fever, the figures becoming lower with the increase in the intensity and duration of the disease. The longer and more intense the infection, the smaller the num- ber of leucocytes. The average number of colorless corpuscles at the height of the fever is about 5000, though in individual cases, it is common to find as few as 4000 or 3000, while records below 3000 are not unusual. In a number of instances the counts have shown less than 2000 leucocytes to the cubic millimetre. The average number of colorless corpuscles during typhoid fever, as shown by an average taken from all our counts without regard to the period of the disease, is 5860. With convalescence the number of leucocytes gradually rises, remaining however, somewhat subnormal during the first several weeks. The idea which has been held by some observers, that an initial leucocytosis occurs during the first week, is definitely refuted by our figures. (4) Analysis of Ilie differential counts of the leucocytes, made in specimens prepared according to the methods of Ehrlich, during the course of typhoid fever and in the first weeks of convalescence. Observations on the Blood in Typhoid Fever. 501 Differential counts of leucocytes in dried and stained specimens, were made in one hundred and eighteen instances. In the great majority of cases over three hundred leucocytes were counted, though a few have been included in which only two hundred were recorded. These counts were made by a number of different house physicians, all of whom had had a good training and ex- perience in the methods of blood examination. Arranged according to the week in which estimates were made, the following table is obtained: table xv. Averages of the differential counts of the leucocytes made during the course of typhoid fever. Small mononuclear. Large mononuclear. Polymorphonuclear neutrophile. Eosino- phile. 1st week, 12 counts, 12.9% 12.4% 74.0% 0.5% 2d week, 39 counts, 14.6 13.4 70.9 0.8 3d week, 34 counts, 21.5 11.6 66.3 0.3 4th week, 19 counts, 20.1 14.4 65.0 0.4 5th week, 8 counts, 18.2 19.7 61.7 0.3 6th week, 4 counts, 22.6 13.5 57 7 6.0 7th week, 1 count, 23.7 34.4 37.3 4.6 8th week, 1 count, 24.2 16.8 56.9 2.1 Reconstructing the table upon the basis of one count a week for each case, the following figures are obtained: TABLE XVI. Differential counts of the leucocytes, the weekly averages based upon one count a week in each case, the average being taken for the week in every case where multiple counts were made. Small mononuclear. Large mononuclear. Polymorphonuclear neutrophile. Eosino- phile. 1st week, 12 counts, 12.9# 12.4# 74.0# 0.5# 2d week, 39 counts, 14.6 13.4 70.9 0.8 3d week, 30 counts, 19.9 11.3 68.3 0.3 4th week, 17 counts, 18.8 14.4 66.2 0.4 5th week, 8 counts, 18.2 19.7 61.7 0.3 6th week, 3 counts, 23.5 12.9 59.2 4.2 7th week, 1 count, 23.7 34.4 37.3 4.6 8th week, 1 count, 24 2 16.8 56.9 2.1 ' A consideration of the figures for the first five weeks, during which period, only, was the number of counts sufficient to be of any great value, reveals three main points: (1) A progressive diminution in the percentage of polymorpho- nuclear neutrophiles. 502 William Sydney Thayer. (2) A progressive increase in the percentage of mononuclear forms, the increase being mainly in the large mononuclear varie- ties. (3) A constantly small percentage of eosinophilic cells. While the diminution in the percentage of polymorphonuclear elements is steadily progressive, the fluctuations of the small and large mononuclear leucocytes show certain irregularities. The cause of this is clear when we consider the character of the mono- nuclear cells seen in typhoid fever, and the manner in which the counts upon which these tables are based, were made. Nothing could be simpler than the distinction between the typi- cal lymphocytes as described by Ehrlich, and the large mononu- clear forms. Unfortunately, structures which lie midway be- tween these two types, which are not, uncommon in the blood under many conditions, are especially frequent in typhoid fever. These are elements possessing a nucleus which is usually round-about the size of or but little larger than that of a typical small or me- dium sized lymphocyte, but taking on a much paler stain. The protoplasm is more abundant relatively to the size of the nucleus than in the typical lymphocyte, and in specimens treated with the triple stain, remains almost, not infrequently, indeed, quite uncolored. These structures range all the way from a size a trifle above that of a red blood corpuscle, to the size, and even above the size of a polymorphonuclear leucocyte. And to draw a definite dividing line between these and similar bodies where the nucleus becomes a little larger or ovoid-typical large mononuclear forms -is sometimes difficult, if not almost impossible. At the height of typhoid fever there is a considerable percent- age of just such elements, many of which may be rather difficult to classify. The writer is inclined to believe that these are early stages in the life history of polymorphonuclear leucocytes, whatever view may be held as to the nature and destiny of the typical lympho- cytes. Yet there can be little doubt that the smallest of these bodies are always, or almost always, classed as lymphocytes. No reference to the classification of such elements is found in Ehrlich's last publication? ' Ehrlich and Lazarus, Die anaemie, 8°, Wien, 1898. Observations on the Blood in Typhoid Fever. 503 As stated in a previous article 1 the writer adopts the following general rule of classification in ordinary routine counts where a finer subdivision of the mononuclear forms is impracticable: " Where the nucleus of a mononuclear element is similar in size and shape to those of the lymphocytes, even though the affin- ity 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 cer- tain extent, more attention is paid to the nucleus than to the 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." In such estimates, then, certain of the smaller of these forms have been classed with the lymphocytes under the heading of 11 Small mononuclear leucocytes "-the class as a whole correspond- ing to Ouskov's " Young " elements. Many others, however, fall into the class of " Large mononuclear forms"-Ouskov's "Ripe" elements. On examining the individual estimates, it becomes clear that there has been some difference of opinion between different ob- servers as to where the line between the large and small mononu- clear elements was to be drawn. This has resulted in the irregu- larities which have just been noted. The fact, however, that the large mononuclear forms are present, on the whole, in a progress- ively increasing percentage throughout the course of typhoid fever, is important and entirely confirmatory of the original ob- servations of Ouskov. The small mononuclear forms may be seen to have maintained throughout, a percentage but little higher that that which is characteristic of normal blood. A tendency to an increase is, however, evident as the disease progresses; and in those cases where the polymorphonuclear neutrophiles are espe- cially reduced in number, the increase in the percentage of small mononuclear forms may be striking. The increase in the percentage of the eosinophilic cells in the last several counts is due to two causes. Tn the first place, one case, in which an unusually large percentage of eosinophilic cells was 1 Op. cit., p. 499. 504 William Sydney Thayer. present throughout, has here exerted an undue influence on the general averages on account of the small number of estimates. But there is probably another reason for this increase. There is a distinct relative increase in the percentage of eosinophilic cells dur- ing convalescence from typhoid fever, just as after many other acute diseases. This fact has been recognized by others, and is well shown by Tables XVII and XVIII. But it will be remem- bered that, in connection with the red blood corpuscles, it was pointed out that some of the later counts made during that slight fever which may sometimes persist for considerable periods after the true infection has run its course, showed, already, an increase in number as compared with the records of previous weeks. And it is probable that the increase in the eosinophilic cells here noted is in part associated with this beginning blood regeneration. Twenty-eight differential counts of the leucocytes were made during convalescence from typhoid fever. The following table shows the averages arranged according to the period after the last day of fever: TABLE XVII. Differential counts of the leucocytes during convalescence from typhoid fever, arranged according to the period after the last day of fever. Small mononuclear. Large mononuclea Polymorphonuclear r. neutrophile. Eosino- phile. 1st week, 12 counts, 20.9% 14.7% 61.3% 3.0% 2d week, 7 counts, 30.7 17.3 49.5 2.3 3d week, 6 counts, 15.4 23.5 57.4 3.5 4th week, 1 count, 14.3 7.9 75.3 2.5 5th week, 1 count, 20.3 18.8 56.7 4.2 9th week, 1 count, 13.2 3.7 70.4 12.7 Rearranging this table on a basis of one estimate per week wherever multiple estimates were made, we have: TABLE XVIII. Differential counts of the leucocytes during convalescence from typhoid fever, arranged according to the period after the last day of fever, the averages being takenrupon a basis of one count a week for each case. Small mononuclear. Large mononuclear. Polymorphonuclear . neutrophile. Eosino- phile. 1st week, 10 counts, 22.3$ 15 % 60 % 2.6% 2d week, 6 counts, 29.2 17.5 50.6 2.6 3d week, 6 counts, 15.4 23.5 57.4 3.5 4th week, 1 count, 14.3 7.9 75.3 2.5 5th week, 1 count, 20.3 18.8 56.7 4.2 9th week, 1 count, 13.2 3.7 70.4 12.7 II. CHART SHOWING THE AVERAGE PERCENTAGES OF THE DIFFERENT VARIETIES OF LEUCOCYTES IN TYPHOID FEVER. CONVALESCENCE, FEBRILE PERIOD) WEEKS. WEEKS. 80% . 70% 60% 50% 40% 30% 20% 10% 2 % AVERAGE NORMAL PERCENTAGE OF POLYMORPHONUCLEAR NEUTROPHILES AVERAGE NORMAL PERCENTAGE OF MONONUCLEAR LEUCOCYTES AVERAGE NORMAL PERCENTAGE OF EOSINOPHILES PLAIN LINE = POLYMORPHONUCLEAR N EUTROPHI LES. DOTTED LINE =MONONUCLEAR AND TRANSITIONAL FORMS. BROKEN LINE = EOSINOPHILES. Observations on the Blood in Typhoid Fever. 505 The number of counts in this table is far too small to be of any great value in showing the actual course of the changes in the percentage of the leucocytes with convalescence. They do, how- ever, clearly indicate that the characteristic changes in the relative proportion of the different varieties of colorless corpuscles persist for at least three weeks after the temperature has become normal. While the figures for the first five weeks give, probably, a fair estimate of the average percentage of the different varieties of leu- cocytes, yet variations from these general averages occur here, as well as in the counts during convalescence. How great the variations during the course of the disease may be, is shown by the following table: Table showing the highest and lowest percentages of mono- and polymorpho- nuclear (neutrophile) leucocytes, arranged according to the period of the disease. TABLE XIX. Highest Lowest Mononu- clear. Polymorpho- nuclear neutrophile. Eosino- phile. Mononu- clear. Polymorpho- nuclear neutrophile. Eosino- phile. 1st week, 7.7$ 92.3« 0 % 47.7^ 52.3^ 0% 2d week, 5.3 94.4 0.3 45.5 53.5 1 3d week, 17.5 82 0.5 75.A 24.6 0 4th week, 11.2 88.8 0 62.6 37.4 0 5th week, 30.5 68.5 1 56 44 0 6th week, 29.1 70.25 0.65 38 52.2 9.8 The high percentage of polymorphonuclear leucocytes in the first week occurred in a case where the number of colorless cor- puscles was continuously high throughout the course of the fever, without any apparent cause. At the time of this count there was a leucocytosis of 15,000. The next differential count in the case was made three days after the temperature became normal. Here, with 11,000 leucocytes to the cubic millimetre, the differential count was: Mononuclear 51.6^ Polymorphonuclear neutrophile 46.7 Eosinophile 1.7 And on the 11th day after normal temperature, with 9000 leuco- cytes, there were: Mononuclear . 43.1 & Polymorphonuclear neutrophile 48.3 Eosinophile 8.6 506 William Sydney Thayer. The remarkably high count in the second week was in an un- complicated case with 8000 leucocytes to the cu. mm. The same patient, in the fourth week, with a count of 7000 leucocytes, show- ed a differential count of: Mononuclear 80.5% Polymorphonuclear neutrophile 68. Eosinophile 1.5 The polymorphonuclear neutrophiles were thus below the gen- eral average for the week. The high count in the third week was in an apparently uncom- plicated case with but 4000 leucocytes to the cu. mm. That in the fourth, was a severe case without apparent complica- tion. The leucocytes were 5600 to the cubic millimeter. This differential count was the only one made. The figures in the fifth week were possibly dependent upon the small number (200) counted. This would seem probable, inas- much as, on the 14th day, there had been but 54# of polymor- phonuclear leucocytes. There were 6000 leucocytes on the 14th day, and 7000 on the date of this count. The increased number of leucocytes might also suggest, however, that some unappre- ciated complication was present. The high estimate in the sixth week was, likewise, from an un- complicated case. The leucocytes were not counted at the time the cover-glass specimens were made, but in the fourth week they had been as low as 4500. The low counts in the third and fourth weeks were from a re- markable case in which five estimates were made during this period, the polymorphonuclear elements ranging from 24.6# to 41.8#. In the same case they had been 70# in the second week. They remained low until the patient's discharge, amounting to 39.6# in the second, and 56# in the third week of normal tempera- ture. A study of these differential counts supports almost absolutely, the original observations of Ouskov, to whom far too little credit has been given by subsequent observers. In his valuable work, " Krov kak Tkan " (The Blood as a Tissue), published in St. Pet- ersburg, in 1890, he called attention to practically all the points which are here emphasized, and which have been noted since that time by a number of others. Observations on the Blood in Typhoid Fever. 507 In conclusion it may be said that the relative proportions of the different varieties of leucocytes one to another, in typhoid fever, show more or less characteristic changes consisting in: (1) A progressive diminution in the percentage of polymor- phonuclear neutrophiles, reaching its maximum, apparently, at the end of defervescence, and persisting for some weeks during convalescence. (2) An increase in the relative proportion of mononuclear ele- ments. The true lymphocytes appear to be but little affected. On the other hand, small mononuclear elements with relatively more protoplasm, which has but slight affinity for coloring matters, become more abundant, while an especial increase occurs in the large mononuclear varieties. The mononuclear cells which are, apparently, most markedly increased, are elements containing nu- clei not much larger than those of lymphocytes, and often present- ing the general appearance of a lymphocyte nucleus, with the ex- ception of the slight affinity for coloring matters. The size of these cells is usually about that, or but little larger than that of the ordinary polymorphonuclear neutrophile. The larger forms of the mononuclear leucocytes, especially those with tabulated, nick- ed nuclei-transitional forms-do not appear to be so essentially increased in number. (3) A reduction, absolute, and relative, of the eosinophilic cells throughout the course of the disease. In some cases there is a tendency to approach the normal toward the end of defervescence, while with convalescence the number increases until, in some in- stances, it is rather above the normal average. part II. The Blood in Various Complications of Typhoid Fever. Estimates of the number of leucocytes have been made in a considerable number of cases of typhoid fever in which complica- tions were present. In some of these instances counts of the red blood corpuscles, estimates of the haemoglobin and differential counts of the leucocytes were also made. Of special interest and importance, from a diagnostic standpoint, is the course of the leucocytes, particularly in those complications associated with inflammatory processes. 508 William Sydney Thayer. Examinations of the blood are recorded in: 11 Cases with haemorrhage from the bowels. 8 " " perforation of the bowels. 7 " " furunculosis. 7 " " phlebitis and thrombosis. 6 " " pleurisy. 5 " " pneumonia. 4 " " severe bronchitis and broncho-pneumonia. 4 " " periostitis. 3 " " lymphadenitis. 3 " " urethritis. 3 " •* cystitis. 3 " " cholecystitis. 3 " parotitis. 2 " " submaxillary abscess 2 " " otitis media. 2 " " pulmonary tuberculosis. 1 " " pregnancy. 1 " " appendicular colic. 1 " " peripheral neuritis. 1 " " peri-rectal abscess. 1 " " erythema multiforme. 1 " " purpura haemorrhagica. 1 " " conjunctivitis. 1 " " pericarditis. 1 " " decubitus. 1 " " convulsions. 1 " " trichinosis!??) In considering these records it seems best to leave the most im- portant subject, that of the behavior of the leucocytes in perfora- tion of the intestine, until the last. HEMORRHAGE FROM THE BOWELS. Case 1.-No. 2983. S. 11th day: R. b. c., 5065000; haemoglobin 80 %; leucocytes, 4000. 13th day: R. b. c., 5286000; 81 %; leucocytes, 6000. 15th day, 5 and 8 A. M.: Slight haemorrhages. 10 P. M.: R. b. c., 4348000; haemoglobin 65%; leucocytes, 9500. 16th day : 'j i ' r Slight haemorrhages. 18th day: f 6 ® 19th day : J 22d day: R. b. c.., 4148000; haemoglobin 57 %; leucocytes 7000. Case 2.-No. 17554. C. 12th day: Two haemorrhages of 300 cc. Between the 12th and 25th, five more haemorrhages of 500, 500, 250, 200, and 250 cc., respectively. 17th day: R. b. c., 2600000; haemoglobin 30 %; leucocytes 4000. 30th day ; R. b. c., 2120000; haemoglobin 28 %; leucocytes 8500. 31st day; Pneumonia of each lower lobe. 34th day: R. b. c., 2000000; haemoglobin, 28 %. Differential count of leucocytes: Small mononuclear 13 % Large " and transitional 10 Polymorphonuclear neutrophile 77 Observations on the Blood in Typhoid Fever. 509 35th day : Severe chill. R. b. c., 2400000 ; hemoglobin 30 % ; leucocytes, 12750. 39th day : R. b. c., 2440000, haemoglobin 28 %; leucocytes, 5300. 40th day: Streptococcus pleurisy on left side. 42d day: R. b. c., 3396000; hemoglobin, 30 % ; leucocytes, 18000. 43d day, 12.30 A. M.: death. The autopsy showed, among other things, a sero-fibrinous (streptococcus) pleurisy. There was a general typhoid and streptococcus septicaemia. Case 3.-No. 20646. K. 12th day; R. b. c., 3648000; leucocytes, 4000. 13th day : Hemorrhage, 650 cc. 14th day: Haemorrhage, 150 cc. 17th day : Hemoglobin, 45 % . 30th day: 6.40 P. M.: Haemorrhage, 460 cc., 8.30 P. M.: R. b. c., 1992000; hemoglobin, 25 %; leucocytes, 5300. 34th day: R. b. c., 2472000; leucocytes, 4000. 35th day : Hemoglobin, 38 %. 37th day: R. b. c., 2328000; hemoglobin, 36 %; leucocytes, 5200. 46th day: R. b. c., 3368000; haemoglobin, 58 %; leucocytes, 4000. 55th day: R. b. c., 3*424000; hemoglobin 60 %; leucocytes, 5000. 75th day: R. b. c., 3224000; haemoglobin, 56%; leucocytes, 7200. 82d day, second day of normal temperature: R. b. c., 4304000; hemoglobin, 45% ; leucocytes, 6000. Differential count: (Only 176 counted.) Small mononuclear 8.5 % Large " and transitional forms 22.6 Polymorphonuclear neutrophile.. 68 Eosinophile 0.5 110th day, 21st day of normal temperature: R. b. c., 5248000; haemoglobin, 66 %; leucocytes, 6000. Small mononuclear 12.5 % Large mononuclear 34.5 Polymorphonuclear 49.2 Eosinophile 3.7 Differential count: (But 136 cells counted.) Case 4.-No. 23914. B. 27th day : Haemorrhage, 200 cc. 34th day : Leucocytes, 8800. 49th day : Leucocytes, 10000. Case 5. -No. 24048. J. 6th day : R. b. c., 4284000; leucocytes, 6000. 7th day, 4 P. M.: Haemorrhage, 100 cc. 8 A. M.: Haemorrhage, 500 cc. 4 P. M.: R. b. c., 3020000; leucocytes, 7000. Case 6.-No. 24603. R. On entrance, signs of tuberculous infiltration at right apex. 5th day : Leucocytes, 6000. 12th day: R. b. c., 4800000; h:emoglobin, 73 %; leucocytes, 7000. Small mononuclear 14.4 % Large " and transitional forms 17.8 Polymorphonuclear neutrophile 66.4 Eosinophiles ... 1.4 Differential count: 15th day : Leucocytes, 6000 Small mononuclear 13.4 % Large " and transitional forms 24.2 Polymorphonuclear neutrophile 61.4 Eosinophiles 1 Differential count: * This figure is entered in the hospital records as 5. The haemoglobin, however, and the accompanying estimates, all show that this must have been a slip of the pen. 510 William Sydney Thayer. 22d day: Leucocytes, 10000. 24th day, 8 A. M.: Haemorrhage, 500 cc. 10.25 P. M.: Haemorrhage, 390 cc. 11 A. M.: Leucocytes, 12000. 10.30 P. M.: Leucocytes, 24800. 25th day, 8 A. M.: Leucocytes, 22000. 2.30 P. M.: Leucocytes, 8000. 6.30 P.M.; " 11000. 26th day : Leucocytes, 9000. 27th day: " 9000. 35th day: " 12000. 37th day, 10.30 A. M.: Leucocytes, 9000. 6 P. M.: Leucocytes, 7000. 38th day: K. b. c., 3348000; leucocytes, 7000. 39th day: Leucocytes, 8000; haemoglobin, 40 %. 43d day : Several bed sores have developed. 45th day : Leucocytes, 16000. Case 7. -No. 25679. B. 8th day: Bronchitis; friction nib on right side; leucocytes, 7800. 10th day: Slight epistaxis. R. h. c.. 8910000: h:vmoe-lohin. 77#: lencocvtea. 6600. Small mononuclear IS.O'S Large " and transitional forms. 14.0 Eosinophile 2.2 Polymorphonuclear neutrophile 64.9 Differential count: 12th day: Leucocytes, 6300. 13th day: " 6200. Noon : Haemorrhage, 380 cc 2 P.M.: " 120 cc. 14th day, 9 A. M.: Leucocytes, 12250. 2.45 P. M.: Haemorrhage, 260 cc. 3 P. M.: Leucocytes, 14300. 5.30 P. M.: Haemorrhage, 60 cc. 6 P. M.: Infusion of salt solution, 300 cc. 15th day, 2.45 A. M.: Infusion of 500 cc. of salt solution. 11 A. M.: Leucocytes, 17400. 5 P.M.: " ' 13500. 16th day, 8.30 A. M.: leucocytes, 11500. 3.30 P. M.: " 9300. 17th day, 2.15 A. M.: Infusion, 500 cc., salt solution. 10 A. M.: Leucocytes, 11300. 5 P.M.: " 9400. 19th day : Leucocytes, 7000. 20th day: " 7400. 21st day: " 5500. 22d day: " 5600. 23d day: " 7200. 24th day: " 5000. 25th day; " 6400. 26th day: " 5800. The patient later developed a submaxillary abscess. Case 8.-No. 27565. M. 24th day: Two stools containing perhaps, 300 cc. blood. 25th day, IIP. M.: Leucocytes, 10500. 26th day, 1 A. M.: " 9500. 27th day, 9 A. M.: " 6400. 11P.M.: " 2500. Observations on the Blood in Typhoid Fever. 511 28th day, 8 P. M.: Since yesterday has had profuse intestinal haemorrhages. Right parotid gland enlarged and tender. Leucocytes, 8800. 29th day, 12 A. M.: Infusion, 1000 cc. 8.30 A. M.: Leucocytes, 8100. 9.30 A. M.: Infusion of 1000 cc., salt solution. 11.30 A. M.: Severe haemorrhage. Death. Case 9.-No. 27845. W. 5th day : Leucocytes, 3200. 7th day: Leucocytes, 8300. 4500. 6000. 5300. 8th day : Haemorrhage of about 200 cc. 10th day: Several small haemorrhages. 7.45 A. M.: Leucocytes, 4000. 9.45 A. M.: " 5000. 11 A. M.: " 3000. 13th day:' Small haemorrhages, yesterday- and to-day. 13th day; Leucocytes, 4100; haemoglobin, 56 %. 14th day : Small haemorrhage. 23rd day : Leucocytes, 7000. 24th day : " 6400. 30th day: " 4200. 33d day: R. b. c., 3208000; haemoglobin, 52%; leucocytes, 2300. 38th day : Leucocytes, 3500. 42d day : Leucocytes, 4100. 45th day : Furunculosis. 47th day : Abscess on nates opened spontaneously. 48th day : Leucocytes, 6200. 55th day : " 7600. 61st day: " 7500. 64th day : More furuncles. 69th day: R. b. c., 4160000; haemoglobin, 54 %; leucocytes, 6600. 75th day : First day of normal temperature. Leucocytes, 6600. Case. 10.-No. 27855. W. 20th day : Leucocytes, 13000. 22d day, 9.30 P. M.: Haemorrhage, 700 cc ; gelatine injection given immedi- ately. 24th day, 8 A. M.: Haemorrhage of 500 cc; second gelatine injection, and infusion of 500 cc. salt solution 4 P. M.: Haemorrhage, 460 cc.; injections of 300 cc., gelatine and 400 cc. salt solution; Leucocytes, 9000. 28th day : Pain in the left arm and shoulder; beginning of thrombosis of left axillary vein. 31st day: Leucocytes, 10000. 32d day : Salt solution infusion, 800 cc. 34th day, 8. A. M.: Leucocytes, 12000. 12.30 P. M.: Death. Case 11.-No. 27884. M. 10th day: Leucocytes, 18000; no apparent cause. 26th day, 10 P. M.: Haemorrhage, 200 cc. 10.30 P. M.: Leucocytes, 3700. 27th day, 8 A. M.: Leucocytes, 7300. 3 P. M.: Haemorrhage, 600 cc. 3.25 P. M.: Leucocytes, 2200; gelatine injection. 11 P. M.: Leucocytes, 2700. William Sydney Thayer. 512 28th day : Leucocytes, 3600, 29th day, 6 A. M.: Leucocytes, 3200. 11 P. M.: " 4500. The further course of the case is considered among those of perforation. On looking over these records it appears that the lowest point to which the blood corpuscles fell after haemorrhages from the bowel, was attained in case 3, where, on the 30th day, after severe haemor- rhages on the 13th, 14th and 30th days, the count showed: Red blood corpuscles 1,992,000. Eighteen days before, there was a record of 3,648,000. This fall was followed, despite the fever, by a gradual increase until, twenty-five days later, there were 3,424,- 000 red blood corpuscles to the cu. mm. Twenty-two days after this, however, there had been a fall of 200,000. With regard to the leucocytes, there are considerable variations in the records. In five instances, cases 2, 3, 9, 10, 11, the haemorrhages ap- peared to have no appreciable effect on the number of leucocytes. In five instances, cases 1, 5, 6, 7 and 8, there was a greater or less tendency toward a leucocytosis. In case 1, there was a slight increase, on the 15th day, after a small haemorrhage, to 9500, the count having been 6000 two days before. On the 22d day, after five days of slight haemor- rhages, there were 7000 leucocytes to the cubic millimetre. In case 5 the leucocyte count, on the sixth day, was 6000. On the twelfth, four hours after the last of two large haemorrhages, causing a loss of 1,264,000 red blood corpuscles to the cubic milli- metre, the count was 7000. In cases 6 and 7 there was a marked leucocytosis. In case 6, this began immediately after a large haemorrhage, reaching its maximum about twelve hours later. In sixteen hours after this, the leucocytes had fallen to 8000, but they remained above 7000 throughout the rest of the course of the case. It is, however, but fair to say that this was a case of pulmonary tuber- culosis, and despite the fact that on the fifth day there were but 6000 leucocytes, and on the twelfth, 4800, yet the tuberculous process may have had some predisposing influence toward a leu- cocytosis. In case 7, twenty-one hours after the first haemorrhage, the leu- Observations on the Blood in Typhoid Fever. 513 cocytes rose to 12,250. Immediately after another haemorrhage on the following day, they were 14,300. On the next day-eighteen hours after another haemorrhage, the maximum number, 17,400 was reached. Six days later the fig- ures were normal for the period of the disease. In case 8, twenty-four hours after a haemorrhage, there were 10,500 leucocytes to the cubic millimetre. Three days after the haemorrhage, they were normal. In case 4 there was no count just before or after the haemor- rhage. In conclusion, it may be said that intestinal haemorrhage in ty- phoid fever may exercise little or no apparent influence on the number of leucocytes in the peripheral circulation. Often, how- ever, there is a tendency toward a leucocytosis which begins imme- diately after the haemorrhage, reaching its maximum in from twelve to twenty-four hours. In from one or two days to a week, the number of leucocytes generally returns to the normal average for the period of the disease. FURUNCULOSIS. Case 1.-No. 16888. F. 3d week : Numerous boils; leucocytes, 8000. No cultures taken. Case 2.-No. 16967. 32d day : Abscess on lower jaw, as large as a good sized grape, opened to-day. 43d day: Small abscess in groin ; leucocytes, 8500. 44th day : Abscess opened ; no count of the leucocytes. Case 3.-No. 21744. K. 3d week : Leucocytes, 6000. 4th and 5th weeks, after slight hemorrhages: Leucocytes, 10300 12800 13500 6500 42d day: Discharge from ear; small abscess of left labium; leucocytes, 26500. 47th day: Abscess of labium incised. 50th day: Abscess under the chin containing about half an ounce of pus, incised. Cultures showed Staphylococcus pyogenes aureus ; leucocytes, 10600. 56th day : All abscesses healed ; leucocytes, 9600. 57th day : Leucocytes, 9000. 75th day: Leucocytes, 10000. Case 4.-No. 23376. J. 11th day: Leucocytes, 7500. 31st day: Numerous boils on back (Staphylococcus aureus) \ leucocytes, 10200. Case 5.-No. 23953. H. 20th day : " Profuse crop of boils." 22d day : Leucocytes, 8200. 514 William Sydney Thayer. Case 6.-No. 27162. P. 7th day : Leucocytes, 6500. 15th day : Leucocytes, 2500. 21st day : Three or four boils on the nates; leucocytes, 9000. Case 7.-No. 27039. A. 2d week: Leucocytes, 9000. 23d day ; Small abscesses in axillae; leucocytes, 10000. 32d day : Leucocytes, 3000. 36th day : Boils over sacrum ; leucocytes, 7000. 50th day : Leucocytes, 9000. 57th day : Leucocytes, 9 500. A summary of these figures shows, as might be expected, that furunculosis in typhoid fever is associated with a slight increase of the leucocytes above the normal average for the period of the dis- ease. In one instance only, and that in case 3, a child of six, with a discharging otitis media as well as a small abscess of one labium, was the count above 10,200. PHLEBITIS, THROMBOSIS. Case 1 No. 10298. B. 16th day: Leucocytes, 7100. 27th day : Left femoral phlebitis; leucocytes, 21250. 33d day: Tenderness almost gone; leucocytes, 10500. Case 2.-No. 16773. V. 44th day : Leucocytes, 4000. 45th and 46th days: Chills. 46th day: Leucocytes, 14000. 49th day : Leucocytes, 4000. 50th day: Distinct evidences of femoral thrombosis in the shape of oedema. Case 3-No. 17936. 11. 37th day: Phjebitis of left femoral; leucocytes, 8500. Case 4.-No. 22399. H. 63d day ; Popliteal phlebitis in preceding week, before entrance; leucocvtes, 8000. 70th day: Leucocytes, 4500. Case 5.-No. 27379. G. 12th day, 3.20 P. M.: Leucocvtes, 11000. 5.15 P.M.: 10500. 13th day : Early in the morning, sudden rapidity of pulse; friction rub in the left chest; sudden fall of temperature from 105° to normal; leucocytes, 8330. The patient soon rallied from this collapse. 20th day : Cries out with apparent suffering, though unable to localize pain. Noon: Leucocytes, 24860. 2.30 P.M.: " 18330. 5.30 P. M.: " 18200. 4.40 P.M.: Collapse; perforation suspected. 7 P. M.: Operation under cocaine; no perforation found. 10 P. M.: Sudden dyspnoea; death. Observations on the Blood in Typhoid Fever. 515 Autopsy. Thrombus in the left iliac vein ; embolus plugging the pulmonary artery. Cultures from the heart's blood, spleen, gall-bladder, pulmonary thrombi and mesenteric glands showed Bacillus typhosus. The thrombosis in all probability began on the 20th, when the patient began to complain of pain and the leucocytosis appeared. Case 6.-No. 27855. W. 20th day: Leucocytes, 13000. No apparent cause for the large number of colorless elements. 22d day : After haemorrhages and salt infusions, leucocytes, 9000. 28th day: Pain in the left shoulder; later, evidences of thrombosis of the left axillary vein. 31st day : Leucocytes, 10000. 34th day : Leucocytes, 12000. 12.30 P. M.: Death from thrombosis of the pulmonary artery. These records show that phlebitis and thrombosis are complica- tions associated with leucocytosis. This appears to be most mark- ed at the onset which is so often associated with chills. In one instance the figures were as high as 24,860. PLEURISY. Case 1.-No. 11963. H. 16th day : Slight friction rub over lower right front. 17th day : Leucocytes, 10000. 21st day: Slight effusion. Leucocytes, 7430. Small mononuclear 8 % Large mononuclear and transitional forms. 4.0 Polymorphonuclear neutrophile 88.0 Eosinophile 0 Differential count: 36th day : Leucocytes, 11500. Small mononuclear 12.0% Large mononuclear and transitional forms. 10.0 Polymorphonuclear neutrophiles 77.5 Eosinophile 0.5 Differential count: Recovery uninterrupted. Cane 2.-No. 17554. C. This case is also summarized among those of htemorrhage from the bowel (Case 2). After repeated haemorrhages, the blood count on the 39th day, showed: R. b. c., 2440000; haemoglobin, 28%; leucocytes, 5300. 40th day: Streptococcus empyaema in left side. 42d day: R. b. c. 3396000; haemoglobin 30% ; leucocytes, 18000. 43d day, 12.30 A. M.: Death. Cane 3.-No. 25249. G. 7th day : Leucocytes, 5800. Small mononuclear 4.3% Large mononuclear and transitional forms. 9.0 Polymorphonuclear neutrophile 86.7 Eosinophile 0 • Differential count: 10th day: Leucocytes, 5500. Small mononuclear 5.3% Large mononuclear and transitional forms. 7.0 Polymorphonuclear neutrophile 87.4 Eosinophile 0.3 Differential count: 516 William Sydney Thayer. 17th day : Leucocytes, 3300. Small mononuclear 29.4% Large mononuclear and transitional forms. 8.9 Polymorphonuclear neutrophile 61.7 Eosinophile 0 Differential count: 20th day: Friction rub in right axilla. 21st day : Signs of effusion ; leucocytes, 5800. Differential count: Small mononuclear 18.5% Large mononuclear and transitional forms. 8.5 Polymorphonuclear neutrophile 73.0 Eosinophile 0 25th day : Friction rub still present. Leucocytes, 5000. Small mononuclear 16.8% Large mononuclear and transitional forms. 10.7 Polymorphonuclear neutrophile 72.2 Eosinophile 0.3 Differential count: 29th day : Friction rub still heard. Leucocytes, 6500. ' Small mononuclear 29.9% Large mononuclear and transitional forms. 10.3 Polymorphonuclear neutrophile 59.8 Eosinophile 0 Differential count: 30th day: Sudden abdominal pain during the night of the 29th ; increase in the effusion. 11 A. M.: Leucocytes, 7700. 6 P. M.: " * 14400. 31st day: Leucocytes, 16600. 32d day, 10 A. M.: Leucocytes, 13400. Differential count: ' Small mononuclear 22.3% Large " and transitional forms. 8.2 Polymorphonuclear neutrophile 69.5 Eosinophile 0.0 33d day: Leucocytes, 11000. 34th day : " 13500. 35th day: " 11500. 36th day: " 7700. Small mononuclear 27.0% Large " and transitional forms. 13.2 Polymorphonuclear 59.5 Eosinonhile . 0.3 Differential count: 37th day : Leucocytes, 7700. 38th day: " ' 8600. 39th day: " 7300. 40th day: " 8400. Small mononuclear 35.6% Large " and transitional forms. 10.6 Polymorphonuclear neutrophile 52.5 Eosinophile 1.3 Differential count: 41st day : Leucocytes, 8000. 44th day: " 7500. Differential count: Small mononuclear 33.5% Large " and transitional forms. 7.4 Polymorphonuclear 57.1 Eosinophile 2.0 50th day: Sudden rise of temperature to 105°; pain in the left side. 4.00 P. M.: Leucocytes, 11000. 7.30 P. M.: " ' 17000. 51st day: " 8300. 53d day : . " 6300. 56th day ; " 8750. Observations on the Blood in Typhoid Fever. 517 70th day : Considerable tenderness over lower left ribs and signs of effusion. Leucocytes, 23000. Differential count: ' Small mononuclear 12.7% Large mononuclear and transitional forms. 17.0 Polymorphonuclear neutrophile 68.5 Eosinophile 1.8 79th day: Aspiration; haemorrhagic fluid with considerable pus; shows B. typhosus on cultures. Leucocytes, 30100. 44500. r, x. „ ,, , „ . . 40900 Operation; no further records of leucocytes. 80th day : Leucocytes, « Case 4.-No. 24062. A. 5th day : Leucocytes, 8000. 11th day: " 8000. 12th day : Pain in abdomen and lower left axilla; stitch in the side; respiration shallow ; no adventitious sounds. 9 A. M.: Leucocytes, 13000. 10 A. M.: " 13000. 11.30 A. M.: " 12000. 1 P. M.: " 12100. 2 P. M.: " 11500. 4.30 P. M.: " 11600. 7 P.M.: " 11600. 9 P. M.: " 13300. 13th day : Better. 6.30 A. M.: Leucocytes, 10000. 8.30 P. M.: " 9000. 23d day : Second day of normal temperature. Leucocytes, 7600. 31st day : Has had slight irregular rises of temperature without apparent cause. Leucocytes, 10300. Case 5.-No. 27227. H. 19th day, 5 A. M.: Leucocytes, 4000. 5 P. M.: " 5000. 20th day : Moribund; friction rub in lower right front and axilla; leucocytes, 3500. No autopsy. Case 6.-No. 27656. R. This case was one of mitral insufficiency and adherent pericardium. There were severe bronchitis and broncho-pneumonia at the onset. 4th day : Leucocytes, 20000. 21st day : The patient had been doing well; sudden stitch in the side to-day with friction over a small area. Severe bronchitis. 5 P. M.: Leucocytes, 17240. 7 P. M.: " 15500. 22d day: Leucocytes, 12000 ; red blood corpuscles 4868000 ; haemoglobin 68 35th day: Patient is steadily convalescing, though the temperature is not yet normal. Leucocytes, 4500. With one exception all these cases show a leucocytosis. This may be slight in cases where there is but a limited dry pleurisy; or extensive, as in cases 2 and 3 where there is an empyaema. In case five the patient who was moribund, showed a friction rub in the right front and axilla, wThile the count revealed only 3500 leucocytes. This was probably an instance of severe general septicaemia. 518 Sydney Thayer. An interesting point in connection with these cases is the char- acter of the changes in the relative proportions of the different varieties of leucocytes, where there is a leucocytosis. In case 1, with 7430 leucocytes in the third week, the differ- ential count shows a characteristic polymorphonuclear leucocytosis. In the sixth week, with 11,500 leucocytes, one notes a distinct modification in the usual figures, in the sense of an approach to- ward the changes characteristic of typhoid fever. In case 3 the differential counts are most interesting. In the beginning, with low leucocyte counts, there was yet a surprisingly high percentage of polymorphonuclear elements. By the seven- teenth day, however, the figures of the polymorphonuclear leuco- cytes were below the normal average for that week of typhoid fever. Four days later, with a friction rub and a slight effusion, there were but 5800 leucocytes, while the percentage of polymorphonu- clear elements was 73. Four days after this, there was no great change. On the 29th day, with the friction rub still heard, there were 6500 leucocytes, with 59.8^ of polymorphonuclear neutrophiles, a percentage below the normal average for this period. On the 32d day, with an increase in the effusion, and a leuco- cytosis of 13,400, there was still a subnormal number of polymor- phonuclear leucocytes. The acute symptoms subsided, and on the 36th day, despite the fact that there were 7700 leucocytes, there were but 59.5^ of the polymorphonuclear variety, but little above what is probably the normal average for the week. And with a count of 8400 leucocytes, and a pleuritic rub still present, the per- centage sank to 52.5, on the 40th day. On the 70th day, with the onset of the empyaema, and a leuco- cytosis of 23,000 there were but 68.5% of polymorphonuclear neu- trophiles. The increased relative percentage of the large mononuclear forms throughout is also striking.1 PNEUMONIA. Case 1.-No. 14000. J. 7th day : Impaired resonance at right base. Oth day : Marked consolidation on right side. 34000 30000 T , Leucocytes, 1Oth day : Death. 1 The excellent records in this case are the work of C. P. Emerson. Observations on the Blood in Typhoid Fever. 519 ( ase 2.-No. 17952. D. 5th day : Admitted, probably with a central pneumonia. 6th day : Leucocytes, 25000. Differential count: Small mononuclear 2.8% Large " and transitional forms. 16.9 Polymorphonuclear neutrophile 77.0 Eosinophile 3.3 7th day : Leucocytes, 19760. 8th day: " 24800. 9th day : " 23200. Definite signs of consolidation to-day. 10th day : Leucocytes, 38000. ' Small mononuclear 9.2% Large " and transitional forms. 5.4 Polymorphonuclear neutrophile 81.2 Eosinophile 4.2 11th day: Differential count: 12th day : Leucocytes, 18000. 13th day: " ' 18600. 14th day : " 13500; red blood corpuscles, 4000000. 15th day : " 14500; " " 4720000. Small mononuclear 9.2% Large " and transitional forms. 7.7 Polymorphonuclear neutrophiles 81.0 Eosinophile 2.0 Differential count 16th day : Leucocytes, 15000. 17th day: " 16000. 18th day: " 15600. 19th day: Leucocytes, 14500. Small mononuclear 14.4 % Large " and transitional forms. 6.5 Polymorphonuclear neutrophile 77.5 Eosinophile , 1.6 Differential count: 20th day : Leucocytes, 10000. 21st day: " 11600. 22d day : " 8000. 23d day : " 9500. 24th day: " 9000. 25th day : Signs of consolidation have practically cleared up ; leucocytes, 6000. 26th day : Leucocytes, 6500. After this the leucocytes behaved as in an un- complicated case. Case 3.-No. 23695. J. 14th day: Leucocytes, 16800. 15th day: " 8400. 16th day: " 6000. 17th day: Pneumonia; characteristic pneumococci in blood-stained expectora- tion. 18th day, 9 A. M.: Leucocytes, 8200. 11 A. M.: " 8000. 12.07 P. M.: Death. Case 4.-No. 27816. B. Case reported under suspected perforation. Severe abdominal symptoms with leucocytes from 6400 to 10400; this was followed by an exploratory laparotomy under cocaine on the 16th day. Nothing found. 520 William Sydney Thayer. 17th day, 8 A. M.: Leucocytes, 15400. 12.30 P. M.: " ' 13400. 8 P. M.: " 6600. 18th day, 8.30 A. M.: " 6200. 1 P. M.: " 5600. 9 P. M.: *• 6000. 19th day, 3 P. M.: " 4000. 4 P. M.: Consolidation discovered in both backs. 20th day, 11 A. M.: Leucocytes, 9600. 6.55 P. M.: Death. Autopsy: Double pneumonia; extensive pleurisy; general septicaemia with Bacillus typhosus and Streptococcus pyogenes. Case 5 No. 28307. J. 18th day: Leucocytes, 10600. 19th day: " 8000. 20th day: " 11300. Repeated salt solution infusions. 22d day, 9 A. M.: Leucocytes, 10600. 5 P. M.: " ' 6500. 23d day, 8.15 A. M.: " 5100. 5.30 P. M.: " 2500. 24th day, 9 A. M.: " 3700. 25th day: " 4400. 26th day: " 6000. 27th day : Pneumonia on right side. 8.30 A. M.: Leucocytes, 10600. 5.30 P. M.; " ' 11100. 28th day, 8.15 A. M.: " 15300. 12 Noon : Death. The autopsy showed a general septicaemia with Staphylococcus pyogenes aureus. A consideration of these tables shows that in three cases (Nos. 1, 2, 5) there was a leucocytosis, while in two (Nos. 3 and 4) the leucocytes were under 10,000. In case 3 there was no essential change in the number of colorless corpuscles, the figures having been rather high throughout. Of the three cases with leucocytosis, two were fatal. Of the two cases without leucocytosis, both were fatal. The largest number of leucocytes was observed in case 1, where, on the day before death, a count of 36,000 was recorded. The two cases without leucocytosis were both terminal infec- tions. In case 3 there was an increase from 6000 on the 16th day to 8200 on the 18th. There had been, however, counts of 16,800 and 8400 respectively on the 14th and 15th days. In case 4, at the onset of the pneumonia on the 19th day, there •> were but 4000 leucocytes to the cu. mm.; while on the 20th, eight hours before death, the count showed but 9600. Observations on the Blood in Typhoid Fever. 521 In both of these cases, then, the number of the leucocytes was above the average for typhoid fever, though within the limits of normal. The differential counts in case 2 show, as did the above-men- tioned records in pleurisy, a relatively slight increase in the poly- morphonuclear leucocytes as compared to the degree of leucocy- tosis. Thus, on the 19th day, with 14,500 leucocytes, the per- centage of polymorphonuclear neutrophiles was but 77. Bronchitis and Broncho-pneumonia. Strictly speaking, bronchitis is present in the great majority of cases, and cannot properly be included among the complications of typhoid fever. The moderate general bronchitis which is ordi- narily present appears to exercise no influence on the number of leucocytes. In this list are included those cases in which the bron- chitis was especially severe, or where it was associated with appre- ciable areas of broncho-pneumonia. Case 1. - No. 24692. W. Onset with cough and bronchitis. 10th day: Leucocytes, 7600. 18th day : Extensive general bronchitis. 19th day : Leucocytes, 10250. 20th day : Leucocytes, 16600. Expectoration muco-purulent, rather tenacious. 21st day : Signs of consolidation on the right side ; leucocytes, 21000. 22d day : Leucocytes, 14500. 25th day: " 12750. No further counts. After this the case pursued a favorable course. Case 2.-No. 24645. A. 11th day: Leucocytes, 6000. 12th day : Signs of broncho-pneumonia ; leucocytes, 4800. 13th day : Leucocytes, 9000. 14 th day: " 7500. 19th day: " 7600. The case cleared up satisfactorily. Case 3.-No. 27656. R. 4th day : Mitral insufficiency and adherent pericardium ; bronchitis with signs of slight broncho-pneumonia. Leucocytes, 20000. 21st day: Stitch in side; pleural friction over a small area; severe bronchitis. 5 P. M.: Leucocytes, 17240. 7 P.M.: " 15500. 22d day: Leucocytes, 12000. 35th day : Convalescence. Leucocytes, 4500; red blood corpuscles, 4868000; hsemoglobin, 68 %. 522 William Sydney Thayer. Case 4. No. 28194. S. 5th day : Leucocytes, 6000. 6th day: " 3000. 7th day, 10 A. M.: Leucocytes, 5800. In the afternoon, great respiratory distress; evidences of extensive bronchitis and some consolidation. 7 P. M.: Leucocytes, 18200 8th day : Leucocytes, 18600. 8 P. M.: Death. At the autopsy there were found acute mitral endocarditis, wide-spread broncho.pneumonia and acute appendicitis, in addition to extensive typhoid lesions. Cultures showed, besides the Bacillus typhosus in the heart's blood, spleen, kid- ney, gall-bladder, a general septicaemia with Staphylococcus pyoyenes aureus, which was also obtained from the vegetations on the valves. The Bacillus coli communis was found in the lung and appendix. In all these cases there was a tendency toward an increase in the number of leucocytes above the normal average, and in three it was sufficient to be called a leucocytosis. One should remember, however, that in all probability, a con- siderable number of cases where death occurs with a subnormal number of leucocytes, show, at autopsy, areas of broncho-pneumo- nia which were unsuspected during life. PERIOSTITIS. Case 1 No. 14191. J. E. 62d day: Tenderness on deep pressure along the course of the femur, lasting about one week. Leucocytes, 10500. Case 2.-No. 23968. C. 13th day: Leucocytes, 7600. 14th day after defervescence: Pain, tenderness, redness and swelling over the middle of the left clavicle. Leucocytes, 13000. Case 3.-No. 25076. S. Typhoid fever in the latter part of September and October; relapse in Novem- ber, followed by periostitis of both femora; also cystitis due to the B. typho- sus. 25/xii; Leucocytes, 6000, 27/xii: " 14000; red blood corpuscles, 44 00000; haemoglobin 55^. 28/xh: " 20000. 30/xii: Leucocytes, 18000. Differential count: ' Small mononuclear 17.0& Large mononuclear and transitional forms. 9.5 Polymorphonuclear neutrophile 72.5 Eosinophile 1.0 31/xii: Leucocytes, 15000. 3/i: " 22000. 5/i: Periostitis much better. First evidences of cystitis. Leucocytes, 20000. Observations on the Blood in Typhoid Fever. 523 Case 4.-No. 28128. A. Ten days after leaving the hospital, convalescent from typhoid fever, developed periostitis of the lower part of the shaft of the femur. Recovery without operation. 15/x : Leucocytes, 17600. 16/x : " 14400. 17/x : " 11200. 19/x: " 12800. 20/x : " 15600. 23/x: " 12200. 25/x : " 9200. 27/x : " 6000. Excepting in the first case, where the nature of the complication was somewhat doubtful, a distinct leucocytosis was present in every instance. In all instances the local process was probably due to the B. typhosus; this was proven in case 2. On examining the differential count in case 3, one is again struck by the fact that with a leucocytosis of 18,000, there were but 72.5# of polymorphonuclear neutrophiles, while the large mo- nonuclear forms were present in an increased relative proportion. LYMPHADENITIS. Case 1.-No. 14170. M. 55th day : A few tender enlarged glands in right groin. Leucocytes, 14000. No further counts. Case 2-No 17310. T. 21st day: Glands slightly enlarged and tender behind both sterno-mastoid muscles. Leucocytes, 8000. Case 3-No. 12881. B. Fourth week: Leucocytes, 8800, 9200. Enlarged tender glands in right groin. These were cases of slight glandular enlargement and tender- ness without apparent cause. Cases 1 and 3 may have been due to phlebitis. A slight in- crease above the average normal number of leucocytes may be noted in cases 2 and 3, while in case 1 there was a leucocytosis. SUBMAXILLARY ABSCESS. Case 1.-No. 25679. B. The early part of the record of this case will be found among the cases of haemorrhage. For a week before.the onset of the submaxillary abscess, the leucocytes had ranged from 5000-7400. 27th day : Slight swelling in both submaxillary regions ; leucocytes, 6200. 28th day: Leucocytes, 7500. 524 William Sydney Thayer. 29th dav: Swelling increasing under the jaw, associated with pain; leucocytes, 6800.' 32d day: Marked increase of swelling and tenderness ; leucocytes, 15200. 33d day: Leucocytes, 14400. 35th day: " 13800. 36th dav: " 17500. 37th day: " 18200. 38th day: Fluctuation in the submaxillary abscesses; leucocytes, 17100. 39th day: Leucocytes, 15100. 40th day: " 17200. Operation: Abscess opened on both sides. Streptococcus pyogenes obtained on culture. 41st dav: " 14600. 42d dav: " 11000. 43d day: " 10200. 44th day: " 9250. 47th day: " 7750. 62d day: R. b. c. 4980000; haemoglobin 70% ; leucocytes, 4000. Case 2.-No. 27884. M. This case was one of haemorrhage and perforation. From the 29th to the 31st day the number of leucocytes bad ranged between 3200 and 7600 to the cu. mm. 32d day : Enlargement of the right submaxillary gland. 9 A. M.: Leucocytes, 5200. 6 P. M.: " 3600. 33d day, 7.30 P. M.: " 5600. 34th day: Collapse ; signs of perforation of the bowel. 2 P. M.; Leucocytes, 11200. 7.30 P. M.: Death. Autopsy: Perforative peritonitis; abscess of the right submaxillary gland; general typhoid septicaemia; polybacterial infection. From peritoneal cavity there were obtained: B. typhosus; B. pyocyaneus ; B. coli communis ; B. lactis aerogenes. In submaxillary abscess there were found: B. typhosus and Staphylococcus pyogenes aureus. (For further records see Perforation, Case 8.) In case 1 there was, as might have been expected, a well-marked leucocytosis, which, however, did not appear until several days after the beginning of tumefaction of the gland; it was apparently associated with the onset of suppuration. In case 2 the absence of leucocytosis is striking. At the time of the onset of the symptoms the patient was in a condition of pro- found prostration, and despite a general perforative peritonitis and multiple infections with malignant pyogenic organisms, the count, eight hours before death, showed only 11,200 leucocytes to the cu. mm. URETHRITIS. Case 1.-No. 24067. P. Gonorrhoea. 10th day: Leucocytes, 11200. 23rd day : Furunculosis ; leucocytes, 8000. 31st day: Leucocytes, 11400. Observations on the Blood in Typhoid Fever. 525 Case 2.-No. 24170. T. 4th day : Urethritis; leucocytes, 9700. Case 3.-No. 26000. McK. Gonorrhoeal urethritis. 4th day : Leucocytes, 12800. 6th day : Red blood corpuscles, 3968000. 10th day: Leucocytes, 13700. 11th day: Differential count of the leucocytes : Small mononuclear 4.0 % Large " and transitional forms. 7.2 Polymorphonuclear neutrophile 83.3 Eosinophile 5.5 12th day : Leucocytes, 15300. In all these cases the number of leucocytes was slightly elevated, especially in case 3, where there was a true leucocytosis. The dif- ferential count in this instance, shows variations from those in the previous cases. Here, excepting for the relatively large number of large mononuclear forms, and the large percentage of eosino- philes, the count is what one might expect in an ordinary leuco- cytosis of moderate extent. The most striking variation from other counts in typhoid fever, is the increase in number of the eosinophilic cells. This is probably an example of the tendency to an increased percentage of eosinophilic cells in gonorrhoea pointed out by Neusser. CYSTITIS. Case 1. -No. 17307. W. 18th day : Cystitis; leucocytes, 10000. Case 2.-No. 23936. N. Cystitis and urethritis, (Bacillus lactis aerogenes'). 14th day: Leucocytes, 18000. 15th day: " 16000. * 19th day: " 14000. 20th dav: " 13200. 25th day: " 12200. Case 3.-No. 23963. C. 13th day: Urethritis and cystitis; leucocytes, 8800. In all of these cases the number of leucocytes was above the normal average for the period of the disease; in one only was a well-marked leucocytosis present. CHOLECYSTITIS. Case 1.-No. 27058. McL. Tenderness and pain in the region of the gall-bladder throughout most of the illness. Irregular temperature; chill on the 34th day. No jaundice at any time. 526 William Sydney Thayer. 33d day: Leucocytes, 21750. 34th day, 12.30 A. M.: Leucocytes, 22500. 9 A. M.: " 28500. 35th day: " 20500. 6 P. M.: " 16500. 36th day: " 16500. 38th day: " 9300. 39th day: " 13000. 45th day: " 19000. 46th day: " 14000. 47th day : " 15000. 48th day: " 20000. 49th day: " 19000. 60th day: " 21000. 81st day: 11th day of normal temperature; Leucocytes, 8500. Caw 2.-No. 27962. W. 6th day : Leucocytes, 7000. 7th day: Jaundice and tenderness over the gall bladder. 10th day : Bile coloring matters in the urine. 15th dav : Leucocytes, 21200. 17th day: " 12400. 20th day: " 10400. Caw 3-No. 28243. S. 10th day: Tenderness over liver and gall bladder. Leucocytes, 6000. After a spoige, leucocytes, 10000. 11th day: Chilly sensations. Morning: Leucocytes, 8100. Afternoon: " 14400. In all of these cases a leucocytosis was present-that in cases 1 and 2 being very well marked. OTITIS MEDIA. Case 1.-No. 23799. H. 32d day: Deafness; R. b. c., 3480000; leucocytes, 12000. Small mononuclear 11.5% Large " and transitional forms 5.3 Polymorphonuclear neutrophile 81.9 Eosinophile 1.3 Differential count of the leucocytes: 33d day : Tenderness under left ear; leucocytes, 14500. After this there is no further entry regarding pain over the ears, though the patient was very dull and drowsy for some time. 38th day : Leucocytes, 15600. 54th day: " 6000. 62d day: R. b. c., 3100000; leucocytes, 9620. 65th day : Leucocytes, 9000. 67th day: " 11200. 78th day: " 9000. Case 2.-27366. G. Meningeal symptoms ; tenderness over ear. 13th day: Leucocytes, 11800. 14th day: " 9400. No further counts were made. Observations on the Blood in Typhoid Fever. 527 In both of these cases there was a moderate leucocytosis. It is interesting to note that, in the differential count on the thirty-second day, the figures are quite what one might expect with a leucocytosis of 12,000. PAROTITIS. Case 1.-No. 23025. J. 10th day: Leucocytes, 8200; red blood corpuscles, 6056000. 19th day: Beginning parotitis on right side; leucocytes, 15500 ; red blood corpuscles, 5756000. 20th day : Swelling increased; no fluctuation; leucocytes, 30500. 21st day : Operation. 23d day: Friction rub in right axilla; leucocytes, 15750. 5.45 P. M.: Death. The autopsy showed pyaemia; general infection with Staphylococcus aureus. Case 2. No. 24101. E. 15th day: Leucocytes, 3000. 24th day : Beginning enlargement of right parotid with tenderness and irregu- larity of temperature ; leucocytes, 3000. 26th day: Swelling not increased; can open the mouth and protrude the tongue; leucocytes, 3000. There was no suppuration. 54th day, 14th of normal temperature : Leucocytes, 5240 Case 3.-No. 27565. C. This case has already been mentioned among those of intestinal haemorrhage. 24th day: Two stools containing, perhaps, 300 cc. of blood. 25th day, 11 P. M.: Leucocytes, 10500. 26th day, 1 A. M.: " 9500. 27th day, 9 A. M.: " 6400. 11 P. M.: " 2500. 28th day, 8 P. M.: Since yesterday the patient has had profuse intestinal haemorrhages. Right parotid gland enlarged and tender. Leucocytes, 8800. 29th day, 12.30 A. M.: Infusion with 1000 cc. of salt solution. 8.30 A. M.: Leucocytes, 8100. 9.30 A. M.: Infusion with 1000 cc. salt solution. 11.30 A. M.: Severe haemorrhage; death. These three cases show marked differences, the striking leuco- cytosis in the first case contrasting sharply with the absence of any change in the number of leucocytes in case 2. In case 3 it is impossible to say whether the parotitis alone is responsible for the slight increase in the number of leucocytes; this might equally well have been due to the haemorrhage. PULMONARY TUBERCULOSIS. In two cases of typhoid fever complicated with tuberculosis nu- merous blood counts were made. The first was that of No. 24,603, 528 William Sydney Thayer. R., which is reported in full under haemorrhage (Case 6). It will be seen that there was nothing unusual about the number of leucocytes or the differential counts. The tendency toward a leu- cocytogis after the haemorrhage appears to have been a little more marked, perhaps, than in most instances. Tn case 2, careful blood examinations were made. The differential counts were so char- acteristic of the ordinary changes in a severe case of typhoid fever, that one was almost tempted to place the record among those from which the general averages were taken. It seemed wiser, how- ever, to follow a definite rule, and place among those counts only the estimates from the absolutely uncomplicated cases. Case 2.-No. 24427. C. Slight tuberculous infiltration at one apex. 5th day: R. b. c., 5420000; leucocytes, 7200. 12th day : Leucocytes, 14200. No apparent cause for the leucocytosis. Small mononuclear 17.0% Large " and transitional forms. 26.8 Polymorphonuclear neutrophile 55.0 Eosinophile 1.2 Differential count: 13th day: R. b. c., 4440000; haemoglobin, 62 %; leucocytes, 9300. 26th day, five days after normal temperature: R. b. c., 4844000; haemoglobin 62 % ; leucocytes, 9600. 27tb day, six days after normal temperature: Differential count of leucocytes: Small mononuclear 7.9 % Large " and transitional forms 50.0 Polymorphonuclear neutrophile 36.2 Eosinophile 5.8 34th day, 13 days after normal temperature: R. b. c., 3396000; h:emoglobin, 76 % ; leucocytes, 4270. Differential count: ' Small mononuclear 14.0 % Large " and transitional forms 38.3 Polymorphonuclear neutrophile 40.7 Eosinophile 7.0 On a previous admission the patient had shown the following Small mononuclear 18.0% Large " 18.0 Polymorphonuclear? 63.5 Eosinophile 0.5 differential count: These cases justify no particular conclusion with regard to the effect of a complicating tuberculosis on the blood in typhoid fever. The leucocytes in both were rather more numerous during the febrile period than in most uncomplicated cases, but the differ- ential counts were, in both instances, strikingly characteristic of typhoid fever. Observations on the Blood in Typhoid Fever. 529 No. 9158. M. 5th week : Leucocytes, 4000. 6th week : Leucocytes, 8000. PREGNANCY. Differential count: Small mononuclear 24% Large " and transitional forms.. 20 Polymorphonuclear neutrophile 55 Eosinophile 1 These figures are in no way remarkable. The differential count is characteristic of typhoid fever at a late period of the disease. No. 27584. B. 10th day: Leucocytes, 9800. 11th day: " " 3700. 15th day, shortly after noon: Severe abdominal pain; suspicion of perfora- tion ; leucocytes, 9900. 2.30 P. M.: Leucocytes, 7100. 3.00 P. M.: " 8400. Operation under cocaine: No general peritonitis or perforation. Appendix was found retro-caecal, thickened, bent upon itself and held down by firm adhesions. Removed. Uneventful recovery. APPENDICULAR COLIC. Case 1.- No. 26902. D. PERIPHERAL NEURITIS. 3250. 5440. 3866. 3065. 3100. 3d week : Leucocytes, 5th week Peripheral neuritis. Leucocytes, 6000. These figures are quite insufficient to justify any conclusions. PERI-RECTAL ABSCESS. Case 1.-No. 28115. K. 12th day: Leucocytes, 21330. No apparent cause for the leucocytosis. 14th day: " 10000. 15th day: " 12000. 19th day: " 14600. 26th day : Pain about rectum. 30th day : Leucocytes, 25100. Large peri-rectal abscess opened. The leucocytosis here is what might have been expected with a large abscess. Whether this may have been present for some time-perhaps long enough to have had an influence in producing the earlier leucocytosis-is a question. 530 William Sydney Thayer. No. 16736. B. ERYTHEMA MULTIFORME. This was a case complicated throughout with extensive erythema multiforme, largely in the form of erythema nodosum. From the beginning to the end of the attack there was a well marked leucocytosis. 25th day : Leucocytes, 25000 ; haemoglobin 70% 32d day: " 28000. 33d day: Differential count of 100 leucocytes: Small mononuclear 10& Large and transitional forms 4 Polymorphonuclear neutropliile 84 Eosinophile 2 60th day : Differential count of 100 leucocytes: Small mononuclear 6% Large " and transitional forms.. 1 Polymorphonuclear neutropliile 92 Eosinophile 1 72d day: R. b. c., 4069000; leucocytes, 18600. 82d day : Leucocytes, 24500. This was a remarkable case. Indeed, there is some doubt as to its being typhoid fever. It occurred before the days of the Widal test. Never, in the course of the case, was the diazo reaction pres- ent. There were no abdominal symptoms excepting for diarrhoea between the 50th and 85th days. The differential counts were too superficial to be of value. PURPURA HEMORRHAGICA. Case 1.-No. 20814. 57th day : Extensive cutaneous haemorrhages and oozing from mucous surfaces. 59th day: Condition continues. R. b. c., 4244000 ; haemoglobin, 62&; leuco- cytes, 3300. This was a case of haemorrhagic typhoid. The single count shows no unusual change in the number of white corpuscles. CONJUNCTIVITIS. No. 24745. II. 4th day : Leucocytes, 7300. 6th day: Conjunctivitis. 7th day: Leucocytes, 9330. Small mononuclear 8.0^6 Large " and transitional forms. 15.5 Polymorphonuclear neutrophile 74.0 Eosinophile 2.5 Differential count: The one count shows a number of leucocytes a little above the normal average. The differential count is not remarkable except- ing for the unusually large number of large mononuclear cells. Observations on the Blood in Typhoid Fever. 531 PERICARDITIS. No. 24135. H. 14th day : Leucocytes, 6200. 15th day: Leucocytes, during cold pack, 16700. " after cold pack, 12250. 18th day: Leucocytes, 6200. 29th day: Pericardial friction rub; leucocytes, 11500. The single record shows an increase in the number of leucocytes to more than double the normal average for the period. DECUBITUS. No. 24603. R. In this case there was a tuberculous infiltration of the right apex. Extensive haemorrhages occurred early in the course of the disease. For about three weeks, however, the leucocytes had ranged from 7000 to 9000. 43d day: Three bed-sores were noted. 45th day: Leucocytes, 16000. The case went on to recovery, but no further blood examinations are recorded. The influence of the bed sores in producing this elevation can scarcely be said to be proven, inasmuch as no further counts were made. CONVULSIONS. No. 21695. M. In this case there was general rigidity, delirium and symptoms suggestive of meningitis. From the 8th to the 24th day the leucocytes, in several counts, varied from 7500 to 8500 per cu. mm. 25th and 26th days: Convulsions. 31st day : Leucocytes, 14500. 39th day : Rigidity of arms ; delirium; Leucocytes: 8500, 14300. In another case, where there were symptoms leading to the suspicion of meningitis (No. 24932. T.) there were, on the 9th day, 15200 leucocytes to the cu. mm. On the 6th day there were but 6800, and on the 10th, when an exploratory lumbar puncture was made, there were 5800. On this latter occasion the differential count showed: Small mononuclear 20. + % Large mononuclear and transitional forms 25. + Polymorphonuclear neutrophile 53. + Eosinophile 1.0 On the 16th day the leucocytes were 9000. TRICHINOSIS (??) No. 25132. M. 14th day : Leucocytes, 5000. 15th day: " 4400. 16th day : " 5660 ; R. b. c., 4560000 ; haemoglobin, 78 %. Differential count of the leucocytes : Small mononuclear 13.6 % Large " and transitional forms 27.7 Polymorphonuclear neutrophile 35.6 Eosinophile 22.9 20th day : Leucocytes, 6000. William Sydney Thayer. 532 Iii this instance there was nothing in the history or course of the case which suggested any complication. Abdominal pain was a prominent symptom, but there were no special indications of trich- inosis, which the differential count immediately suggested, nor were there any signs of helminthiasis. And yet in view of the regularity with which the percentage of eosinophiles in the course of typhoid fever is normal or subnormal, it is hard to believe that these figures are not the indication of some undiscovered complication. There are cases of trichinosis in which the muscular pains are no more severe than those ordinarily associated with some general infections,' while the leucocytes may show little or no increase in number. Such a case was reported by the author at the 12th International Medical Congress (Lancet, 1897, vol. ii, p. 787). PERFORATION. Systematic examinations of the leucocytes have been thought to be especially important in connection with the early detection of perforation, the diminished number of colorless corpuscles dur- ing typhoid fever contrasting sharply with the leucocytosis which might be expected with a general peritonitis. There are, in our records, eight cases of perforation in which examinations of the leucocytes have been made. The importance of the question justifies a more or less careful consideration of each case. Case 1.-No. 13485. D. 7th day : Admission. Leucocytes, 3000 to the cmm. 23d day, 4 P. M.: Sudden abdominal pain with symptoms of perforation. 9.20 P. M.: Leucocytes, 16400. 10 P. M.: Operation by Dr. Finney ; general peritonitis ; perforation 16 cm. above the caecum ; death 24 hours later. No bacteriological examination of the peritoneal exudate; no autopsy. Case 2-No. 21656. F. K. 13th day : Admission ; leucocytes, 7500. 16th day, 6 P. M.: Abdominal pain and diarrhoea ; signs suggestive of perfora- tion. ' During the last summer we have had another remarkable case of trichinosis closely simulating typhoid fever. An almost characteristic typhoid roseola was present, and trichinosis would hardly have been suspected, had it not been for the marked eosinophilia. As it was, the case would probably have been recorded as one of typhoid fever, but for the fortunate demonstration of trichinae in some muscle removed from the arm. Observations on the Blood in Typhoid Fever. 533 17th day, 5.30 P. M.: Leucocytes, 22600. 9 P. M.: " 18000. 18th day : Symptoms of peritonitis more suggestive. 9 A. M.: Leucocytes, 23400. 1P.M.: " 15600. 7.50 P. M.: Death. Autopsy: Large perforation 1 cm. in diameter; general peritonitis. Bacillus coll communis grew in the cultures from the peritoneal exudate. Case 3. - No. 23698. H. 9th day : Leucocytes, 8400. 13th day: In the morning complained of abdominal pain; vomiting. Leuco- cytes, 9600. At noon signs suggestive of perforation; leucocytes, 14000. 1 P. M.: Leucocytes, 16000. Exploratory laparotomy by Dr. Cushing. A perforation 2 mm. in diameter was found in the ileum; general conges- tion of the peritoneum; cultures from the peritoneal exudate negative; no cultures taken from the substance flowing from the perforation. 19th day : Leucocytes, 6600. There was a good recovery from operation, excepting that on the second day a ftecal discharge appeared from the wound. 25th day, 9 P. M.: Sudden collapse; sweating; hiccough; abdominal pain; leucocytes, 4000. 10 P. M.: Leucocytes, 13000. 10.30 P.M.: Operation; nothing found. 27th day, 30 hours later: Leucocytes, 20000; evidences of intestinal obstruc- tion. 8 A. M.: Operation; relief of the obstruction due to a kink of the ileum and omentum in the adhesions to the parietes. No further records of examinations of the blood. Case 4-No. 23970. N. 30th day : Abdominal pain; slight distension ; no tenderness on palpation. 10 A. M.; Leucocytes, 7500. 8 P. M.: " 8400. 31st day: Collapse; vomiting; movable dullness in abdomen; peritoneal facies ; pleural friction on the right side. 9 A. M.: Leucocytes, 6000. 10 A. M.: " " 7200. 11A.M.: " 6800. 12.15 P.M.: " 6400. 1.30 P. M.: " 6000. 2 P.M.: " 7000. 1.30 P. M.: Operation under cocaine. Three perforations in the ileum ; fluid fyeces in the abdomen. Death four hours later. Cover-slips showed many organisms -" Some cocci, but mostly bacilli of various shapes and sizes and a great number of pus cells. No streptococci were seen. Nothing was grown out on culture but the Bacillus coli com- munis." No autopsy. Case 5.-No. 23987. B. 16th day : Leucocytes, 5600. 20th day: General abdominal pain; no rigidity or tenderness; leucocytes, 10400. 23d day: Leucocytes, 1280Q. 534 William Sydney Thayer. 24th day, 12 noon : Leucocytes, 13000. 4 P. M.: Leucocytes, 13600. 11 P. M.: " 15200. 25th day, 5 P. M.: " 11600. 11 A. M.: " 12300. General pain but no marked tender- 26 th day, 10 A. M.: " 9600. [ness. 27th day, " 11000. 28th day: Leucocytes, 8000. In the afternoou, for the first time, pain on pres- sure on the abdomen. 29th day, 8.30 A. M.: Leucocytes, 6800. In the evening, more pain and symp- toms suggestive of perforation. 11.50 P. M.: Leucocytes, 4300. 30th day, 1.00 A. M.: Operation; general peritonitis; perforation 10 cm. above the ca:cum; sero-purulent peritoneal .exudate. The fluid showed numerous streptococci and various other organisms. Cultures showed Streptococcus pyogenes, Bacillus coli communis, Bacillus ladis aerogenes and a yeast fungus. Death eight hours later. Case 6.-No. 27337. M. 3d day: Leucocytes, 8000. 7th day: Considerable bronchitis; slightly impaired resonance in right axilla. Morning, leucocytes 14750; at night, 7000. 13th day: Leucocytes, 8000. 1.00 P. M.: Began to complain of abdominal pain; slight rigidity, suggestive of possible meningitis. 3.00 P. M.: Leucocytes, 15000 and 13000. 4.15 P. M.: Leucocytes, 8000. 5.30 P. M.: Pleuritic friction rub in left axilla; leucocytes, 9800. 9.20 P. M.: Leucocytes, 7550. 14th day, 12.45 A. M.: Leucocytes, 12000. 10.45 A. M.: Leucocytes, 9260. 10.50 A. M,: Sudden intense abdominal pain. 15th day: Collapse; legs drawn up; pleural friction murmur. 18th day: Impaired resonance in lower right back; enfeebled respiration; numerous fine rilles. 19th day: Abdomen flat; resistant. 21st day: Evidences of consolidation in left lung. Heart's action suddenly be- came extremely rapid. Leucocytes, 4000. 22d day: Abdomenrigid. 11.00 P. M.: Leucocytes, 3700. 23d day: Sudden fall of temperature to a subnormal point; vomiting; col- lapse; rigidity of abdomen. 8.30 A. M.: Leucocytes, 6550. 5.45 P. M.: Leucocytes, 5800. 11.30 P. M.: Leucocytes, 3530. 24th day, 1.00 A. M.: Death. Autopsy: General peritonitis; perforation of the ileum; thrombosis of both common iliac veins; haemorrhagic infarction of the lung. The peritoneal exudate showed Streptococcus pyogenes and Bacillus pyocyaneus. Case 7.-No. 27665. H. 16th day : Abdomen rather resistant; leucocytes, 5000. 18th day, 5.35 A. M.: Sudden pain between the umbilicus and pubis; vomiting; hiccough ; distension ; rigidity. 7.00 A. M.: Leucocytes, 4800. 8.00 A. M.: " ' 6600. 9.00 A. M.: " 10400. 10.00 A. M.: " 8600. 10.30 A. M.: " 9000. Observations on the Blood in Typhoid Fever. 535 11.00 A. M.: Operation; perforation 8 inches from caecum; sero- purulent peritonitis ; streptococcus on coverslips. 11.50 A. M.: Immediately after operation; leucocytes, 16100. 2.00 P. M.: Leucocytes, 14000. 4.00 P. M.: " 16000. : 6.00 P. M.: " 13000. ] 9.00 P. M.: " 9600. J Salt solution infusions repeatedly employed. 19th day, 1.00 A. M.: " 11000. 8.00 A.M.: " 9000. 2.30 P. M.: " 11200. 25th day, 9.00 A. M.: Leucocytes, 7000. Owing to persistence of hiccough and general symptoms, a second operation was performed. General perito- nitis found. Cavity irrigated with salt infusion and enterostomy performed at the seat of the old incision. Death 10 hours later. Autopsy : Combined general infection with B. typhosus and Streptococcus pyogenes. Case 8 No. 27884. M. 10th day : Leucocytes, 18000, without apparent cause. 26th day, 10.00 P. M.: Haemorrhage, 200 cc. 10.3*0 P. M.: Leucocytes, 3700. 27th day, 8.00 A.M.: " 7300. 3.00 P. M.: Haemorrhage, 600 cc. 3.25 P. M.: Leucocytes, 2200; gelatine injection. 11.00 P. M.: " * 2700. 28th day : Leucocytes, 3600. 29th day, 6.00 A. M.: Leucocytes, 3200. 11.00 P. M.: " 4500. 30th day, 7.10 A. M.: Considerable abdominal pain; great distension; fall of temperature to normal point this morning. 8.30 A. M.: Leucocytes, 6000. 9.00 A. M.: Salt infusion. 10.00 A. M.: Hiccough. 5.30 P. M.: Leucocytes, 5320. 31st day: During an infusion ; leucocytes, 7600. 32d day : Enlargement of the right submaxillary gland. 9.00 A. M.: Leucocytes, 5200. 6.00 P. M.: " * 3600. 33d day, 7.30 P. M.: " 5600. 34th day: Condition much worse ; collapse; liver dullness obliterated; infu- sion of 1000 cc. salt solution in the morning. 2.00 P. M.: Leucocytes, 11200. 7.30 P. M.: Death. Autopsy : 10.00 A. M. on following day. General peritonitis; perforation 3 cm. above ileo-caecal valve ; abscess of the right submaxillary gland; cultures from the peritoneal cavity and lung show the Bacillus coli communis and the Bacillus lactis aerogenes ; the perito- neal cavity, Bacillus pyocyaneus and Bacillus typhosus] lung, Streptococcus pyogenes and Staphylococcus pyogenes aureus] heart's blood, spleen, mesen- teric glands and submaxillary glands, Bacillus typhosus] submaxillary abscess, Staphylococcus pyogenes aureus] pancreas, Proteus vulgaris. A consideration of these cases shows great variations in the be- havior of the leucocytes in different instances. 536 William Sydney Thayer. In case 1 there was a well-marked leucocytosis five and a half hours after the perforation.1 In case 2, likewise,- a yet more marked leucocytosis was present twenty-three, thirty-nine and forty-seven hours after the prob- able time of perforation, the last count being made four hours before death. In case 3, immediately after the perforation, there were 9600 leucocytes; several hours later, there was a distinct leucocytosis of 16,000. Tn case 4, in which the perforation probably occurred on the afternoon of the 30th day, the highest count, on the evening of the probable day of perforation, was 8400, while on the following day and up to the time of death, the leucocytes varied between 6000 and 7200, showing no especial tendency to increase in num- ber. In case 5, where there had been abdominal pain for several days, and the leucocytes had varied between 6800 and 13,600, the per- foration occurred probably between 8 P. M. and 12 midnight on the 28th day. The leucocytes fell on the following day, to 6800 and 4300. Laparotomy was performed one hour and ten minutes later; death 8 hours afterward. There were no further blood counts. In case 6 the perforation clearly occurred on the afternoon of the 22nd day. The leucocytosis which had existed before, might well have been accounted for by the pleurisy or by a beginning iliac phlebitis.2 The record of the colorless corpuscles on the pre- vious day had been as low qs 4000, the patient being in a condition of profound prostration. The perforation had apparently no influ- ence on the number of leucocytes, the figures upon the evening of the 22d day being 3700, and on the 23d day ranging between 3530 and 6550. Tn case 7 the perforation occurred probably early on the morn- ing of the 18th day, about five and a half hours before operation. The leucocytes showed a slight increase during the morning hours 1 The time of perforation is here understood to mean the probable moment at which a communication became established between the intestine and the general peritoneal cavity. 2 Thiscase was unfortunately omitted from those considered under " Phlebitis." Observations on the Blood in Typhoid Fever. 537 but not above 10,400. After operation, there was a leucoeytosis of 16100. With the further development of the peritonitis, how- ever, there was a tendency to a reduction in their number, the count ten hours before death showing but 7000. In case 8, the immediate time of the perforation is not very clear. It probably occurred in the night between the 33d and 34th day. The patient was in a state of great prostration at the time, and the perforation appears to have had but slight effect upon the leucocytes, although the number (11,200) is more than twice the normal average for the fifth week of the disease, and would thus correspond to over 15,000 leucocytes under normal circumstances. Thus, in cases 1, 2 and 3 there was a well-marked leucoeytosis. In cases 4, 5 and 6 there was a complete absence of leucoeytosis. In cases 7 and 8 there was a slight but yet distinct increase in the number of leucocytes. When we inquire further into the histories of the cases showing a marked leucoeytosis, it is interesting to note that in case 1, no cultures were made, and in case 3, no growths were obtained at the time of operation; in case 2, the autopsy showed the peritonitis to be due to the Bacillus coll communis. All these cases were in tol- erably good condition at the time of the perforation. Of the three cases in which absolutely no leucoeytosis was pres- ent, in the first (case 4), the patient was in good condition before the perforation, which was followed rapidly by symptoms of great prostration, the patient having the appearance of one who was in a state of profound intoxication. Laparotomy was performed fully 24 hours after the perforation. No autopsy was obtained, and though only the Bacillus coli communis grew in the cultures at operation, cocci were seen in the coverslips. The second case (case 5) was also one with excessively malig- nant symptoms. The perforation was immediately followed by great collapse, and a fall in the number of leucocytes. The pa- tient had been in tolerably good condition up to the time of per- foration; the slight abdominal pain and l&ucocytosis, occurring be- tween the 20th and 27th days, probably depended on a previous peritonitis about deep ulcers. The autopsy showed that the peri- tonitis was due to a streptococcus infection. 538 William Sydney Thayer. In the third case (case 6), where the patient had already been in a condition of profound prostration, perforation occurred clearly on the afternoon of the twenty-second day, and produced no effect unless it was a fall in the number of leucocytes. Here again, the peritonitis was due to streptococcus infection. Of the two cases in which there was a slight increase in the num- ber of the leucocytes, the first (case 7) was a patient who was in tol- erably good condition up to the time of the perforation, which oc- curred probably at 5.30 A. M. on the 18th day; the operation followed five and a half hours later. The leucocytosis which suc- ceeded the operation, disappeared before death. At operation, streptococci were found in the peritoneal exudate. The autopsy revealed a general typhoid and streptococcus septicaemia. The second case (case 8) was that of a patient who at the prob- able time of perforation, the night between the 33d and 34th days, was in a condition of great prostration. It is a question whether the fall of temperature on the 29th and 30th days may not have been due to preliminary local peritonitis. Though the leucocytes were only 11,600 five and one-half hours before death, yet this is just double the number noted on the day before. The case was one of poly-bacterial infection, the peritonitis itself being due to the B. typhosus, and B. pyocyaneus. Thus, of the three cases with a well-marked leucocytosis: In one there were no cultures. In one the peritoneal exudate showed the B. coli communis. In one the cultures were negative at the time of operation, no culture being taken from the seat of perforation. In the three cases without leucocytosis: In one there was no autopsy, but the B. coli communis was cultivated at the time of operation. Cocci were also seen. In one, cultures from the peritoneal cavity at autopsy showed Streptococcus pyogenes, B. coli communis, B. lactis aero- genes, B. typhosus, and a yeast fungus.- In one, cultures from the peritoneal cavity showed Strepto- coccus pyogenes and B. pyocyaneus. In the two cases with slight increase in the number of leucocytes: In one there was a general streptococcus and typhoid septi- caemia. Observations on the Blood in Typhoid Fever. 539 In one there was a poly-bacterial infection. In the peritoneal cavity there were found: B. typhosus, B. pyocyaneus, B. coli communis, and B. lactis aerogenes. Of three cases of streptococcus peritonitis: In two there was no leucocytosis from the onset. In one there was a slight increase in the leucocytes at first, with a tendency to diminish as the case progressed. In another instance of general streptococcus septicaemia, with double pneumonia, No. 27,681, there were but 4000 leucocytes at the time of onset of the pneumonia, and 9600 twenty hours later- eight hours before death. Of the cases where the patient was in good condition at the time of onset of the perforation: In three cases (1, 2, 3), there was leucocytosis. In two cases (4, 5), there was no leucocytosis. One of these was a colon peritonitis, and one a streptococcus case. In one case (7) there was a slight leucocytosis, which later di- minished. The case was one of general typhoid and strep- tococcal infection. Of the two cases in which the patient was in a condition of pro- found prostration at the time of onset of the perforation: In one (case 6) there was no leucocytosis-a case of strepto- coccus and pyocyaneus infection. In one (case 8) there was a slight leucocytosis, the case being one of poly-bacterial infection, the B. typhosus and B. pyocyaneus being present in the peritoneal exudate. On considering these facts, one cannot fail to be impressed with the probability that the absence of a marked leucocytosis is an evi- dence of the malignity of the infection, or the lack of resistance of the patient. It may then be a point of considerable prognostic importance. It is probable that slight local peritonitides always produce a greater or less degree of leucocytosis, unless the individual be already in a condition of profound general septicaemia. On the 540 William Sydney Thayer. other hand, a sudden infection of the peritoneum with large quan- tities of excessively malignant organisms may often result in com- plete absence of a leucocytosis, or in a relatively slight rise, which is later followed by a fall. But after all, if the absence of a leucocytosis does obscure the diagnosis in some instances, there is yet compensation in the thought that surgical interference is less likely to be of value in these cases than in those in which leucocytosis is present. 'I'he prognostic importance of the absence of a leucocytosis in severe infections of a nature usually associated with an increase in the number of colorless corpuscles, is no new observation. The bad outlook in cases of pneumonia with an absence of leucocytosis has long been known, while in 1892 Werigo1 showed that the same rule held in animals after intravenous injections of various organisms. A point of importance in connection with these cases is that of the presence or absence of the so-called pre-perforative leucocy- tosis. There is no doubt that in some instances perforation is preceded by a local peritonitis of a greater or less extent, in connection with the presence of deep ulcers-and in these cases there is, prob- ably, as a rule, more or less of a leucocytosis. Such a leucocytosis was present in case 5, and possibly in case 6, although, in the latter instance, it may well have been due to other complications. Abdominal pain in association with such a leucocytosis, should always be regarded as a suspicious symptom. In conclusion, the following reflections appear to be justified: 1. Perforation of the bowel in typhoid fever is usually fol- lowed within a few hours, by an increase in the number of leu- cocytes in the peripheral circulation-a point of considerable diag- nostic importance. 2. This elevation may be considerable (above 15,000) or slight (under 10,000) and appreciable only in comparison with previous counts. 3. In some instances, a slight increase in the number of leu- cocytes present shortly after the perforation, may tend to dimin- ' Annales de 1'institut Pasteur, 1892, VI, 478. Observations on the Blood in Typhoid Fever. 541 ish and disappear with the aggravation of the symptoms. It is not impossible that this may be the rule. 4. Not infrequently, there is a complete absence of leucocy- tosis, and sometimes a diminution in the number of leucocytes after perforation. 5. The absence or diminution in a leucocytosis following a perforation is an indication of the malignity of the infection, or the prostration of the patient. 6. The prospect for relief by surgical interference is best in those cases with a leucocytosis. 7. A pre-perforative leucocytosis, due to local peritonitis about deep ulcers, may occur. In connection with the cases of perforation, it may be inter- esting to summarize four instances in which perforation was sus- pected, and exploratory laparotomy performed, the condition prov- ing to be dependent upon other causes. CASES OF SUSPECTED PERFORATION. Case 1.-No. 23702. P. 8th day : Leucocytes, 9000. 32d day: Vomiting, abdominal distension; leucocytes, 4500. 33d day : Phlebitis of left popliteal. The temperature was practically normal from the 38th to the 51st day, when it rose rather suddenly. 52d day, 10 A. M.: Leucocytes, 9600. 11 P. M.: " 8000. 53d day: Vomiting; Midnight; Leucocytes, 16200. 54th day, 1A.M.: Leucocytes, 16600. 2 A. M.: " 16000. 9 A.M.: " 12000. 3 P.M.: " 10600. 7P.M.: " 10000. At this time the patient still complained of pain in the leg when rubbed. In the afternoon there was tenderness in the abdomen and in both calves. 55th day, 1.30 A. M.: Child cried out with sudden severe abdominal pain; nausea and vomiting. The pain was different from that which she had previously had. 3.30 A. M.: Leucocytes, 8200. 6 A. M.: Exploratory laparotomy; nothing found. 1 P. M.: Leucocytes, 8000. The relapse continued a gradual course, recovery being uninterrupted. 67th day : Leucocytes, 5500. Case 2.-No. 27379. G. 12th dav, 3.20 P. M.: Leucocytes, 11000. 5.15P.M.: " 10500. 13th day : Early in the morning, sudden rapidity of pulse; friction rub in left chest. Sudden fall of temperature from 105° to normal. Leucocytes, 8330. 542 William Sydney Thayer. The patient soon rallied from this collapse. 20th day . Cries out with apparent suffering, but unable to localize pain. Noon; Leucocytes, 24860. 2.30 P. M.: Leucocytes, 18330. 5.30 P.M.: " 18200. 4.40 P. M.: Collapse. 7 P. M.: Operation under cocaine; no perforation found. 10 P. M.: Sudden dyspnoea and death. Autopsy. Thrombosis of left iliac vein, with an embolus plugging pulmonary artery. Cultures from heart's blood, spleen, gall-bladder, pulmonary thrombi and mesenteric glands showed U. typhosus. In this instance the leucocytosis was doubtless due to thrombosis. Case 3.-No. 27584. B. 10th day : Leucocytes, 9800. 11th day: " 3700. 15th day: Shortly after noon, severe pain in the region of the-umbilicus. Suspicion of perforation ; leucocytes, 9900. 2.30 P. M.: Leucocytes, 7100. 3 P. M.: Leucocytes, 8400. Operation under cocaine. No general peritonitis or perforation. "Appendix was found retro-caecal, thickened, bent upon itself and bound down by firm adhesions." Removed. Uneventful recovery. Case 4.-No. 27681. B. 4th day : Leucocytes, 1800. 9th day: " ' 9800: 11th day: " 9200. 13th day: " 7000. 14th day: Complained of abdominal pain while in the tub; this disappeared after passing urine. Leucocytes, 7800. 15th day ; Leucocytes, 6400. 16th day, 11 A. M.: Leucocytes, 8400. Noon: Chilliness; vomiting; extremely rapid pulse and respiration ; muscular resistance ; peritonitis suspected. 3 P. M.: Leucocytes, 10400. 4 P. M.: " ' 5000. 4 P. M.: Operation. No cause for symptoms discovered. 17th day, 8 A. M.: Leucocytes, 15000. 12.30 P.M.: " 13400. 8 P. M.: " 6600. 18th day, 8.30 A. M.: " 6200. 1 P. M.: ■ " 5600. 9 P. M.: " 6000. 19th day, 3 P. M.: " 4000. 4 P. M.: Consolidation discovered in both backs. 20th day, 11 A. M.: Leucocytes, 9600. 6.55 P. M.: Death. Autopsy. Double pneumonia ; extensive pleurisy; general septicaemia with Bacillus typhosus and Streptococcus pyogenes. In all these cases the symptoms quite justified the operative in- terference; and, with modern technique, operation under cocaine is, doubtless, the safest course in many of these suspicious cases. In case 1 the cause of the symptoms is by no means clear. The Observations on the Blood in Typhoid Fever. 543 fact that phlebitis had previously occurred in the legs, suggests that the later symptoms may well have been due to involvement of abdominal veins. In case 2 the iliac thrombosis was clearly the cause of the sus- picious symptoms. Case 3 was one of appendicular colic. In case 4 the cause of the abdominal symptoms is obscure. General Conclusions. The Red Blood Corpuscles. (1) A diminution in the number of red blood corpuscles be- comes evident shortly after the onset of typhoid fever. (2) This diminution increases gradually throughout the course of the disease. (3) Our figures suggest that the fall in the number of red blood corpuscles may be somewhat accentuated during the fourth week of fever. (4) The reduction in the number of the red blood corpuscles is greatest at about the end of defervescence. (5) In cases of short duration, the diminution may continue into the first week of convalescence. (6) In longer cases, with mild persistent fever, it is not uncom- mon for regeneration of the blood to begin well before the end of defervescence. (7) The average maximum loss of red blood corpuscles in ty- phoid fever is about 1,000,000 to the cu. mm. (8) Considerable transient elevations in the number of red blood corpuscles per cu. mm. may follow diarrhoea, vomiting or sweating. (9) Sudden losses of a greater or less extent may be caused by haemorrhage from the bowels. (10) Where the loss after haemorrhage is severe, a certain amount of regeneration may occur during the course of the dis- ease. In cases of long duration, however, there may be a subse- quent fall. The Hcemoglobin. (1) The percentage of haemoglobin pursues a course similar, ap- parently, to that of the red blood corpuscles. 544 William Sydney Thayer. (2) Study of individual cases suggests, however, that in in- stances where the anaemia has been appreciable, the return to the normal point is, as in most secondary anaemias, more gradual than that of the red blood corpuscles. The Colorless Corpuscles. (1) The number of the colorless corpuscles in the peripheral circulation is subnormal throughout the course of typhoid fever. (2) The diminution is progressive with the increase in the se- verity and duration of the disease. (3) The average number of the leucocytes per cubic millimetre at the height of the disease, is about 5000. Much lower figures are, however, common. (4) In cases with persistent fever there may be a tendency, in the later weeks of the disease, toward a slight elevation in the aver- age number of leucocytes, as compared with that at the height of the infection. (5) The normal limits of variation of the number of colorless corpuscles in different cases, and in the same case, are considerable. An increase to above 10,000 to the cubic millimetre, however, is usually an indication of some foreign influence (cold baths, in- flammatory complications, haemorrhage, etc.). (6) Cold baths cause an immediate transient increase in the number of leucocytes in the peripheral circulation, an increase which may amount to three or four times the number before the bath. (7) The relative proportions of the different varieties of leu- cocytes one to another, during typhoid fever, show characteristic variations from the normal percentages. (a) The percentage of small mononuclear leucocytes shows, at first, no great change, though it is distinctly in- creased at the height and toward the latter part of the dis- ease, as well as in the first weeks of convalescence. (b) This increase is not as marked in the typical lymphocytes as in small forms with palely staining nu- clei and a relatively large amount of transparent or nearly transparent protoplasm. Observations on the Blood in Typhoid Fever. 545 (c) The relative percentage of the large mononuclear leucocytes increases progressively with the course of the disease, the elevation continuing well into convalescence. (cl) The increase of the largest varieties and of the tran- sitional (lobulated nuclei) forms is, as a rule, not marked. (e) The elements most increased in number are cells about the size of polymorphonuclear leucocytes with pale nuclei, often scarcely larger than those of lymphocytes, and transparent or palely staining protoplasm. (f) The percentage of polymorphonuclear neutrophiles diminishes progressively throughout the course of the dis- ease, the diminution keeping pace with the increase in large mononuclear forms. The average of eight counts for the fifth week was 61.7^; of three for the sixth week, 59M (g) The limits of variation in the percentage of the polymorphonuclear neutroplriles is considerable. Fig- ures below 50^ are not uncommon. (h) The percentage of eosinophilic cells in typhoid fever is diminished, the average throughout the course of the disease being under 1^. (i) With convalescence the percentage of eosinophiles increases, sometimes to a point rather above the normal average. (j) In long continued cases with persistent fever, where regeneration of the blood sets in before complete defervescence, the percentage of eosinophiles may in- crease to the normal average, or above this, before the end of the febrile period. (k) In the leucocytosis following cold baths, the rela- tive proportions of the different varieties of colorless ele- ments are unaffected. (8) Inflammatory complications of typhoid fever are associated with an increase in the number of leucocytes similar to that oc- curring under ordinary circumstances. (9) It is not impossible, though our observations are insufficient to justify a positive conclusion, that the figures, in complications occurring at the height of the disease and during convalescence, 546 William Sydney Thayer. are lower than those usually observed with similar processes occur- ring under other conditions. (10) The most extensive leucocytoses have been observed in connection with large abscesses, phlebitis, peritonitis, pleurisy, pneumonia, periostitis, cystitis, cholecystitis. (11) The extent of the leucocytosis depends, apparently, more upon the nature of the local lesion, than upon the species of micro- organism which may be its cause. (12) Tn some cases in which the complication is associated with a particularly malignant infection, especially if the patient be al- ready in a condition of prostration, the count of the leucocytes may not only fail to show any increase, but even reveal a tendency to- ward a diminution in number. In other similar conditions a slight increase in the number of colorless elements may be follow- ed by a subsequent diminution. (13) Hcemorrhage from the bozvels may be followed by an in- crease in the number of leucocytes, which begins immediately after the haemorrhages, reaching its maximum inside of twenty-four hours. Within a week, however, the number of leucocytes gen- erally returns to about the normal average for the period of the disease. (14) In some of our cases, however, haemorrhage had no appre- ciable influence on the number of colorless corpuscles in the periph- eral circulation. (15) Perforation of the bowel is usually followed, in a few hours, by an increase in the number of the leucocytes in the peripheral circulation. (16) This elevation may be considerable (above 15,000) or slight (under 10,000), and appreciable only in comparison with previous counts. (17) In some instances a slight increase in the number of leu- cocytes, succeeding the perforation, may tend to diminish and dis- appear with the aggravation of the symptoms. It is not impos- sible that this diminution may be the rule. (18) Not infrequently there is, after a perforation, a complete absence of leucocytosis, and sometimes a diminution in the number of colorless corpuscles. (19) The absence or disappearance of a leucocytosis following Observations on the Blood in Typhoid Fever. 547 a perforation, is an indication of the malignity of the infection or the prostration of the patient. (20) The prospect of relief by surgical interference is best in those cases with a leucocytosis. (21) A pre-perforative leucocytosis due to local peritonitis about deep ulcers may occur. (22) In the leucocytoses associated with the inflammatory com- plications of typhoid fever, especially if these occur late in the course of the disease or during the early weeks of convalescence, the relative proportions of the different varieties of colorless cor- puscles may show well-marked variations from the usual figures. (23) These variations consist in a tendency toward the figures characteristic of typhoid fever-a diminution in the percentage of the polymorphonuclear neutrophiles, associated with an increase in that of the large mononuclear forms. The deviation from the figures characteristic of an ordinary leucocytosis may be so marked that, with over 20,000 leucocytes to the cubic millimetre, there may yet be under 70# of polymorphonuclear neutrophiles. Baltimore, September, 1900. Dr. Thayer.-Within the last two years I have seen two very interesting eases of pernicious anaemia with symptoms of involvement of the cord. . In the first instance, seen last year with Dr. Watson, the patient developed a very high degree of ataxia of both lower and upper extremities and loss of reflexes. There was incontinence of urine and faeces. The second case I saw about two weeks ago with Dr. Beck. The first symptoms of her anaemia began during the heated term last summer. During the fall she began to have diffi- culty in using her fingers and her hands became weak. There was considerable numbness and tingling. She was unable to button her clothes. Shortly afterwards she began to have the same sensations in her feet and noticed a certain unsteadi- ness of gait. On several occasions she fell. When seen the patient showed a high degree of anaemia, only about 1,500,000 red corpuscles; there was no marked atrophy in the upper extremities, but great weakness of the muscles in the arms and hands. A distinct increase of the reflexes at the elbows and wrists. There was fairly well-marked ataxia, especially of the right hand, the patient being unable to unbutton her clothes. There was no atrophy in the legs or thighs, no fibrillary tremor; knee-jerks diminished but still present. On superficial examination sensation to touch and pain was normal throughout. The patient distinguished the head and point of a pin well in both arms and legs. With regard to the question of treatment of pernicious anaemia, it is interesting to note that Dr. Cabot, who has seen a large number of cases, is of the impression that arsenic is of little or no value. lie states that rest, fresh air and judicious feeding are the most important points in treatment. I must say that this statement has seemed to me rather sur- prising. The observation of the cases which have occurred during the last eleven years in Dr. Osler's clinic has led us to believe that the drug is of value in many instances. Discussion. OBSERVATIONS ON THE FREQUENCY AND DIAGNOSIS OF THE FLINT MURMUR IN AORTIC INSUFFICIENCY. BY WILLIAM SYDNEY THAYER, M.D., OF BALTIMORE. ASSISTANT PROFESSOR OF MEDICINE IN THE JOHNS HOPKINS UNIVERSITY. From the Transactions of the Association of American Physicians 1901 OBSERVATIONS ON THE FREQUENCY AND DIAGNOSIS OF THE FLINT MURMUR IN AORTIC INSUFFICIENCY. By WILLIAM SYDNEY THAYER, M.D., OF BALTIMORE. In 1862, Austin Flint, in an article on cardiac murmurs,1 called attention to the occasional existence, in uncomplicated aortic insuffi- ciency, of a presystolic murmur limited to the region of the cardiac apex, and distinct from the characteristic murmur of aortic regurgi- tation. This sound occurred in the latter part of diastole, was loud and blubbering, and had all the characteristics of a mitral direct presystolic murmur. Flint recognized it as such, and offered the following explanation : " The explanation involves a point con- nected with the physiologic action of the auricular valves. Experi- ments show that when the ventricles are filled with a liquid the valvular curtains are floated away from the ventricular sides, approximating to each other and tending to closure of the auricular orifice. In fact, as shown by Drs. Baumgarten and Hamerik, of Germany, a forcible injection of liquid into the left ventricle through the auricular opening will cause a complete closure of this opening by the coaptation of the mitral curtains, so that these authors contend that the natural closure of the auricular orifices is effected not by the contraction of the ventricles, but by the forcible current of blood propelled into the ventricles by the auricles. How- ever this may be, that the mitral curtains are floated out and brought into apposition with each other by simply distending the ventricular cavity with liquid, is a fact sufficiently established and easily verified. Now, in cases of considerable aortic insufficiency the left ventricle is rapidly filled with blood flowing back from the aorta, as well as from the auricle before the auricular contraction takes place. The distention of the ventricle is such that the mitral cur- tains are brought into coaptation, and when the auricular contraction 1 American Journal of the Medical Sciences, 1862, iv. s., xliv. 29. 2 THAYER, takes place the mitral direct current passing between the curtains throws them into vibration and gives rise to the characteristic blubbering murmur. The physical condition is, in effect, analogous to contraction of the mitral orifice from an adhesion of the curtains at their sides, the latter condition, as clinical observation abundantly proves, giving rise to a mitral direct murmur of similar character." In 1883, Dr. Keyt,1 while disputing Flint's explanation of the origin of the murmur, suggesting that it might arise at the aorta in systole, proposed that it be called the murmur of Flint, a term which has since been used by many. In 1883, Flint2 recorded another observation of the same nature, and in 1886 discussed the subject at length in an article in The American Journal of the Medical Sciences.3 Since this time the phenomenon has been recognized by numerous clinicians. Most observers who have recognized the Flint murmur have agreed on considering its occurrence unusual. Guiteras, however, sixteen years ago,4 expressed the belief " that obstructive functional mitral murmurs are of frequent occurrence in aortic regurgitation." He suggested that the obstruction offered by the partially closed mitral valves, at the time of the entrance of the auricular blood, might serve in the manner of a safety-valve and help to prevent over-distention of the ventricle. Guiteras5 reported three character- istic cases and expressed a modification of Flint's theory as to the manner of origin of this murmur, asserting that in aortic regurgita- tion the mitral leaflets are not " floated upward," but are actively driven against the auricular blood by the force of the general arterial tension; that such force is, in all probability, often exerted against the anterior leaflet of the mitral valve by a regurgitant cur- rent which falls directly upon it. Osler6 also asserts that this murmur occurs in a considerable pro- portion of all cases. In Gibson's recent work,7 after a thorough discussion of Flint's description of this murmur, and a review of the literature on the 1 Boston Medical and Surgical Journal, 1883, cix. 30. 2 Lancet, London, 1883, i. 131. 8 American Journal of the Medical Sciences, 1886, xci. 35. 4 Medical News, Philadelphia, 1885, xlvii. 533. 5 Transactions of the Association of American Physicians, 1887, ii. 39; also, Boston Medical and Surgical Journal, 1887, cxvii. 6 Practice of Medicine, New York, 1898, 8vo., 3d ed., p. 714. 7 Diseases of the Heart and Aorta, Edinburgh, 1898, 8vo. p. 497. FLINT MURMUR IN AORTIC INSUFFICIENCY. 3 subject, there appear the following words: " Being thoroughly conversant with Flint's views since the appearance of his second paper, the points under discussion have been diligently sought for by us ; so far, however, without result. Cases have frequently presented themselves, no doubt, in which, with absolute evidence of aortic disease, there has been a presystolic murmur, but in every one of these, without exception, post-mortem examination has revealed mitral obstruction as well as aortic lesions." My attention was first called to the subject fourteen years ago by Guiteras' article, and two years later, while house physician at the Massachusetts General Hospital, I had the good fortune to observe a case in which my diagnosis of Flint murmur was confirmed by necropsy. Since that time I have been impressed with the fact that the Flint murmur is a far commoner manifestation than might be inferred from the usual statements in literature. It has, therefore, seemed to me that it might be of considerable interest to analyze the clinical and pathologic records of those cases of aortic insuffi- ciency which have come to necropsy in Professor Osler's clinic at the Johns Hopkins Hospital. A majority of these cases have been under my personal observation. The purpose of this investigation is to reach some conclusion as to the frequency of this phenomenon and the grounds upon which a diagnosis may be made intra vitam. Inquiry into the exact physical cause of the murmur will be beyond the limits of this communication. * * * Since May, 1889, 74 cases of aortic insufficiency have come to necropsy at the Johns Hopkins Hospital. In 45, or 60.8'per cent., of these cases there was heard, at some time during the observation of the patient, a rumbling, echoing murmur in diastole,'limited to the region of the apex, and differing from the diastolic murmur of aortic insufficiency; in other words, a murmur exactly similar to that characteristic of stenosis of the mitral valve. This'murmur, in the great majority of instances, was truly presystolic in time, ending sharply in the first sound, or in a systolic murmur. In some cases it was separated by a short interval from the first sound, occurring in the middle of diastole. In 12, or 26.6 per cent., of these cases there existed a stenosis of the mitral valve as well as aortic insufficiency. 4 THAYER, In 33, or 73.3 per cent., the mitral orifice was of normal or in- creased circumference. In all of the 12 cases in which there was an actual mitral stenosis, the anatomic lesion was an endocarditis. In one instance there was also general arterio-sclerosis. Of the remaining 33 cases without mitral stenosis, the endocardial changes were part of a general arterio-sclerotic process in 16; in 17 there was chronic or acute endocarditis. In 4 of these latter instances there was a general arterio-sclerosis as well. Of the 33 cases of aortic insufficiency in which, without mitral stenosis, a rumbling, vibratory presystolic murmur limited to the region of the apex was observed, the condition of the mitral valve, beyond the dilatation of the orifice which is the rule in well-marked aortic insufficiency, was absolutely normal in 17 instances. In 16 greater or less change was present. Of these 16 cases, in 4 instances the changes consisted simply in a slight thickening of the free edges of the curtains; in 8 the changes were those of chronic endocarditis without stenosis; in 3 there was subacute vegetative endocarditis, quite insufficient to have caused the presystolic murmur; in 1 there were rather large fresh vegetations, which might have been sufficient to cause a murmur in diastole. Of the 16 cases in which there were changes in the mitral valve other than stenotic, the lesions were part of a general arterio-sclerotic process in 4, or 25 per cent.; in 12, or 75 per cent., the changes were those of chronic or acute endocarditis. In one of these cases there was also a general arterio-sclerosis. Of the 17 instances in which the mitral orifice was normal, in 12, or 70.5 per cent., the changes in the aortic valve were secondary to a general arterio-sclerosis and atheroma of the aorta ; in 5 there was chronic valvular endocarditis; in 3 of these latter cases there was also a general arterio-sclerosis. In 29, or 39.1 per cent., of the 74 cases of aortic insufficiency no presystolic murmur was heard. In 4 of these cases there was mitral stenosis. Of the remaining 25 cases, in 10, or 40 per cent., the mitral valves were essentially normal; in the other 15, or 60 percent., more or less marked chronic or acute alterations in the valves or chordae tendinae were present. FLINT MURMUR IN AORTIC INSUFFICIENCY. 5 In 16, or 64 per cent., of these cases the process was apparently secondary to a general arterio-sclerosis; in 8, or 32 per cent., the condition was the result of chronic or acute endocarditis; in 1 the lesion of the aortic valves was apparently congenital. * * * On considering these figures one or two interesting facts become evident : With Regard to the Frequency of Mitral Presystolic Murmur in Aortic Insufficiency Uncomplicated with Mitral Stenosis. Out of 58 cases such a murmur was heard in 33, or 56.8 per cent. One might insist that this percentage is too large in that I have included among these 33 instances 16 in which chronic or acute changes other than stenotic were present in the mitral valve. Might not these changes, after all, have played a certain part in the pro- duction of the presystolic murmur? While it may be, as held by Phear,1 that marked shortening of the chord® tendin® alone may sometimes result in a presystolic murmur, yet this event is assuredly rare. And the following figures suggest that changes in the mitral valve other than stenotic have little effect on the production of a presystolic murmur : Out of 27 cases of aortic insufficiency in which the mitral valve was anatomically absolutely normal, a presystolic murmur was heard in 17, or 62.8 per cent. Out of 31 instances of aortic insufficiency in which the mitral valve showed greater or less change other than stenosis, a presystolic murmur was heard in 16 instances, or 51.6 per cent. It would then appear to be clear that disease of the mitral valve other than stenosis has, in our cases, played no essential part in the production of a presystolic murmur. The majority of our cases, then, of aortic insufficiency have showed, on careful examination, a Flint murmur-that is, a presys- tolic or late diastolic rumbling or echoing murmur heard in the region of the apex-a murmur clearly independent of organic mitral stenosis. 1 Lancet, 1895, vol. ii. p. 716. 6 T H A Y E H , Is it Possible to Distinguish, Intra Vitam, Cases of Aortic Insufficiency with Flint Murmur from those Complicated with Mitral Stenosis? It may be well to consider, first, the relative frequency of some of the more characteristic physical signs of mitral stenosis. The following are, perhaps, among the more important: 1. The character of the pulse, which, as a rule, is small, and, in condition of good compensation, of tolerably good tension, often irregular. 2. The Character of the Cardiac Impulse. The sharp, tapping, systolic shock is, perhaps, one of the most constant and character- istic signs of mitral stenosis. 3. The thrill, presystolic or sometimes mid-diastolic in time, and limited closely to the apex region. 4. The evidences of right-sided hypertrophy and the accentuated second, pulmonary sound, which, however, are not especially impor- tant in the present consideration. 5. The Presystolic Murmur. There are few more characteristic signs than the rumbling, rasping or softer echoing, vibratory, cres- cendo, presystolic murmur, ending sharply, as it usually does, in a snapping first sound. Sometimes, when the heart's action is slow, there may be a momentary separation between the end of the rumbling murmur and the occurrence of the first sound. 6. The Snapping First Sound. The modification of the first sound is also a very characteristic element in mitral stenosis-the first sound which has the short, snapping, valvular character of a second sound. An element of this snapping sound is often present^ even when a well-marked systolic murmur occurs. In many instances when thrill and presystolic murmur are entirely absent a snapping valvular first sound, in connection with a small pulse, a dilated right heart, and an accentuated second pulmonic sound, may be sufficient to justify a diagnosis. An analysis of the physical signs in 22 cases of uncomplicated mitral stenosis which have come to necropsy at the Johns Hopkins Hospital reveals the following facts : 1. Pulse. In all but three of these cases (86.3 per cent.) the pulse was of small size. In three instances where the stenosis was of very slight extent the pulse was described as of fairly good size. 2. Thrill. A thrill was present in 12, or 54.5 per cent., of the cases. FLINT MURMUR IN AORTIC INSUFFICIENCY. 7 3, Systolic Shock. A tapping systolic shock was present in 15, or 68.1 per cent., of the cases. 4. Snapping First Sound. A characteristic snapping, valvular first sound was audible in 15, or 68.1 per cent. 5. Presystolic Murmur. A presystolic murmur, the most char- acteristic of the cardiac signs, was present in 17, or 77.2 per cent., of the cases. The most important signs, then, of mitral stenosis in order of frequency are the presystolic murmur, the tapping shock of the first sound, the short, valvular, snapping first sound, the presystolic thrill, in association with the small pulse, the accentuated second pulmonic sound, and the enlargement of the right side of the heart. Are these signs modified in cases of mitral stenosis combined with aortic regurgitation ? Let us examine our records with regard to the character of the signs in cases of this nature. Sixteen such cases came to necropsy. In 2 of these 16 cases there were no symptoms whatever of mitral stenosis. One of these was a case of marked aortic stenosis, with insufficiency and slight narrowing of the mitral orifice; in another case, seen only in extremis, but a slight presystolic thrill at the apex was noted. 1. Pulse. In 1 of these 16 instances, that combined with aortic stenosis, there was, naturally, a small pulse ; in 4 the pulse was large and collapsing, but in 1 the statement is made that it was not of a typical Corrigan quality; in 3 it was noted that the pulse was of moderate size and collapsing; in 1 a collapsing character alone was mentioned; in 3 it was noted that the pulse was small, but col- lapsing ; in 3 the pulse was small, but no especial mention of its aortic character was noted ; in 1 it was especially noted that the pulse was not of aortic quality. 2. Thrill. Of these 16 cases, a presystolic thrill was present in 8, or 50 per cent. 3. Systolic Shock. A tapping systolic shock was noted in 7, or 43.7 per cent. 4. Snapping First Sound. A snapping first sound was heard in 12, or 75 per cent. 5. Presystolic Murmur. A presystolic murmur was present in 12, or 75 per cent. 8 THAYER, The most constant and characteristic symptoms here, as in uncom- plicated mitral stenosis, are the presystolic murmur and the tapping character of the first sound. In 10 of these cases, where the aortic lesion was the more impor- tant, the degree of hypertrophy of the left ventricle was marked. In five, however, where the mitral stenosis was of considerable extent, there was but a moderate enlargement of the left side in association with a rather small pulse. In 1, where the aortic lesion was apparently primary, there was marked hypertrophy, with a small collapsing pulse. The following table may serve to emphasize the modifications of the more essential signs of mitral stenosis observed in cases com- plicated with aortic insufficiency : Table I. Uncomplicated Mitral stenosis and mitral stenosis. aortic insufficiency Small pulse .... . 86.3 per cent. 37.5 per cent. Thrill . 54.5 50 Tapping systolic shock . 68.1 43.7 Snapping first sound . . 68.1 75 Presystolic murmur . 77.2 75 " A consideration of these figures would appear to show that the ordinary signs of mitral stenosis are not essentially changed when this condition is complicated with aortic insufficiency, with the exception of the fact that the pulse in the latter condition is often of a larger size and collapsing and-a modification of some interest -that the tapping character of the systolic shock is considerably less frequent. Let us now compare with these figures the results of our analysis of the symptoms in 33 cases of aortic insufficiency with Flint murmur. 1. The Pulse. Of 33 cases of aortic insufficiency uncomplicated with mitral stenosis in which Flint murmur was heard, 1 was asso- ciated with aneurism of the aorta; 1 with a slight aortic stenosis, while in another the patient was moribund and the pulse was impal- pable at the wrist. In 1 no satisfactory note could be found, and in another instance the only note was made toward the fatal termi- nation of the case, during a pericarditis. In the remaining 28 cases a typical Corrigan pulse was noted in 14, or 50 per cent. In 4 the pulse was of typically aortic character, FLINT MURMUR IN AORTIC INSUFFICIENCY. 9 with the exception of the fact that the size was hardly as large as is commonly noted. In 4 the pulse was collapsing, but no note was made of the size. In 1 the statement is made that the pulse is slightly collapsing in character. In 3 the pulse was said to be of a somewhat aortic character. In 2 it was simply noted that the pulse was compressible. In 1 the statement is made that the pulse was of fair volume and good tension. In none of these instances was the pulse described as small. 2. Thrill. In 33 cases of aortic insufficiency with Flint murmur a palpable thrill was observed in 14, or 42.4 per cent. 3. Tapping Systolic Shock. A characteristic tapping systolic shock was noted in but 5, or 15.1 per cent., of the cases, and in 2 of these instances the tapping character was slight or inconstant. 4. Snapping First Sound. Of 33 cases of aortic insufficiency with Flint murmur the first sound was of a snapping valvular character in but 10, or 30.3 per cent. In 2 of these instances the snapping character was very slight, and in a third inconstant, having been noted only during attacks of tachycardia. A better estimate of the differences in the physical signs in aortic insufficiency complicated with true stenosis may be made from a study of the following table in which the symptoms in cases with Flint murmur are placed side by side with those in uncomplicated mitral stenosis and combined mitral stenosis and aortic insuffi- ciency. For the sake of a fairer comparison only those cases of true mitral stenosis and mitral stenosis complicated with aortic insufficiency have been tabulated in which a presystolic murmur was present. Uncomplicated Mitral stenosis and Aortic insufficiency mitral stenosis. aortic insufficiency. with Flint murmur. (17 cases.) (14 cases.) (33 cases.) Small pulse . . 82.3 per cent. 28.5 per cent. .0 per cent.* Presystolic thrill . 64.7 50 42.4 Tapping systolic shock 76.4 " 50 15.1 Valvular first sound . 64.7 " 78.5 30.3 * Based upon thirty cases; see above. Table II. These tables bring out certain fairly well-marked clinical differ- ences between the cases of aortic insufficiency with Flint murmur and those complicated with true mitral stenosis. The character of the presystolic murmur is essentially the same in both conditions, 10 THAYER, with one exception : a Flint murmur is never as rasping and loud as are the more marked murmurs of true mitral stenosis; it is com- monly echoing and of moderate intensity. It is fair, however, to remember that in a very large proportion of cases of true mitral stenosis the murmur is also of this same character. Out of the 22 fatal cases of mitral stenosis above referred to the sound was absent or was described as an echo or as a faint rumbling murmur in 12, or 54.5 per cent., of the cases. The presystolic thrill is« also less frequent and less intense, but perhaps the most striking difference between the two conditions is in the character of the systolic shock. In but a very small propor- tion of the cases of aortic insufficiency with Flint murmur does the apex impulse have the tapping character so significant of a true mitral stenosis; this appears, however, to be present in about half the cases of aortic insufficiency combined with true mitral stenosis. In the majority of instances of Flint murmur the systolic impulse has the usual characteristics of that observed in aortic insufficiency ; it is a forcible but rather heaving lift. The snapping valvular first sound is also rare. In the instances with Flint murmur the first sound, if it be not replaced by a systolic murmur, is commonly dull, humming, prolonged, indeed, as is often the case in aortic insufficiency, almost more an impulse than a sound. * * * But, apart from the physical signs related to the heart itself, there are other points which may be of considerable help in diagnosis. Most important among these is the pulse. The pulse in aortic insufficiency complicated with true mitral stenosis was recorded as small in over a quarter of the cases. In uncomplicated aortic insufficiency with Flint murmur the pulse is almost always character- istically large and collapsing. The condition of the peripheral arteries and various points in the history of the case may also be of assistance in diagnosis. Thus, out of 16 cases of aortic insufficiency complicated with mitral stenosis, in all but 3, or 81.2 per cent., there was a distinct history of rheumatism or chorea, or symptoms justifying a diagnosis of acute endocarditis. In 3 cases the process was clinically arterio-sclerotic. Out of 33 cases of aortic insufficiency with Flint murmur there was a clinical history of acute rheumatism, or chorea, or signs justi- fying a diagnosis of endocarditis intra vitam in but 13 instances, or FLINT MURMUR IN AORTIC INSUFFICIENCY. 11 39.3 per cent., while in 18, or 54.5 per cent., there was clinical evidence of a general arterio-sclerosis. Anatomically the changes in the valves were part of a general arterio-sclerosis or an atheroma of the aorta in 20, or 60.6 per cent., of the cases. In 13, or 39.3 per cent, of the cases, the condition was an acute or chronic endocarditis. In 4 of these cases there existed also arterio-sclerosis. In 25 cases of uncomplicated aortic insufficiency without Flint murmur the percentages were essentially the same. In 16, or 64 per cent., the process was a part of a general arterio-sclerosis; in 8, or 32 per cent., the condition was due to endocarditis; in 1 the defect in the valve was congenital. As might be expected, there are certain slight differences in the average age of the cases with Flint murmur and those of aortic insufficiency complicated with mitral stenosis-differences depending clearly upon the fact that, in the one condition, the changes are more commonly due to arterio-sclerosis which is generally a senile change, and in the other to endocarditis which so frequently occurs in early life. This is well shown by the following table: Table III. Years. 1-10 Aortic insuffi- ciency with Flint murmur. . 1 Aortic insufficiency complicated with mitral stenosis. 0 10-20 . . . . 5 3 20-30 . 4 3 30-40 . 9 5 40-50 7 2 50-60 . . . . 5 2 60-70 . 1 0 70-80 . 1 1 Totals . 33 16 Thus, it will be seen that 57.5 per cent, of the cases of Flint murmur occurred in individuals under forty years of age, against 68.7 per cent, among the cases of true mitral stenosis. But these differences are too slight to be of any diagnostic importance. That there is nothing essential in the arterio-sclerotic process which predisposes to the development of a Flint murmur is shown by the fact that out of 32 cases of uncomplicated aortic insufficiency where the lesion was purely arterio-sclerotic in origin, a Flint murmur was heard in 50 per cent., while in 21 instances where the lesions 12 THAYER, were due to an acute or chronic endocarditis the percentage of Flint murmurs was actually greater, namely, 60.9 per cent. The diagnostic importance of demonstrable arterio-sclerosis lies in the fact that while arterio-selerotic cardiac lesions are usually confined to the aortic orifice, in endocarditis, on the other hand, the possi- bility of simultaneous affection of the mitral valves, and hence the probability of a true stenosis, is appreciably greater. Broadbent1 believes the Flint murmur to be more frequent in cases where the insufficiency is combined with stenosis of the aortic valves. In three of our cases there was aortic stenosis as well as insuffi- ciency, but in only one was a Flint murmur heard. In the other two instances, despite the existence of true mitral stenosis in one, there was no presystolic murmur. * * * To sum up the results of these comparative observations it may be said that a positive diagnosis of a functional mitral presystolic murmur may be difficult to make. The character of the murmur differs in no way from that of true mitral stenosis. In true mitral stenosis, however, even if complicated with aortic insufficiency, the tapping systolic shock and the snapping first sound are common. The Flint murmur, on the other hand, is usually associated with the characteristic heaving impulse of aortic insufficiency, and the dull, ill-defined, prolonged first sound. A tapping impulse and a snapping first sound, may, however, be present. Of special importance is the character of the pulse. In cases of aortic insufficiency with Flint murmur the pulse is large and col- lapsing; in instances combined with true mitral stenosis there is generally an appreciable modification of the size of the pulse. The diagnosis of Flint murmur is fairly safe when a rumbling or echoing presystolic murmur in the region of the apex is present in aortic insufficiency occurring in an individual with well-marked general arterio-sclerosis, especially where there is no history of any acute malady ordinarily associated with the development of endo- carditis, and in the absence of a marked systolic shock or snapping first sound. If, on the other hand, the patient be an individual with soft peripheral arteries and a history of attacks of acute rheu- 1 Heart Disease, London, 1900. 8vo., 3d ed., p. 150. FLINT MURMUR IN AORTIC INSUFFICIENCY. 13 matism or chorea, or other evidences suggestive of the existence of an endocarditis, the probability of concomitant affection of the mitral valve is greater, and the possibility of arriving at a definite diagnosis is correspondingly less. While, as a rule, the Flint murmur is not of very great intensity, is associated with little or no thrill, with no marked tapping systolic shock, and rarely with a snapping first sound, there may be striking exceptions to this rule. The following case may serve to show how careful one should be in assuming the existence of a true mitral stenosis from the presence of nearly all the classical signs, if aortic insufficiency be present. D. B., a colored laborer, aged between forty-five and fifty-five years, was admitted to the Johns Hopkins Hospital on July 22, 1896, complaining of shortness of breath and swelling of the legs. His family history was nega- tive, as was his personal history, except for what was, apparently, an attack of sciatica which lasted for about four months. For several months before entry he had been suffering with shortness of breath, which had steadily increased. For four weeks there had been swell- ing of the abdomen. Two months before entry he had to give up work on account of shortness of breath. Physical Examination. The patient was a fairly well-nourished colored man with well-marked arcus senilis. The radial arteries were moderately thickened. There was edema of the legs and ascites. Examination of the lungs showed fine moist rales at both bases. Heart. The cardiac impulse was in the fifth interspace about in the mam- millary line. There was no marked systolic shock, but a slight presystolic thrill was to be felt. On auscultation at the apex there was heard a slight presystolic murmur ending in a snapping first sound, followed by a soft sys- tolic murmur; the second sound was not audible at the apex. Passing upward toward the base a well-marked diastolic murmur of aortic character became audible. It was of maximum intensity at the left third and fourth cartilages. The pulse was collapsing. Under rest, diuretics, and potassium iodid the patient improved greatly, and left the hospital on August 31st. From this time up to the date of his death the patient was admitted to the hospital five times. On September 21, 1896, the following note was made by Professor Osler : " At the apex-beat a loud systolic shock is preceded by a somewhat rough murmur in diastole, which does not run quite up to the beat." And, again, on September 25, 1896 : " At the sixth interspace a rough presystolic murmur is well heard, and the shock of the first well felt; no thrill. The systolic shock is marked." On October 2d : " The shock of the first sound is well marked on palpa- tion." 14 THAYER, On April 2, 1897, the following note was made by Dr. Thayer: " The pulse is collapsing and rather large, but not as large as often seen in aortic insufficiency. At the point of maximum impulse there is no distinct thrill. The first sound is rather sharp and followed by a slight systolic murmur which is lost in the mid-axilla. As one passes outside the point of maximum impulse the snapping character of the first sound is rather suggestive. The second sound at the point of maximum impulse is followed by a slight, soft, diastolic murmur. Almost immediately after the second sound there begins another murmur, which at first is extremely difficult to separate from the aortic diastolic, but which is of a different pitch. This is heard best in the fifth space just in the mammillary line, where it has an echoing quality and increases in intensity, ending in the first sound. It is not heard above the fifth rib or inside the parasternal line, and is lost a short distance outside the point of maximum impulse. Above and inside this area a soft systolic and diastolic murmur are to be heard. The diastolic murmur is audible in the aortic area, but is loudest along the left border of the sternum at about the fourth space ; it has a soft aortic character. In the aortic area it does not entirely replace the second sound. The second pulmonic is not particu- larly loud; systolic and diastolic tone in the carotids." April 9, 1897, Dr. Osler: " Systolic shock is well felt at the apex and base. . . . The presystolic murmur has all the characters of a true stenotic murmur." The patient died on October 30, 1898. Repeated notes were made by Professor Osler, by Drs. McCrae and Futcher, and by myself. The valvular snapping character of the first sound was constantly referred to. The thrill was of moderate intensity and was often absent. The presystolic murmur also varied greatly in intensity. Owing to the nature of the systolic shock and the snapping character of the first sound, a diagnosis of true mitral stenosis in association with aortic insufficiency was universally concurred in. The necropsy, however, showed general arterio-sclerosis with moderate thickening and retraction of the aortic valves. The mitral curtains were absolutely normal. * * * A word before closing as to the cause of this interesting phe- nomenon. As stated in the beginning, Flint1 assumed that the back-flow of blood from the aorta resiflted in a floating upward of the valvular curtains so that they were brought approximately into apposition, thus causing a practical stenosis of the mitral valve at the time of contraction of the auricle. Keyt's2 view that the murmur arises at the aortic orifice in systole is scarcely worth considering. Guit^ras,3 as has been said, adopted a modification of Flint's view. 1 Op. cit. 2 Op. cit. 3 Op. cit. FLINT MURMUR IN AORTIC INSUFFICIENCY. 15 " Ue forgets, it seems to me," he says, " that in aortic regurgitation the leaflets are not floated upward, but are actively driven against the auricular blood by the force of the general arterial tension. I maintain that these propagated murmurs are, in fact, mitral obstructive murmurs, and that they are more apt to develop when the posterior aortic segment is affected, because in such cases the recurrent stream is brought to bear directly against the anterior leaflet of the mitral valve." Sansom1 asserts that the development of a presystolic murmur would be impossible if, as Flint suggested, the mitral curtains were actually brought into coaptation. ^I cannot imagine that, the mitral curtains being brought into coaptation, and the orifice being itself closed, any force proceeding from the auricle could separate them or cause the blubbering sound. It would be quite otherwise, however, if they were brought together without completely closing the auriculo-ventricular aperture. In such a case two explanations will be possible. (a) The lifting force of the current impinging upon the under surface of the great anterior mitral curtains might so obstruct the current from the auricle as to create a de facto impediment at the end of each disastole ; or (6) The vibrations might be directly communicated by the regurgitant stream from the aorta to the great mitral curtain. The nearness of the posterior segment of the aortic valve-diseased, perhaps, so that the morbidly-produced orifice in diastole presents ragged or fringed borders-to this mitral flap may well account for such vibrations. These vibrations may attain only to an intensity and rapidity sufficient to cause murmur somewhat late in the dias- tolic period. The force of the auricular systole would necessarily amplify and intensify such vibrations of the free edge of the flap until the commencement of ventricular systole or the tug of the chordse tendinre abruptly stopped them, bringing both curtains of the valve together and completely closing the auriculo-ventricular orifice. It occurs to me that this is a more probable explanation than that which postulates the production of a virtual stenosis of the orifice by the fluid pressure of the aortic regurgitant stream. u 1 The Diagnosis of Diseases of the Heart and Thoracic Aorta, London, 1892, p. 385. 16 FLINT MURMUR IN AORTIC INSUFFICIENCY. Potain1 is inclined to accept the idea that " the retrograde blood current from the aortic orifice which is insufficient, presses back the great curtain of the mitral, whence a relative narrowing of the mitral orifice. This great curtain is then between two parallel cur- rents of varying rapidity, the retrograde current of aortic insuffi- ciency and that produced by the blood coming from the auricle. Under the influence of these two currents the mitral valve enters into vibration, which results in the production of a thrill appreciable by the hand and of the presystolic murmur or rumble perceptible to the ear." Essentially the same view is held by Broadbent.2 This explanation of the origin of the murmur is similar to that of Guiteras, and would seem, upon the whole, reasonable. * * * In conclusion, one may be justified in saying that in uncompli- cated aortic insufficiency a rumbling, echoing, presystolic or mid- diastolic murmur limited to the region of the apex of the heart is very common, occurring, when carefully looked for, in fully half of the cases. The characters of this murmur are in no way different from those commonly observed in true mitral stenosis, with the excep- tion of the fact that it is usually of moderate intensity. It is, how- ever, rarely associated with a tapping systolic impulse and a snapping first sound, which are the rule in true mitral obstruction, while the pulse is large and characteristic of uncomplicated aortic insufficiency In the absence of these signs and with a large pulse, the functional character of an apex presystolic murmur in aortic insufficiency is to be suspected, especially in cases where there is no history of acute infectious processes such as are ordinarily associated with endocar- ditis, and where there is evidence of well-marked arterio-sclerosis. A Flint murmur may, however, be associated with many of the clinical features of a true organic mitral obstruction. 1 Gaz. d. Hop., Paris, 1893, Ixvi. 295. 2 Op. cit. ON THE OCCURRENCE OF STRONGYLOIDES INTES- TINALIS IN THE UNITED STATES BY WILLIAM SYDNEY THAYER, M. D. Associate Professor of Medicine in the fokns Hof kins University From THE JOURNAL OF EXPERIMENTAL MEDICINE Vol. VI, No. i, November 29, 1901. ON THE OCCURRENCE OF STRONGYLOIDES INTES- TINALIS IN THE UNITED STATES. By WILLIAM SYDNEY THAYER, M. D., Associate Professor of Medicine in the Johns Hopkins University. Plate IX. Historical. In 1876 Normand (1876),* a French naval surgeon, discovered a small nematode in the dejecta of patients who had contracted severe diarrhoea in Cochin China. This parasite, present in enormous num- bers, was afterwards studied more carefully by Bavay (1876), who described it as Anguillula stercoralis. The worm, according to Bavay, differs but little from the terrestrial anguillula, Bhabditis terricola Du- jardin, genus Leptodera of Schneider. The parasites were usually met with, in the stools, as larvae, measuring about 0.33 x 0.022 mm. in size. When the stools were kept in uncovered vessels at a sufficiently warm temperature, these larvae underwent development, reaching full growth and sexual differentiation in about five days. The length of the full grown female was about 1mm.; its breadth about 0.04. The body was cylindrical, slightly diminishing in size anteriorly and taper- ing to a sharp point posteriorly. When the worm retracted forcibly, slight transverse furrows were to be seen. The mouth as described by Bavay, possessed three distinct lips, and was continuous with the triangular oesophagus, which, after a stricture, dilated again into a second ovoid enlargement. The intestine, which followed, was fairly visible, and ended in a little protrusion on one side of the body near the base of the tail. The intestine was pushed slightly aside by the uterus. A little below the middle of the body, and on the ventral side, opened the vulva, leading to the uterus, which extended from the intestinal ventricle to a point near the anus. Here the eggs were massed in varying number. In some instances the young had actually broken the shell of the eggs, and were free in the uterus, though more often the eggs, on deposition, contained well formed, motile embryos. * References to authors are arranged alphabetically at the end of this article. 76 Strongyloides Intestinalis in the United States The male was about one-fifth smaller than the female. The peri- intestinal cells were more clearly outlined, and were accompanied by another long gland, which seemed to consist of small rounded globules. This organ, doubtless the testicle, ended at the base of the tail in two small, horn-like spicules with tapering extremities curved inward; these spicules contained canals. They were of equal length, and were situated symmetrically on a transverse plane. The tail, which was coiled also in the same direction as the spicules, was twice as short as that of the female. The authors further described copulation, the laying of eggs and the development of larvae. Neither Normand nor Bavay were able to cultivate the adult animal from the second gene- ration. In the following year Normand (1877) discovered a second nematode, present, in association with these parasites, in the small intestine of a patient dying from Cochin China diarrhoea. Bavay (1877 112), who afterwards found this parasite in a number of autopsies upon similar cases, described it as a distinct species, which he termed Anguillula intestinalis. It was met with only in the female form, the length of which was 2.20 mm.; the average breadth 0.03. The body, a little tapering anteriorly, terminated, rather suddenly, posteriorly in a coni- cal tail, the extremity of which was appreciably rounded, and even a trifle dilated. With a sufficient magnification, the surface showed a very delicate transverse striation. The mouth, without horny arma- ture, showed three small lips. It opened into an oesophagus, practi- cally cylindrical, which occupied about one-fourth of the length of the animal, and showed neither swellings nor striations. It was followed by an intestine, with which one might readily confound it, without a marked change of color. This intestine extended nearly to the pos- terior extremity of the body, but it almost ceased to be visible in the middle part, w'hich was occupied by a very large, elongated ovary. The vulva was situated in the posterior third of the animal, and, in its neighborhood, the uterus contained usually five or six rather elongated eggs. The anus, a transverse slit, was situated toward the base of the tail. The eggs and the viscera were of a yellowish green color, rather opaque and apparently finely granular. All individuals observed were oviparous females. Bavay questioned whether the absence of males was due to their prompt disappearance after coupling, or whether, as Schneider has shown to be the case in certain nematodes, the worm is unisexual when free, and hermaphroditic with a female habitus when parasitic. These worms were abundant in the duodenum, rarer in the jejunum; William Sydney Thayer 77 they were not found as far down as the ileum. Once, they were found in considerable numbers with embryos of A. stercoralis in fluid coming from the stomach. In intestines where the worm was found, it was not uncommon to find also series of eggs, often joined together, some- times isolated. In some of these the embryo, in the process of forma- tion, showed a definite row of dorsal cells; in others its development was more advanced. These parasites were hardly ever found in the stools. Bavay (1877 2) found the worm in six cases, and in five of these only at autopsy. The development of the eggs was not observed, but Bavay (1877 2) makes the following statement: " In three diarrhoeic stools which we had preserved to follow the develop- ment of the Anguilhila stercoralis, we found, at the end of several days, that they contained larvae different from the first. These were, as a matter of fact, longer, with a cylindrical oesophagus descending down to about the middle of the body, and a tail, which, instead of terminating in a fine point, was, on the contrary, apparently truncated at its extremity. Al- though the culture of these larvae could not be carried far enough to estab- lish in an irrefutable fashion their identity with the Anguillula intestinalis, yet we had no doubt with regard to this point. Indeed, two of the patients who presented this form in their stools, have succumbed since then, and the autopsy has shown us the complete form. The third case still lives." Both Normand and Bavay were inclined to regard the parasites, especially Anguillula stercoralis, as important etiological factors in Cochin China diarrhoea. These observations were partly confirmed in 1877 and 1878 by La- veran (1877 11 2), Libermann (1877 2), Roux (1877) and Chastang (1878) in patients from China, and by Chauvin (1878) in a case origi- nating in Martinique. Their observations related almost entirely to the discovery of rhabditiform embryos in the stools. Chauvin, how- ever, states that he was able, in cultures, to follow the deposition of the eggs by the adult female, and that he noted the presence, together with the embryos of the new generation, of a longer, thinner and more motile worm, " probably that which has been mentioned by Normand."* In 1878 Grassi (1878, 1879 112) and Parona (1879) discovered A. intestinalis at a number of autopsies in Pavia, and published a careful description of the mother worm, of the eggs and of the embryos de- veloping from them. The mother worm was found throughout the upper gastro-intestinal tract, especially in the lower part of the duodenum and the upper * Normand (1877) quotes Bavay (1877 2); vide supra. 78 Strongyloides Intestinalis in the United States part of the jejunum, though they were occasionally met with through- out the jejunum and in the upper part of the ileum. They have been found in the stomach. In some cases the intestinal mucosa appeared to he perfectly healthy. The eggs, deposited in the intestinal tract, hatched almost immediately after being laid. They were found, as a rule, in close proximity to the mother worm. It was extremely rare to find the eggs in the stools. The embryos in the faeces, which were almost exactly similar to those described by Normand and Bavay as A. stercoralis, were identical with those found in the intestine. In cultures kept at room temperature in July, the faeces being moistened with a little water, these worms were found to grow gradually, until, after four or five days, sometimes longer, they measured about 0.6, while the breadth diminished to about 0.015. The two bulbous en- largements disappeared from the oesophagus, which occupied more than a third of the entire length of the animal, and was bordered by granu- lations. The genital rudiment had disappeared. After ten or twelve days, many of the worms were 0.75 long, but the longest were only about 0.029 or 0.03 in width; the oesophagus occupied one-half the length of the animal. It was pointed out that, at this stage, the embryos were similar to those forms observed by Bavay and Chauvin in faeces which had been kept for some time; forms which Bavay (18722) had believed to be larvae of A. intestinalis. They failed to observe in their cultures, at autopsy, or in the stools, a single sexually differentiated A. stercoralis. Grassi (1879 ') placed the worm in a special genus, closely allied to Strongylus, which he termed Strongyloides, and later (1879 2) he sug- gests the specific term Strongyloides intestinalis. This classification has been accepted by the best authorities. At the same time Perroncito (1880 V6, 1881, 1882, 1883) called attention to the presence of Anchylostoma duodenale and also Anguillula intestinalis and A. stercoralis in the intestinal tract of workers in the St. Gothard tunnel. He (1881, 1882) succeeding in cultivating, from rhab- ditiform embryos found in the fresh faeces, adult Anguillula stercoralis, which he termed Pseudo-rhabditis stercoralis (Bavay). The original rhabditiform embryos were, from his descriptions, essentially similar to those described by Normand, Bavay, Grassi and Parona. He described and pictured with accuracy the development of the adult male and female forms from the rhabditiform embryos in the stools, their copula- tion, the laying of eggs, the hatching of these, and the gradual transition of the young embryos of the second generation into filariform larvae, William Sydney Thayer 79 very closely similar to those described by Grassi and Parona as the final stage of the metamorphosis of the rhabditiform embryos, the descent of which from Anguillula intestinalis they had traced. Perroncito also described A. intestinalis, but contrary to the observa- tions of Grassi and Parona, he asserted that the eggs of this worm appeared in great numbers in the stools, and were, at some stages, in- distinguishable from those of Anchylostoma duodenale. In cultures, the larvae developing from these eggs were closely similar to those of Anchylostoma, the differences described being extremely slight. The differences between the larvae of Anguillula intestinalis and A. stercoralis, Perroncito believed to be slight but yet characteristic. He maintained, however, that the larvae of A. intestinalis and Anchylostoma were never found in recent faeces. In his own words: " This is suffici- ent of itself to establish the diagnosis" (1880 3). These observations were followed by a rather spirited controversy, Grassi (1882, 1883 1> 213) maintaining, and proving beyond a doubt, that Perroncito had fallen into error in assuming that the eggs of A. intes- tinalis were passed in any number in the faeces. He showed, clearly, that Perroncito had been dealing purely with Anchylostoma eggs. He insisted that the rhabditiform embryos found in the dejecta were direct descendants of the strongyloid so-called Anguillula intestinalis, and, in view of the apparently clear evidence that these embryos often develop, in cultures in the free state, into sexually differentiated adult parasites, so-called Anguillula stercoralis, he advanced, in 1882, the hypothesis, based upon a number of observations, that Anguillula intestinalis was a dimorphobiotic parasite like Ascaris nigrovenosa; that the mother worm in the intestine was parthenogenetic or hermaphroditic; that the rhabditiform embryos developing from the eggs of these and escaping in the dejecta, developed into a sexually differentiated generation out- side of the body; that the descendants of this sex-ripe generation were capable, after ingestion, of developing again, into the parthenogenetic or hermaphroditic parasitic mother worm. In the same year there occurred, in the clinic of Gerhardt at Wiirz- burg, a case which was carefully studied by Seifert (1883 112), Grassi, and Leuckart (1883), which was destined to shed much light upon this disputed question. Seifert sent specimens of the dejecta to Leuckart in Leipzig. These contained great numbers of typical rhabditiform embryos, unquestionably similar to those described by Normand, Bavay, Perroncito on the one hand, and by Grassi and Parona on the other. In cultures, these developed into sexually differentiated Anguillula stercoralis. The new embryos developing from the eggs of these under- 80 Strongyloides Intestinalis in the United States went the course of development described by Normand, Bavay and Perroncito, changing, eventually, into characteristic filariform larvae. Leuckart was convinced that these filariform larvae must pass over into a suitable host to return to complete development and sexual maturity, and from analogy with what he had previously observed in Ascaris nigrovenosa, he agreed with Grassi in assuming that these various forms were but different phases in the cycle of a single heterogenic parasite. " The structure of the filariform larvae is such that they cannot possibly develop again into the rhabditis form. There must be another worm which develops from them, a variety which, in the shape of its body and the structure of the oesophagus resembles these." And Anguillula intestinalis possesses these characters. Owing to the entire absence of males he believed, as did Grassi, that the parasitic mother worm, of female habitus, was hermaphroditic or parthenogenetic. While he expressed no positive opinion, he was inclined to suspect that, as Schneider had shown to be the case in the analogous stage of Ascaris nigrovenosa, the so-called Anguillula intestinalis was hermaphroditic. More recently, however, Rovelli (1888), who has investigated this question, has come to the conclusion that the worm is parthenogenetic. Leuckart was strengthened in his views concerning the life history of the parasites by the fact that Grassi and Parona (1879) had demon- strated the origin of the rhabditiform embryos found in the dejecta from A. intestinalis, while both Bavay and Grassi (also Chauvin (1878)) had described filariform larvae in old cultures. He suggested for the parasite the name Rhabdonema strongyloides, and in conclusion says: " The Rhabditis stercoralis itself is to be erased from the list of essential parasites; it represents, like the Rhabditis ascaridis nigrovenosa, despite its sexual differentiation, an intermediate generation, developing extern- ally, which forms a link in the chain of development of the Anguillula intestinalis.'' At the suggestion of Grassi, who also observed this case, the patient was given on several occasions large doses of male fern, santonin and thymol. On one occasion, after an anthelmintic followed by a purge, two examples of the mother worm were recognized by Grassi (Seifert^ 1883 2) in the faeces; both, however, were dead and had undergone considerable post-mortem change. On another occasion, after adminis- tration of apomorphia, a considerably degenerated A. intestinalis was found in the vomitus. No examples of sexually differentiated adult A. stercoralis were ever observed in the fresh stools. In the same year Grassi (1883 x) emphasized the interesting fact that filariform larvae, identical with those into which the primarily rhabditi- AVilliam Sydney Thayer 81 form embryos of the free living generation develop, may arise by direct transformation from the rhabditiform embryos of the parasitic mother worm, namely, the embryos found ordinarily in the dejecta. This direct transformation had been clearly described by Grassi and Parona (1879) four years before, and in the experience of the former, represents the ordinary method of development. In support of these observations showing that the rhabditiform embryos of the parasitic mother worm may, under some circumstances, change directly into the filariform larvae, without the interposition of the sexually differentiated free living generation, Grassi (1883 x) notes the fact that exacerbations of the infection in patients who have been living in regions where fresh infection by the mouth is out of the question, are not uncommon. He also points out that it is not infre- quent to find, in the cadavers of individuals who have remained in hospitals for several months, small and rather immature examples of A. intestinalis. Such a parasite was passed by the Wurzburg patient. There is no evidence that the sex-ripe intermediate generation ever develops in the intestinal tract during life. Such forms are never found at autopsy. The presence, then, of immature forms of A. intestinalis at autopsy, and the increase in the number of embryos in the stools during life, must depend upon a direct transformation of the rhabditiform embryos into the mother worm without the interpolation of the sexually differentiated generation. In 1884, Golgi and Monti (1884, 1885) made a careful study of this question in cases observed in Pavia. They confirmed in toto the observa- tions of Grassi and Parona, and agreed with these observers in pointing out Perroncito's error in assuming that the sexually differentiated, free living generation is a separate parasite. They followed in cultures the direct transformation of the rhabditiform embryos of the parasitic mother worm into the filariform larvae, as well as the indirect change through the free living, sexually differentiated generation. They agreed with Grassi in believing the former cycle to be the commoner. In the meantime a number of other observers had described cases in which this worm was present: Breton (1879) in China; Sahli (1882) and Bozzolo and Pagliani (1880) in cases from the St. Gothard Tunnel, Ribeiro da Luz (1880) and Lutz (1885) in Brazil; Radetski (1886) in Russia; while Grassi (1878), Grassi and Calandruccio (1884), Grassi and Segre (1887), Lutz (1885), and others described similar parasites in other animals. Since then Calandruccio (1889 112) and Barbagallo (1897) have found the parasite in Sicily; Sonsino (1889, 1891), Riva (1891) and de Silvestri (1895) in Italy; Ilberg (1892) in a case from the 82 Strongyloides Intestinalis in the United States Dutch Indies; Sonsino (1896) in Egypt; while Leichtenstern (1898, 1899) and Wilms (1897) have described a number of cases occurring especially in brickworkers along the Rhine, and Poppenheim (1899), a sporadic case in East Prussia. Perez Valdes (1897) has observed the parasite in Spain, and Strong (1901) in the Philippine Islands. The most important work of recent years has been done in the clinic of Leichtenstern. As a result of fourteen years' study of fourteen cases, this observer comes to the following conclusions (1898): " (1) The direct metamorphosis of the Anguillula embryos into the filariform is the rule. In some of my patients with Anguillula, this method of development was observed exclusively for weeks and months, however one might vary the conditions under which the cultures were made. " (2) The development of the sex-ripe intermediate generation, Rhabditis stercoralis, takes place commonly, but by far not so con- stantly and regularly as the direct metamorphosis. " (3) In those cases' again, which, in my experience, are unusual, where the development of the sex-ripe intermediate generation pre- dominated continually or for transient periods, I have never failed to observe the direct metamorphosis as well. " It is then a matter of purely facultative, by no means exclusive or obligatory heterogenicity." As to the reason why, in one instance, the direct method of trans- formation should prevail, and in another the indirect, there has been much question. Wilms (1897), in Leichtenstern's laboratory, has proved definitely that it is not due to the existence of two distinct varieties of worm. This observer administered to human beings filari- form larvae which had developed by the method of direct transformation from rhabditiform embryos of the parasitic mother worm. After seventeen days, rhabditiform embryos began to appear in the patient's stools. In culture experiments these characteristic rhabditiform em- bryos underwent, in part, a direct metamorphosis into new filariform larvae, but in part, developed into the sexually differentiated, free living generation, the so-called Rhabditis stercoralis, from the eggs of which, in turn, there arose rhabditiform embryos changing rapidly into filariform larvae. Experiments with culture media, variations in the temperature, mois- ture, etc., to which the cultures are exposed, have failed to reveal any definite law as to the reason for the prevalence of one or another of these methods of development. Leichtenstern (1899), in his last article, has pointed out the fact that the sex-ripe intermediate genera- William Sydney Thayer 83 tion is apparently commonest in cases which have been but recently imported from the tropics, while the direct metamorphosis is the rule among those instances originating in Italy, Belgium, Germany and Holland. It is, however, probable that all these worms were ultimately of tropical origin. So that one may be led to believe that the parasite, after entering into temperate regions, has adapted itself to the less favorable climatic outward conditions, in that in temperature zones, it tends to follow the direct method of transformation into the filariform larvae, a method which is simpler, more rapid and less dependent upon outward influences. And yet, despite this, in any given case there may, for a certain time, occur a change, as a result of which the development of the sexually differentiated intermediate generation prevails. The cause of such variations in the type of the cycle of development is quite obscure. The only observer of recent years who has failed to recognize the heterogenicity of the parasite is Teissier (1895 112), who in 1895 re- ported a remarkable instance in which the stools contained worms which he believed to be identical with the rhabditiform embryos above described. In cultures they developed into sexually differentiated free living parasites closely similar to those described by Bavay, Perroncito, Grassi and others. In the circulating blood, however, there were also found numerous small larvae which he believed to be the earliest stages of these embryos. Contrary to the experience of almost all other observers, Teissier found adult, sexually differentiated forms, not only in cultures, but also in the fresh dejecta, and concludes that Anguillula stercoralis is a separate and distinct parasite. There are, however, certain points in which his observations vary materially from those of others. In the embryos found in the blood, and the smallest forms observed in the faeces, which were from 220/2 in length, by 10-12/2 in breadth, no internal structure could be made out. All recent observers, however, have noted that excepting perhaps, in the very earliest stages, the embryos developing from the eggs of both parasitic and free-living generations, show, already, the characteristic double oesophageal enlargement. Teissier's description of the adult parasite also varies from those given by Normand, Bavay, Grassi, Per- roncito and others, in that he was able to distinguish but one spicule in the male, instead of two, as noted by all other authors. The character of the young larvae, the presence of adult forms in the fresh dejecta, the slight differences in the structure of the male parasite, might give rise to the suspicion that Teissier may have been dealing with a different species of a closely allied parasite. 84 Strongyloides Intestinalis in the United States In a later article Teissier describes remarkable results obtained by inoculating these parasites into frogs-results which, if confirmed, would support this idea. After inoculation he believed that the worms developed in the intestinal tract and lungs of the frog, into giant forms. It is not impossible that these giant forms may have been Ascaris nigrovenosa [= Rhdbdonema nigrovenosum]. It should be remembered, however, that Teissier is not the only observer who has recognized what he believed to be adult forms of Anguillula stercoralis in the fresh dejecta. Normand (1877) stated that he had met with all known forms of the worm at autopsy. In 1878 he asserted that " nothing is rarer than to see Anguillula stercoralis in a state of complete development in dejecta of recent origin "-a state- ment which would justify the inference that he had seen such forms. In this latter article he also expresses his positive opinion that the adult forms do develop in the gastro-intestinal tract. In consideration of the fact that these views are at variance with those of most other observers, and of the somewhat indefinite character of Normand's statements, it has been assumed (Leuckart, 1883) that the sexually differentiated A. stercoralis may develop in the intestine, but only after death when the conditions are essentially the same as in cultures outside of the body, a theory which would account for one of Normand's statements. It must be acknowledged, however, that this does not cover his apparent assertion that he had met with adult forms in fresh dejecta. In view of the statements of these two observers, it would, perhaps, at the present time, be unwise to deny the possibility that, in rare in- stances, the sexually differentiated intermediate generation may de- velop within the human host. CLASSIFICATION. The following classification has been generally adopted: Family: Angiostomidae. Genus: Strongyloides Grassi, 1879. Syn.: Pseudo-rhabditis Perroncito, 1881. Rhabdonema Leuckart, 1882, pro parte. Species: Strongyloides intestinalis (Bavay, 1877). Syn.: Anguillula stercoralis (Bavay, 1877). Rhabditis stercoralis (Bavay, 1877). A. intestinalis (Bavay, 1877). Leptodera stercoralis (Bavay, 1877) Cobbold, 1879. Leptodera intestinalis (Bavay, 1877) Cobbold, 1879. William Sydney Thayer 85 Strongyloides intestinalis (Bavay, 1877) Grassi; 1879. Pseudo-rhabditis stercoralis (Bavay, 1877) Perroncito, 1881. Rhabdonema strongyloides Leuckart, 1883. Rhabdonema intestinale (Bavay, 1877) R. Blanchard, 1885. It may perhaps be well to emphasize one point in connection with the synonymy. Most of the recent text-books-Railliet (1895), Moniez (1896), Braun (1895), Weichselbaum (1898)-in their synonymy, refer to the special term Strongyloides intestinalis as having been introduced by Grassi in 1883. I have searched the literature with considerable care, but have been unable to find any reference to the worm under this name in Grassi's publications of that year. The name, however, was first used by Grassi four years before. In an article in the Rendic. r. 1st. lomb., Milano, 1879, xii, ser. 2, p. 228, he proposes the generic name Strongyloides, and in a review of his own article, in La med. contemp., Milano, 1879, iii, 495, he says: "He concludes by referring Anguillula to a new genus, Strongyloides, which " (Anguillula') " should therefore be called Strongyloides intestinalis." I have been unable to find any reference to this name in later publications by Grassi. In his articles appearing in 1883, he apparently accepted the classification of Leuckart-Rhabdonema strongyloides. PATHOLOGICAL SIGNIFICANCE. The fact that the worms were so frequently present in the severe diarrhoeas of Cochin China led Normand (1876, 1877, 1878) to assume that they played an important part in the jetiology of the disease. At that time, of course, the so-called Anguillula intestinalis and Anguillula stercoralis were regarded as distinct species. Normand (1877) recog- nized the fact that the parasites may exist in the intestinal tract for considerable periods of time without producing any serious symptoms. Man may harbor the worm for years with little or no inconvenience; there may be noted, perhaps, only a slight softness of the dejecta, or occasional transient attacks of diarrhoea. Anything, however, which tends to diminish the resistance may offer to the worms the opportunity to produce those intestinal changes which result in the clinical picture of Cochin China diarrhoea. This view was upheld by Laveran (1877 112), Davaine (1877), Dounon (1879), Roux (1877) and Ribeiro da Luz (1880). Libermann (1877 2), however, was very reserved in his views as to the part played by the worm. On the other hand, Chastang (1878), Breton (1879), Lutz (1885) and Calmette (1893) were inclined to doubt its pathogenicity. Grassi (1879 *) found the parasites in the stools of many healthy individuals 86 Strongyloides Intestinalis in the United States and while confessing that it was hard to believe that their action was not in some way harmful, yet he had never been able to make out any special symptoms attributable to the infection. He did not believe that the parasite was the cause of Cochin China diarrhoea. Later (1883 2) he asserts positively that " Anguilluhe are innocent commensals of man." Golgi and Monti (1884, 1885), however, found distinct anatomical changes which they believed to be dependent upon the irritative influ- ence of the worms, evidences such as could leave no doubt that, in some cases at least, the parasites must have a pathological significance, while Sonsino (1891) in a study of two fatal cases found evidence that the embryos may actually penetrate into the mucosa. He, as well as Golgi and Monti, frequently found worms occupying the lumina of Lieber- kuhn's ducts, while later, in the same cases, Venturi (Sonsino (1891)) discovered eggs and embryos in the depths of the villi and mucosa. Sonsino is strongly of the opinion that the worm may cause serious and even fatal changes. Riva (1891) likewise, from the study of a fatal case, is convinced of the pathogenic importance of the parasite, which he is inclined to consider the essential causal agent of the disease. The action of the worms is, he believes, wholly mechanical. More recently, Askanazy (1900) also has demonstrated that the worms may actually penetrate into the submucosa. Teissier (1895 112), indeed, has reported a remarkable instance in which small filariform larvae were found in the circulating blood, worms corresponding closely to the larvae of a parasite present in the stools, and identified by him as Anguillula stercoralis. As has been mentioned, however, there were peculiarities about the case observed by Teissier which are sufficient to give rise to some doubt as to the identity of the larvae present in the blood. Leichtenstern (1898), who has observed the constant presence, through years, of great numbers of the rhabditiform embryos in the stools of individuals in a relatively normal condition, while recognizing the fact that the presence of such enormous numbers of parasites may have a marked effect in increasing the severity of a diarrhoea when present, yet feels convinced that such a diarrhoea must owe its origin to some other primary cause, a view similar to that previously expressed by Calmette (1893). Perroncito's (1880 11213> 6) theory that the parasite played an equal part with Uncinaria duodenalis in the production of the severe anaemias observed in miners and tunnel workers, has long since been disproven. The removal of Uncinaria by proper treatment is sufficient to dispel William Sydney Thayer 87 all symptoms of miners' disease, despite the fact that great numbers of the rhabditiform embryos of Strongyloides intestinalis frequently persist in the dejecta for long periods of time after the disappearance of all evidence of the sister worms. The weight of evidence appears to be in favor of the view that, while the parasites may exist in the intestine for long periods of time without ill effects, they are by no means, as Grassi says, " innocent commensals of man." It would seem probable that this parasite alone may be the primary' agent in many cases of chronic diarrhoea. The deleterious influence of the worm is generally supposed to be purely mechanical [Golgi and Monti (1884, 1885), Sonsino (1891), Riva (1891), Askanazy (1900)], although Calmette (1893) suspects that the parasite may give rise to substances acting as chemical irritants. CLINICAL MANIFESTATIONS. The clinical picture described by Normand (1877) in his cases of Cochin China diarrhoea is that of a chronic diarrhoea, rather than of a dysentery. This commonly begins with mild dyspeptic symptoms, eructations, loss of appetite, etc., and a diarrhoea of moderate intensity, the stools being soft and pasty-three or four a day; the actions are often more frequent in the early morning hours. Not uncommonly, this condition is interrupted by temporary exacerbations; the attacks are sometimes dysenteric in character, the stools showing mucus and blood; in other instances more choleraic, the dejecta consisting of an abundant flux of a liquid yellowish material, while there may be vomiting, cyanosis and collapse. In many instances recovery occurs early in the course of the disease, the symptoms gradually clearing up. In other cases the patients pass-on to a condition of extreme emacia- tion with great prostration. The anaemia is not, as a rule, very severe. Intercurrent dysentery is not uncommon and may terminate fatally. Barbagallo (1897) and de Silvestri (1895) have reported cases in which certain nervous manifestations (headache, vertigo, tinnitus aurium, feeling of prostration) played a prominent part in the clinical picture. In de Silvestri's case there were no intestinal symptoms. All these manifestations ceased with the disappearance of the parasites under treatment with male fern. 88 Strongytoides Intestinalis in the United States TREATMENT. The treatment, beyond those measures of rest and diet such as are applicable to all similar conditions, is not especially satisfactory. Normand (1877) fancied that the use of large quantities of olive oil was of a certain value purely from its mechanical action. Perroncito (1881) believed that he had obtained results from large doses of the ethereal extract of male fern, doses as large as 12 grammes repeated daily until the disappearance of the parasite. In other in- stances he gave from 15-30 grammes in three doses during the morn- ing, and repeated these daily, until the disappearance of the parasites from the stools. De Silvestri (1895) and Barbagallo (1897) in single cases, also report good results from the use of male fern. Perroncito insists particularly upon full and repeated doses, and believes that the failure to obtain good results depends upon the fact that observers have used insufficient quantities of the drug through too short a period of time. On the other hand, Seifert (18 8 32) found that, in doses as large as 20 grammes, the ethereal extract of male fern was without effect. He obtained better results from large doses of thymol. Grassi (18832) also vigorously opposes the view that any known anthelmintic is of particular value in the treatment of this disease. This is based upon his own experience and upon the fact that adult parasites are hardly ever found in the stools even after the adminis- tration of large doses of the drugs. Golgi and Monti (1884, 1885) and Riva (1891) also found that repeated and large doses of these anthelmintics appeared to have little or no result. Cases. The three cases which are here briefly reported are, I believe, the only instances which have been observed in the United States. The first of these occurred in the Johns Hopkins Hospital nearly four years ago, and was recognized and studied by R. P. Strong, who was, at that time, a fourth-year medical student. Lieutenant Strong, who is now the director of the LT. S. Army Pathological Laboratory William Sydney Thayer 89 at Manila, has made a careful study of this case, which will be reported later by him, in the Johns Hopkins Hospital Reports.* He deserves entire credit for the discovery and recognition of the first instance of this disease noted in this country. Case I.-Amoebic dysentery. Intestinal infection with Trichomonas intesti- nalis and Strongyloides intestinalis. Abscess of the liver. Death. Autopsy. K., a German tailor, aged 52, was admitted to the Johns Hopkins Hospital December 7, 1896, complaining of pain and swelling in the right side of the abdomen and over the lower ribs. The family history Was negative. He had had measles in childhood, but had, otherwise, been a healthy man. He denied venereal disease. Up to six years before he had lived in Austria. Three years before entry, he began to suffer from diarrhoea which has continued since that time. There were, daily, from two to five operations, which occasionally contained a little blood; these were never associated with pain. Three weeks before entry, he began to notice a painful swel- ling on the right side over the lower ribs. He had had no chills, and, so far as he knew, no fever. For two weeks before entry, there had been a slight cough without expectoration. On physical examination the patient appeared emaciated and feeble. The heart and lungs were negative. The abdomen was somewhat distended; there was slight movable dulness in the flanks. On the right side, over the cartilages of the tenth and eleventh ribs, there was a large fluctuating swelling, 7% cm. in diameter; no tenderness or redness. Between this and the spinal column there was another swelling, about 15 cm. in diameter, extending from the median line to the spinous processes, and from the twelfth rib over the crest of the ilium, downward for a distance of 7 cm. The skin over this was adherent, red and thin. The hepatic flatness was not increased. Immediately after entrance this abscess was incised and evacuated. The cavity contained a large amount of thick puriform material with dark shreds and considerable greyish debris. The cavities extended into .the liver. About one and a half pints of fluid were evacuated; this con- tained many large, actively motile amoebae, showing the ordinary char- acteristics of Amoeba coli. The patient had daily, from one to four fluid, brownish, foul-smelling stools, which contained, besides Amoeba coli, considerable numbers of Trichomonas intestinalis, as well as numerous small nematodes identified by Mr. Strong as the rhabditiform embryos of Strongyloides intestinalis.^ The wound and the colon were irrigated with a solution of quinine, 1/1000. The patient gradually failed and died on December 26. * Since the completion of this article Strong's paper has been published. (See Bibliography.) + The conclusions of Mr. Strong were confirmed by Dr. Charles Wardell Stiles of the U. S. Bureau of Animal Industry. 90 Strongyloides Intestinalis in the United States The protocol of the autopsy reads: "Amoebic dysentery; ulceration of the large intestine; retroperitoneal abscess; operation wounds; parenchy- matous and fatty degeneration of the kidneys; fatty liver; fatty heart; intestinal infection with Trichomonas intestinalis and Stronyyloides intesti- nalis." " The abscess cavity measured 7x5 cm. on the surface of the liver and extended about 4 cm. into the substance of the organ. Scrapings from the wall showed numerous amoebae." The rectum and colon are the seat of widespread ulceration. The ulceration, which, for the most part, is shallow, leads in the rectum, into an eroded, thickened, haemorrhagic ap- pearance. The ulcers vary in size; the largest are irregular in shape, measuring about 3 cm. in length by 2 in width. A typical ulcer of mod- erate size might be described as follows: " Shallow, smooth base, some- what striated, evidently formed by the muscular coat of the intestine; white and shining, covered with whitish shreds. The outline of the ulcer is irregular but rather clean-cut, the edges are slightly elevated and are haemorrhagic, neither shredded nor undermined." There are a large num- ber of small pea-sized, and smaller, yellowish, slightly elevated areas, with red margins, which on careful study, appear as shallow ulcers, filled with a tenacious yellowish material. As they grow larger, they become like the typical one described above. About the middle of the transverse colon are two perforating ulcers, rather more hfemorrhagic about the edges; the mucous membrane is turned outward. Coverslips from the ulcers show active amoebae. The small intestine is free from ulceration; here and there is a slight ecchymotic patch. The abscess of the liver communicates with the large retroperitoneal abscess opening outward as first described. All along the tract Mr. Strong and Dr. Stiles found embryos of Strongyloides intestinalis. The parthenogenetic mother worms were found in the duodenum and jejunum. Careful studies by Mr. Strong resulted in the cultivation of but one adult male of the free living generation; adult females were never found. The direct transforma- tion of the rhabditiform embryos into the filariform larvae was apparently the rule. A similar observation has been previously made by Grassi and Segre (1887), who found that, when the direct trans- formation predominated, the sexually differentiated forms found in the cultures were always males. The point of origin of the infection in this case was not apparent. The disease may have been brought from Austria. The patient lived in the city, and drank city water. Case II.-Chronic diarrhoea. Rhabditiform embryos of Strongyloides intes- tinalis in the dejecta. Great improvement. N. P., a boy seventeen years old, presented himself at the dispensary of the Johns Hopkins Hospital May 10, 1899, complaining of diarrhoea. William Sydney Thayer 91 The family history was good. There was no history of pulmonary trouble or of hereditary disease. The grandmother, however, had suffered from diarrhoea for five years. Personal History.-The patient had lived all his life in Richmond, Vir- ginia, where he had been a newsboy. He had had measles, whooping cough and mumps as a child, and had suffered, off and on, from indefinite pains in both legs. Five years before entry, he had tertian ague. There was no history of pneumonia, typhoid fever, acute rheumatism, pleurisy, scarlet fever or chorea. Present Illness.-Three years before entry, the patient began to suffer from diarrhoea, the attack coming on during the summer. The operations were very thin and yellowish in color, containing at times, a small amount of blood, though this had not been noticed for a year and a half. The passages occurred mainly at night, as many as seven or eight in twenty- four hours, but of late, only about four. There was, at first, considerable mucus in the stools, but this had been practically absent during the two years before entry. The diarrhoea had never been associated with pain. The patient, however, had grown gradually weaker, and during the second year of his illness, he had been compelled, on one occasion, to take to bed for two weeks. Four months before entry, he gave up work on account of weakness, though up to that time he had felt tolerably well. The appetite was good; there were no dyspeptic symptoms. Physical examination showed a slight, emaciated boy, of sallow color. The lips and mucous membranes were somewhat pale; tongue clean. The chest was long and narrow; the intercostal spaces, deep. Examination of the heart and lungs was negative. The abdomen was not distended. The spleen was not palpable. No peristaltic movements were visible. There was no enlargement of the liver; no glandular enlargements; no scars upon the shins. There was an irregular chloasma-like pigmentation over the cheeks, forehead and temples, and also over the lower thorax and lateral abdominal regions. The urine showed no abnormalities. The blood showed no marked leucocytosis; no apparent increase in the eosinophilic cells. A rectal tube was introduced and a little, brownish, foul-smelling material was obtained which, besides muscle fibres, vegetable cells, granular debris and bacteria, contained a number of actively motile worms. In the fresh stools these measured all the way from 0.225 to 0.45 mm. in length by 0.02 to 0.03 mm. in breadth. They showed the characteristic structure of the rhabditiform embryos of Strongyloides intestinalis, and manifested a very active serpentine motion. The worm diminished slightly in size toward the head, and gradu- ally tapered down to a slender sharp-pointed tail. The periphery was somewhat refractive, while within, the substance was filled 92 Strongyloides Intestinalis in the United States with glistening, refractive, fat-like granules, which were rather larger toward the head than toward the tail. The digestive tract was clearly visible. The oesophagus, between one-third and one- fourth the length of the worm, showed a long bulb-like enlargement at the head, followed by a constriction, which was succeeded by a second, round or ovoid enlargement. The digestive canal was readily seen to pass through these enlargements, the anal outlet being situ- ated at a distance equalling about one-tenth the length of the worm from the tip of the tail. The anterior lip of the anal outlet was slightly raised. The mouth of the worm appeared, as far as could be made out, to consist of a simple funnel-shaped depression. In some instances the lumen of the digestive canal appeared to pass, as a straight line, directly through the oesophageal enlargements. In others, a distinct triangular opening was to be seen in the middle of the second of the oesophageal enlargements; the outlines of this opening were glistening and refractive, indicating clearly the tridentate, chitinous armature described by other observers (Plate IX, Fig. B). In many of the active worms repeated and violent muscular contractions of the oesophagus were observed; these were especially marked about this tridentate opening, which appeared to open and shut with considerable force. The outlines of the cells bordering the digestive tract, of which, in some instances, a slight suggestion could be made out, were as a rule entirely hidden by the glistening granules above mentioned. A little below the middle of the worm, on the same side as the anal opening, was a small clear elliptical area-the rudiment of the sexual apparatus. The boy refused to enter the hospital, and was observed in the out-patient department off and on up to June 21. As far as possible he was kept in bed, placed upon a liquid diet and given large doses of bismuth. On May 21 he was given santonin 0.25 (gr. IV) fol- lowed by castor oil, but no adult worms were found in the discharges. He was also given high rectal irrigations with a 1/2500 solution of quinine; on several occasions thymol was administered, a dose of 2. (gr. XXX) being given on successive hours, followed by a castor oil purge. William Sydney Thayer 93 The diarrhoea gradually diminished and the stools became semi- solid in character, but still contained parasites. No adult forms of the worm were ever found. The parasites always died a few hours after the stools were obtained, possibly owing to the fact that urine was mixed with the dejections. On June 21, the patient went home, but returned to the hospital on July 7. He was immediately put to bed, and given a liquid diet. The stools, at this period, were from three to four in number in the twenty-four hours. They were at first of a pea-soup consistency, having a peculiar, foul smell, and showing considerable numbers of the rhabditiform embryos. For a time the only medicinal treatment consisted of large doses of bismuth. The stools were collected, free from the urine, and various culture experiments were made. In some instances the faeces were placed in the thermostat and kept at body temperature. In others, they were kept near the thermostat at a temperature of about 30-35° C. Other specimens were kept at room temperature, 20-30° C. When but few parasites were present, the method suggested, by Leichten- stem (1898) was followed. In the semi-solid or solid faeces an exca- vation was made into which a little water was poured. Some hours later considerable numbers of parasites were usually to be found in this fluid. The best results were obtained in those cultures made at a temperature of 30-35° C. The smallest worms, found immediately after the passage, meas- ured about 0.22 mm. in length. During the next several hours they were observed to grow considerably until the largest measured about 0.55. Within twelve hours the greater number of the worms in the cultures had lost the distinct oesophageal enlargements, and had become somewhat longer and more delicate in structure, measuring usually from 0.4 to 0.55 mm. in length and, in one recorded instance, as much as 0.7 mm. Sometimes examples were found measuring under 0.4 mm. The transverse measurement "was from 0.016 to 0.022 mm. All trace of the rudiment of the sexual gland disappeared. The anal opening was not evident and the digestive tract was visible 94 Strongyloides Intestinalis in the United States only through about half the length of the worm. In the posterior half of the worm the granules were darker and apparently more abundant than in the anterior portion. Though the parasite, as a whole, was more delicate than the younger embryo, the tail, as shown in the draw- ing (Plate IX, Fig. C), was blunter, and more truncated.* The para- sites became rather more active, showing most striking serpentine movements, the appearance coinciding entirely with that of the filari- form larva? of Strongyloides intestinalis. Though the stools were carefully studied during the patient's entire stay in the hospital from July 7th to August 26th, and though cul- tures were made daily, no examples of the sexually differentiated, free living generation were found. In many of the specimens, worms were seen in which the outer layer had the appearance of a refractive capsule, but no constant relation between this appearance and the development of the para- site was traced. The moulting or escape of the parasite from this capsule was not observed. In one or two instances the worm was noted, under observation, to become suddenly motionless, while the capsule became shrunken and greatly wrinkled. The finer points in the internal structure of the worm were no longer to be made out. Although, as has been noted, the stools were examined several times a day through a long period of time, only two eggs were ob- served. These were similar in appearance. Drawings and meas- urements were made of one seen on the twenty-fifth of May. These eggs were of elliptical shape, with a thin, clear, yellowish shell, and granular contents which could be clearly seen to be in segmentation. The measurements were about 0.0675 by 0.0375 mm. The appearances have been admirably reproduced by Broedel in Plate IX, Fig. A. The condition of the patient improved greatly during his stay in the hospital. During the greater part of the time, he received subnitrate of bismuth 1.3 grm. (grains XX) three times a day. On several occasions thy- * The truncation of the tail was not noted in the detailed observations, which were made before a careful study of the literature was undertaken. In the admirable drawings, however, made from life by Broedel, this point is clearly brought out. William Sydney Thayer 95 mol was given, in two doses of 2. (gr. XXX) each, and on July 28 the patient took two doses, separated by an interval of an hour, of 4. (3i) each, of fluid extract of male fern, followed by a purge. Neither eggs nor mother worms were found in the stools. The stools gradually became more solid, though never formed; they diminished in frequency until, finally, there were only one or two in the twenty-four hours. The diet was gradu- ally increased, and, on July 24, he was allowed the regular ward diet. On August 26 the patient was, at his own request, discharged; he had gained twenty-two and one-half pounds in weight. On discharge, however, the pasty stools still showed moderate numbers of the rhabditiform embryos. Through friends of the patient it has been learned that he has, since this time, regained his normal weight and strength. He has resumed his occu- pation and considers himself well. Case III.-Arteriosclerosis. Chronic diarrhoea. Embryos of Strongyloides intestinalis in the dejecta. Secondary ancemia. Great improvement. J. S., a farmer, a native of Anne Arundel County, Maryland, was admitted to the Johns Hopkins Hospital July 19, 1900, complaining of diarrhoea and swelling of the feet. Family history, good. Personal History.-The patient had been a farmer all his life; his habits had been good; he had had no serious illnesses, excepting chills and fever fifteen years before entry. He had always lived in Anne Arundel County, having never been out of the State of Maryland, excepting for occasional visits to Washington. Present Illness.-He had considered himself a healthy man up to six months ago when he began to suffer from diarrhoea and progressive weak- ness. The stools, very frequent and sometimes involuntary, were fluid but never contained blood. They were small in quantity. During two months before entry, the patient had, on several occasions, vomited a yel- lowish fluid. For two days he had had sharp, griping pains in the lower abdomen. For a month there had been oedema of the feet and legs. There had been no increase in the quantity of urine, though there was increased frequency of micturition. During the last two months he had lost considerably in weight and much in strength. The examination by Dr. Futcher, on January 20, showed a rather sparely nourished man with a sallow complexion; moderate thickening of the radial arteries; no arcus senilis. Physical examination of the lungs was negative. Heart sounds, feeble, but free from murmurs. The abdomen was slightly full, bulging in the flanks, everywhere flat excepting in the umbilical region, where there was tympany; hepatic flatness, continuous with the abdominal flatness. On July 19, a count of the leucocytes showed 21,500 to the cubic milli- metre. Rectal examination showed numerous external haemorrhoids; the mucous membrane felt rather soft; the prostate was enlarged and firm. The dejecta were fluid, containing considerable pus, great numbers of leucocytes, a few red blood corpuscles and a moderate number of charac- teristic rhabditiform embryos of Strongyloides intestinalis. The urine showed, throughout, a rather low specific gravity, 1005-1015, a trace of albumin, and occasional hyaline and granular casts. The quan- tity was not accurately estimated. 96 Strongyloides Intestinalis in the United States The temperature was slightly elevated, 100.6°, on entry, but, with the exception of an occasional rise to a point between 99° and 100°, it remained sub-normal during the greater part of the patient's sojourn in the hospital. On July 26, a blood count showed: Red blood corpuscles 3,560,000; haemo- globin 57%. On entry the patient was given a milk diet, and powders containing: Tannogen 0.65 grm. (grains X), bismuth, subnit. 2. (gr. XXX) every four hours; also diuretin, citrate of potassium and strychnine. On the following day, the medicines, with the exception of the strychnine, were omitted. On the 24th, tannogen 0.65 (gr. X) every four hours, was again ordered, as well as diuretin 0.325 (gr. V) every four hours. There was little improvement in the condition of the patient up to August 12, on which date he was given thymol 0.325 (gr. V) every four hours, which resulted in an apparent improvement for about two weeks, after which time the diarrhoea returned. On August 21 the tannogen was discontinued, and the patient was given subnitrate of bismuth 1.3 (gr. XX) every four hours. On August 31 the bismuth was omitted and the tan- nogen was discontinued again September 4, and salol 0.325 (gr. V) every four hours was ordered. On August 13, the thymol was discontinued and four doses of santonin were given at hourly intervals without any striking results. The number of movements, however, became somewhat reduced and the general condition of the patient was considerably better. There was a gain of twenty-one and a half pounds in weight between July 29 and September 17, the date of his discharge. Cultures from the faeces, made according to the same methods as in the last case, showed the direct transformation of the rhabditiform embryos into the filariform larvae; the change was complete, in many instances, within twelve hours. No adult forms of the sexually differentiated, free-living generation were observed. No eggs were found in the stools, nor were any examples observed of the parthen- ogenetic mother worm. These three cases are interesting in that they are the first which have been observed in this country. Of especial import- ance is the question regarding their point of origin. In the first case it is possible, though scarcely probable, that the disease may have been acquired in Austria. In the second and third, however, the disease must have originated here. The behavior of the parasite on culture was similar to that com- monly observed in cases arising in temperate climates. In all three cases, the direct transformation of the rhabditiform embryos into the filariform larvae predominated. In one instance only, was a single William Sydney Thayer 97 sexually differentiated form of the intermediate, free generation ob- served. Question might be raised with regard to the nature of the eggs observed in Case II. The size of the one in which measurements were made, exceeded that attributed to the eggs of the partheno- genetic mother worm by many authors. Thus, Grassi and Parona (1819) give the measurements of the eggs as 0.06 x 0.04 mm., while Braun (1895), in his manual, gives the measurements as 0.050 to 0.058 x 0.030 to 0.034 mm., and Railliet (1895) gives the same measurements. Again, most authors are unanimous in stating that the eggs are present in the stools only with the greatest rarity. There can, however, be little doubt as to the nature of the two eggs observed in this case. (1) In the first place it will be remembered that they were found only upon two occasions, although a careful daily search was made through several months. Moreover, all authors who have had much experience with the parasite, have noted the occasional presence of eggs in the fresh stools. (2) Their general conformation agreed entirely with that of the eggs of the parthenogenetic mother worm. (3) The measurements, though larger than those given by Grassi and Parona and in most text-books, agree, however, with those given by Golgi and Monti (1884, 1885) in their careful and accurate study, and also by Riva (1891). These observers state that the diameters vary from between 65 and 70 n in length, by 30-39 p in breadth. Another objection which might be opposed to the assumption that these were eggs of Strongyloides intestinalis, is the fact that, in each instance, they were in the process of segmentation, and did not yet contain the completely developed embryo. Might they possibly have been the eggs of Uncinaria duodenalis? This can be easily ruled out, both on account of their greater size, as well as because of the fact that they were found on but two occasions. In uncinariasis the eggs are always numerous. They could not have belonged to the sex-ripe intermediate gene- ration; (1) because, on careful search, the adult parasites were never 98 Strongyloides Intestinalis in the United States found; (2) because they were found in fresh stools. It may not be impossible that these special examples may have represented eggs in which the process of development had, for some reason, been arrested. Another question which arises in connection with this case is the following: Do these instances represent an outbreak of the disease due to parasites which have been imported within recent years, or are we to assume that this worm has long existed among us? When one considers the infrequency with which systematic ex- aminations of the faeces are made, it seems to me unnecessary to assume that the worm has been recently imported. It is highly desirable that, both in our hospitals and in private practice, more systematic and thorough examinations of the faeces should be under- taken than are at present customary. It is safe to say that if micro- scopical examination of the faeces were carried out as regularly and systematically as is the microscopical examination of the urine and the blood, a number of interesting and important observations would follow. An especially interesting point in connection with the history of this parasite is its frequent association with Uncinaria duodenal is. Grassi (1879 *) early emphasized the frequency of combined infec- tions, while Perroncito (1880 V6, 1881, 1882, 1883), Sahli (1882), and others have also brought out this fact in connection with their studies of the epidemic among the workers in the St. Gothard Tunnel. Of 30 of Grassi's autopsies in Milan in which Anguilhda intestinalis was found, Uncinaria was also present in 25. Lutz (1885) in Brazil, in 35 cases of infection with this parasite, found a combined infection with Uncinaria in 30, or 85.7^. The conditions under which the two parasites flourish seem to be similar, and the discovery that one of the worms exists among us, should open our minds to the possibility of the presence of the other.* Especially should it empha- size the importance of a careful examination of the stools in all sus- picious cases of anaemia. * While this article is in press, Dr. John L. Yates, Assistant in Pathology, Johns Hopkins University, has discovered at autopsy a case of Uncinariasis (Anchylos- tomiasis) at the Baltimore City Asylum at Bay View. William Sydney Thayer 99 I he relation of the parasite to the diarrhoea in these three instances is somewhat questionable. In Case 1, the exciting cause of the pro- cess is uncertain, the parasite having been associated with Amoeba coli. In Cases II and III, however, there was no apparent cause for the diarrhoea other than the presence of these nematodes. And while, in both instances, the parasites were present upon the discharge of the patient, improvement was associated with a great reduction in their number. In conclusion one may be justified in emphasizing the following points: (1) Diarrhoea associated with the presence of Strongyloides intesti- nalis occurs in the United States. (2) The observation, in the J ohns Hopkins Hospital, of three cases within three years, cases originating probably in Maryland and Virginia, suggests that this parasite may be more frequent than has hitherto been supposed. (3) As in most cases originating elsewhere, in temperate climates, the development of the sexually differentiated, free living generation was in these instances apparently unusual, the direct transformation of the rhabditiform embryos into filariform larvae predominating. (4) The discovery of the existence of Strongyloides intestinalis should emphasize the possibility that Uncinaria duodenalis may also occur in this country. (5) More systematic examinations of the faeces both in public clinics and in private practice are much to be desired. BIBLIOGRAPHY. Askanazy, 1900. Ueber Art und Zweck der Invasion der Anguillula intestinalis in die Darmwand, Centralb. f. Bakteriol. u. Parasitenk. I Abth., 1900 xxvii, 5G9. Barbagallo, 1897. Sopra un caso di anguillulosi intestinale. Gazz. d. osp., Milano, 1897, xviii, 165. Bavay, 1876. Sur I'anguillule stercorale. Compt. rend. Acad. d. sc., Par., 1876, Ixxxiii, 694. Bavay, 1877. (1) Sur I'anguillule in testinale (Anguillula intesti- nalis), nouveau ver nematoide trouve par le Dr. Normand chez les malades atteints de diarrhee de Cochinchine. Ibid., 1877, Ixxxiv, 266. 100 Strongyloides Intestinalis in the United States Bavay, 1877. (2) Note sur l'anguillule intestinale (Anguillula intes- tinalis), nouveau ver nematoide trouve par le Dr. Normand chez les malades atteints de diarrhee de Cochinchine. Arch, de med. nav., Par., 1877, xxviii, 64. Bertrand and Fontan, 188G-7. De I'entero-colite chronique ende- mique des pays chauds. Arch. de. med. nav., 188G, xlv, 211, 2G6, 321, 406; xlvi, 37, 101, 241, 342, 401; 1887, xlvii, 50, 99. Blanchard, 1890. Traite de zoologie medicale, Paris, 1886-90, t. ii, 70. Blanchard, 1895. Traite de path. gen. (Bouchard). Paris, 1895, ii, 787. Bozzolo. See Pagliani and Bozzolo. Braun, 1895. Die thierischen Parasiten des Menschen, etc. Wurz- burg, 1895, 215. Breton, 1879. Note sur les parasites de la dysenteric et de la diar- rhee dite de Cochinchine. Arch, de med. nav., 1879, xxxi, 441. Bugnion, 1881. L'ankylostome duodenale et l'anemie du St. Goth- ard. Revue med. de la Suisse Rom., Geneve, 1881, i, 269. van der Burg, 1880. Over de zoogenamde Diarrhee de Cochinchine. Geneesk. Tijd. v. Nederl. Indie, Batav., 1880, n. s., ix, 160. Calandruccio, 1889. (1) Animali parassiti dell'uomo in Sicilia. Bollettino mensile deW Accademia Gioen. di scienze naturali in Catania, 1889, 4. s., ii, 6. Calandruccio, 1889. (2) Animali parassiti dell'uomo in Sicilia. Atti dell' Acc. Gioen. d. sc. nat. in.Catania, 1889, ser. iv, 11. Calandruccio. See Grassi and Calandruccio. Calmette, 1893. Etude experimentale de la dysenteric ou entero- colite endemique d'extreme orient et des abces du foie d'origine dys- enterique. Arch, de med. nav., 1893, lx, 207, 261, 335. Chastang, 1878. Diarrhee dite de Cochinchine. Quelques notes sur son origine parasitaire et son traitement par la chlorodyne. Arch, de med. nav., 1878, xxx, 29. Chauvin, 1878. L'anguillule stercorale dans la dysenteric des Antil- les. Arch, de med. nav., 1878, xxix, 154. Cobbold, 1879. Parasites-A Treatise on the Entozoa of Man and Animals, including some Account of the Ectozoa. London, 1879, 234. Davaine, 1877. Traite des entozoaires et des maladies vermineuses de l'homme et des animaux domestiques. 2me ed., Paris, 1877. Dounon, 1877. Etude sur l'anatomie pathologique de la dysenteric chronique de Cochinchine. Arch, de physiol, norm, et path., 1877, 2. s., iv, 774. William Sydney Thayer 101 Dounon, 1879. Des causes de ]a diarrhee de Cochinchine et du moyen de la prevenir. Bull. Soc. de med. pub. (1877-8), 1879, i, 272. Fol, 1883. L'anguillule intestinale (Rhabdonema strongyloides Leuck.). Revue med. de la Suisse Rom., Geneve, 1883, iii, 578. Fontan. See Bertrand and Fontan. Golgi and Monti, 1884. Intomo ad una questione elmintologica. Rendic. r. 1st. Lomb., Milano, 1884, 2. s., xvii, 285. Also Gazz. d. osp., Milano, 1884, v, 218. Golgi and Monti, 1885. Sulla storia naturale e sul significato clinico- patologico delle cosi-dette anguillule stercorali e intestinali. Atti d. r. Accad. d. sc. di Torino, 1885, xxi, 55. Also, Arch, per le sc. med., Torino, 1886, x, 93. Grassi, 1878. L'anguillula intestinalis. Gazz. med. ital. lomb., Milano, 1878, xxxviii, 471. Grassi, 1879. (1) Sovra l'anguillula intestinale. Rendic. r. 1st. Lomb., Milano, 1879, 2. s., xii, 228. Grassi, 1879. (2) Parassitologia umana. Rivista. Med. contemp., Milano, 1879, iii, 495. Grassi, 1882. Anchylostomi e anguillule. Gazz. d. osp., Milano, 1882 (21 May), iii, 325. Grassi, 1883. (1) Un ultra nota sulle anguillule e sugli anchilostomi. Gior. di r. Accad. di med. di Torino, 1883 (Feb.), 3. s., xxxi, 119. Grassi, 1883. (2) Un ultima parola al Prof. Perroncito. Gazz. med. ital. lomb., Milano, 1883 (30 June), 8. s., v, 260. Also review, Ibid., 379. Grassi, 1883. (3) Intorno ad una questione parasitologica. Un ultissima parola al Prof. Perroncito. Gazz. med. ital. lomb. Milano, 1883, 8 s., v, 391. Grassi, 1885. Contribuzione allo studio della nostra fauna. Atti del. Acc. Gioenia di Catania, 1885, 3. s., xviii. Grassi and Calandruccio, 1884. L'anguillula (Rhabdonema). Gazz. med. ital. lomb.. Milano, 1884, 8. s., vi, 492. Grassi and Calandruccio, 1888. Bolletino mensile dell' Accademia Gioenia di scienze naturali in Catania, 1888. Grassi and Parona, 1879. Sovra l'anguillula intestinale (dell'uomo) e sovra embrioni probahilmente d'anguillula intestinale. Arch. per le sc. med., Torino, 1879, iii, No. 10, p. 1. Grassi and Segre, 1887. I. Nuove osservazioni sull'eterogenia del' Rhabdonema (Anguillula) intestinale. TT. Considerazioni sull'etero- genia. Rendic. r. Accad. dei Line., Roma, 1887, Ann. cclxxxiii, 4. s., iii, 100. Also, summary, in Centralbl. f. Bakteriol. u. Parasitenk., 1887, ii, 413. 102 Slrongyloides Intestinalis in the United States Ilberg, 1893. Demonstration before the Berliner Verein f. innere Med. Deutsche med. Wchnschr., 1892, xviii, 334. Laveran, 1877. (1) Note relative an nematoide de la dysenterie de Cochinchine. Gaz. hebd. de med., 1877, 2. s., xiv, 42. Laveran, 1877. (2) Deuxi^me note relative aux anguillules de la diarrhee chronique de Cochinchine. Gaz. hebd. de med., 1877, 2. s., xiv, 116. Leichtenstem, 1898. Ueber Anguillula intestinalis. Deutsche med. Wchnschr., 1898, xxiv, 118. Leichtenstem, 1899. Zur Lebensgeschichte der Anguillula intesti- nalis. Centralbl. f. Bakteriol. u. Parasitenk., I Abth., 1899, xxv, 226. Leuckart, 1883. Ueber die Lebensgeschichte der sogenannten An- guillula stercoralis, &c. Ber. lib. d. Verhandl. d. K. Sachs. Gesellsch. d. Wissenschaft. zu Leipzig. Math.-phys. Cl. (1882), Leipzig, 1883, 85. Leuckart, 1886. The Parasites of Man, &c., Edinb., 1886. (Trans- lated by W. E. Hoyle.) Libermann, 1877. (1) Diarrhee de Cochinchine. Gaz. d. hop., Par., 1877, i, 237. Libermann, 1877. (2) Observations de diarrhee de Cochinchine suivie de quelqucs reflexions. Union med., 1877, 3. s., xxiii, 737. Lindner, 1890. Beitrage zur Kenntniss der Biologic und hygien- ischen Bedeutung der mit Vorliebe den Essig bewohnenden Anguil- luliden. Deutsche med. Ztg., 1890, xi, 25. Looss, 1898. Zur Lebensgeschichte des Ankylostoma duodenalc. Centralbl. f. Bakteriol. u. Parasitenk., T Abth., 1898, xxiv, 441, 483. Lutz, 1885. Ueber eine Rhabdonemaart des Schweines so wie uber den Befund der Bhabdonema strongyloides (Anguillula intestinalis und stercoralis') beim Menschen in Brazilicn. Centralbl. f. klin. Med.. 1885. vi, 385. Moniez, 1896. Traite de parasitologic animate et vegetate appliquee a la medecine. Paris, 1896, 306. Monti. See Golgi and Monti. Mosier and Peiper.* 1894. Anguillula intestinalis. Specielie Patho- logic und Therapie, herausgegebcn von H. Nothnagel, Bd. vi, Thier- ische Parasiten, Wien, 1894, 257. Neumann, 1892. Parasites and Parasitic Diseases of Domesticated Animals. Lond., 1892, 387. (Translated by George Fleming.) Normand, 1876. Sur la maladie dite diarrhee de Cochinchine. Compt. rend. Acad. d. sc., 1876, Ixxxiii, 316. * This article is surprisingly incorrect in text, references and figures. William Sydney Thayer 103 Normand, 1877. Memoire sur la diarrhee dite de Cochinchine. Arch. de med. nav., 1877, xxvii, 35, 102. Normand, 1878. Du role etiologique de l'anguillule dans la diarrhee de Cochinchine. Arch, de med. nav., 1878, xxx, 214. Oerley, 1886. Die Rhabditiden und ihre medizinische Bedeutung. Berlin, 1886, 47. Pagliani and Bozzolo, 1880. L'anemia al traforo del Gottardo. Giorn. d. soc. ital. d' igiene, 1880, ii, 345. Peiper. See Mosier and Peiper.. Perez Valdes, 1897. Contribucion al cstudio de la anguillulosis estercoralis. Bev. de med. y drug. pract., Madrid, 1897, xl, 5. Perroncito, 1880. (1) Communicazione preventiva. Sopra stndii elmintologici relativi alia malattia del Gottardo. Osservatore, Torino, 1880, (25 May and 8 June), xvi, 321, 357. Perroncito, 1880. (2) Observations helminthologiques et recherches experimentales sur la maladie des ouvriers du St. Gothard. Compt. rend. Acad. d. sc., 1880. xc, 1373. Perroncito, 1880. (3) Osservazioni elmintologiche relativi alia malat- tia svilluppatasi endemica negli operai del Gottardo. Atti e rendi- eonti della r. Accad. del Line., Roma, 1879-80, Anno cclxxvii, s. 3a, mem. della class, d. sc. fis., mat. e nat., vii, sed. 2 (Magg.). Perroncito, 1880. (4) Azione di reagenti chimici e di sostanze medi- camentose diverse sopra le larve del Dochmius duodenalis e sopra qnelle di anguillule. Osservatore. Torino, 1880 (18 June), xvi, 389. Perroncito, 1880. (5) On the action of chemical agents and medi- cinal substances on the larva* of Dochmius duodenalis and Anguillulse; including therapeutical considerations relative to the cure of patients from Mont.-St. Gothard. Veterinarian, Lond., 1880, liii, 824. Perroncito, 1880. (6) L'anemia dei contadini fornaciai e minatori in rapporto con l'attuale epidemia negli operai del Gottardo. Ann. d. r. Accad. di agricoltura d. Tor., 1880, xxiii. Also (summary), L' anemic des mineurs au point de vue parasitologique. Arch. ital. de biol., Turin, 1882, ii, 315; hi, 7. Perroncito, 1881. Observations sur le developpement de 1'Anguil- lula stercoral is (Bavay) Pseudorhabditis stercoralis (Mihi) hors de 1'organisme humain. J. de l'anat. et physiol, 1881, Par., xvii, 499. Also Sulla sviluppo della cost delta anguillula stercoralis (Bavay), Pseudo- rhabditis stercoralis (Bavay') Mihi, fuori dell' organismo umano. Arch, per le sc. med., Roma, 1882, v, No. 2, 24. Perroncito, 1882. Les ankylostomes (ankylostome duodenale de 104 Strongyloides Iniestinalis in the United States Dubini) en France, et la maladie des mineurs. Compt. rend. Acad. d. sc., Par., 1882, xciv, 29. Perroncito, 1883. Osservazioni alia nota del Dott. Grassi fatte nella seduta in cui essa venne letta. Gior. d. r. Accad. di med. di Torino, 1883 (Feb.), xxxi, 3. s., 121. Poppenbeim, 1899. Ein sporadischer Fall von Anguillula intesti- nalis in Ostpreussen. Centrafbl. f. Bakteriol. u. Parasitenk., I Abth., 1889, xxvi, 608. Radetski, 1886. Sluchai Anguillula stercoralis. Russk. Med., St. Petersb., 1886, iv, 190. Railliet, 1895. Traite de zoologie medicale et agricole, Par., 1895, 2me edition, 557. Ribeiro da Luz, 1880. Investigates helmintbologicas com applica- Qao al pathologia Brasileira, Rio de Janeiro, 1880. Summary in Arch, de med. nav., 1880, xxxiv, 462. Riva, 1891. Sopra un caso di anguillullosi intestinale. Lavori d. Cong. d. med. int., Milano, 1891. iv, 396. Also at greater length, Speri- mentale, 1892, xlvi, t. ii, 40. Roux, 1877. De l'anguillule stercorale et de son role dans 1'etiologie de la diarrhee de Cochinchine. Th^se, Paris, 1877. Rovelli, 1888. Ricerchc sugli organi genitali degli Strongyloides (Anguillula, Rhabdonema). Como, 1888. Also summary, Centralbl. f. Bakteriol. u. Parasitenk., I Abth., 1888, iv, 660. Sahli, 1882. Beitrage zur klinischen Geschichte der Anamie der Gotthardtunnelarbeiter. Deutsches Arch. f. klin. Med., 1882-83, xxxii, 421. Schneidemuhl, 1895. Lehrbuch dcr vergleichenden Pathologic und Therapie, Leipzig, 1895, 305. Segre. See Grassi and SegrA Seifert, 1883. (1) TTeber Anguillula stercoralis und Cochinchinadiar- rhoe. Sitzungsb. d. phys.-med. Gesellsch. zu Wiirzb., 1883, 22. Seifert, 1883. (2) TTeber ein Entozoon. Verhandl. d. Cong. f. innere Med., 1883 (April), ii, 337. De Silvestri, 1895. Fenomeni nervosi da Anguillula intestinalis. Gazz. d. osp., "Milano, 1895, xvi, 1509. Also, Gior. d. r. Accad. di med. di Torino, 1896, 4. s., lix, t. ii, 52. Sonsino, 1889. Anchilostomiasi nei dintorni di Pisa e il timolo contro il trichocephalo. Piv. gen. ital. di din. med., Pisa. 1889, i, 284. Sonsino, 1891. Tre casi di malattia da Rhabdonema intestinale e Rhabdonemiasi. Suppl. al Pir. gen. ital. di clin. med., Pisa, 1891, iii, p. 47. William Sydney Thayer 105 Sonsino, 1896. Contribute alia entozoologia d' Egitto. Mem. de I'lnst. Egyptian, 1896, 329. Strong, 1901. (1) Circulars on tropical diseases, No. 1, p. 36. Chief Surgeon's Office, Manila, P. I., Feb., 1901. Strong, 1901. (2) Cases of infection with Strongyloides intestinalis (first reported occurrence in North America). The Johns Hopkins Hospital Reports, 1901, x, 91. (Both of these articles were published after completion of this paper.) Teissier, 1895. (1) De la penetration dans le sang de 1'homme des embryons de 1'anguillule stercorale; rapports de la presence de ces embryons dans le sang avec certaines fievres des pays chauds. Compt. rend. Acad. d. sc. Par., 1895, Ixxi, 171. Teissier, 1895. (2) Contribution a 1'etude de 1'anguillule stercorale. De la penetration dans le sang des embryons de 1'anguillule stercorale. Arch, de med. exper. et d'anat. path., 1895, vii, 675. Teissier, 1896. Nouvelle contribution a 1'etude de 1'anguillule ster- corale. Anguillulose experimentale de la grenouille. Arch, de med. exper. et d'anat. path., 1896, viii, 586. Veterinarian, The, 1877. New Human Parasite. The Veterinarian, Lond., 1877, L, Pt. i, 19. Vogt, 1878. Die Herkunft der Eingeweidewiirmer des Menschen. Basel, Lyon, 1878. Wehenkel, 1876. Diarrhee de Cochinchine, occasionee par I'anguiL lula stercoralis. Ann. de med vet., Brux., 1876, xxv, 699. Weichselbaum, 1898. Parasitologic, in Weyl's Handbuch der Hy- giene, 1898, ix, 2 Lief., 317. Wilms, 1897. Anchylostomum duodenale und Anguillula intesti- nalis. Schmidt's Jahrbuch., 1897, cclv-cclvi, 272. Ziirn, 1882. Die tierischen Parasiten auf und in den Kbrper unserer Haussaiigetiere, &c. Weimar, 1882, 280. DESCRIPTION OF PLATE IX. These figures were drawn from life by Max Broedel, Leitz, Objective 7, Ocular 3. A. Egg of Strongyloides intestinalis (parasitic mother worm) found in stools of Case II, on May 25, 1899. B- Rhabditiform embryo of Strongyloides intestinalis from the stools. C. Filariform larva of Strongyloides intestinalis derived, by direct transformation, from a rhabditiform embryo. THE JOURNAL OF EXPERIMENTAL MEDICINE. VOL. VI. PLATE IX. Discussion. Dr. Thayer.-This is, so far as i know, the first case of this disease which has been recognized in Baltimore, de- spite the fact that for several years we have had our eyes well opened to the probability of its occurrence in these regions. The fact that in the past four years we have observed in this hospital three cases of diarrhea associated with Strongyloides intestinalis, a parasite which is found under very much the same conditions and often in associa- tion with Uncinaria, has led us to expect that we should 1 soon discover cases of this nature. This parasite was first ob- served by Dubini in 1838 in the intestinal tract of a young woman dying in a hospital at Milan. The recognition of its pathological importance dates from Griesinger's discovery in 1851, that it was the cause of the so-called Egyptian chlorosis, a very grave and often fatal form of anaemia pre- valent in Egypt. The worm became an object of yet greater interest to the medical world in 1880, at the time of the excavation of the St. Gothard tunnel. Among the tunnel- workers there developed an anaemia associated often with diarrhea and occasionally with bloody stools, which pre- sented many of the features of progressive pernicious anaemia. The dejecta of these patients were found to contain numer- ous eggs of Uncinaria, together often, with embryos of the allied Strongyloides intestinalis. The disease was studied by Perroncito, Sahli, Bozzolo and Pagliani, Grassi and others. While the eggs of Uncinaria and those of Strongyloides intestinalis are extremely similar, indeed, scarcely to be dis- tinguished, those of the former alone appear in the stools; the eggs of the Strongyloides hatch within the intestinal tract excepting in very rare instances. In several cases of infection with Strongyloides intestinalis studied carefully for months, we found myriads of larvse, but only two eggs. The larva? of Strongyloides intestinalis when first passed are from 200-400// in length and extremely active. They are in many ways similar to those of Uncinaria, which, however, are never found in the fresh stools. The eggs of Uncinaria duodenalis are elliptical structures from 55-60/z in length by 30/z in breadth, and when passed are in the stage of segmentation. From twelve hours to two or three days after passage, if kept at about 25° C., the larvae begin to escape, and after four to eight days reach the limit of development of which they are capable outside of the human body. It is probable that in most instances they are introduced into the organism through water, uncooked vegetables, or by the hands themselves. While the disease is widely spread in Europe, Asia, Africa, South America and in the Antilles, but few cases have been reported in this country. The disease is especially common among miners, brick-workers and tunnel-workers. While infection with Uncinaria duo- denalis results in grave and often fatal symptoms, Strongy- loides intestinalis is a much less malignant parasite, being associated, in the majority of instances, with chronic diar- rheas, which, when properly treated, are rarely fatal; often, indeed, the parasite may be present for long periods of time without producing any symptoms. The importance of recognizing the eggs of Uncinaria duodenalis in the stools is great, in view of the fact that the worms may be easily expelled. Treatment with large doses of male fern or thymol causes the entire disappearance of the parasites with recovery. It is an interesting fact that while the symptoms associated with the presence of Strongy- loides intestinalis are much milder, and amenable often, to treatment by general measures such as are adopted in any case of chronic diarrhea, yet it is often extremely difficult to rid the patient of the worms; the treatment which is so efficacious in the case of Uncinaria is often almost wholly ineffectual in the case of Strongyloides. The occurrence of this case should emphasize the great importance of systematic examinations of the stools, par- ticularly in cases of grave anaemia. \/ A CASE OF iESTI VO-AUTUMNAL FEVER WITH UNUSUALLY FEW PARASITES IN THE PERIPHERAL CIRCULATION. By William Sydney Thayer, M. D. [From The Johns Hopkins Hospital Bulletin, Vol. XIII, Nos. 131-132, February-March, 1902.] A CASE OF /ESTIVO-AUTUMNAL FEVER WITH UNUSUALLY FEW PARASITES IN THE PERIPHERAL CIRCULATION. By William Sydney Thayer, M. D. The patient that 1 wish to show you this evening is a young woman, 18 years of age, who was admitted to the hospital on the 8th of September. There are no facts of importance in her family or personal history excepting that in the spring and fall of 1900 she suffered from chills and fever. Five days before entrance she began to complain of general malaise and on the following day had a chill. This was repeated on the succeeding day, and two days later she took to bed. On entrance the physical examination showed little of importance; the temperature was 100.7°; the thorax and abdomen showed nothing remarkable; the spleen was not palpable; there w'as some hypogastric tenderness, due probably to a distended bladder. The colorless corpuscles were reduced in number. No malarial parasites were found after several examinations. The temperature fell gradually, reaching a normal point on the 12th of September, four days after entrance to the hospital, and remained normal during five days. On the 17th it touched 99°. On the 19th it rose again to a point a little above 99°, and on the evening of the 21st it was a little above 100°. On the 22nd there was a chill followed by fever. The temperature remained elevated something over twelve hours, just how long it is impossible to say as it was not recorded with sufficient frequency. At 8 A. M. on the 22nd it was normal, but in the evening it rose again to 101.3°, reaching the normal point on the morning of the 23rd. Again on the 23rd there was a febrile paroxysm, the 159] 1 temperature reaching 103° and falling gradually to a sub- normal point on the evening of the following day. During this time the patient complained much of headache and of abdominal pains localized for the most part, in the region of the bladder. There was retention of urine, necessitating catheterization. Repeated examinations of the blood failed to show malarial parasites. Several counts of the leuco- cytes were made, showing always a subnormal number. Over the right clavicle there was slight dulness; the expira- tion was somewhat prolonged, and on several occasions a few fine moist rales were heard. Later there was tenderness in the region of the spleen. From the 26th to the 30th there was slight, rather irregular fever ranging between 98.5° and 101.5°. On the 2nd of October the temperature rose to 103.2°, and on the following day it again touched a point about 103°, varying during the next week between normal and 103°. The fever continued, the temperature occasionally remitting but never falling below 98.5°, until the 14th of October. During this period the blood had been repeatedly exam- ined without result, but on the 14th a moderate number of crescentic and ovoid aestivo-autumnal parasites were found. Hyaline bodies were found on the following day. Treat- ment by quinine was started immediately-0.325 (gr. V) every four hours. The temperature fell to the normal point on the following day and has remained normal or subnormal ever since. The spleen, which at first was impalpable, was just to be felt in the latter part of her illness and was dis- tinctly tender on palpation. No hyaline forms were noted after the 15th of October, though two ovoid pigmented bodies-gametocytes-were found on careful search on the 4th of November, two days before discharge. There are several points in connection with this case to which I would like to direct your attention. (1) The irreg- ular and continuous fever. Such charts, due solely to ma- larial infection, are not common in these regions; yet they are occasionally met with, and the explanation is not difficult. The remarkable periodicity of the febrile manifestations, [59] 2 one of the most striking symptoms of malaria is, as is well known, especially marked in tertian and quartan infections, where the paroxysms occur with almost clock-like regularity. The cause of this periodicity is intimately associated with the life history of the parasites. The tertian and quartan organisms exist in the blood in great groups, all the mem- bers of which pass through their life cycle in unison, the sporulation of all the parasites in such a group occurring within relatively few hours, and the paroxysms have been shown to be definitely connected with the sporulation of these groups of parasites. Every now and then, however, one finds, even in tertian and quartan infections, the pres- ence of a multiplicity of groups, or a tendency toward lack of the definite arrangement of the parasites in groups, which, as one might expect, results in the occurrence of more or less irregular or continuous fever. This, however, is very unusual in tertian and quartan infections. But in aestivo-autumnal fever the state of affairs is differ- ent. The majority of cases of sestivo-autumnal fever in this climate show well defined and fairly regularly intermittent fever with chills. In many cases, however, the fever if untreated tends to become continuous or irregular. This is probably due chiefly to the development of a multiplicity of groups of parasites or to the spreading out of the period of sporulation of the existing groups, so as to unduly prolong the paroxysms until they overlap one another. In aestivo- autumnal fever, as has been repeatedly observed, the charac- teristic stages of the paroxysm are often absent-" dumb chills." It has also repeatedly been shown that insufficient treat- ment with quinine tends to disturb materially the regularity of the fever. It is not impossible that this depends upon an interference with the development of some of those parasites which are not actually destroyed, which results in a disturb- ance of the regular arrangement in groups. (2) The second point to which I would call your attention is the remarkable scarcity of parasites in the peripheral cir- culation. There was considerable question as to the nature of this case. The suspicious signs at the right apex, as well [59| [60] 3 [60] as the nature of the chart, suggested that the fever might be due to an incipient tuberculosis. Typhoid fever was thought of but was not considered probable. Could such a fever be due entirely to malaria without the discovery of the parasites in the blood on reasonably careful examinations ? How are we to account for the gradual dis- appearance of fever after entrance ? A very interesting fact has been developed on close ques- tioning of the patient, namely, that after the first chill she took two doses of quinine of uncertain amount. This, to- gether with the favorable conditions, rest in bed, and general treatment in a hospital, doubtless accounted for the tem- porary disappearance of fever, and also, in part, for the absence of parasites on entrance to the hospital. The re- duction in the number of leucocytes, the clearing up of the suspicious signs at the apex, and the absence at all times of expectoration, rendered the diagnosis of tuberculosis im- probable. There was little, on careful observation of the case, to suggest typhoid fever, and the absence of Widal reaction even at this late period speaks against it. These facts, in connection with the specific effect of quinine, leave little doubt that the case was, from beginning to end, due to malarial infection. The great infrequency of the parasites in the peripheral circulation is an extremely rare occurrence, but it is well to recognize the fact that it is a condition occa- sionally met with. In quartan fever the parasites are found at all stages of their development in the peripheral blood as well as in the spleen and internal organs. In tertian infec- tions the state of things is a little different, in that the parasites are found during the latter stages of development with much greater frequency in the blood of the spleen than in the peripheral circulation. In the majority of instances of aestivo-autumnal fever this tendency is more marked, in that only young forms are found in the peripheral circula- tion, and often in cases where the parasites are fairly well arranged in groups, few, if any, organisms are to be found in the peripheral circulation during the paroxysm. But there are cases, like that before us, in which almost the entire cycle of development of the parasites takes place in the inter- 4 nal organs; where examination of the peripheral blood, at whatever period it may be made, reveals but very little. The same condition may be seen-with great rarity, however-in tertian infections. Happily, those instances of aestivo- autumnal fever in which the parasites are not to be found in the peripheral circulation, are rarely cases of great severity. In the great majority of cases of pernicious fever the para- sites are numerous in the circulating blood; and, even in aestivo-autumnal fever, the number of parasites in the peripheral circulation is generally a fair index of the severity of the infection. But this does not always hold. I have recently seen a case of pernicious malaria where death oc- curred during my visit, in which the number of parasites in the peripheral circulation was moderate-a parasite perhaps in every tenth field. There was, however, a moderate num- ber of characteristic macrophages, containing large masses of pigment, cells rarely seen excepting in very severe infec- tions. In all cases of doubt it is wise not to rely entirely upon examinations of the fresh blood. While examination of the fresh specimen is usually the most satisfactory method of studying the blood, it must be acknowledged that the small hyaline forms of the malarial parasites are only to be recog- nized by an individual who is thoroughly familiar with the examination of fresh blood in normal and pathological con- ditions. The unskilled observer is sure*, to be confused by the vacuolization and decolorization of the red corpuscles so common, particularly, in certain febrile and anaemic condi- tions. In such cases it is better to resort to dried specimens stained by Romanovsky's method.1 Any one who has studied [601 1 In connection with these remarks it may be well to quote Lazear's (Johns Hopkins Hospital Reports, 1901, Vol. X, 1), description of his method of preparing Nocht's modification of Romanovsky's stain. The eosin, which gives the best re- sults is that from the Hbchst's factory, either A. G. or B. A. If prepared by the following method all good methylene blues give satisfactory results. " Polychrome methylene blue is care- fully neutralized. This is done by first adding dilute acetic acid until the solution is acid. When litmus paper is dipped into the solution, it is colored by the methylene blue, but on the 5 [61] fresh specimens and later examined dried cover-glass smears prepared by this method, will acknowledge that the stained parasites are much more readily picked out than the delicate hyaline bodies in the fresh blood. It is probable that, in a case like that before us, an occasional parasite would have been demonstrable by this method. (3) An important point in connection with this case is the striking proof afforded by the chart of the therapeutic value of quinine. Few things are more impressive than the instantaneous and specific effect of quinine as observed in a case of this nature. And in connection with such a chart it is perhaps fitting to emphasize again the fact that quinine is a true specific-that wherever one may meet with a case of continued fever, no matter in what part of the world, if the [60] margin of the moist portion the acidity causes a red line to appear. The solution is now brought back to the neutral point by the addition of more polychrome methylene blue until the red line fails to appear on the blue litmus paper. The poly- chrome methylene blue may be obtained already prepared. It can, however, be readily made by heating for several hours, on a water-bath, a solution consisting of- Methylene blue 1 part. Caustic soda 1 part. Water (distilled) 100 parts. After cooling, the solution is to be filtered. To this polychrome methylene blue an equal quantity of distilled water is added, and then, a saturated solution of or- dinary methylene blue, until the red color Is completely lost, the solution appearing simply blue. For this purpose about one part of the saturated aqueous solution to ten parts of the diluted polychrome solution will be used. A solution of eosin is now prepared, according to Nocht, by adding three or four drops of a one per cent aqueous solu- tion of eosin to one or two cc. of eosin. This is practically a 0.2 per cent solution; it can be made up in quantity. To three or four cc. of the eosin solution, Nocht adds the methyl- ene blue solution until the red color disappears. At this point a fine precipitate is thrown down, and a scum begins to form on the surface. I found it more satisfactory to keep the two solutions in burettes, as is done by Bastianelli and Bignami. The solutions may be made in large quantity, and the proper proportions in which they should be mixed may be determined once for all 6 vigorous use of quinine be followed by no definite break in the temperature curve, the case is not malarial. It has been definitely proved that continued fevers which resist quinine are due to other causes. The diagnoses of " Simple con- tinued fever " and of " Typho-malarial fever/' which were once so common in this very town, and are still, alas, only too frequent in certain parts of our country, all melt away before accurate laboratory methods, and resolve themselves generally into plain typhoid fever. Discussion. Dr. McCrae.-It is very often a debated question when one has overlooked a condition whether one prefers not to by a few experiments. The methylene-blue solution varies a great deal in the amount of the unknown nucleus-staining ma- terial which it may contain. One solution may require three parts of the eosin solution to each part of the methylene blue, while another, made in the same manner, may require only one part of the eosin solution to three parts of the methyl- ene blue. When the proper proportion is once determined for a given solution, it remains constant. The eosin and methylene blue solutions should be mixed im- mediately before use, and the mixture used only once. When kept a day or two, such a mixture may sometimes give the chromatin stain, but always feebly. Nocht fixed the blood-smears by placing them in equal parts of absolute alcohol and ether, but I obtained my best results by treating with a one-fourth per cent solution of formalin in 95 per cent alcohol, for one or two minutes. The formalin may be kept in 10 per cent aqueous solution, four or five drops of this being added to 10 cc. of 95 per cent alcohol, just before using. Before placing the specimen in the staining solution, the scum should be carefully removed by means of filter paper. It is best to use a staining-dish with concave bottom, placing the cover-slip on the bottom with the preparation side down. The specimen is left in the stain for from three to twenty- four hours. The scum should be carefully removed before taking out the cover-glass, as it tends to adhere to the speci- men if it comes in contact with it, making the examination difficult or impossible." The hyaline forms of the parasite appear as delicate blue rings. The central part of the parasite is occupied by a large colorless nucleus, at one side of which is a small spot of chro- matin substance which takes a deep carmine violet stain. [61] 7 [61] have considered the possibility of it or prefers to remember that it was considered and discarded. The way the tem- perature fell after admission made us think it was one of febrieula. With the onset of sudden chill and fever we at once thought of malaria and felt no doubt that we had over- looked that cause at first but repeated examinations of the blood were negative. The patient had definite signs at one apex, there was the continued fever with repeated sweats and she was going down hill very rapidly, so that I personally thought the case one of tuberculosis, although no tubercle bacilli could be found. It is a reproach often brought against the profession south of Mason and Dixon's line, that in tuberculosis time is often lost by treatment for malaria, and .1 suppose it is only fair that we should now have a chance to check up a case on the other side. I did think very decidedly that the case was one of tuberculosis of the lungs with secondary involvement of the peritoneum as the cause of the abdominal pain. 8 | Reprinted from American Medicine, March 1, 1902. | REMARKS ON THE DIAGNOSIS OF PANCREATIC DISEASE.1 BY WILLIAM SYDNEY THAYER, M.D., of Baltimore, Md., Associate Professor of Medicine in the Johns Hopkins University. It is not wholly encouraging to reflect upon the slight extent of our diagnostic abilities with regard to disease of the pancreas, to realize how limited are our resources for the detection of other than the most advanced and fatal stages of pathological change in what is perhaps the most important of our digestive organs. And yet the reasons for this condition are plain. Changes in the position, size, motility and secretory ability of the stomach are readily appreciable by simple methods of physical examination. In like manner many affections of the liver are easily recognizable. Interferences with its circulation produce demonstrable changes in other organs supplied by the portal system, while undue retention of its secretion becomes immedi- ately evident with the development of jaundice. Enlargements, circulatory disturbances and malpositions of the spleen are easily detected by palpation and often, indeed, by inspection. The pancreas, however, is so far removed from the surface of the body and so hidden by surrounding organs from the inquiring eye and the exploring hand that any moderate change in its size or consistency is wholly inappreciable. The points at which the ducts of the pancreas open are such as to render it beyond our power to study changes in the amount and character of the pancreatic secretion. While retention of bile is imme- diately recognized by jaundice, retention of the pan- creatic juice may be suspected only when grave sequels such as acute pancreatitis develop. The studies of recent years concerning the physiology and pathology of the pancreas have brought us valuable 1 Read before the New York State Medical Society, at Albany, on January 29,1902. 2 clinical assistance, yet today we possess no diagnostic sign of pancreatic disease. In the few remarks that I shall make this afternoon, I propose to consider briefly: 1. What criteria do we possess for recognizing gross anatomical changes in the pancreas? 2. What means have we for appreciating disturbances of function of the pancreas ? 3. The diagnostic features of the more important changes in the pancreas. 1. What criteria do we possess for recognizing gross anatomical changes in the pancreas ? The pancreas, situated behind the stomach and colon and extending from the duodenum to the hilus of the spleen, lies for the most part to the left of the median line across the epigastrium. The head, embraced by the descending part of the duodenum, lies just to the right of the median line in the closest connection with the common bile-duct. In the normal individual the pancreas is impalpable. In thin subjects, however, with separated recti, it may be possible to feel the body of the gland indistinctly. Enlargements of the pancreas due to inflammatory changes are rarely, if ever, palpable, owing to the tenderness and the consequent tenseness of the abdominal wall. Suppurative pancreatitis, however, is followed often by abscess of the omental bursa. This results in a tumor which has certain important charac- teristics. It is deeply situated behind the stomach and colon. It is immobile and does not descend with respiration. It fills the left hypochondrium and extends across the epigastrium ; it differs from a renal tumor mainly in its immobility and in the fact that it does not extend back into the flank. 2. What means have we of appreciating disturbance of function of the pancreas ? The digestive powers of the pancreatic juice are ex- tremely varied. It possesses a digestive ferment for albu- minoids, a fat-splitting and emulsifying ferment, an amy- lolytic ferment, as well as a ferment capable of coagulating milk. Perhaps the most specific of its powers is the fat- splitting action. This function is shared by the secretion of no other organ in the body, though a considerable amount of fat-splitting may be accomplished by intestinal bacteria. Observations of recent years have shown that the pancreas possesses another extremely important function in addition to its digestive powers. The classical observa- 3 tions of von Mering and Minkowsky,1 followed by those of L6pine,2 Hedon3 and others, have shown that the pancreas exerts an important influence upon the meta- bolism of sugar in the organism. Complete extirpation of the gland is always followed by rapidly fatal diabetes. Very large portions of the gland may be removed with- out apparent effect. If, however, but a very small frag- ment of the organ be left in the body, transient or ali- mentary glycosuria follows. (Minkowsky.4) If after complete removal of the pancreas bits of the organ be transplanted subcutaneously no diabetes occurs so long as the transplanted fragment remains in good condition. Atrophic changes in the transplanted bit of the gland re- sult in the reappearance of the diabetes (Minkowsky5 and Hedon)6 It is probable that this remarkable influence of the pancreas on the oeconomy is due to an internal secre- tion, but what this may be and what are its relations to the oeconomy are as yet unknown. The recent observa- tions of Opie,7 and Ssobolew,8 however, render it ex- tremely probable that its point of origin is in the lymphoid islands of Langerhans. From these circumstances it may be easily seen that in cases in which the symptoms suggest disease of the pancreas, the presence of glycosuria would be an impor- tant corroborative symptom. Indeed, the existence of diabetes itself is extremely suggestive of pancreatic dis- ease. In eight out of 16 cases of diabetes which have come to necropsy at the Johns Hopkins Hospital, Dr. Opie has discovered pancreatic changes, the one constant lesion being hyaline degeneration of the islands of Lang- erhans. The possible diagnostic importance of alimentary gly- cosuria as an indication of pancreatic diseaseis suggested by the observations of Minkowsky9 and Wille.10 The former showed that in instances of partial extirpation of the pancreas alimentary glycosuria occurred in cases in which, on a meat diet, sugar was completely absent. The clinical observations of Wille are also important al- though the pathological reports are unfortunately incom- plete. This author made observations upon 800 patients, 1 Arch. f. Exp. Path., 1889, xxvi, 371. « Lyon M6d , 1889, Ixii, 308. 3 Arch, de m6d. exp., 1891, ill, 41, 341, 526. ♦Centralbl. f. klin. Med., 1890, xi, 81. 5 Verhandl. d. xi Cong. f. Inn. Med , Wiesbaden, 1892, 89. 6 Arch, de physiol, norm, et path. 1892, 5 s., iv, 617. 'J. Exp. M.. N. Y., 1901, v, 397; Do. p. 527. 8 Centralbl. f. allg. Path. u. path. Anat., 1900, xi, 202. 'L. c. 10 Deutsch. Arch. f. klin. Med., 1899, Ixili, 546. 4 examining the urine in each instance after the adminis- tration by the mouth of 100 grammes of grape-sugar. The experiment was repeated in the positive cases. In 17 of these instances there was alimentary glycosuria. Of the 800 patients 77 came to autopsy. Of these 15 patients had shown alimentary glycosuria during life. In all of these cases marked pancreatic changes were found. Dis- ease of the pancreas, though in a much lesser degree, however, was found in other cases in which alimentary glycosuria did not occur. Unfortunately, an adequate description of the nature of the changes is not given, no attention having been paid to the islands of Langerhans. The experimental observation that a very large part of the pancreas may be destroyed without the subsequent development of glycosuria is supported by the histories of many cases of acute pancreatitis, notably those reported by Chiari,1 in which the greater part of the organ was discharged per ani without serious results. Wneiher, in such cases, temporary or alimentary glyco- suria would occur must remain for further observations to settle. It is, however, on the other hand, true that a very considerable proportion of cases of fatal diabetes show no demonstrable lesion of the pancreas. Experimental suppression of the pancreatic juice results in a material interference with the absorption of fat, and in some instances an excess of undigested fat may be clinically demonstrable in the stools even to the naked eye. But the presence of fat, excepting in very large quantities, may be' found under other circum- stances than pancreatic disease (jaundice, diarrhoea), while in many instances of far advanced destruction of the pancreas the examination of the stools by ordinary methods has revealed little that is striking. More elabo- rate analysis of the dejections tends to show that in addi- tion to the presence of an increased quantity of fat, the diminution of the fat splitting process as well as the presence of a relatively small proportion of soaps in com- parison to the fatty acids and neutral fats are conditions pointing to insufficiency of the pancreatic secretion. Oser 2 sums up the matter by saying: " We may positively assume only that disturbed digestion of fat may be an important symptom in pancreatic disease. The increased presence of fat in the stool is of itself, however, no reason for the assumption of a pancreatic 1 Wiener med. Wchnschr, 1880, xxx, 139,142, 164. 2 Die pathognostischen Symptome der Pankreaserkrankungf n. Die deutsche Klinik, &c., Berlin, 1901,151. 5 disease. If there be no icterus and no disease of the intestine; if an increased peristaltic action, with rapid passage of the fseces through the intestine, be not the cause of the insufficient digestion of fat, then suspicion of pancreatic disease is certainly justified." Interference with the digestion of albuminoids is also characteristic, though not diagnostic, of extensive pan- creatic disease. The presence in the stools of an unusal number of undigested muscle fibres is suggestive. Sahli's1 glutoid capsule test may prove of value in determining the albumin digesting powers of the pan- creatic juice. It is of course self-evident that in many cases of acute disease the diet of the patient is such as to interfere with the possibility of making certain of these observations. Time alone will determine their diagnostic value in other instances. Oser2 asserts that he has observed in a number of cases of pancreatic disturbance that a large part of the nourishment passes directly through the intestinal canal without being properly digested. " The constant loss of weight, despite ample diet, in association with abun- dant pasty or solid dejecta, a quantity which appears to exceed even that of the nourishment taken by the mouth-this is a striking symptom which demands the especial attention of the physician." (3) The diagnostic features of the more important changes of the pancreas. Acute Pancreatitis.-Acute pancreatitis, as has been demonstrated by a number of observers, usually arises as a result of the entrance through the duct of irritating sub- stances, chemical or bacterial. Opie3 has recently called attention to the extremely common association of pancre- atitis and cholelithiasis, and has demonstrated experi- mentally and clinically the method of origin of the dis- ease under these circumstances. A remarkable demon- stration of this method of origin is afforded by Halsted's recent case? In a smaller number of instances the con- dition has followed direct injury to the pancreas, as in a recent case of Selberg,5 in which the disease followed a kick in the epigastrium by a horse. 'Deutsche Med. Wchnschr.. 1897, xxiii, 6; Correspondenzbl. f. Schweiz. Aerzte, 1898, xxviii, 289, 329; Deutsches Archiv. f. klin. Med., 1898, 1x1, 445 ; Fromme, Muenchen. med. Wchnschr., 1901, Ixviii, 591. 2 Oser, Op. clt. 3 Amer. Journ. Med. Sci., 1901, cxxi, 27; Johns Hopkins Hosp. Bull., 1901, xii, lb2. 4 The Johns Hopkins Hosp. Bull., 1901, xii, 179. 6 Berl. klin. Wchnschr., 1901, xxxvlii, 923. 6 With regard to the diagnosis of acute pancreatitis, there is little to add to the masterly expositions of Fitz,1 who opened the path for the clinical appreciation of dis- eases of the pancreas. The patient is usually of adult life or middle age, corpulent, and in a considerable pro- portion of instances, of alcoholic habits. The history of attacks of biliary colic is not infrequent. The clinical picture of acute pancreatitis is so charac- teristic that it should be much more commonly recog- nized. The day has passed when the diagnosis of acute pancreatitis should be regarded as a good guess. The symptoms begin, as a rule, with sudden intense epigas- tric pain ; this may be referred to a point exactly in the median line, sometimes slightly to one or the other side, often indefinitely localized in the epigastrium. The abdomen, especially in the epigas'ric region, is dis- tended, rigid and tender ; in some instances the pain may be aggravated by pressure over the lower left ribs, which is communicated directly through the spleen to the tail of the pancreas. The pain is commonly of an agonizing character, resisting even large doses of morphia and sometimes necessitating the use of chloroform. There is vomiting of mucus, frequently bile stained. Constipa- tion is generally present, though diarrhoea may follow. The temperature is but little, if at all elevated; the pulse is usually accelerated, greatly, just before death. Cyanosis may be a striking symptom. In a large pro- portion of cases these symptoms are associated with pro- found prostration, and rapidly succeeded by collapse and death within three or four days. At first the symptoms may be confounded with an attack of biliary colic which may, indeed, as in one of my own cases, usher in the symptoms. Especially sig- nificant is the character of the pain which is more intense and constant than that of gallstones. Its intens- ity, its diffuse epigastric character, with occasional local- ization on the left side, the profound collapse, so com- monly present, should, however, suggest the true con- dition. Often a diagnosis of intestinal obstruction has been made, but the epigastric localization of the pain, its peculiar intensity, the absence in the great majority of instances of stercoraceous vomiting, the sudden and pro- found collapse should direct the mind of the clinician in the right direction. Especially important is the fact that in these instances the abdominal tenderness and disten- 1 Boston Med. and Surg. Jour., 1889, cxx, 181, 205, 229. 7 tion are commonly localized in the epigastrium, and that distended intestinal coils and peristalsis are never observable. The distinction from a perforative peritonitis is more difficult, but here also the suddenness and intensity of the symptoms, especially of the pain, the early collapse and the absence of previous history of gastric or duode- nal ulcer are important points. In instances of perfora- tion of the gall bladder following cholecystitis the symp- toms are in most instances localized in the right side. The possibility of mesenteric infarction should also be considered, and the differential diagnosis may be diffi- cult. The position and intensity of the pain and tender- ness may here be valuable points of distinction, together with the absence of those conditions commonly associ- ated with mesenteric embolism or thrombosis (cardiac disease- -arterio-sclerosis). It is rarely, if ever, possible to feel the inflamed pancreas owing to the tenderness and consequent tenseness of the abdominal walls. While this is the common picture of acute pancreati- tis, yet milder attacks may occur in which a diagnosis may be difficult or impossible. In any severe attack of epigastric pain the nature of which is not clear, pancrea- titis should be considered, especially if the pain be located to the left of the median line. If the possibility of acute pancreatitis be borne in mind errors in diagnosis will be less frequent. The continuance of these symptoms generally in a rather milder form, for days or weeks with the appearance of fever should suggest the development of suppurative, necrotic or gangrenous changes. In such cases as this careful study of the urine and fieces may reveal evidence of disturbance of pancreatic diges- tion (fatty stools, glycosuria, fragments of the pancreas in the dejecta, evidence of imperfect digestion of albu- minoids). While suppurative pancreatitis is usually a sequel of acute hemorrhagic inflammation, yet the onset may be more gradual and indefinite, associated with a continued or irregular fever, perhaps with chills, with epigastric ten- derness and rigidity. These may be the only symptoms for a considerable period of time, palpable tumor being often absent. Later, with the development of parapan- creatic abscess, the detection of a deep mass in the pan- creatic region renders the diagnosis much easier. How far the symptoms may be masked when the abscess of the pancreas is small is shown by a case which 8 came under my observation while I was a house physi- cian in the Massachusetts General Hospital. A localized abscess of the pancreas at the juncture of the head and tail caused by pressure, the complete obstruction of the com- mon bile-duct, resulting in a clinical picture suggesting carcinoma of the head of the pancreas or of the common duct. There was moderate hepatic enlargement and great distention of the gall bladder which was easily pal- pable. Death resulted from cholamiia.1 The successful results of operation with drainage in instances of suppurative pancreatitis have been so fre- quent as to render its detection of great clinical import- ance. It has been said previously in this paper that the retention of pancreatic secretion result in no symptom analogous to the jaundice which reveals the existence of biliary obstruction. Opie,2 however, has recently made a suggestion which may permit us to modify this s ate- ment. The disseminated fat necroses so commonly associated with acute pancreatitis have been shown to depend upon the action of the fat-splitting ferment of the pancreatic juice.3 While limited fat necrosis between the lobules of the pancreas may follow the escape of small quantities of steapsin such as may occur under a variety of circumstances, the more widespread lesions are only seen in association with acute pancrea- titis. The extent of these fat necroses is in some instances so great that it would be remarkable if some of the fat-splitting ferment did not enter the circulation. If this be the case may it not be demonstrable in the blood and in the urine? In a case occurring several months ago at the Johns Hopkins Hospital in which a diagnosis of acute pancre- atitis was made by Dr. McCrae, and confirmed at operation and at necropsy, Dr. Opie, in a small quantity of urine obtained post mortem made the following test for the presence of the fat-splitting ferment. The technique was that proposed by Professor Cassell and Mr. Loevenhardt and depends upon the decomposition by the ferment of carefully purified ethyl butyrate with the resulting 1 Fitz, Trans. Assoc. Am. Phys., 1890. v, 192. 2 Ke marks before the Johns Hopkins Hospital Medical Society, to appear shortly in the Johns Hopkins Hospital Bulletin. ■'Langerhans, Arch. f. path. Anat. (&c.), Berl, 1890. cxxii, 252; Festschr. Rudolf Virchow. 1891; Hildebrand, Centralbl. f. Chir.. 1895, xx, 297 ; Dettmer, Experimenteller Beitrag zur Lehre von den bei Pan- creatitis Heemorrhagica beobaehteten Fettgewebesnkrosen und Blu- tungen. Inaug., Diss., Gottingen. 1895; Flexner, I Exp. M., N. Y., 1897, ii, 413. 9 formation of butyric acid. The urine was neutralized by potassium dioxide and divided into two parts to one of which was added a few drops of ethyl butyrate together with a small quantity of litmus solution. The second part, used as a control, was boiled in order to destroy the ferment if present and ethyl-butyrate and litmus were added. Both specimens were kept for 24 hours at 37° C. At the end of this time the unboiled specimen had acquired a well marked acid reaction, while the control specimen showed little if any, change. Unfortunately the quantity of urine was so small that the test could not be repeated. Opie's observation and suggestion appear to me to be of very great clinical importance and well worthy the careful attention of clinicians. If it be possible to demonstrate the presence of a fat-splitting ferment in the urine of acute pancre- atitis we shall have our first diagnostic sign of pancreatic disease. Five cases of acute pancreatitis have occurred in the Johns Hopkins Hospital, three instances of acute luem- orrhagic pancreatitis, two of suppurative pancreatitis. The first case was that mentioned in Osler's textbook in which the patient was brought in as an instance of intes- tinal obstruction and immediately placed upon the oper- ating table, laparotomy revealing the true diagnosis. In the other four cases a correct diagnosis was made in three instances; once by Dr. Bloodgood, once by Dr. McCrae and once by myself. Both cases of suppurative pancreatitis presented palpable tumors greatly facilitat- ing the diagnosis. Pancreatic Hemorrhage.- The diagnosis of those instances of explosive hsemorrhage (pancreatic apoplexy) occurring in the absence of acute pancreatitis is based mainly upon the sudden onset of acute pain in the pan- creatic region, with vomiting, followed almost immedi- ately by collapse and death. The symptoms differ from those of acute pancreatitis only in their greater acute- ness and in their more rapid course. Chronic Pancreatitis.-Opie, in an article shortly to ap- pear in the American Journal of the Medical Sciences, re- ports observations upon 29 instances of chronic interstitial pancreatitis which have come to necropsy at the Johns Hopkins Hospital. The commonest cause of the disease appears to be obstruction of the duct by pancreatic calculi, biliary calculi in the terminal portion of the common duct, or carcinoma of the head or body of the gland. Ascending infection may result from lesions of the bile-passages or 10 duodenum. Persistent vomiting may favor an ascend- ing infection of the duct with resultant sclerotic changes. Chronic interstitial pancreatitis is not infrequently asso- ciated with cirrhosis of the liver, and is apparently dependent upon the same general causes. In the pan- creatitis associated with duct obstruction and ascending infection the lesion is interlobular, invading the lobules only secondarily and sparing the islands of Langerhans. Diabetes results only when the disease is far advanced. In that form of chronic pancreatitis occurring with hepatic cirrhosis and in that observed in hemochromato- sis the process is interacinar and invades the islands of Langerhans. With extensive disease of these structures diabetes appears to be the rule. A positive diagnosis of chronic interstitial pancreatitis is rarely possible. It is, however, strongly to be suspected in cases of diabetes developing in the course of well-marked cirrhosis of the liver or heemochromatosis, especially if examination of the fieces suggests insufficiency of the pancreatic juice. Pancreatic Lithiasis.-The diagnosis of pancreatic cal- culi is rarely to be made during life. Most cases are associated with grave chronic interstitial changes in the pancreas resulting often in diabetes. The sensations of epigastric pressure or pain mentioned in a number of these cases present little that is characteristic and, as Korte 1 has pointed out, may in many instances be due rather to secondary inflammatory conditions of the pan- creas than to the movement of stones. In but few instances has a correct clinical diagnosis of pancreatic calculi been recorded. In Lancereaux's2 case attacks of epigastric colic were followed by diabetes. In Lichtheim's3 case the patient suffered for a period of six years with severe attacks of epigastric pain, vomit- ing and fever, associated with constipation. Seven years later diabetes developed, resulting in death within a year. After the onset of diabetes the patient suffered with diarrhoea, the stools containing numerous fat crys- tals and an unusually large number of well preserved muscle fibres. In the case of Minnich4 and Holzmann 5 the patient, aged 68, had previously suffered from severe attacks of gall stone colic. Subsequently he became sub- ject to attacks of intense pain in the epigastrium and 1 Die chirurgigchen Krankheiten und die Verletzungen des Pan- kreas. 8° Stuttgart, 1898. 2 Bull. Acad, de m6d., Par.. 1888, 2 s., xlx, 601. 3 Berl. kiln. Wchnschr., 1894, xxxi, 185. 4Berl. klin. Wchnschr.. 1894. xxxi, 187. 6Muenchen., med. Wchnschr., 1894, xli, 3S9. 11 left hypochondrium. This began with a deep, pressing, girdling sensation in the epigastrium and at the left cos- tal margin, which caused the patient to take deep breaths, to press upon the part with his hands, and to move to and fro in the room. The pain increased in severity, but became localized under the left costal mar- gin inside of the mamillary line. At the height of the attack the pain radiated around to the spine and up under the left shoulder blade. As the attack passed off it became again localized in a single spot. The stools showed no fat crystals and no gall stones, but characteris- tic small round gray concretions were found on various occasions, the largest as large as a cherry-stone. Micro- scopically, these stones were amorphous, while analysis showed them to consist mainly of carbonate and phos- phate of lime. The case later developed intermittent glycosuria. Leichtenstern 1 has also observed a case in which, after attacks closely resembling biliary colic, but without jaundice, calculi consisting mainly of carbonate and phosphate of lime were passed in the stools. The diagnosis of pancreatic colic can be positively made only in association with the passage of stones. The attacks are closely similar to those of biliary colic, and may be associated with chills and fever. The limi- tation of the pain more particularly to the left side may be helpful in doubtful cases. Two instances of pancreatic lithiasis have come to necropsy at the Johns Hopkins Hospital. In both of these there were grave sclerotic changes in the pancreas, and in one mild diabetes was present. In neither case were there symptoms justifying an ante-mortem diag- nosis. Both cases have been reported by Opie.2 Tumors of the Pancreas. 1. Cysts.-Cysts form the largest tumors arising from the pancreas. The larger cysts, those which are clinically recognizable, have been shown by Lazarus3 to be, as a rule, true proliferating glandular cystomata, though large cysts following injury occasionally occur. The smaller retention cysts and those following degeneration, softening, auto-digestion and haemorrhage are rarely palpable. There is little in the history of these cases that is characteristic. Clinic- ally, the cyst appears as a large retroperitoneal tumor, presenting, as a rule, in the epigastric and umbilical 1 Handbuch Spec. Therapie, von Penzoldt abd Stintzing, 1896, Bd. v, 953. 2 J. Exp. M., N. Y , 1901, v, 397, 527. 3Zeitschr f. Heilkunde, 1901, xxii, (N. F., ii), H. vi, 165 and H. x, 216. 12 regions, particularly upon the left side, and extending out from the costal margin well past the median line. The largest of these tumors fill the greater part of the abdomen. They must be differentiated from cystic renal tumors, hydatid cysts of the liver, mesenteric cysts, retroperitoneal sarcomata and large abdominal aneurysms. From renal tumors they are usually dis- tinguishable by their immobility and in the fact that they do not reach back into the flank. From hydatid cysts they differ mainly in their deep position. The differentiation from retroperitoneal sarcomata is based mainly upon the fact that the latter are solid, while cystic tumors in this region are in the majority of instances pancreatic. Puncture of the cyst and examina- tion of the fluid may be of diagnostic value, though at the present day an exploratory laparotomy is advisable. The presence of bloody fluid or of any of the pancreatic ferments is suggestive of pancreatic origin. Three large pancreatic cysts have occurred in the Johns Hopkins Hospital within the last 12 years. In two of these the correct diagnosis was made before operation. Malignant Growths of the Pancreas.-Secondary in- volvement of the pancreas is rarely recognizable during life. The diagnosis of primary cancer of the pancreas often presents considerable difficulty. Large tumors, while they may occur, are unusual. Out of 10 instances of cancer of the pancreas occurring in the Johns Hopkins Hospital in which a positive diagnosis was made post mortem or at operation, in only three was a palpable tumor present. The differentiation of a large palpable solid tumor of the pancreas from retroperitoneal sarcoma may be extremely difficult. The presence of glycosuria or of evidence of deficiency of the pancreatic secre- tion would be strongly suggestive of pancreatic involve- ment. The commonest seat of cancer of the pancreas is in the head, which results in the early involvement or compression of the common bile-duct. The usual symp- toms of cancer of the pancreas are those of a complete obstructive jaundice with great distention of the gall bladder and rapid emaciation. These symptoms were present in seven of our 10 cases. Extensive metastases in the liver are unusual. In none of our cases were liver metastases demonstrable intra vitam. The condition is to be differentiated from primary cancer of the bile- duets, involvement of the glands at the hilus of the liver and obstructive jaundice from impacted stone. A posi- tive differential diagnosis between primary cancer of the 13 ducts and cancer of the head of the pancreas is often im- possible. The great dilation of the gall bladder which is frequently visible and palpable serves to distinguish the condition from impacted gall stone, where the gall bladder is rarely greatly distended. The symptoms are more suggestive if glycosuria, fatty stools or other evidence of retained pancreatic secretion are demonstrable. CONCLUSIONS. In conclusion, it may be said that while we possess as yet no diagnostic symptom of pancreatic disease, unless indeed, further observation should confirm the possibility of the demonstration in acute pancreatitis, of the fat-splitting ferment in the urine, yet clinical and pathological experience have taught us certain combina- tions of symptoms which justify a diagnosis in various forms of pancreatic disease. Acute pancreatitis should be recognized in many instances. The importance of an early recognition of those cases which go on to extensive necrosis and to suppurative parapancreatitis is easily appreciable. Chronic interstitial pancreatitis is to be suspected under the following conditions: (1) Instances in which glycosuria develops in an indi- vidual with chronic cholelithiasis. (2) In eases of glycosuria in association with cirrhosis of the liver. (3) In glycosuria in the course of hsemochromatosis. (4) In glycosuria following attacks suggestive of pan- creatic colic. Pancreatic lithiasis is recognizable only when calculi are found in the stools. Cysts the pancreas are usually to be recognized on " ■ their location. i r r cancer of the pancreas is often latent. The obstructive jaundice with distended gall- ' rapidly developing cachexia, in association >r no hepatic enlargement, is suggestive of this . Is-in the absence of diarrhoea or jaundice th indications of interference with the di- iminoids, are valuable confirmatory evi- :ency or absence of the pancreatic secre- tion. American Medicine FOUNDED, OWNED AND CONTROLED BY THE MEDICAL PROFESSION OF AMERICA George M. Gould, Editor Martin B. Tinker, Assistant Editor G. C. C. Howard, Managing Editor Subscription, $4 a year in advance A subscription to American Medicine is an endorse- ment of professional journalism LAENNEC. By WM. SYDNEY THAYER, M.D. Read Before the "Laennec," At the Johns Hopkins Hospital, February 7, 190^. REPRINTED FROM Maryland Medical Journal, March, 1902. LAENNEC. By Wm. Sydney Thayery M.D. READ BEFORE THE "LAENNEO" AT THE JOHNS HOPKINS HOSPITAL FEBRUARY 7, 1902. Rene Theophile Hyacinthe Laennec was born at Quimper, in Lower Brittany, on the 17th of February, 1781. His father was an advocate, a man of considerable education and scholarly tenden- cies. A classical student of no mean ability, something of a poet himself, he appears to have shared some of the traditionally ortho- dox finalities of poets, in that he gave little care or attention to the serious duties of life. In the words of Pariset, "There are men who, like Jean La Fontaine, with their eyes closed to the future, abandon themselves with cheerful thoughtlessness to the dangerous pleasure of remaining children all their lives." And when his wife died of consumption, the father manifested little responsibility for the care of his children, placing them under the protection of one of his brothers, who was the cure of the parish of Etian, at a time when Rene was but five years of age. Later, at the time of the general repression of the clergy, young Laennec was placed under the charge of another uncle, Guillaume Franqois Laennec, an eminent practitioner and professor of medicine in the Faculty of Nantes. Under the protection and stimulation offered by his excellent uncle he developed his first fancy for the studies to which he was later to give his life. Here, and later in Paris, he devoted himself with par- ticular assiduity to the study of Latin and Greek. Especially did he cultivate Latin, which he wrote and spoke with unusual fluency. He was familiar with his native Breton tongue, and devoted a good deal of time to the study of Celtic dialects, in which he became deeply interested. Under his uncle's guidance he began the study of medicine, and soon made his mark as a man of unusual ability. For awhile, in 1799, although he was as yet unqualified to practice, he was attached to the medical department of the army. In 1800, at the age of nine- teen, he entered the University of Paris, attaching himself especially to the clinics at the Charite. He became a favorite pupil of Cor- visart, whose name is well known as the expounder of Avenbrug- ger's great work on percussion. Laennec early attained distinction among his colleagues. In 1801, at the Concours, he obtained the first two prizes in surgery and medicine. His assiduity was remarkable, but, in addition to this, he showed a discriminating system in all that he did. In three years as a student he drew up minute histories of nearly 400 cases of disease, observations which were the basis of all his future work. He early began to communicate the results of his studies. His first 2 three publications in 1802 related, respectively, to a case of diseased heart, histories of inflammation of the peritoneum, and a review of Bell's "Treatise on Venereal Diseases." In 1804 he took his doctor's degree, his inaugural thesis being entitled "Propositions stir la doctrine d'Hippocrate appliquee a la medecine pratique." Bayle said, apropos of this publication, that it proved him to be no less accomplished in his knowledge of the Greek language than deeply read in the writings of the father of physic. After graduation, for five years he conducted, as chief editor, the Journal de medecine, and for two years lectured upon pathological anatomy. From 1805 to 1821 he was extremely active in the "So- ciete de 1'ecole,'" a medical society connected with the school. The nature of his work may be suggested by the following titles of pub- lications appearing during this time: 1802-3.-treatise on peritonitis in the Journal de Medecine. 1803-4.-A treatise on the capsule of the liver. 1804.-Description of an anatomical process by the aid of which the internal membrane of the ventricles of the brain can be dis- sected, of which the anatomists admitted the existence by analogy, but without having demonstrated it with the scalpel. 1804.-A treatise on pathological anatomy. 1805.-Monograph on vesicular worms, containing a description of several new species, and of the diseases and organic changes to which the presence of these worms gives rise in the human body. 1806.-A treatise on the melanoses, etc. 1806.-A treatise on angina of the chest; a treatise on a new species of hernia. In the Dictionary of the Medical Sciences Laennec also wrote on "Pathological Anatomy," "Hydatids," and "Encephaloides." Again, in the Journal de Medecine there appeared essays on "Sui- cide," "Disease of the Heart," "Hydrocephalus," as well as an ar- ticle on the "Brunonian System of Medicine," and the "Works and Doctrines of Gall." He was also a member of the Societe Anatomique. During this period Laennec devoted himself especially to patho- logical anatomy, bringing together numbers of careful and accu- rate scientific observations. He was one of the first to appreciate the fact that the clinical comprehension and appreciation of disease could rest only upon a thorough knowledge of the actual nature of the changes present, and that such knowledge could be gained only by careful and continued study of post-mortem appearances, and by comparing these with accurately-recorded clinical observations. His observations brought him into constant controversy with Brous- sais and his school, a controversy which was waged on both sides with considerable spirit, and in all these discussions the careful scientific spirit of Laennec became ever more apparent. The accuracy with which Laennec's observations were made is interestingly shown in these words from the preface to his great 3 work. He says : "I have always tried * * * to omit no detail, and especially those which serve to picture the object described, and to lead the reader, with the greatest possible independence, to weigh of himself the judgment of the author, in order that, if there be a chance, he may discover that which the author himself has not per- ceived. Indeed, I have not shut out some details which seem dis- connected with the case which we are endeavoring to investigate. An extract of an observation made with any particular end in view proves but little, and deserves little confidence. "All these observations have been collected in the following man- ner : When a patient enters the hospital it is the duty of a pupil to collect from him those anamnestic facts which he can give concern- ing his disease, and to follow their course. On examining the pa- tient myself, T dictate the principal symptoms which I observe- those especially which may serve to establish the diagnosis or indi- cations for treatment. And I confirm my conclusion, unless I may have to change it, by subsequent observations. This dictation, which is made in Latin for reasons easily appreciated, is taken down by the pupil in charge of the patient, and at the same time on a sep- arate sheet which I call the 'diagnostic leaf,' to keep which, in order that it may be shown to me and read whenever required at each visit, is the especial duty of another pupil. If a new sign appear, such as might modify the first diagnosis, I have that also added. If a pa- tient die, the account of the autopsy is collected by the pupil in charge of the case. I read this account before all those who have been present at the autopsy, and if any correction is to be made, I make it on the spot, after having consulted with them." Surely, one could ask today for no more satisfactory method of observation. While Laennec is especially known for his remarkable discovery of the value of mediate auscultation and the invention of the stetho- scope, there can be little doubt that even had he failed to discover this particular method of research, yet the records of his clinical and pathological studies, and the scientific influence which he ex- erted on those about him, could not have failed to leave a strong mark upon the history of medicine. His discovery of the stetho- scope, and his demonstration of the diagnostic value of the facts which might be brought out by its use, will, however, always stand out as the most striking incident in his career. One day, while traversing the court of the Louvre, Laennec is said to have seen some children playing about a long beam. One would place his ear at the end of the beam and listen, while another tapped lightly at the other end, the sound, of course, being well transmitted through the solid body. Several days later the idea came to him which led to the great discovery of his life. The his- tory of the first application of the stethoscope is rather entertaining, and it may be well to quote Laennnec's own description: "I was consulted in i8r6 by a young person who presented the 4 general symptoms of disease of the heart, with whom the applica- tion of the hand and percussion gave little result on account of her embonpoint. The age and sex of the patient rendering impossible the method of examination of which T have spoken (direct auscul- tation), I happened to remember a well-known acoustic phenome- non. If one place the ear at the extremity of a beam, one hears very distinctly the tap of a pin which is made at the other end. It oc- curred to me that one might perhaps make use of this property of bodies in the case with which I was concerned. Taking a sheet of paper, I made a tightly-rolled cylinder, one end of which I placed upon the precordial region, and putting my ear at the other end, I was as much surprised as satisfied to hear the beats of the heart much more clearly and distinctly than I had ever heard them by the immediate application of the ear. * * * "It occurred to me, incidentally, that this manner of examination might become a useful method, applicable not only to the study of the beats of the-heart, but also to that of all movements which might produce sound in the thoracic cavity ; that it might, therefore, be of value in the exploration of respiration, voice sounds, rales, and, per- haps, of the fluctuations of an effusion of fluid in the pleura or peri- cardium. With this conviction, I began immediately at the Necker Hospital [to the staff of which he had been appointed in 1816] a series of observations, which I have continued ever since. As a result I have discovered new and positive signs which are, for the most part, striking, easy to comprehend, and capable of rendering the diagnosis of almost all diseases of the lungs, pleura, and heart more certain and perhaps more circumstantial than surgical diag- noses established by the aid of a sound or the introduction of a finger." In May, t8i6, he read a memoir upon these methods of observa- tion before the Societe de 1'ecole, and on the 14th of that month he gave his first public demonstration of the stethoscope. His first stethoscope was turned in wood in the form of a straight cylinder, one and a-third inches in diameter and twelve inches long, with a bore one-third of an inch in diameter, extending quite through it. The tube was divided into two parts in the middle, so that it might, if necessary, be taken apart. In some instances, however, in listen- ing to the heart sounds, he used a solid wooden instrument. To this instrument he gave the name of stethoscope. By means of this new method of investigation valuable observa- tions were rapidly accumulated, and in June, 1818, he read an out- line of his method and the results obtained from it before the Acad- emy of Sciences. A committee, consisting of Portal, Pelletan, and Percy, was appointed to look into this communication. They ren- dered a cordial, but not especially enthusiastic, report. The follow- ing are the closing words: "Your commissaries, in extending to Dr. Laennec, who is already very favorably known by learned re- 5 searches upon divers medical subjects, all the justice which is his due, have further the honor to assure the Academy that this physi- cian, of whose titles to public confidence and esteem it is well aware, has merited its particular appreciation and an especial testimonial of its satisfaction for the new work by which he has done it honor." In 1819 he published the first edition of his famous work entitled "Del'auscultation mediate; ou,traite du diagnostic des maladies des poumons et du coeur, fonde principalement sur ce nouveau moyen d'exploration." It is scarcely possible in a paper of this sort to enter into an extensive description of this work which is one of the epoch- making publications of the century, but I cannot resist a quotation from the preface, which expresses, perhaps, as clearly as anyone has expressed it since, a few plain truths concerning the method of ap- proa,ching the study of medicine. He has spoken of the absolute necessity of a division of his work upon a basis of pathological an- atomy. "I have," he says, "moreover, gained much in clearness and brevity by adopting this anatomical method. Pathological anatomy is a much more exact science than symptomatic nosology, and presents more distinct objects for study. It is much easier to describe tubercles and to indicate their symptoms than to define the pulmonary phthisis of clinicians, and to seek to establish diagnoses according to causes. Emphysema of the lung, a description of which will be found in this volume, is an alteration which may be described exactly in a few words, while its signs may be easily exposed in such a manner as to lead to their recognition. One would not easily ar- rive at a like precision by studying asthma in the manner of Sau- vages. Before arriving at anything positive one would have to con- secrate a volume to generalities. One may, perhaps, say that the anatomical method has the inconvenience of founding distinctions, the principal characters of which cannot well be verified excepting by the opening of the cadaver. It is scarcely worth while to contra- dict this objection. One might as well say that surgeons are wrong in distinguishing a fracture of the neck of the femur from a disloca- tion of the head of this bone, and that one should not distinguish as different conditions pulmonary catarrh and peri-pneumonia. "The alteration of organs is, without comparison, that which is most fixed, most positive, and least variable in local diseases. It is upon the nature and the extent of these alterations that the danger or the curability of these diseases always depends. It is, therefore, that which should characterize or distinguish them. The disturb- ances of function which accompany these alterations are, on the con- trary, very variable. They may be the same under the influence of totally different causes, and, as a result, one may rarely rely upon them to distinguish conditions very different, indeed, from one another. "One would be wrong, moreover, in thinking that nosological dis- tinctions, established according to the results of pathological re- 6 search, cannot be recognized excepting in the cadaver. They are, on the other hand, easier to recognize in the living individual, and present, even then, to the mind something much clearer and more positive than any nosological distinction founded upon symptoms. Peritonitis is certainly a disease easy to recognize in the living, and among twenty physicians with a good foundation in pathological anatomy whom one might call about a patient affected by this dis- ease, not one would fail to recognize it, nor would one differ from the others as to its designation. Could one, however, say the same of physicians accustomed to see nothing in their diseases but the symptoms ? Would not the necessary result be that one would see an ileus, another an hepatic colic, a third a puerperal fever, etc.? One may say the same of peri-pneumonia, of nephritis, hepatitis, etc., and I hope that, after reading this work, all will agree that the same holds in connection with the greater part of the diseases of the lungs, of the pleura, and of the heart. "Pathological anatomy is, then, unquestionably the torch which will most surely guide the physician as well to the recognition of disease as to the treatment of those which are susceptible of cure." The appearance of this work in 1819 created widespread interest. One would be far from appreciating the true significance of Laen- nec's work if he assumed that this treatise represented only a dem- onstration of the possible results to be obtained by a new method of exploration. It is full of accurate clinical observation and reason- ing, and contains many valuable anatomical observations. He was the first to describe the anatomical condition of the lungs in emphy- sema. To his descriptions of bronchiectasis there is little to add today. His views upon the unity of tuberculous processes, which were bitterly assailed at the time, have, in the light of the observa- tions of the last twenty years, been wholly upheld. Laennec's success as a pathologist, a clinician, and teacher rap- idly increased, but his industry and enthusiasm led him to work far beyond the limits of his physical strength, and in 1820, broken down in health, he was compelled to leave Paris for his home in Brittany. His condition at this time appears to have been one of neurasthenia, associated with marked mental depression. An out-of-door life and the fresh sea air soon brought back health and spirits. His improve- ment was so great that he was loth to leave his home, and it was only from a sense of duty that, after two years, he returned again to Paris to renew his labors. On his return he supplied the chair of Halle at the College de France, and in 1823 he succeeded his master, Cor- visart, as professor of clinical medicine. His success as a teacher and a practitioner increased. He became the physician of the Duchesse de Berri, and of one of the Cardinals. As a teacher his fame grew apace, and among those seeking his clinics were many foreigners. At the same time he undertook a complete revision of his treatise on auscultation. This, with his many other duties and cares, was no light task, and his health began rapidly to fail. He was, how- 7 ever, able to finish the revision of his work, and then, in 1826, a phy- sical wreck, advanced in pulmonary tuberculosis, he retired for the last time to his native Brittany. He was no exception to the common rule, and at the end declined to recognize in himself that which he would have been the first to discover in another. He died on the 13th of August, 1826, at the age of forty-five. In 1868, by the subscriptions of French and foreign physicians and of his compatriots of Brittany, there was erected in the Cathe- dral Square at Quimper a monument which bears this inscription: "A 1'inventeur de l'auscultation, Laennec, Rene Theophile Hyacinthe, Ne a Quimper, le 12 fevrier 1781, Mort a Plouare en 1826; Professeur a la Faculte de Medecine de Paris et au College de France, Membre de 1'Academic de Medecine. Ce monument a ete eleve par 1'Association generale des Medecins de France, par la Bretagne, et par les Medecins franqais et etrangers, 1868." Personally, Laennec must have been an interesting character. Very slight and small, with a delicate complexion, he was apna- rently a singularly simple and attractive person. Even-tempered, mild and genial in his manners, he was especially courteous and considerate to his students, and particularly to the foreigners who flocked to his clinic. With certain of his own countrymen, especi- ally the supporters of Broussais, Laennec was, however, not espe- cially popular. Opposed with vigor, even with virulence, by Brous- sais' school, Laennec's wppGipiUoR-was so spirited that it could but have caused irritation. He is said to have been in many ways inde- pendent, refusing often the calls of the rich, while his charity placed him always at the service of the poor. Although slight in stature, he was yet very fond of outdoor exercises and field sports, and took particular pleasure in referring to his strength and prowess in these pursuits. Remarkably interesting are the closing words of Pariset's eulogy: "Rare man, who combined with so many talents so many excellent qualities, especially justice and tolerance; singular man, of puny stature and delicate complexion, who, disdaining the subtle and deep intelligence with which nature had endowed him, put his pride in his superiority in physical exercises, in social arts and in certain mechanical industries. But, after all, if we but listen to Cuvier, Cuvier was not a naturalist-he was an administrator; if we listen to Girodet, Girodet was not a sublime painter-he was a poet, and in like manner Laennec was but a breath of air, and he thought himself a Hercules. He transposed the facts, and the vigor of his mind he placed in his muscles. Innocent failings, impercep- tible blots, especially on the brilliancy of those great and exemplary lives, so full of glory because they are useful." Remarks on Typhoid Fever BY WILLIAM SYDNEY THAYER, M D. BALTIMORE, HARYLAND. FROM THE ST PAUL MEDICAL JOURNAL 1902 [Reprinted from The St. Paul Medical Journal, April, 1902. v REMARKS ON TYPHOID FEVER* By William Sydney Thayer, M. D., ASSOCIATE PROFESSOR OF MEDICINE IN THE JOHNS HOPKINS UNIVERSITY BALTIMORE. Among the conclusions of the admirable report of Reed, Vaughan and Shakespeare on typhoid fever in the army during the Spanish war are found the following statements: "(6) Typhoid fever is so widely distributed in this country that one or more cases are likely to appear in a regiment within eight weeks after assembly. * * * "(45) About one-fifth of the soldiers in the national encamp- ments in the United States in 1898 developed typhoid fever. * * * "(46) Army surgeons correctly diagnosed about one-half the cases of typhoid fever." And in the text, under this latter conclusion, one finds the fol- lowing statement: "Moreover, we have shown in the body of our report that in recognizing nearly half the cases of typhoid fever the army surgeon probably did better than the average physician throughout the country does in his private practice." We know today, that typhoid fever is, in the truest sense of the word, a filth disease. We have learned in recent years much concerning its etiology and much concerning the manner of in- fection. We know that it is a preventable disease, and we know a great deal which should help us toward preventing it, which has, in other regions, led to measures reducing the disease to a minimum. Yet typhoid fever still prevails among us in the United States to a degree which is a reproach to our country. Whose fault is it? I fear that it is in part our own. The public at large are distressingly ignorant of the first principles of protection against the disease, and the burden of the instruction of the public falls upon us, and on us alone. And a share of the responsibility for the fact that, as Dr. Osler put it a few years ago, "This is God's own country, with man's own back yard and the Devil's own cess pool," comes back to us. As to the cause of these facts and the methods which may be employed to bring about a change in affairs, there is far too much for me to even attempt to say. And I mean today, in rather a rambling manner, to touch only upon a few special points; to say a few words with regard to diagnosis, a few with regard to treatment and a few with regard to certain special measures of precaution upon which we, as physicians, should insist. •Made before the Worcester Section of the Massachusetts Medical Society, at Wor- cester, April 10,1901. 2 It is not long since typhoid fever was classed in the text books among the diseases of the intestines, and today the term "en- teric fever" is far too prevalent. It is true that intestinal lesions are the rule in typhoid fever, that intestinal symptoms are fre- quent ; but the intestinal manifestations play often a relatively small part in the general symptomatology of the disease, and are very frequently absent, while in a certain smaller proportion of cases the intestinal lesions even may be entirely wanting. What is typhoid fever? Typhoid fever is a general infec- tion due to the entrance into the economy of a specific micro-or- ganism, the bacillus of Eberth. This, as is well known, enters, in the great majority of instances, through the gastro-intestinal tract. Whether the organisms multiply to any great extent in the intestinal canal is as yet an unsettled question. It is probable that this multiplication is not extensive. From the intestinal canal they are absorbed through the lymphatic apparatus and tend to accu- mulate in certain special points, namely, the solitary follicles and Peyer's patches in the intestine, in the mesenteric glands and the spleen. They are, however, distributed throughout the body and may be found in considerable numbers in the liver and in the bone marrow and other organs. In the majority of cases of typhoid fever the bacilli are probably present in the blood through- out much of the course of the disease; that is, a true septicemia exists. In ii out of 15 cases from which Dr. Cole has recently taken cultures, using large quantities of blood, typhoid bacilli have been obtained. From these especial points of accumulation a poison is produced which brings about the essential symptoms of typhoid fever. As is well known, this poison is not set free in the culture medium by growths of the typhoid organism outside of the body, as is the diphtheria toxine; it has been shown to be in some way intimately connected with the substance of the bacterium itself, as in the case of the spirillum of Asiatic cholera. For a cer- tain length of time the growth of the bacilli and the development of the poison increase, but gradually the organism reacts, and there appear in the blood serum substances capable of destroying and di- gesting the micro-organisms, which eventually result in the eradi- cation of the infection and the subsidence of the symptoms of the disease. The essential features of typhoid fever are caused by the gen- eral intoxication, and not by the intestinal lesions. As has been said, the essential seat of the infection is not of necessity in the in- testinal canal, but in various points within the organism. At these points where the typhoid bacilli tend especially to accumu- late, there arise the more marked anatomical lesions. These le- sions may reach a degree of intensity sufficient to cause local manifestations which may play an important part in the disease picture. But these Ihcal manifestations are not absolutely essen- tial and are very variable in extent. 3 When we consider typhoid fever in this light, we must realize that the more essential symptoms of the disease are those of a general septicemia. There is not one single necessary symptom of typhoid fever, nay more, there is not one pathognomonic symp- tom. Let us consider for a moment what are the more essential manifestations of typhoid fever, those due to the general in- fection. (i) Fever, which is usually of gradual onset and subsidence, which is generally continued, and which, as a rule, lasts about three weeks. But how many variations do we see to this common picture! (a) In the first place, with regard to onset, it is not rare for typhoid fever to begin suddenly. It is common for the onset to be associated with chills. These have occurred in nearly one-fourth of Dr. Osler's cases. (b) With regard to defervescence, there are instances, though rare, in which the disease ends almost by crisis. (c) With regard to the continuous character of the fever, there are great variations in exceptional instances. (d) With regard to the duration, it should be remembered that abortive cases lasting no longer than a week are by no means very unusual, while instances of typhoid fever of many weeks' duration are not uncommon. (e) Lastly, there are apparently undoubted instances on rec- ord in which the fever has been practically absent. (2) The second general symptom of importance is the evi- dence of a general intoxication which often has, to be sure, cer- tain rather striking characteristics-the familiar "typhoid condi- tion." The patient tends to be dull and drowsy and apathetic. The low muttering delirium, the picking at the bed clothes, the subsultus and tremor characteristic of more severe cases, it is un- necessary to emphasize. But there are many cases in which scarcely any of these symptoms are present, and all may occur in severe septicemias from other causes. Indeed, in the majority of instances well cared for from the beginning, a slight dullness or drowsiness or apathy is the only one of these symptoms which is observed, while the patient may be bright and nervous through- out. (3) Enlarged spleen. Splenic enlargement is always present, but often not demonstrable. The spleen, however, was palpable in 71 per cent, of Osler's 829 cases. But again enlarged spleen is the rule in all septicemias. (4) The characteristic roseola is an important sign when present, but it may be absent or very slight and may be simulated in other conditions. Thus, in one case of trichinosis we have ob- served a very similar rash, which is in accord with the observa- tions of Blumer in an epidemic in Albany. The rash was present in 80 per cent, of Dr. Osler's 829 cases. 4 (5) Bronchitis. A slight bronchitis is one of the most con- stant and often early symptoms of typhoid fever, but it is in no way pathognomonic. These are, I think it is fair to say, the more essential symp- toms of the typhoid intoxication. With the exception of rose spots they differ but little from those often met with in other septicemias; frequently thev may be the only symptoms present. Of particular help, however, are those symptoms which depend upon local lesions due for the most part to the changes resulting from the accumulation at those points of the typhoid bacilli. (i) The first of these is diarrhea, which, it is fair to say, may be in part dependent upon the general intoxication. While diar- rhea is a common manifestation both at the onset and during the course of typhoid fever, it is far from being a necessary symp- tom, as is testified to by the fact that out of 829 cases in Dr. Osler's clinic, it was present in only 38.8 per cent, before en- trance to the hospital, and in but 19 per cent, while under treatment in the hospital. (2) Abdominal tenderness, especially in the ileo-cecal region, is sometimes present in the early stages, but often absent. (3) Tympanites, again, is a symptom present only in occa- sional cases. (4) The graver complications of hemorrhage and perforation may be the first symptoms which reveal the true nature of the case. (5) Lastly, there are the various complications due to focal disturbances produced by special localization of the typhoid bacil- lus or by secondary infections, such as phlebitis, periostitis, chole- cystitis, parotitis, pleurisy, etc., certain of which, especially com- mon in typhoid, may at times help in the diagnosis. How then are we to make a diagnosis of typhoid fever if there be no diagnostic sign? In the same manner in which we should arrive at a diagnosis in the majority of conditions with which we have to deal. Diag- nostic signs are rare. We must carefully observe our patient clinically, and, by a process of judicious exclusion and careful association of the various points in the history of the case and in the symptoms presented, we shall in most instances be led to the proper conclusion. Of great help is the examination of the blood and of the urine. In the urine we find commonly, after the first week, Ehrlich's diazo reaction. In the blood there is a complete absence of the leucocytosis which is so generally present in acute febrile processes associated with local inflammatory foci. Of prime im- portance is the Widal reaction which appears usually after the eighth or tenth day of the disease; when present in a sufficient dilution it is almost pathognomonic. The Widal reaction may, however, be very late in appearing. Of great significance are the results obtained by blood cul- tures taken according to the method recently practiced by Dr. Cole in Professor Osler's wards. By making bouillon cultures and using 8-10 cc. of blood in a large quantity of the medium, Cole obtained positive results in n out of 15 cases,* the blood having been taken at various stages in the disease. In several of these instances the bacilli were obtained from the blood before the appearance of the Widal reaction. But such cultures are often impracticable. The- Widal reaction may not come on until late. The rose spots are not seen until the end of the first or in the second week. It is important to remember that it is rarely possible, under the best circumstances, to make a positive diagno- sis of typhoid fever before the latter part of the first week, and in many instances up to the appearance of the Widal re- action the diagnosis must be readied by a careful process of exclusion, after weighing all the symtoms. But the physician who has intelligently observed much typhoid fever will arrive a* a proper conclusion before the appearance of the Widal reaction in a majority of instances. Why then should three experienced and intelligent observers make the statement that probably less than half the cases of typhoid fever occurring in this country are recognized ? The rea- sons are various. The most important, however, is probably de- pendent upon our methods of medical education. To make a proper diagnosis of typhoid fever requires a certain amount of clinical experience. This cannot be gained by book knowledge. And yet, up to a very few years ago, how many young men started out in the practice of medicine without ever having followed a case of typhoid fever from beginning to end! How many, alas, are compelled to do so to-day! What sort of a picture do these men have in their minds of typhoid fever. They see often a typical Liebermeister's typhoid curve. They believe in cer- tain "cardinal symptoms" of the disease; the presence of rose spots, diarrhea, "intestinal symptoms," the "typhoid condition," a palpable spleen, a fever which lasts 14 or 21 or 28 days. If the majority of these symptoms be absent the case cannot be typhoid fever. But rose spots, abdominal symptoms, palpable spleen, the "typhoid condition" are not only occasionally, but are frequently, absent. Upon the time-honored but absolutely groundless belief in the relation of the duration of fever to the week, it is scarcely nec- essary to insist. There is no evidence whatever to support the idea of critical days in tyhoid fever. In the absence of these symptoms the individual whose knowl- edge of typhoid fever is derived from books is often at sea. And with a mortality of under 10 per cent, and a percentage of autop- sies outside of hospitals so low that it is hardly worth mentioning, how are men deprived of hospital experience to learn? A few 5 •These cultures, continued during the past year under Dr. Cole's observation, have given positive results in over 80 per cent, of the cases. 6 months as a student in a tyhoid fever ward gives one the experi- ence acquired in years of private practice-experience acquired, moreover, before the mind is laden with crystalized, preconceived ideas and while the cerebral arteries are yet soft. Let us consider a few points which may assist in the diag- nosis of typhoid fever in cases where rose spots and abdominal symptoms are absent, where the Widal test is impossible or not yet positive. The commoner conditions with which typhoid fever is con- founded are infections of other sorts, in which the primary seat is not evident, especially ulcerative endocarditis, general tubercu- losis and certain forms of malaria. Some cases of influenza may, for a time, give rise to serious suspicions of typhoid fever, and finally there are occasional instances of late syphilitic fever which may cause confusion. The confusion in the case of influenza disappears with time, though at the onset, and for several days, there may be no positive method of differential diagnosis. With regard to other infections: Almost all of these show a leucocytosis in addition to the common tendency toward irreg- ularity of temperature. The presence of a well-marked leucocy- tosis is strong evidence against the existence of uncomplicated typhoid fever. And in almost all of these infections careful con- sideration of the history or thorough physical examination will reveal the point of origin. Iodide of potassium clears up the case in the event of syphilis. General tuberculosis without local manifestations is happily not common. In cases of general tuberculosis with continued fe- ver, without leucocytosis, especially if there be enlarged spleen and a diazo reaction, confusion for a time is almost inevitable. Time alone will here reveal the true nature of the case. In considering the relations between typhoid fever and ma- laria we come to a point which cannot be too much emphasized and which has been far too little recognized. The confusion of typhoid and malaria which exists in this country to-day is appall- ing, and it is not limited to any special region. Let me give you a few facts concerning this question: In the year ending 1890 more deaths from malaria were reported in the city of Brooklyn than from typhoid fever, and yet we know today that of these fatal cases of so-called malaria the great majority were probably typhoid fever, pure and simple. During the Spanish war an enor- mous proportion of the cases of typhoid fever were classed by army surgeons as malaria. In the report of Reed, Vaughan and Shakespeare we find the following figures: "The total number of probable cases of typhoid fever among the 92 regiments studied was 20,738. Of these 10,428, or 50.27 per cent, were diagnosed as typhoid fever either by regimental or hospital surgeons. Most of the cases improperly diagnosed were sent to military hos- pitals or to civil hospitals with a diagnosis of malaria. In 7 80 out of 85 cases sent from the Fifth Maryland to civil hospitals in Baltimore, the diagnosis was changed from malaria to typhoid fever. Out of 98 cases sent from the Eighth New York to hospitals in New York City on September 9th, all were recognized as typhoid fever by the physicians in charge of the hospitals, while the majority of these cases had been entered on the sick reports under other diagnoses'." Ninety-two cases of supposed remittent fever from 20 regimental organizations of the Second Army Corps at Camp Alger were transferred to Fort Myer, Virginia. Here they were carefully studied, with the following result: In 31 cases the disease was found to be of an absolutely different nature, the diagnosis being changed to rheumatism, febricula, debility, heat prostration, pleurisy, pneumonia, acute bronchitis, acute diar- rhea and acute conjunctivitis. Of the remaining 61 cases of sup- posed remittent fever the diagnosis was changed in one case to tertian intermittent fever, and in 60, or 98.3 per cent, to typhoid fever. Of 101 cases of supposed malarial fever transferred to the hospitals at Hartford and New Britain, Connecticut, by the First Connecticut Infantry on its departure from Camp Alger, Virginia, September 7th, 1897, 98 received the diagnosis of ty- phoid fever and only three the diagnosis of malaria; this diagnosis was based on the fever curve and not on blood examinations. This is a state of things which is, alas, only too frequent, and such mistakes are largely based on the failure to appreciate a fact which is as definitely proven as anything in the practice of medi- cine, namely, that quinine is a specific for malaria, and that no fever which resists quinine, properly administered, is malarial fever. If treatment be instituted at the beginning of an attack and the patient be put to bed, the temperature will always break in three or four days, usually before. The therapeutic test is absolute and definite. In the United States, continued fever without apparent cause, which is resistant to quinine, espe- cially if there be no leucocytosis, is in the vast majority of in- stances, typhoid fever. Wherever such a case occurs one is justi- fied in making a probable diagnosis of typhoid. What are the mild continued fevers which, in the words of the reporter, "present none of the symptoms of typhoid fever," and are resistant to quinine? What are the continued fevers which, not infrequently, begin with a chill and last several weeks without special local manifestations-the so-called "typho-ma- larial fevers?" In the great majority of instances they are defi- nite, unmistakable typhoid fever. Wherever hospitals and labora- tories and trained clinical observers have advanced, the diagnoses of "simple continued fever," of "typho-malarial fever," and of the "third fever" have disappeared. Where proper blood examina- tions and autopsies are made, the justification of this fact is ever forthcoming. The common continued fever of the United States, north, south, east and west, is tyhoid fever, and the sooner we recognize it and acknowledge it the better. 8 There exists among the public and among the medical pro- fession, and justly, the feeling that the prevalence of typhoid fever in any district is a reproach to the community. It is well that such a feeling should exist, but it occasionally brings about rather distressing results. It is extraordinary to see how far one's local pride may influence one's good judgment. This has, perhaps, been better shown by the behaviour of a large part of the public, including, unfortunately, a considerable number of medical men with regard to yellow fever, and even more recently in connection with bubonic plague. If the physician has any duty plainly before him, it is to acknowledge openly the existence of any preventable infectious disease which occurs in his neighborhood. But in epi- demics of typhoid fever there are, unfortunately, some of us whose wish is father to the erroneous diagnosis of "malaria." Today, with our present knowledge, every physician should realize that it is far better to err on the other side,-to suspect typhoid fever, and institute or strengthen proper precautions with regard to the case and the community. A word with regard to methods of treatment. We have no specific against typhoid fever. We possess no antitoxine such as we have against the poison of diphtheria; we know as yet of no method by which we can definitely stop the growth of the or- ganism. In a large proportion of cases of typhoid fever, in all at the beginning, we have no local lesion which we can in- fluence by active treatment. We are confronted by a general septicemia, and the essential principles of the treatment of typhoid fever are the same as if we were dealing with an instance of ul- cerative endocarditis, namely, (i) complete rest; (2) a diet as nourishing as the condition of the patient will allow; (3) meas- ures to relieve the hyperpyrexia and to keep the skin and muscles in as good condition as possible; (4) an ever careful watchfulness for the various dangerous complications. A word with regard to the diet. It should be generally recog- nized that the diet is a very important point in the treatment of typhoid fever; perhaps not in the sense that we must absolutely restrict our patient to milk and liquids, but in that we must adapt our diet to the condition of the patient. There is no question of the fact that liquid diet is best adapted to most cases of typhoid fever, but there are many instances with few ab- dominal symptoms, a reasonably good general condition and a fairly good appetite throughout, in which considerable latitude of diet may be allowed, and in which variety is really important. I can do no better than to refer you to the excellent article by Dr. Shattuck upon the diet in typhoid fever in the Journal of the American Medical Association [1897, XXIX., 51]; As Shat- tuck justly says, we must treat out patient, and not the disease. It is necessary in text book articles to lay down certain gen- eral rules, but he who blindly practices medicine from text book 9 rules has a small conception of his duty to the community. If medicine could be practiced by rule, the function of the physician would be small. , The value of the cold bath treatment of typhoid fever, which was well recognized by Nathan Smith, of New Haven, in 1824, is unquestionable. It should be remembered, however, that its value is not alone in reducing temperature. The general effect upon the circulation and the nervous system, and the judicious massage which should always accompany the sponge or the bath, probably play an important part in contributing to the good ef- fect. With regard to the care of the bowels in typhoid fever, the conclusion which has been generally reached by most experienced clinical observers is that it is undesirable to administer laxatives by the mouth or to interfere any more than is absolutely necessary with the function of the intestine during the course of the fever. Considering the nature of the lesions which are commonly present, it seems to me that this is the rational course. In Professor Osler's clinic it is the general rule to give enemata every other day in case of constipation, but otherwise to strictly let the case alone. With regard to the so-called intestinal antisepsis, the main reasons which seem to me to render attempts in this direction in- advisable at present are: (1) That the demand for the so-called intestinal antisepsis is based upon a misconception. At the time when we begin treat- ment it is probable that the number of typhoid bacilli in the in- testinal canal is inconsiderable; the symptoms are due entirely to bacteria which are already within the organism and out of our reach. (2) That to accomplish anything like effective intestinal an- tisepsis is utterly impossible. (3) That there is no evidence of any value in support of the efficacy of intestinal antisepsis so-called, in the treatment of ty- phoid fever. With regard especially to a certain "method" of treatment which has been extensively advertised, the same reasoning ap- plies, and, in addition, there are, it seems to me, other excellent arguments against its employment. It is extremely important that the patient with typhoid fever should be disturbed as little as possible, but the constant dosing, such as is associated with this method of treatment is the worst type of meddlesome therapeutics. In addition to this, diarrhea, which may be caused by the calomel, is unquestionably harmful in some cases. There is no evidence that the treatment is of value. This method has, so far as I know, only one recommendation: it is good for the nervous family. The essential features of the treatment of typhoid fever are rest, diet, bathing and massage, proper nursing, together with watchful symptomatic and stimulating treatment, and, as I have 10 said, careful, intelligent observation of the case in order to rec- ognize at the earliest moment the more dangerous complications. This latter point is one of the most important in the treatment of typhoid fever. The complication which it is most important to recognize is, I need not say, perforation. But a few years ago perforation following a typhoid ulcer was regarded as necessarily fatal. In 15 cases of typhoid perforation operated upon by sev- eral surgeons connected with the Johns Hopkins Hospital in the last few years, there have been 6 recoveries, or 40 per cent. In Professor Osler's clinic alone, 11 cases have been recognized and operated upon, with 5 recoveries, a percentage of 45.4 per cent. This percentage is unquestionably higher than is likely to be obtained in private practice owing to the advantages offered by a hospital for careful observation of the patient. The one im- portant point in the treatment of typhoid perforation is that it be recognized as early as possible. But the onset of the perfora- tion is frequently extremely difficult to determine, and a diag- nosis is often to be reached only by the careful weighing of every symptom. Frequently recorded observations of the patient, of his pulse, of his respiration, his temperature, the condition of his leucocytes, are of the utmost importance; and in carrying out such observations the physician in a hospital has a great advan- tage over the colleague in private practice. This advantage is largely due to the multiplicity of assistants and the freedom from disturbances by injudicious friends. A hospital in which clinical instruction is given offers distinct advantages over one in which stridents are not admitted to the wards. This is a point which has become very strongly impressed upon me during the last several years, since which time several students have been as- signed to each ward in the Johns Hopkins Hospital as clinical clerks. It is a point which I should like to emphasize. The pub- lic and many physicians are too often afraid of students. It is not uncommon to hear of hospital trustees refusing to allow clini- cal instruction in the wards out of a fancied regard for the wel- fare of their patients. But to any who have observed carefully hospitals in which clinical instruction is and is not given, the ques- tion is as clear as day. That ward which has most student assist- ants, subject, of course, to proper regulation, offers the best treat- ment to its patients. I feel sure that several lives have been saved within the last year or two in oiir wards owing to the possibility of keeping proper records of the blood alone; these lives would have been lost five years ago, when such records would have been impossible. That patient receives the best treatment whose case is most studied. For an interesting and valuable consideration of the early recognition of perforation in typhoid fever I would refer you to Professor Osler's article in the Lancet for February 9, 1901. One word with regard to the dangers of operation. In the hospital ward where the patient can be moved with facility an 11 exploration of the abdomen under cocaine may be made today al- most without shock, and in many suspected cases of typhoid per- foration exploration is the conservative course. * * * That typhoid fever should prevail among us to the extent' in which it does is, as I have said, a reproach to our country, and its prevalence is doubtless due in part to the ignorance of the general public with regard to its manner of origin and the possi- bilities of its prevention. What are the ordinary sources of infection? Primarily the infection always comes from man, the original sources from which the disease spreads being the fecal and uri- nary discharges of an infected individual. Any substance taken into the gastro-intestinal canal may be the bearer of infection. The world, however, has come to look upon water as the main or only source of danger. It is true that infected water has been at the bottom of many of the largest typhoid epidemics, especially in the larger cities and towns, but in the enormous number of cases of typhoid fever which developed during the late war an infected water supply played probably a relatively small part. It is easy to see how almost any article of food may become in- fected, and many articles of food constitute excellent culture media for the typhoid bacillus. Thus the epidemics depending upon infected milk, due to the watering of milk or the washing of cans with infected water, are familiar to all. A number of typhoid organisms, which might perhaps be harmlessly ingested by a healthy individual, may, if introduced into a vessel of milk, develop into a culture which may suffice to spread the disease to many families. But the transmission of the bacteria by water is by no means the only method of spreading the disease. The nurse or attend- ant not infrequently contracts typhoid fever from direct contact with soiled clothes or the body of the patient, and too great care in washing the hands before handling articles of food cannot be insisted upon, for the attendant may not only infect himself, but may readily, from his hands or clothes, spread the infection to other articles of food or to other individuals. It is more tha,n probable that dried fecal matter with bacilli yet living may be spread to a certain extent in dust, and if the infection by inhala- tion be impossible, which it is fair to say is not proven, yet the mere dissemination by dust may serve to deposit organisms capa- ble of growing upon various articles of food which may constitute good culture media. An extremely important method of transference of infected material to articles of food has been shown to be carried on through the agency of flies. It is probable that many of the cases in the military camps during the last war were due to the direct trans- mission of the bacilli from uncovered fecal matter to articles of food. L. O. Howard has shown that the domestic fly which 12 haunts kitchens, will often lay its eggs in human feces; and in one military encampment he observed, walking upon the food, flies whose legs were stained white from the lime which had been put into the common pit used by the company. An especially dangerous source of infection is revealed by the recently demonstrated fact that virulent typhoid bacilli may re- main present in the urine for long periods of time after recovery from the disease. These facts suggest of themselves certain elementary steps which should be taken everywhere. In the first place it is a crying shame that all our large cities should not adopt measures properly protecting the basin from which their water is drawn, or install proper filtration plants. It is humiliating to hear our countrymen so frequently advise their friends and relatives to avoid drinking water in European cities, while at home they use with freedom water which is infinitely more dangerous. Where the water supply is imperfect, we should always boil all water used for domestic purposes, and we should remember that there is danger, not only in the water we drink and in that with which we wash our dishes, but in that with which we wash our bodies and clean our teeth. We should also recognize and remember the fact that typhoid bacilli may, and unquestionably do, live for considerable periods in ice. He is inconsistent who boils his water and uses ice, con- cerning the origin of which he is uncertain. Park has recently shown that typhoid bacilli may remain virulent for as much as eighteen weeks in ice. » We should remember that any uncooked article of food which has been washed in, or exposed to contaminated water may be dangerous. It is more than probable that lettuce and greens employed for various salads have more than once conveyed the disease; in- deed, manure consisting of human feces is sometimes employed for bleaching lettuce and celery. Of prime importance is it to impress upon the public the danger of neglecting to exercise the utmost care with regard to the disposition of the excreta of typhoid patients. Tn country districts these should always be disinfected, and should never be deposited where they may be left uncovered- When we consider the prevalence of flies at the height of the typhoid season, and the ordinary privy arrangements of the simple country houses, how easy it is to appreciate the possibility of the transmission of infection by means of flies. It should be the duty of every physician who has a case of typhoid fever under his care to instruct the family in the nature of the process, and in the danger of failing to insist upon proper measures of caution, and the State and County and Town Health Boards should see to it that such measures are carried out. 13 I have already, in these rambling remarks, said more than I had intended, and yet, before I close, I cannot resist mention- ing one point which has been strongly impressed upon my mind by the report upon typhoid fever in the army to which I have so frequently referred. One cannot but be struck, despite the favorable comparison which the authors think they are justi- fied in drawing between the army surgeons and physicians in general-one cannobbut be struck with the proportion of mis- taken diagnoses. One reason for these mistakes they have not mentioned. These are days of specialism. In our larger cities few surgeons do any extensive medical practice, and yet medical officers of our militia are almost invariably selected from the sur- geons rather than from the practitioners of internal medicine. In one regiment, with which I am familiar, in which large numbers of cases of typhoid fever occurred, almost none of which were rec- ognized by the Surgeon in Chief, the staff consisted of two sur- geons and a neurologist. The proportion of soldiers dying from disease is, as a rule, considerably greater than those dying from wounds, and this fact should be recognized in the appointment of medical officers to our volunteer troops. It is excessively im- portant that there should be at least one man with every regiment who is familiar with those diseases which prevail most commonly in camps; and there should be some recognized division of duty and responsibility. I would close with the plea that our medical schools should arrange their courses of instruction so that students, before grad- uation, may have had a certain amount of actual ward experience, such as is required in many foreign, especially English, univer- sities. Such experience is absolutely necessary. There are no difficulties in the way of such instruction which cannot be over- come in time, and the sooner that time arrives, the better for us all. The St. Paul Medical Journal. EDITED AND PUBLISHED BY TF|E RAMSEY COUNTY MEDICAL SOCIETY, Lowry Arcade, St. Paul, Minn. A Monthly Medical Journal, owned by a ; Medical Society and conducted in the in- I terest of the Profession. It contains selected [ Original Articles, Society Reports, Editor- [ ials, and Book Reviews. It reviews the world's Medical Periodicals, making a spe- I cial feature of the Scandinavian literature, which has heretofore been largely lost to the world, due to the scarcity of competent translators. i ONLY ETHICAL ADVERTISEMENTS ' RECEIVED. Minimum Circulation 2.500. Subscription $2.50 ; per annum. C=5T=».<=^_=5^3 <=«=» ==3 £== JI Notes on a Case of Acute Haemor- rhagic Polymyositis. BY WILLIAM SYDNEY THAYER, M.D., Associate Professor of Medicine in the Johns Hopkins University, BALTIMORE, MD. Reprinted from the Boston Medical and Surgical Journal, Vol. cxlvii. No. 12, pp. 313-317, September 18, 1902. BOSTON DAMRELL & UPHAM, PUBLISHERS 283 Washington Strbbt 1902 NOTES ON A CASE OF ACUTE HAEMOR- RHAGIC POLYMYOSITIS.1 BY WILLIAM SYDNEY THAYER, M.D., BALTIMORE, MD., Associate Professor of Medicine in the Johns Hopkins Uni- versity. It is only within the last fifteen years that our attention has been called to the various forms of acute polymyositis apart from that occurring with trichinosis. Since the publications of Wagner,2 Hepp,8 Jackson 4 and Unverricht5 in 1887, a con- siderable number of observations have, however, been reported. Lorenz in his excellent study of diseases of the muscle in Nothnagel's Handbuch di- vides the polymyositides into the suppurative and non-suppurative forms. Acute non-suppurative polymyositis he distinguishes from instances of myositis in association with peripheral neuritis such as have been reported by Senator, Siemerling and others. The acute polymyositides Lorenz di- vides into (1) dermato-myositis ; (2) polymyositis haemorrhagica; (3) polymyositis in association with erythema multiforme ; (4) a number of unclassifi- able cases. All these forms of acute polymyositis have, however, much in common, and it is a seri- ous question whether one should regard such a classification as that of Lorenz as more than 1 Read in part before the Association of American Physicians at Washington in May, 1902. 3 (a) Archiv. d. Heilkunde, 1863, iv., 282; (b) Deutsch. Arch. f. klin. Med., 1886-1887, xl, 241. 3 Berl. klin. Wchnschr., 1887, xxiv, 297. 4 Boston Medical and Surgical Journal, 1887, cxvi, 498. 5 Zeitschr. f. klin. Med., 1887, xii, 533; Munch. Med. Wchnschr., 1887, xxxiv, 488; Cor. bl. d. allg. aertytl. Verein v. Thiiringen, Weimar, 1887, xvi, 207. 2 a mere division for clinical convenience. The main symptoms of that type of polymyositis to which Unverricht has given the name dermato- myositis consist in the development, usually after prodromal symptoms of weakness and malaise, of local muscle swelling and tenderness and pain in association with extensive oedema and .cutaneous eruptions of varying character and extent. The oedema in the affected areas is often extreme and commonly is of a hard, board-like character. The affected area may at first be slight, as in the case of L6pine,6 or it may involve the greater part of various large muscle groups. The muscles in the affected region are tense, swollen and usually very tender. The tenderness may be extreme. The cutaneous eruption may be erythematous, papular, urticarial, and in some instances has shown the characteristics of erythema nodosum. Parsesthesiae in the affected extremities are not uncommon. These changes usually spread from one part to another, involving sometimes the ma- jority of the voluntary muscles. Fever is almost always present, though it may be of moderate ex- tent. (Edema of the face and eyelids, as in trichi- nosis, is a frequent symptom. The spleen is pal- pable. In several cases there has been more or less subsequent muscular atrophy. The course of the disease is generally progressive, death co- curring in the majority of instances from exhaus- tion or affection of the pharyngeal or laryngeal muscles. Recovery occurred in but five of twenty cases tabulated by Steiner.7 (In this article, the advance sheets of which have been kindly lent me by Dr. Steiner, there will be found full refer- ences to the literature and an exhaustive discus- sion of the subject.) The affected muscles in the 6 Rev. de m^d., 1901, xxi, 426. 7 Unpublished manuscript of an article to appear in the Jour- nal of Experimental Medicine. 3 acute stage show marked oedema, together with various degenerations, granular, waxy, fatty and vacuolic. In the earlier stages there is more or less interstitial small celled infiltration in the af- fected areas. From this class of cases Lorenz distinguishes polymyositis haemorrhagica. Here the onset is apt to be somewhat more sudden and associated with less fever, though this is by no means always the case. In most instances the onset is asso- ciated with the development of a relatively small, nodular, tender area generally in one of the mus- cles of the extremities ; this is rapidly followed by more or less extensive cedema, which may be as marked as in dermato-myositis. The skin may show an haemorrhagic or measly eruption, while later a yellowish green discoloration may give evidence of the presence of deeper extravasations of blood. The course is much as in dermato-myo- sitis, the percentage of recoveries among the re- ported cases being, however, somewhat higher - four out of ten cases which I have collected.8 I have included among these ten cases only those instances the haemorrhagic nature of which is rea- sonably certain. There are other cases in litera- ture which probably belong to this class, as for instance, two of those of Levy.9 The general symptoms are usually less severe than in derma- to-myositis, and as Lorenz says : "The muscle dis- ease as such, that is the inflammatory affection of each separately diseased muscle, represents a more or less individual process which runs its 8(a)V^ron: Arch, de m^d. et de pharm. mil., 1888, xi, 481; (b) Prinzing; Munch. Med. Wchnschr., 1890, xxxvii, 846; (c) Fenoglio: Rivistaclin. Arch. Itai, diclin.med., 1890, p.497; (d)Buss: Deutsch. Med. Wchnschr., 1894, xx, 788; (e) Lorenz: Op. cit.; (/) Neubauer Centrbl. f. innere Med., 1899, xii, 289; (^) Bauer: Deutsch. Arch. f. klin. Med., 1899, Ixvi, 95; {h) Struppler: Deutsch. Arch., f. klin. Med., 1900, Ixviii, 407; (i) Georgievskyi: Bolnitsch. Gaz. Botkina, 1901, xii, 696; (j) Thayer: (Present case.) Berl. klin. Wchnschr., 1893, xxx, 420, 449, 475. 4 course independently of the inflammation in other muscles, and affects the general condition of the patients, either because of the implication of vital muscles, or as a result of the great number of muscles affected." Lorenz especially emphasizes the frequency of circulatory symptoms due to affection of the heart muscle. In some instances, as in the case of Fen- oglio,10 marked atrophy may follow the acute symptoms. The excised muscle has shown changes varying from simple haemorrhages be- tween unchanged muscle bundles, as seen in the case of Neubauer,11 to appearances similar to those observed in cases of dermato-myositis with the addition of a greater or less amount of interstitial haemorrhage. At a later stage more or less marked atrophic and sclerotic changes may be found. In addition to these types Lorenz places in a separate class the myositis sometimes observed in association with erythema multiforme. The clin- ical symptoms are, in most respects, similar to those observed in the preceding classes, and the excised muscle in one instance showed like changes. In another group Lorenz places a few atypical cases which he has been unable to clas- sify. The aetiology of polymyositis is as yet uncertain, and various theories have been advanced. Its association in a number of instances, with other infectious processes, together with the fever and severe constitutional symptoms sometimes ob- served, has suggested its probable infectious origin. The observations of Bauer,12 Georgiev- skyi13and Bacialli14 would tend to support this theory. 10 Rivista clin. Arch. Itai, di clin. m^d., 1890, xxix, 497. 11 Centrbl. f. inn. Med., 1889, xii. 289. 12 Deutsch. Arch. f. klin. Med., 1899, Ixvi, 95. 13 Bolnitsch. Gaz. Botkina, 1900, xii, 696. u II Policlinico, 1902, No. 13, Sez. m^d., fasc. 1 e 2, 16. 5 The first of these observers reports the case of a man of thirty-nine who died in the tenth week of an acute haemorrhagic polymyositis. The im- mediate cause of death was, as has been the case in so many instances, the involvement of the heart muscle. There was severe pain in the af- fected areas, but little fever, the temperature dur- ing eight days of observation ranging between 37° and 38.6° C., only three times reaching a point above 38°. Sections of the muscles and of the area of involvement in the wall of the left ventri- cle showed haemorrhages, and in areas marked degeneration of the muscle fibres with a striking increase in the nuclei. This instance, however, differed from most of those which have been re- ported in the existence of an abundant infiltration with leucocytes, which almost justified the classifi- cation of the case as a suppurative process. Pure cultures of staphylococcus aureus were obtained from the muscle. Bauer believes that this ob- servation justifies the conclusion that a part, at least, of the severe instances of polymyositis de- pend upon septic infection. Georgievskyi's observation relates to a charac- teristic case of polymyositis of thirty-three days' duration, ending in recovery. There was but lit- tle fever, but evidence of marked inflammatory changes in the muscles and skin. There were very tender, firm swellings of the muscles, and areas of hard, cedematous infiltration of the skin. These manifestations were fleeting, rapidly chang- ing from one place to another, and having a dis- tinct hiemorrhagic character. From a vein of the forearm 10 cc. of blood were taken, from which there developed on agar several colonies of staph- ylococcus albus. The author was further con- vinced that these colonies indicated a true systemic infection by the fact that he was able to 6 demonstrate the presence in the serum of the pa- tient of a substance preventing the liquefaction of gelatine cultures of the same organism. Bacialli reports a characteristic case of poly- myositis of five months' duration, belonging more particularly to Lorenz's division of dermato-myo- sitis. During a febrile period a bit of muscle was removed from the left leg. In the blood flowing from the wound a coccus was found microscopi- cally. After twenty-four hours, however, no colo- nies had appeared on an agar culture. From the tube in which the muscle had been placed a pure culture of staphylococcus albus was obtained. From these results the author concludes that the case may be regarded as an instance of general infection with the staphylococcus albus. In view of the universal presence of the staphylococcus albus in the deep layers of the skin the results in the two latter cases can, however, hardly be con- sidered as conclusive. The following case, which would seem to fall into Lorenz's class of polymyositis haemorrhagica, is believed to be worth reporting on account of the rarity of the condition : X, thirty-four years old, married; a patient of Dr. Barshinger of York, Pa., consulted me on Feb. 21, 1902. His mother died of tuberculosis. In other re- spects his family history was good. He had had mea- sles, mumps and whooping cough as a child. At one period as a young man he was rather dissipated, but of late years has been temperate; urethritis fourteen years ago. For fifteen years he has had what he calls " rheumatism." In his own words: " As well as I can remember I was troubled with rheumatism about fif- teen years ago and off and on ever since that time. The worst attacks did not stay with me more than a day or two at a time. It starts in the different joints and feels like an electric shock going through the joints and muscles of my arm and leg, jumping from the right 7 arm to the left arm and from the right leg to the left leg, my worst pains acting and feeling about like the worst shock you gave me yesterday. The pain shoots through the joints and muscles and makes them twitch and cause me a great deal of pain, but if I remain very quiet, it generally passes off in a few minutes. At times I have to remain quiet or in bed for the best part of a day before the pain will cease. Very often when it attacks me in the afternoon, by going right to bed it will pass off by the next morning. While these atA tacks were very seldom years ago, of late years damp- ness or cloudy weather brings them on." On Dec. 21, 1899, while doing some heavy lifting he "wrenched" his arm and "it appeared as if the joint in the shoulder had jumped out of the socket." There was no great pain, but the whole arm became greatly swollen. This was especially the case in the upper arm. There was some slight dull pain in the shoulder. The forearm and hand showed a softer oedema. The upper arm was hard and board-like, especially along the region of the biceps, and was of a purplish color, looking as the patient expressed it, as "if a vein had burst." After three or four days everything cleared up. Six or eight months later the arm again became greatly swollen and purplish along its flexor side and somewhat so on the forearm. There was also slight pain in the front of chest running back through the shoulder. This lasted for about ten days, after which he was quite well until one day last autumn when after a fall, he felt a slight snap in the dorsum of his left foot. This was followed by oedema of the foot and leg which lasted for several weeks. His phy- sician states that the foot at this time was very red and somewhat mottled in appearance, but he is uncertain as to whether there was any distinct muscular hard- ness in the leg. The oedema of the leg disappeared after several weeks, but the foot remained somewhat cedema- tous for several months. Excepting for these attacks the patient has felt perfectly well, though whenever he lifts any heavy weight, a slight transitory swell- ing of his right arm and shoulder commonly follows. " It seems that from that time " (the initial attack) " on, my arm was weak, and if I exercised it or lifted any- thing heavy with it, I would get pain in the shoulder and it would commence to swell up again." In a letter he says: "There is seldom if ever a day goes by that I do not have a little shooting pain in some of my 8 joints or muscles. My right arm for the last two years has felt more or less numb at times and very often feels as if pricked with needles. This has been getting worse, and at the present time this numbness or sleepi- ness very seldom, if ever, leaves my arm. My hand and fingers are seldom without the numb feeling, and nearly always feel as if they were pricked with needles. This feeling may leave me on a very bright, clear day but while today is a very bright and cheerful day, I have this numb feeling in my right arm and my hand feels numb, as if it was pricked with needles, something like taking an electric shock all the time." Six or seven days ago, at about three in the after- noon, without apparent cause, the right arm suddenly began to swell. This was associated with a slight tingling, stinging sensation. By the end of five hours the swelling of the upper arm was so great as to en- tirely fill out a loose shirt sleeve. The skin was red and hard and board-like, though there was slight pitting on firm pressure. Three days after this the forearm and hand became oedematous - a soft oedema. There was no severe pain except for occasional slight stinging, lancinating sensations in the affected area and a general feeling of numbness extending down into the hands, a sensation as if a bee were stinging him. Twenty hours ago when he went to bed there was marked oedema of the right forearm and hand. On waking up in the morning he found that this had entirely cleared up. While the swelling had diminished to a certain extent in the upper arm, he noticed a fresh swelling of the right breast. There is a slight stinging pain at the present time in his right chest and arm. There has never been any very great tenderness in the affected area. He feels perfectly well in all other respects. The doctor thinks there has been no fever. Physical Examination.- The patient is a healthy looking man; lips and mucous membranes of good •color; tongue clean; skin cool. The right arm and shoulder are considerably swollen, as is also the right pectoral region as compared with the left. The swell- ing of the arm extends from the shoulder to the elbow, and is limited almost entirely to the bicipital region. The posterior part of the deltoid is also distinctly swollen. There is an enlargement of the pectoralis major on the right, the external fold being clearly thickened. The biceps is apparently greatly enlarged, 9 standing out as if in marked contraction. On the right as the arm is hanging by the side, it measures at its largest point, 35.4 cm.; on the left, 29 cm. The skin over this area is tense and somewhat reddened. Above it is not oedematous; below it is more reddened, and over about the lower third of the arm, extending, on the inner side, a little further up toward the axilla than it does in front, it is of a deeper, more cyanotic color and very hard and board-like; it pits however, on firm pressure. About 6 or 8 cm. above the elbow there is a transverse, purplish, discolored area about 4 by 1 cm. in extent. In the axilla and around below the pectoral fold there is a distinct yellowish green discoloration of the skin, suggestive of deep haemorrhage. There is a slight enlargement of the right mammary gland. The redness, the patient says, is much diminished. There is, apparently, no swelling whatever of the triceps. The infraspinatus and teres muscles are very prominent on both sides. There is a well-marked crepitus about the shoulder-joint as the pa- tient moves the arm up and down, marked on the right, slight on the left. This appears to arise in the substance of the deltoid muscle. The power of the right biceps seems to be fairly good. On account of the condition of the muscle it was deemed inadvisable to allow the patient to make marked effort. It is striking that al- though the swelling of the arm gives the impression of a contracted biceps, yet the movements of the muscle are scarcely to be felt when the patient actually flexes his forearm. Heart.- The apex impulse is visible and palpable in the fifth space 9| cm. from the median line; sounds clear; first, slightly reduplicated at the apex; the sec- ond sounds are of normal relative intensity. The lungs are clear throughout. The abdomen is negative except that the spleen is just palpable. On the following morning, the swelling of the arm appeared to be slightly diminished, though the dis- coloration in the axilla was a little more evident. A piece of tissue about 2 cm. in length by 2 to 3 cm. in depth, together with a little skin, was removed under cocaine by Dr. Tinker from about the middle of the an- terior surface of what was supposed to be the biceps. On cutting through the skin there was some oedema, due in part probaby to the cocaine which was used; no apparent thickening of the skin; no evidence of in- flammatory changes. There was very free bleeding 10 from a small subcutaneous vein. On cutting into what was supposed to be the muscle there was a gush of about 50 cc. of blood-stained serum. On squeezing the arm there presented at the opening a mass of old, dark clot, dating probably from early in this attack. About 10 cc. of this were squeezed out. The tissue re- moved was very pale and oedematous in appearance, somewhat yellowish in color, with dark haemorrhagic streaks. The urine was of rather pale color; acid; specific gravity, 1013; no albumin, no sugar; sediment inap- preciable. The blood showed: Red corpuscles, 4,328,000; color- less corpuscles, 4,000 to the c. mm. Dried specimens colored by Ehrlich's triple stain, showed nothing re- markable in the appearance of the red blood corpus- cles. A differential count of the leucocytes showed: Small mononuclears, 23.1%; large mononuclear and transitional forms, 9.1%; polymorphonuclear neutro- philes, 65.8%; eosinophiles, 1.7%; mastzellen, 0.1%.' The patient left for his home immediately after the removal of the tissue from his arm. Dr. Barshinger reported that eight days later, the arm had returned to its normal size, and the stitches were removed, the wound having healed by first intention. Sections of the tissue removed on Feb. 22 and har- dened in Zenker's fluid, were stained by a variety of methods, haematoxylin and eosin, methylene blue and eosin, van Giessen's stain, Mallory's stain, etc. Dr. MacCallum, who kindly studied the specimens, makes the following report: "The specimen consists of skin with underlying subcutaneous tissue and supposedly part of the biceps muscle. Sections were made verti- cally through the skin in two directions at right angles to one another and stained by various methods. The skin with its appendages is normal. The small blood vessels are surrounded by a loose network filled with cells of the type of plasma cells. Among the connec- tive tissue vessels of the corium are many red blood corpuscles lying free. The subcutaneous tissue is ex- tremely oedematous and there are considerable haemor- rhages throughout it. In the wide spaces between the tissue elements there is a fine fibrillar network, pos- sibly partly fibrin. In these meshes there are rather numerous round cells, somewhat larger than a poly- morphonuclear leucocyte with single ovoid, or slightly irregular nucleus and abundant protoplasm, in which 11 lie granules of a yellowish brown color, probably iron containing pigment produced by the destruction of blood in the adjacent haemorrhages. As the tissue was fixed in Zenker's fluid, tests such as Perl's ferrocyanide tests are inapplicable. The subcutaneous fat lies in little masses through which abundant blood vessels run. Some of these look as though new-formed. One of these is packed with leucocytes, and its walls are infiltrated with similar cells. Below these bundles of fat cells we reach a denser connective tissue in which the fibres are not so widely separated. There, as in the more superfi- cial layer, there are elongated cells with ovoid nucleus, lying between the separated fibre bundles which seem to be at least very young elements. These fibroblast- like elements seldom, if ever, contain the haematoidin pigment shown by the free round cells lying among them. Below this tissue lies a still more dense layer of connective tissue made up of coarse bundles of wavy fibres, seen in Mallory's and van Giessen's stain, to be made up of connective tissue. In the interstices of this tissue the blood vessels are extremely numer- ous. " Underlying this, which has the appearance of a fas- cial layer, there are only widely scattered bundles of mature connective tissue fibres embedded in a tissue, made up almost entirely of one type of cell, but abun- dantly furnished with blood vessels. This tissue varies in its density and in alternating layers through which the characteristic cells are the same, although the in- tercellular substance may be more or less compact. The cells have an elongated vesicular nucleus, and a very long cell body which runs out at each end into a long delicate fibril. Often the cell body is branched, the process like the cell body of the simpler forms being drawn out to long, sharp "points. The quantity of intercellular substance varies as stated very mark- edly. It stains well with the connective tissue stains. In the interstices there are great quantities of red cor- puscles lying free. There is no muscle to be seen any- where in the section. There is therefore beneath the fascia a great new growth of tissue, the main mass consisting of cells of the type of embryonic connective tissue cells with numerous new-formed blood vessels. Both in the connective tissue cells and in the walls of the vessels mitotic figures are very abundant. This tissue, as well as the overlying subcutaneous tissue, is evidently cedematous and full of haemorrhages." 12 These remarkable appearances, together with the clinical observation that the apparently greatly swollen biceps muscle could not be felt to contract when the arm was flexed, would appear to indicate that the muscle itself was buried in a mass of subfascial oedema and haemorrhage, the clot undergoing a process of rapid organization. June 27, 1902. The patient was visited at his home today. He states that although in good health, he has been unable to lift heavy weights with his right arm, and is under the impression that when he at- tempts to do so a slight swelling of the biceps follows. He complains of weakness on that side, especially on lifting his arm to his head, and of numbness and tin- gling particularly in damp weather. The "shooting pains" of which the patient previously complained, "are increasing instead of diminishing." On inspec- tion he looks well. The arms appear to be about equal in size though the biceps is perhaps a little smaller on the right than on the left. The forearms are equally well developed. There is still a slight discoloration at the point where the purpuric patch was previously ob- served. The extensor muscles stand out rather strik- ingly, more so apparently on the right than on the left. On the right side the arm measures 29.7 cm., the left, 29. The right pectoralis major below and outside of the nipple appears to be slightly atrophied as compared to the left. The posterior part of the deltoid seems also rather less prominent on the right than on the left, while there is a distinct flattening in the infra- spinous region. The same rather general plump- ness of the muscles is observed as on the first exami- nation. The grip of the hands is good, slightly less powerful on the right than on the left. The power of the flexors of the fore'arm is also apparently slightly dimished on the right. There is distinct loss of power in the right deltoid and pectorals. Sensation to touch is everywhere good. Sensation to pain (prick of pin) is rather remarkably dull all over the body, but not more so on the right than on the left. The patient not infrequently fails to distinguish the head from the poinP of the pin unless the stab be very sharp. The deep reflexes at the elbow and wrist are with difficulty elicited on both sides. There is no tenderness over the nerve trunks. After the tests of strength the patient complained of numbness and 13 tingling in the right hand and fingers; the sensation, however, remained good. Electrical examination shows a general dimished ex- citability to both galvanic and faradic currents in the biceps and flexors of the forearm on the right side, in the deltoid, and very strikingly in the muscles of the right infraspinatus region in which but little response could be obtained. The difference between the reac- tions on the right and left to both nerves and muscles appear to be quantitative rather than qualitative. July 13, 1902. The patient came to Baltimore today. He had been feeling well and nominally attending to business, although doing but little work. Niue days ago he moved into the country for the summer, and at that time did a little more lifting than usual. About a week ago he began to suffer from pains in the calves of his legs and in his right arm. The pain in the legs was of an aching character with occasional sharp lightning- like flashes darting into his calves. This, at times, has been bad enough to interfere somewhat with his sleep. Yesterday afternoon at about four or five o'clock his arm became more painful. At the same time there was an aching pain in the calves of his legs. He felt hot and thirsty and ill and was compelled to lie down. The right arm then began to swell, especially just above and inside of the elbow and on the inner side of the fore- arm. There was also some swelling about the shoulder. Both calves seemed to be somewhat swollen, and the patient asseits that he felt distinctly feverish. He " seemed to be swelled up all around." The pain in the arm and legs lasted for some time into the night, the arm feeling as if it were enveloped in a hot band- age. There was profuse sweating, limited to the arm. On examination the right arm was found to be swollen, especially just above the elbow joint on its inner side and over the ulnar group of muscles in the forearm; there is a slight greenish yellow discoloration of the skin extending about 5 or 6 cm. upwards on the inner side of the arm and downwards over the ulnar group of muscles for about 8 cm. In the middle of this area is a group of small purpuric spots. The skin feels tense as compared with the same area on the left side, and there is a hard subcutaneous oedema pitting quite deeply on pressure. The right forearm as it hangs by the side measures at its largest point 29| cm.; the left about 27| cm. Just above the elbow at the base of the internal condyle the right arm measures 14 27 cm.; the left 23| cm. The right pectoral fold is a little fuller than the left. There is nothing striking about the condition of the calves, despite the fact that the patient feels sure that they were swollen last night. The grip of the right hand is materially less powerful than that of the left. Sensation to touch appears to be good everywhere. Sensation to pain, dull on both sides. The patient can touch the back of the head with the right hand, but touches the top of the head with difficulty and considerable effort. The difficulty with which these movements are carried out is quite out of proportion to the plumpness of the muscles in the shoulder girdle, especially the right deltoid, which is considerably plumper than the left, the digitations standing out rather strikingly. The temperature is 99°, the pulse, while the patient is standing during ex- amination is 100. On the following morning, July 7, 1902, Dr. Thomas very kindly saw the patient with me, and a careful electrical examination was made. The following rec- ord was made at this time: Well built, muscular man. The muscles of the left arm are well developed. They appear to be somewhat larger than one might naturally expect, especially the triceps and the teres major and minor. The superficial veins on the arm and forearm are remarkably promi- nent. On the right side the enlargement of the deltoid, which was so striking yesterday, is more marked; all its digitations are plainly visible and the muscle feels tense. It is not tender on pressure. The yellowish discoloration of the arm has spread further downward and now extends upwards to the outer attachment of the pectoralis major, where it is most marked. The supra- and infraspinous regions on the right side ap- pear flattened. With the arm semi-flexed, the left upper arm measures 29.5 cm., the right 34.5 cm. The right arm hanging by its side measures at its largest point 33 cm. Measurements of forearm, elbow semi-flexed. Right. Left. 5 cm. below the olecranon 28.7 27 10 " " " " 28.5 26.6 15 " " " " 24.6 22 8 20 " " " " 19.8 19 Eyes.- The pupils are moderately contracted and re- act well to light and accommodation. Movements of 15 the eyeballs are free and equal in all directions. There is no ptosis. The forehead muscles act well and equally on both sides. There is no weakness of the orbicularis of the eyes or mouth. The muscles of mastication are normal; the tongue protrudes straight. The move- ments of the neck are strong. The patient shrugs his shoulders well and resists efforts to forcibly depress them. He approaches the scapulae and depresses the raised elbow with normal strength. The left pectoral muscle is strong. The right pec- toral muscle is contracted and seems rather large, but is very weak, much weaker than the pectorals on the left. In extending the hands forward the scapulae re- main close to the chest wall. The patient can raise the left hand above the head with fair strength, but is un- able to hold the right hand when lifted above his head; it gradually falls (weakness of deltoid). On the left side abduction of the shoulder is very strong. Ad- duction is also strong, as are rotation outwards and in- wards. Flexion and extension of the elbow are strong, as are similar movements of the wrist joint. The in- trinsic muscles of the hand are all strong. On the right side abduction is weak, as is adduction, rotation outward and rotation inward. Rotation out- ward is weaker than rotation inward. Flexion at the elbow is considerably weaker on the right than on the left side, as is also extension. The wrist muscles are also weak. Flexion and extension are both weak; the ulnar extensors are stronger than the radial. The in- trinsic muscles of the right hand are weaker than those of the left. The left calf measures 35.5 cm.; the right, 36.5 cm. Electrical reactions.- On the left side the nerve roots (brachial plexuses) give to the faradic current a quick normal response from all of the muscles supplied. On direct stimulation all the muscles act promptly, the only abnormality noticed being that there is a ten- dency toward a tetanic contraction, which persists for an appreciable time after the current is broken. Right side-The brachial plexus gives a response to faradic stimulation in all muscles supplied, but the re- sponse is less prompt and active than on the left side- All parts of the deltoid can be very easily stimulated, but here the response is also somewhat less than on the left. The biceps reacts very slightly to direct stimula- tion. A current which forces the left biceps into active, strong tetanus causes but a slight contraction of the 16 right. In the muscles of the back of the forearm the difference in response is little between the two sides. On the palmar side of the right arm in the oedematous area (ulnar group) there is response only to a very strong current. The supinator longus reacts equally on the two sides. Over the ulnar nerve at the elbow on the right (the point of maximum oedema) the reaction is but just obtained with a very strong current. At the wrist there is practically no difference between the two sides in the reactions to ulnar stimulation. Galvanism.- On stimulation of left deltoid K.C.C.= 4M.-A.; on the right K.C.C. T^A.C.C. K.C.C.=3 M.-A. Biceps.- Left, K.C.C.=3| M.-A.; right, K.C.C.=12 to 15 M.-A , a sharp and quick reaction. Triceps.- Left, K.C.C.=3 M.-A.; right, K.C.C.=4 M.-A. Reflexes.- The deep reflexes at the elbow and wrist are not to be obtained. The knee jerks are very slight if present. The patient has considerable difficulty in re- laxing his muscles. The ankle reflex (tendo Achillis) is diminished, if indeed, it be present. The patient states that at times during the night he has noticed that his right arm has been unconsciously lifted. He has waked up on several occasions to find himself holding his right arm with his left. Some- times the right arm comes forward at night and strikes him in the face so that he " sees stars." He is not sure whether this is due to the fact that it is raised during his sleep and falls across his face or to an active spasm which brings it sharply up to his face. He was recommended to take strychnine, .0015, three times a day, the dose to be gradually increased to .003. He was further advised to have light massage with pas- sive motions for fifteen minutes daily for the right arm and shoulder, after the swelling had disappeared. The patient has not been seen since this exam- ination, though in a recent letter he states that there has been no further return of his trouble. The essential features of this remarkable case appear to have been recurrent attacks of acute swelling with but little tenderness, in various muscle groups. The more severe attacks have been associated with evidences of deep haemor- rhage (widespread discoloration of the skin) and areas of marked, hard subcutaneous oedema. Dur- 17 ing one of the attacks there was a deep, almost erysipelatoid reddening of the skin in the cedema- tous area. Subsequently there have been un- doubted evidences of atrophy in some of the af- fected muscles. There are certain points in the course of the case which are of especial interest: (1) The mildness of the subjective symptoms of pain. No case so far as I have been able to discover, has shown such marked muscle swelling with so little pain and disability during the at- tack. (2) The mildness of the febrile manifestations. The fever has, however, been moderate in other cases of marked severity, notably those of Strup- pler and Georgievskyi. It should be remembered also that we have no records of the temperature in this case at the time of the onset of the various attacks. (3) The widespread cutaneous discoloration, indicative of deep haemorrhage, almost without purpuric manifestations, is a striking and interest- ing feature of this case. Georgievskyi states that in his patient the haemorrhages into the muscles could be clearly seen through the skin, but I know of no instance in which exactly this condition has been described. (4) The crepitus in the deltoid muscle. This remarkable manifestation is described only by Fenoglio. With regard to the aetiology of this case little can be said. Cultures were unfortunately not taken at the time of removal of the muscle from the arm. The abruptness of onset of some of the attacks has been almost like that of an angio-neu- rotic cedema. With regard to prognosis the future alone can answer. In the meantime the case appears to be of a nature sufficiently unusual to justify this note. PURITAN PRESS, BOSTON. ON THE TEACHING OF PHYSICAL DIAGNOSIS. BY WILLIAM SYDNEY THAYER, BALTIMORE, Associate Professor of Medicine in the Johns Hopkins University. Reprinted from the Boston Medical and Surgical Journal Vol. cxlvii, No. 26, pp. 689-694, December 25, 1902. BOSTON THE OLD CORNER BOOK STORE (Incorporated) 283 Washington Street 1902 ON THE TEACHING OF PHYSICAL DIAGNOSIS.1 BY WILLIAM SYDNEY THAYER, BALTIMORE, Associate Professor of Medicine in the Johns Hopkins University. The educated physician who interests himself in medical conditions.in the United States can scarcely fail to be impressed with the fact that those points in which the profession as a body is most deficient depend upon the need of a more thorough early training in the fundamental methods of physical diagnosis and of a more extensive bedside experi- ence in the observation of disease during the in- struction in the medical schools. The association of medical schools has lengthened the course of study required for a degree of doctor of medicine to four years, and most of the states have adopted examinations requiring evidence of proficiency on the part of the applicant for a license to practice which in some instances are excellent. Yet none of these laws and but few of our schools insist upon an amount of training in clinical observation equal to that which is demanded, for instance, in England. There is no uniformity in our state laws, and as far as the four-years' work goes, little is required beyond the fact that those years shall have been spent in study or in attending courses of lectures. The student may to-day, as he could forty years ago. graduate and enter into the practice of medicine with a minimum of actual clinical experience. In the last two decades, however, great changes have come about in our methods of medical instruc- tion. The didactic lecture, the demonstration - forms of instruction designed to bring out facts with 1 Read before the Suffolk District Section of the Massachusetts Medical Society in Boston on Oct. 25, 1902. 1 as much economy of time as possible before large classes-are rapidly disappearing, giving way to more practical methods of teaching with smaller bodies of men. We seek to-day not so much to lay facts clearly before a class as to teach the student methods by which he can himself control the state- ments of his instructors and his books, by which he may become independently competent to investigate and to clear up the nature of any anatomical or physiological abnormality with which he may meet. These changes have occurred not only in methods of clinical instruction but in the laboratories them- selves. He has a poor knowledge of anatomy who is familiar only with the gross forms, but it is not merely to recognize minute histological changes that the student now demands ; he must have a practical familiarity with those methods of prepara- tion and staining without which he is helpless. And not in medical teaching alone have these changes come about. We seek to teach the child at school, as well as the student of medicine, how to think, how to work, how to investigate, how to help himself ; to guide him rather than to push him in the way that he should go. We are but following a method urged by Montaigne about three hundred and fifty years ago. "On ne cesse," says he. " de criailler d nos aure- illes, comme qui verseroit dans vn entonnoir; et nostre charge, ce n'est que redire ce qu'on nous a diet: Ie vouldrois qu'il corrigeast cette partie; et que de belle arriv^e, selon la portae de I'dme qu'il a en main, il commenceast d la mettre sur la montre, luy faisant gouster les choses, les choisir et discerner d'elle mesme ; quelquefois luy ouvrant chemin, quelquefois le luy laissant ouvrir. Ie ne veulx pas qu'il invente et parle seule; ie veulx qu'il escoute son disciple parler d son tour. Socrates et depuis Arcesilaus, faisoient premi- erement parler leurs disciples et puis il parloient d eux. . . . Qu'il luy face tout passer par I'estamime, 2 et ne loge rien en sa teste par simple auctorit^ et d credit . . . s'il embrasse les opinions de Xenophon et de Platon par son propre discours, ce ne serontplus les leurs, ce seront les siennes: qui suyt un aultre, il ne suyt rien, il ne treuve rien, voire il ne cherche rien."^ These methods of instruction are bringing to us a different class of men, men trained to independent thought, who are no longer contented with bare statements of fact, but demand proofs and explana- tions and ask embarrassing questions. At the end of the second year in most of our medical schools, these men have been occupied for nearly a year in studying the manifestations of dis- ease in the pathological laboratory. They are now confronted by a new question, namely, the recog- nition of these same pathological changes in the living subject. (1) THE NECESSITY OF A GOOD KNOWLEDGE OF REGIONAL ANATOMY AND OF PRACTICE IN THE PHYSICAL EXAMINATION OF THE NORMAL SUBJECT. For the proper study and comprehension of nor- mal and pathological anatomy a certain amount of technical skill must be acquired, - the technique of dissection and necropsies and the more elaborate technique of preparation of tissues for microscopical 2 " They [teachers] are eternally dinning in our ears as if they were pouring into a funnel; and our part is but to repeat what they say to us. 1 would have the teacher amend this procedure; and from the beginning, according to the character of the mind with which he is treating, he should endeavor to stimulate its action, making it taste, choose and judge of things of its own impulse, sometimes opening the path himself, sometimes allowing the pupil to make his own way. I would not have him alone suggest and speak; he should allow his disciple to speak in his turn. Socrates, and later Arcesilaus, insisted that their pupils speak first and then took up the subject themselves. . . . " Let him [the teacher] make him [the pupil] Investigate every- thing and lodge nothing in his head through simple authority and on trust ... if he embrace the opinions of Xenophon and of Plato through his own powers of reason, these opinions will be no longer theirs; they will be his own. He who follows another fol- lows nothing, finds nothing, nay, he seeks nothing." (Montaigne: Essais; Edition variorum, 8°, Paris, 1854, Charpentier, T. 1: De 1'in- stitution des enfants, pp. 202, 203, 204, 205). 3 examination, as well as that of bacteriology. For the examination of the living subject, a new tech- nique, which may be fully as complicated, is also required. The first step toward acquiring this tech- nique consists in the study of the fundamental methods of physical investigation, - inspection, palpation, percussion, and auscultation. These methods will, however, be of little or no value in helping the student to determine anatomi- cal or physiological changes in internal organs without an accurate knowledge of their normal posi- tion and outline, and of the evidences which they give to the eye, the hand and the ear of their normal function. The middle or end of the second year is, in most medical schools, just the period at which the student should, theoretically, be most familiar with topographical anatomy. Neverthe- less, an essential part of the course in physical diagnosis should, I believe, consist in practical demonstrations of regional anatomy. Why is this necessary? Let me answer by asking a question. How much of the regional anatomy, which is abso- lutely necessary for the diagnostician, does the average student at the end of the second year know? Let any one who has not tried it ask a member of his class to mark out, upon the living subject, the outlines of the heart; to draw upon this figure the limits of the different chambers visi- ble when the sternum is removed ; the points on the front of the chest opposite which the different valves lie ; the outlines of the pleurae ; the lower limits of the lungs; the average extent of the complementary space in the axillary line. Ask another student the position of the left auricle; the direction of the axis of the mitral valve ; of the aortic valve, and many other questions the accurate knowledge of every one of which is necessary for the proper interpretation of the information which these new methods of research are to bring and 4 what surprising answers one obtains ! Again, how many students are familiar with the sounds pro- duced during the normal function of the heart and lungs, at the time when they enter upon a course intended to teach them to recognize pathological changes? Few, if any. Why is this? The answer seems to me to be simple. Few minds retain long facts the relations and practical applicability of which are obscure. All these things the student may have been told ; all have been before his eyes and ears, but he will tell you, and quite naturally, " he has never thought about them." Once teach him practical methods of determining these outlines on the living subject and testing these physiological functions, - in other words, give him the power of controlling and verifying the statements made by his teachers and his books, - and with little experience he will never forget them. I have often thought it would be an ideal plan to give instruction in the palpation of such internal organs as might be reached, and in topographical percussion at the time the student is occupied with his course in regional anatomy, and in auscultation as he studies the physiology of the heart and lungs. But, whether this instruction be begun earlier or later, it is, at all events, important for the student to thoroughly familiarize himself with the facts which may be determined by inspection, palpation, percussion and auscultation of normal subjects be- fore attempting to recognize pathological changes. Familiarity with regional anatomy, the normal percussion outlines and the normal cardiac and pulmonary sounds stands in the same relation to physical diagnosis as does a knowledge of normal anatomy and histology to pathological anatomy. If some of us were, for instance, more familiar with the palpation of the normal abdomen, there would, perhaps, be fewer unnecessary nephrorrhaphies. The first step, then, in the teaching of physical 5 diagnosis, the earliest instruction in the simpler methods of physical research upon the normal sub- ject, should be associated with thorough and practical demonstrations of regional anatomy in the fresh subject, in dissections, in frozen sections and in models. (2) THE IMPORTANCE OF UNDERSTANDING THE PHYSI- CAL BASIS OF AUSCULTATION AND PERCUSSION. The signs elicited by auscultation and percussion are purely physical signs. They give to us informa- tion only as to the physical condition of the under- lying tissues. There is little or nothing specific in any sound brought out by percussion or heard on auscultation. No book or no lecturer can teach the student how to apply the information these methods of research bring unless he has studied and learned, as far as possible by personal observation, the physi- cal basis upon which these phenomena depend. A student ■who attempts to learn by heart, from a book, the conditions under which dullness may occur in the chest, has accomplished little if he be unfa- miliar with the conditions in and outside of the chest under which such sounds may be produced - the nature of tympanitic and non-tympanitic reso- nance, as illustrated by open vessels, bladders and lungs outside of the body. No mere statement of these facts is sufficient. The student must control them himself. Indeed, his whole previous instruction, if it has been what it should be, will have taught him to demand an opportunity so to do. The student should have a good practical training in topographical percussion of normal organs ; he should be thoroughly familiar with the normal cardiac and respiratory sounds and the theories as to their physical causes before he begins to study the deviations from the normal. 6 (3) THE NECESSITY OF A GOOD TRAINING IN PATHO- LOGICAL ANATOMY. With a good training in anatomy and physiology, and in the theory and practice of the fundamental methods of physical examination, the intelligent student needs only careful guidance and experience to build up his diagnostic powers - provided he has had a good training in pathological anatomy, and that he has, along with his studies in physical diag- nosis, constant opportunities for the observation of disease in the cadaver. Without this, methods and experience are of little value. The most important part of physical diagnosis is learned in the patho- logical laboratory. No one can hope to learn to intelligently recognize in the living that with which he is unfamiliar post-mortem. It is especially im- portant that the student should see necropsies per- formed on cases which he has studied clinically ; should see the necropsies, if possible, not only the organs after removal. Nothing is so instructive and enlightening as the control of one's clinical diagnoses by the revelations of the necropsy, not communicated by word of mouth, but observed and studied in person. This is the only method by which one can safely count upon improving his diagnostic abilities. (4) THE IMPORTANCE OF APPROACHING THE SUBJECT OF PHYSICAL DIAGNOSIS WITHOUT PRECONCEIVED IDEAS. The student now approaches for the first time a patient whose thoracic or abdominal organs show signs of pathological change which may be recog- nized by physical examination. He begins the study of physical diagnosis proper. The method by which he is introduced to this work may have an important influence on his career, so important that I am by no means sure that many men would 7 not progress better if left to themselves than inju- diciously led. "Obest plerumque iis qui discere volunt, auctoritas eorum, qui docent " 3 What I sin- cerely believe to be the most important point for the teacher to remember at this stage was first impressed upon me as a student by one of the wisest clinical instructors I have known. On entering upon the subject his first request to the class was that they avoid all books on the question until the course was over - a piece of advice for which 1 have always been grateful. The student may approach his work in two ways. He who is properly led meets the case which he is to study without preconceived ideas. By applying those methods of physical examination which he has already practised on the normal subject, he will dis- cover abnormalities one by one independently of his instructor, or under his judicious guidance; he is compelled to apply his own reason to their explana- tion - and it is more and more encouraging to me every year to see how quickly and accurately the majority of students reason. And when the obser- vation is over, and the diagnosis made, the observer has in his mind the picture of an actual case. That sound which he has heard replacing the normal sec- ond aortic sound would naturally suggest that some- thing had interfered with the proper performance of the physiological act which is the cause of the nor- mal sound - namely, the closure of the aortic valves. But the examination has revealed changes in the size and functions of the heart, all of which might be explained by assuming the existence of an aortic incompetency. How such a sound might well be produced by the reflux of blood through a small opening in the aortic valves is brought out or demonstrated by the instructor. In reaching 3"The authority of those who teach is often injurious to those who wish to learn?' (Cicero : De Natura Deorum. Quoted by Mon- taigne, Op. cit., p. 203.) 8 this conclusion the student will probably enter into considerable speculation as to why this murmur is heard in just the region in which it is audible ; why it is transmitted as it is ; why it is of greatest intensity below rather than at the aortic orifice. He must pass through many questions of differential di- agnosis, and the exercise, the course of reasoning and the clinical picture will long remain in his mind. Let us suppose, however, that the other course has been pursued. The student has "read up" the subject. He is familiar with the descriptions in books of the character of the signs occurring in aortic insufficiency, and their causes. The case is carefully demonstrated and explained by the in- structor. But the mind of this student is already occupied by a picture based upon what he has read and heard a picture which, however near it may approach that which he is to find, can never be identical with it. His task is not one of pure ob- jective reasoning as to the meaning of what he dis- covers ; unconsciously he finds himself comparing two pictures, - that of the reality and that acquired from his books. And then he has a new duty, one which it may be very hard to accomplish, - to for- get the erroneously preconceived ideas. But sup- pose even that he can accomplish this ; the exercise has been but the demonstration of a single case. The only real demands which have been made upon his energies have been upon his eyes and ears and hands - little or no appeal has been made to his reason, and he has missed that which is almost the most important part of the exercise, - the training in differential diagnosis. He has seen a picture ; his fellow has made a discovery. But, alas I it is not easy to forget one's precon- ceived ideas, and many physicians spend their lives mentally comparing their individual cases with a type founded, not on their own experience or ob- 9 servation, but on some preconceived notion ac- quired, perhaps, from a lecture or a book before they had ever actually met with the disease clini- cally. That man who is fortunate enough to have a large hospital service shortly after graduation may acquire the experience which will displace all artificial pictures, but memory through the course of years plays strange pranks. That which we have heard and learned as a fact takes on the form of experience. What was once theory is now doc- trine. Statements made to us in our early years, which have remained uncontradicted, become in later life convictions - and then experience comes too late. Typhoid fever and pneumonia have be- come sharply defined pictures in our minds. That which does not conform to these pictures is strange and new. These epidemics of continued fever " show none of the symptoms of typhoid fever," and must be a " third fever." Pneumonia is wholly different now from what it used to be. It is a mel- ancholy fact that the results of this old way of teach- ing are to be seen throughout the country to-day. Early training in objective methods is invaluable. The man who can say with the vicaire Savoyard : "Je sais settlement que la v&rit& est dans les choses et non pas dans mon Esprit qui les juge, et que moins je mets du mien dans les jugemens que j'en porte, plus je suis stir d'approcher de la viriti " 4- that man has taken a great step forward. The student, having learned to detect deviations from the normal, should be encouraged to work out his own diagnoses and to rely on himself. In this manner he should be brought face to face with the important thoracic and abdominal abnormalities, and it is desirable that as many instances as possible of 4" I know only that the truth is In the things themselves, and not in my mind which is considering them, and the less of myself that enters into my conclusions, the surer I am of nearing the truth." ^Rousseau: CEuvres, 8vo, Paris, Garnery, 1823, T. vii, p.145 [Emile, livre iv, Profession de foi du vicaire Savoyard].) 10 each disease be seen in order that he may appreciate the infinite variety of the clinical manifestations of any one pathological process. (5) THE ADVANTAGES OF SUBDIVISION OF CLASSES INTO SMALL SECTIONS. To accomplish this the class must be divided into small sections among a considerable number of in- structors. This is unavoidable. In order that each student in the section may study every feature of the case, I have found that it is necessary to limit the sections to six or seven students for an exercise lasting two hours. Each student should control every statement or observation made by another. For the auscultation of the heart I have found of considerable use the combined stethoscope with multiple ear pieces, which can be used at the same time by student and instructor. Each student thus hears the same sound at the same time, and the com- parison of their statements as to what they hear is often of interest and value. (6) THE IMPORTANCE OF PRACTICE IN AN OUT-PATIENT DEPARTMENT AS A PART OF THE COURSE IN PHYSICAL DIAGNOSIS. With the systematic, didactic, or demonstrative exercises the course in physical diagnosis proper often ends - unwisely, it seems to me. Training in an out-patient department in the observation not of selected subjects but of patients as they come along, should form a part of the course in physical diagnosis. Such a training is of particular value in that the student has an opportunity to practice methods of physical diagnosis directly under the eye of his instructor, for this work needs careful supervision. It is in this part of the student's work that he has his main opportunity to practise methods of examination of the abdomen and topographical percussion. It is in dispensary practice, also, that 11 the student first begins to appreciate the relative frequency of the various abnormalities which he has been studying, the relative infrequency of the graver forms of disease which have been selected and placed before him in the set clinics of his school course. * * * Such a plan we are attempting to carry out with our classes. The second-year class has, during three months, two exercises a week upon the sim- pler methods of physical diagnosis applied to the normal subject. These exercises are informal and are carried on partly as recitations and partly as demonstrations. A number of students are, for in- stance, asked to put their hands upon the trachea of the patient while he is talking and to describe the sensation. They are then asked for the physical explanation of what they have found. From a dis- cussion of the opinions expressed the true explana- tion is finally elicited. The pectoral fremitus is then studied in a similar manner. The entire class, in a number of sections, compares the vocal fremi- tus on the two sides of the chest in the infraclavicu- lar region. The individual opinions as to whether the vocal fremitus on the two sides is equal, and if not so, what variations have been found, are then recorded on the blackboard. A comparison of the conclusions brought out in this manner usually emphasizes the truth. The causes of the difference between the fremitus on the two sides are then considered and illustrated by the demonstration of models and anatomical speci- mens. At the end of the exercise I always elicit from the class, by questioning, a list of the physical conditions under which the vocal fremitus might be expected to be increased or diminished. The theories as to the physical causes of percus- sion sounds are illustrated by bladders, fresh lungs and receptacles of various sizes. 12 The practice of topographical percussion on the cadaver is of special importance. I always endeavor to have several exercises in which the outlines of the heart are percussed out on the fresh subject in the necropsy room ; these are fixed by the introduc- tion of pins, the positions of which are later revealed by dissection. Such an exercise teaches more than the demonstration of many models. Auscultation is taught in a similar manner. I have been in the habit of asking the student to listen to the respiration over the trachea and in the second interspace in the mid-clavicular line and to note (1) the general character of the sounds; (2) the difference between inspiration and expiration (a) as to general character, (&) as to length, (c) as to pitch, (d) as to accent. The matter is then dis- cussed and the opinions recorded in tabular form on the blackboard. Points about which there is a difference of opinion are settled by reference to selected normal cases. The theories as to the phy- sical causes of vesicular and tubular respiration are then considered, and, as in connection with palpation and percussion, the class is questioned as to the physical conditions which might cause deviations from the normal type of respiration. At the end of the course the class is given several hours' work in sections under a number of instructors in the topographical percussion of the normal sub- ject and in careful comparison of vesicular and tubular breathing. In connection with the subject of auscultation of the heart, especial attention is paid to the anatomi- cal arrangement of the valves and cavities and their relation to the character of the heart sounds. Of great value in this connection are preparations of the heart made by injecting the cavities with a formaline solution and hardening while the heart is yet unopened. Windows cut into the cavities at various points show in a very satisfactory manner 13 tne relation of the different valvular orifices one to another. At the beginning of the third year the question of physical diagnosis proper is taken up. The class is divided into small sections, each containing about six men. These sections have one two-hour exercise a week - fifteen to sixteen exercises in the first half year. These small sections study, in the dispensary and in the wards, typical cases of the more important diseases of the heart and lungs, while once a week the entire class meets for a recitation in which the whole subject is systematically taken up, beginning with a recapitulation of the studies which they have previ- ously made upon the examination of the normal subject. In addition to this, there are, throughout the year, two one-hour dispensary clinics a week before the whole class, in which attention is paid mainly to diagnosis. During the second half-year the students do a regular out-patient department practice. The in- struction is divided among seven men in such a manner that no instructor shall have more than three men at an exercise. Each student receives a schedule of the instructors to whom he is to report on each given date. This arrangement is made in such a manner that the student meets every instructor as far as possible an equal number of times. The students are given cases just as they come to the out-patient department, and are expected to take the regular history and to make a thorough physical examination, percussing out the heart, lungs, liver and spleen. When this is done they report to the instructor, who goes over their work and superin- tends the final record which is made upon the dis- pensary history and signed by the student. There are sixteen such exercises. A class book is kept in which there are recorded: (1) the work done by each section during the first 14 half-year, with the names, hospital numbers and diagnoses of every case shown ; (2) the record of each student during the second half-year, each case which he has seen being recorded in the same manner. At the end of the year, we have thus a full record of the character of the work done by the student, as well as of every case which he has seen. * ♦ * (7) THE NECESSITY OF BEDSIDE EXPERIENCE AS A PART OF THE SCHOOL TRAINING OF THE STUDENT OF MEDICINE. With the course in physical diagnosis proper the training in diagnosis usually ends, except in so far as it is kept up by dispensary experience, by clinics and, perhaps, by ward visits ; but this is not enough. Clinics once or twice a week with oc- casional ward visits cannot fit a man for prac- tice. Some supply this want by spending a year or more after graduation in a hospital, but this op- portunity is not open to all, and many enter prac- tice every year who have never followed a case of pneumonia or typhoid fever from beginnning to end. These men are not fitted to begin the practice of medicine. They are acquiring experience at the expense of the public, which has, it seems to me, a right to demand more. There is much that actual clinical experience alone can teach, and a reasonable amount of this can and should be compulsory during the course in the medical school. An instance oc- curring under my observation not many years ago im- pressed me with the real harm which must often be done by men compelled to enter practice immediately upon graduation from the ordinary medical school. The physician was a graduate of one of the best schools in this country, a man of average ability and intelligence. Shortly after the beginning of his hospital service a case of pneumonia of extreme 15 gravity was admitted to his ward. The patient, a man of forty or fifty, was in a state of profound prostration, dull and apathetic, while on one side there was a small area of dullness with increased fremitus, bronchophony and tubular respiration. The student recognized the consolidation, but not the general picture. Struck by the fact that the scanty urine contained a large trace of albumen and very numer- ous granular casts, he was led to the conclusion that the man was uraemic and that the pneumonia was the lesser element in the case. The patient was given a hot-air bath and pilocarpine - hardly orthodox treatment for pneumonia. The necropsy on the fol- lowing day revealed an extensive pneumonia, the kidneys showing no changes other than those which might be expected under such circumstances. The house physician was not a fool; he had seen but a very few cases of pneumonia on occasional ward visits ; he had never followed a case throughout its course, and he knew nothing of the stupor of the profound intoxication in some severe cases. A few months' experience as clinical clerk in the wards of a large hospital, and daily or frequent ward visits with the instructor through at least the same period of time, would have beeh worth more than several years' instruction by clinics given to large classes. Objection has been made in this country to the adoption of the English system of clinical clerks. There is a feeling that students in the wards are an- noying to the patients, and interfere with their proper treatment. No fancy can be more unjustified. Four or five students under proper restrictions, in a ward of twenty patients, are of invaluable assistance. Such students are so many more trained assistants. I have never known them to injure a patient, while their assistance in carefully and accurately studying the manifestations of disease is very great. More than one life has, I am sure, been saved in the past several years in Professor Osler's wards, owing to the 16 increased means of investigation afforded by their presence. The student who has pursued a four years' course in one of the better schools of this country, the entrance requirements of which amount practically to the "Physicum" of the German course, should thus accumulate a fair experience in the observa- tion of the more important diseases with which he is to meet, and while further hospital experience is desirable, yet he should be in a condition to safely begin practice, and to profit by the experience which he may acquire. Without practical objective train- ing in physical diagnosis such a physician is more than likely to make many unnecessary and, per- haps, costly errors, and to lose a large part of the benefit which he might gain from just this experience. * ♦ * But I have already spoken at sufficient length. And I have, perhaps, said little or nothing that is new. The problem in teaching physical diagnosis is exactly the same as that involved in the teaching of any branch of learning, namely, to find that method which will best excite the interest of the student and stimulate him to work, to study and to investigate. Such methods cannot be set or fixed, and my desire here is only to emphasize certain general points which I believe to be important. (1) An essential part of the teaching of physical diagnosis consists in the demonstration of those points in regional anatomy, an accurate knowledge of which is necessary to the diagnostician. Such demonstration should be accompanied by exercises in the application of the fundamental methods of physical examination to the normal individual. (2) It is desirable that the student should learn, as far as is possible, by actual observation and prac- tice, the physical causes for the signs to be noted on inspection and palpation and elicited by auscul- 17 tation and percussion of the normal subject; with- out this a proper interpretation of pathological deviations from these signs is impossible. (3) A thorough training in pathological anatomy is an absolute necessity for the student of diagnos- tic methods, and frequent demonstrations in the necropsy room of the lesions with which the student is meeting in the living individual form an impor- tant part of the course in physical diagnosis. (4) The study of physical diagnosis should be approached without preconceived ideas, beyond those acquired from the study of the normal indi- vidual. The student should not be allowed to con- sult books upon the subject until he has already learned to detect upon the living individual the more important physical manifestations of disease. He who begins the study of diagnosis in the textbook is in grave danger of acquiring habits of mind which may seriously affect his diagnostic abilities in later life. (5) To properly train the student in this manner necessitates the subdivision of a class into small sec- tions, in order that each man may personally control every observation which is made during the exercise. (6) As a part of the course in physical diagnosis the student should have a fair experience in the examination of patients as they come, in the ordi- nary course of events, to an out-patient clinic, in order that he may acquire skill in the taking of histories, in the practice of topographical percussion and in the habit of forming his diagnosis without help or assistance. This work should, if possible, be under the direct supervision of instructors. (7) No man is properly fitted to begin the practice of medicine who has not had a reasonable amount of actual bedside experience in the observation of the more important diseases which he is to meet in his practice. This can be easily accomplished (1) by insisting, according to the English system, that the 18 student shall have several months' experience as a clinical clerk in the wards of a hospital; (2) by providing for daily or frequently repeated ward visits with an instructor for at least an equal length of time. The presence of medical students as clinical clerks in the wards of a general hospital is in no way detrimental to the interests of the patients or of the institution. On the contrary such an arrangement is perfectly feasible and of great assistance to patients, physicians and hospital. * * * But, after all, the exact method of teaching is per- haps the smaller part. Much, indeed, the greater part depends upon the instructor. We are not try- ing to inculcate knowledge in the minds of passive listeners. Medicine can neither be studied nor practised in a perfunctory manner. The men to whom we address ourselves must be interested and enthusiastic students of an absorbing subject, and the same interest, the same methods of thought and action they must carry into their later practice, for there is no essential dividing line between the study and practice of medicine. The teacher's main task is to excite and stimulate such a spirit in his pupils, and to accomplish this he must himself possess it in at least an equally high degree. The words of Rostand's 5 priest are as applicable here as to any other aspect of life : - Frere Trophime. " Ah ! 1'inertie est le seul vice, maitre Erasme! Et la seule vertu, c'est . . . Erasme. Quoi? Frere Trophime. L'enthousiasme! " 6 Rostand: La princesse lointaine, 8vo, Paris, 1898, Charpentier et Fasquelle, p. 11. 19 SAMUIL USHER, BOSTON. Reprinted from The New York State Journal of Medicine, January, 1503. On Arteritis and Arterial Thrombosis in Typhoid Fever. By William Sydney Thayer, Baltimore, Md., Associate Professor of Medicine, Johns Hopkins University. ON ARTERITIS AND ARTERIAL THROMBOSIS IN TYPHOID FEVER.1 BY WILLIAM SYDNEY THAYER, Baltimore, Md., Associate Professor of Medicine, Johns Hopkins University. THE object of these remarks is not so much to bring before this Association anything which is new as it is to call attention to certain complications of typhoid fever which, though infrequent, are, when met with, of serious import. These complications have long been recognized and described, especially by French students. In this country, however, they have attracted but little attention. The recent obser- vation of several cases has suggested that it may be of some value to bring up the subject once more. Let me begin by mentioning these: Case I. Typhoid fever-general convulsions-death. On autopsy: Acute arteritis with thrombosis of branches of the left middle cerebral artery. The first case, which has already been reported in part by Professor Osler, was under my observation throughout its course. A strong, vigorous young man, 22 years of age, was seized suddenly, on the ninth day of an apparently mild attack of typhoid fever, with gen- eral convulsions. These occurred repeatedly at short intervals for about an hour. During the convulsions * he' was profoundly unconscious, though between times his mind seemed partially clear. He answered a few simple questions and seemed to understand what was said to him, although he had a confused and frightened look. After an intermission of about four hours the convulsions returned, recurring with great severity at ' Kead before the New York State Medical Association, at New York, Octobet 22, 1902. Note.-The omission of diphthongs and certain minor orthographical changes from the author's orig- inal text are in accordance with the standards of spelling adopted by the Journal. 1 c ui paip inaped aq; uaqM 'sjnoq xis joj spAjajui severe paroxysm. The convulsions were general and began apparently at the same time on both sides, though the movements were more marked upon the right. There was well marked conjugate deviation of the eyes upward and to the left. The necropsy, made by Dr. Flexner, showed a severe hemorrhagic enteritis in addition to characteristic ty- phoid intestinal lesions with several early ulcers. The ileum was the seat of a marked hemorrhagic enteritis, which also involved the jejunum, though to a less extent. The mucous membrane was hyperemic, and actual ex- travasations of blood had taken place into the substance. Near the valve and covering an area of 15 cm. in length there were several ulcers in Peyer's patches. They were superficial, partly extending beneath the mucosa, the largest not more than 1.5 cm. in length; above it the mucous membrane was hemorrhagic. The mesenteric glands were enlarged and softened; the heart showed no abnormalities. The lungs were free from adhesions, much congested and edematous. On section blood- stained fluid flowed freely from them. "Brain. There was an area of thrombosis in certain of the convolutions of the left cerebral hemisphere. At the time of the necropsy this was seen to involve the branches springing from the middle cerebral artery; but at that time the dissection was not completed. "Subsequently in the formalin-hardened specimen it was seen that thrombi were situated in the ascending parietal and parieto-temporal branches of the middle cerebral artery. The meninges over these vessels con- tained small hemorrhages and the brain substance cor- responding to them, while not softened, showed small extravasations of blood, although the surrounding tissue was quite firm. Small, but quite extensive, punctiform hemorrhages could be seen to occupy the cortex and adjacent white substance in the immediate neighbor- hood of the thrombosed vessels. The areas extend sometimes for a distance of 2 cm. (usually toward the convexity) from the vessels. "The internal carotid artery was free from thrombosis, as likewise the Sylvian branch. The ascending parietal and parieto-temporal arteries, including the points of their origins in the middle cerebral artery, were oc- cluded by an adherent, partly decolorzied and quite firm thrombus. More recent dark thrombi w'ere traceable into the branches of these arteries; for example, into the branches running in the Rolandic fissure, the sulcus between the ascending frontal gyri and the ascending frontal convolutions, and the branches supplying the lempero-parietal region generally. The inferior ex- 2 ternal frontal artery and the arteries of the anterior perforated spaces were free from thrombi. "On section of the brain there were no gross anatom- ical lesions. The ventricles were not dilated. " 'The cultures from the spleen, mesenteric glands, liver, kidneys, both lungs and heart muscle showed the typhoid bacillus. From the lungs streptococci were obtained; from the peritoneal cavity the bacterium coli commune. Bile and bone marrow (ribs) were sterile.' " I have recently re-examined the gross specimens and, in addition, sections have been made through the plugged vessels and examined microscopically. These show evi- dences of a most extensive arteritis. In the less affected parts of the vessel wall the muscular coat takes on a very pale stain, while in many places the fibers, which seem swollen, are separated by vacuolic spaces. At some points these are so numerous that the tissue has an almost reticulated appearance, consisting of a loose, wavy, palely staining material in which traces of elastic tissue may still be seen, and containing numerous larger and smaller clear spaces. The muscle nuclei are in many instances swollen and deformed. The internal elastic membrane has in great part disappeared. In many places the distinction between the individual coats of the artery is wholly lost, the entire wall being in- filtrated with a mass of cells, the nuclei of which are extensively fragmented. Most of these appear to be polymorphonuclear leucocytes. In some places the in- filtration seems more marked toward the lumen of the vessel; in other places it involves the whole wall. In some areas, where the infiltration of the vessel wall is greatest and the nuclear fragmentation most marked, the infiltrated cells are surrounded by a refractive pink (the specimens were stained with eosin and hematoxy- lin) substance, apparently fibrin. Outside and surround- ing the vessels there is an acute meningitis, the meshes of the pia being filled with a fine refractive, somewhat granular, eosin-staining, fibrin network containing great numbers of cells. Many of these contain large vesicular nuclei, while there are also many polymorphonuclear leucocytes. In some places there is considerable frag- mentation of the nuclei. The changes in the walls of the vessels are by no means limited to the larger plugged artery alone. In many smaller vessels the lumen of which is clear, the structure is entirely lost, the walls being packed with a mass of cells with polymorphous and fragmenting nuclei, and fibrin. In some it is almost impossible to distinguish the dividing line between the vessel wall and the surrounding exudate. The structure of the thrombus presents points of con- 3 siderable interest. Professor Flexner, who has very kindly examined the specimens, regards it as of undoubt- edly agglutinative origin. The thrombus mass con- sists in great part of a pinkish, irregular framework in which definite corpuscles are contained. This frame- work is not particularly refractive; it is not perfectly homogeneous and may be seen in places to inclose clear spaces which agree in shape and size with those of the red corpuscles outside. The interior of the framework is almost free from white cells. Toward the periphery there arc appearances which suggest that it is formed through the coalescence of undoubted red corpuscles. The transformation from the denser red corpuscles into the finer framework can apparently be followed. The thrombus appears to contain little or no fibrin. At one or two points there has been an invasion of the thrombus by a number of polymorphonuclear leucocytes, in some of which the nucleus has become fragmented.* When one considers the brief duration of the clinical symptoms, the character of the thrombi, and the extent of the vascular changes, together with the fact that these changes are also visible in vessels in which no throm- bosis has occurred, it would seem clear that the arteritis was the earlier change. Case II. Severe typhoid fever-sudden occlusion (probably thrombotic) of the left femoral artery- gangrene of the foot and lower part of the leg-death. Necropsy not allowed. N young girl, 1G years of age, was admitted to the Johns Hopkins Hospital on June 16, 1902, on what was stated to be the fifth day of a severe typhoid fever. The Widal reaction was sharply positive on entrance. The patient had been delirious from the onset. There was a marked general bronchitis, and on the 19th of June, the eighth day of her illness, areas of dulness with tubular respiration appeared at the left apex and at the right base. Two counts of the leucocytes on this date showed respectively 6,000 and 5,000 to the cubic centimeter. On the eleventh day there was a slight leucocytosis, 12,000. On the twelfth and thirteenth days the patient seemed better, the mind being clearer, although the area of consolidation in the right back had increased. On the evening of the 25th of June, the fourteenth day of the disease, on removing the patient from the tub, her right foot and leg below the knee were found to he *A more complete description of the anatomical changes in this case is reserved for a later communication. 4 very white and much cooler than on the left side. The coolness extended above the knee in front. There was no swelling of the leg or foot. Two hours later there was a purplish mottling of the heel and under side of the calf and popliteal space. The femoral artery could be followed by its pulsation half-way down the thigh. No pulsation was palpable in the popliteal or dorsalis pedis arteries. The patient, who had been growing worse during the day, was at this time delirious and in a condition of profound intoxication. The leucocytes were 17,000 to the cubic centimeter. On the 26th of June the temperature remained ele- vated, ranging between 102 and 104 degrees. Dr. Fut- cher made the following note: "Pulse of fair volume and tension, 148 to the minute. This morning the toes and dorsum of the right foot are absolutely colorless and quite cold. Over the heel and instep and through- out the leg to a point at the base of its upper and second quarters, the skin is of a distinct purplish tint. The entire right leg below the level of the tubercle of the tibia is distinctly cooler than the left. The leg is not swollen. No pulsation of the right popliteal or dorsalis pedis arteries is to be made out. On the left side it is distinct. Both femoral vessels pulsate in Scarpa's tri- angle. The heart sounds are quite forcible at the apex; no murmurs audible. The aortic second is rather feeble, the pulmonic second distinctly accentuated." On June 28th, the seventeenth day of the disease, the general condition was much the same. The tempera- ture was slightly lower. The right leg had become decidedly more bluish in color and the color did not disappear on pressure. At one or two spots in the leg and above the heel the skin appeared to be upon the point of breaking. There was a fair degree of warmth down to the ankle. The dorsum of the foot was cold and white. Two days later, the nineteenth day of the disease, Dr. McCrae made the following note: "Little further extension of the process up the back of the leg. The purple area has rather a greenish tinge. The lower half of the leg is of a plum color with a slight green- ish tinge. The upper half of the foot is somewhat colored, though not so much so as the leg. The toes are now becoming dry and somewhat shriveled at the ends. The foot is cold. The general condition is fair." The blood count showed: Red blood corpuscles, 3,- 212,000 to the cubic millimeter; colorless corpuscles, 19,000. On the 1st of July the following note was made by Dr. McCrae: "Patient's general condition is fairly 5 good. The tongue is coated but moist. Pulse, 35 to the quarter, small, but regular. "Heart: Point of maximum impulse is rather hard to make out. By the stethoscope it is localized probably in the fifth left interspace, 8.5 cm. from the mid-sternal line. The sounds are loud and booming and appear to be clear throughout. No murmur heard. "Lungs: Note now clear over the fronts; slightly im- paired over the right back. Over the whole right back there is tubular breathing. Everywhere else the breath sounds are loud and high-pitched. "Abdomen: Natural, everywhere soft, no fresh rose spots. . . . The patient cries out when the right leg is moved more than she has done previously. It is im- possible to determine whether this is because of pain. 1'he color of the skin over the lower half of the leg is gradually becoming deeper purple; the toes are shrivel- ing quite rapidly; the lower half of the foot is quite white." Measurements of the two legs: Six cm. above the patella, right leg, 27 cm. in cir cumference; left, 24.5. Ten cm. below the patella, right leg, 28} cm. in cir- cumference ; left, 23} cm. Largest part of calf, right, 29 cm.; left, 23 cm. Just above the malleoli, right, 18.5 cm.; left, 18 cm. Leucocytes, 18,625 to the cubic centimeter. On the following day the line of demarkation between the dead and living tissue, which was becoming more marked, reached, at its highest point, 12 cm. below the lower end of the patella. The patient, however, was distinctly failing. Leucocytes, 18,700. Despite stimula- tion she grew steadily weaker and died early on the morning of the 3d of July, the twenty-second day of her disease. The delirium was throughout so marked that it was never possible to determine whether there was any tenderness along the course of the vessels above the area of gangrene. No necropsy could be obtained. It is, of course, impossible to say with certainty whether this was an instance of thrombosis or of em- bolism. The heart's action was rapid throughout the disease, but there was no evidence of dilatation, -and the sounds were always clear. There were no evidences of embolism elsewhere. In view of all these circum- stances it seemed probable to Dr. McCrae, who was in charge of the case, as well as to the writer, who saw the patient from time to time, that it was a thrombosis rather than an embolism. Case III. Typhoid fever-szvelling and tenderness in 6 the course of the left femoral and popliteal arteries- great diminution in pulsation of all arteries of the ex- tremity-coldness of the foot-slight swelling of the thigh and leg. Recovery, zvith return of pulsation in affected vessels. J. H. T., 18 years of age, a laborer in the "make-up department" of a newspaper, entered the Johns Hop- kins Hospital on July 5, 1902, the third day of typhoid fever. The Widal test was sharply positive the day after entry. The course of the disease was at first uneventful, the temperature on the thirty-first and thirty-second days having reached nearly a normal point. On the thirty-fourth day, however, it rose to a point above 100 degrees, fresh rose spots appeared and a relapse set in. On the fortieth day of his disease, the seventh of the relapse, the patient began to complain of pain on the inner side of the left thigh, which was distinctly swollen, the swelling extending also up on to the anterior sur- face. There was deep tenderness; the skin could be readily lifted between the fingers without causing pain, while deep pressure caused the patient to flinch. No cord was felt in the course of the saphenous vein. There was a slight leucocytosis, 13,200. Two days later it was noted that the entire left leg was somewhat swollen, the thigh being hotter than on the right side. There was, however, no redness; the temperature in both feet was about the same, and the pulse was distinctly felt in the left dorsalis pedis artery. On the next day, the forty-third day of his disease, I made the following note: "The left leg is distinctly swollen as compared with the right, and the tempera- ture is decidedly lower, the foot and ankle feeling quite cool. On the right side the pulsations of the posterior tibial and dorsalis pedis arteries arc readily felt. On the left the foot is cold and slightly cyanotic, while the pul- sations of the dorsalis pedis and posterior tibial arteries are with difficulty to be made out. There is no tender- ness in the calf. The thigh is also larger than on the right side and there is a little tenderness along the course of the vessels in Scarpa's triangle and below on the inner side of the thigh. The pulsation of the femoral artery in Scarpa's triangle is not to be made out on the left side, though the deep epigastric is to b< felt as it emerges and passes upward. On prolonged examination, however, there is, perhaps, some sugges- tion of a very slight femoral pulsation. On the right side the pulsation of the external iliac artery is clearly felt above Poupart's ligament; it is not to be felt on the left." 7 The following measurements were taken of the two legs: Right. Cm. Left. Cm. 3 cm. below patellar tubercle.. .. 24 25 6 cm. below patellar tubercle.. . . 22.9 24.5 9 cm. below patellar tubercle.. . . 22.2 23.8 12 cm. below patellar tubercle. . . . 21 22.3 Measurements of the thighs were also taken. Right. Cm. Left. Cm. 10 cm. above middle of patella. . .. 25.7 30.5 20 cm. above middle of patella. . . 30.6 36 30 cm. above middle of patella.. . 33 37.9 The surface temperature, taken on the inner side of the thighs, about midway between the knees and pubis, was 78 degrees Fahrenheit on the right, 76 on the left. On the following day the pulsations of the dorsalis pedis and the posterior tibial arteries had improved a little, as well as the pulsation of the femoral, though this was still very indistinct. There was distinct tenderness in Scarpa's triangle and along the course of the vessels in the thigh. At the latter point the pulsation was bet- ter felt than on the day before, while the swelling had somewhat diminished. There was no cord to be felt. On the forty-fifth day Dr. Cole noted a very slight edema over the anterior surface of the foot and ankle. Two days later the following note was made: "Pul- sation of the arteries of the foot is much better, also that of the femoral, although there is still a material difference between the pulse of the two sides. The tenderness has disappeared and the swelling is no longer apparent on inspection. The vessels in the left Scarpa's triangle are not as readily felt as on the right, and one feels as if there were a thickening of the tissues about the sheath of the vessels." On the forty-ninth day the boy began to hold his leg somewhat flexed. The whole leg became more swollen, and marked tenderness developed in the pop- liteal space, where there was also distinct swelling. On the fifty-first day I found that there was evident enlargement of the lower part of the thigh and calf, while the swelling and tenderness in the popliteal space had increased. The pulsation of the posterior tibial and dorsalis pedis arteries remained about as in the last note, still considerably less than on the right side. Several large veins under the skin on the inner side of the left leg and knee had become more evident. There was tenderness on deep pressure in the calf, especially 8 about in the middle line. Leucocytes, 18,800 to the cubic centimeter. On the following day the sensitiveness in the calf had increased and the leg felt hotter than the other, while the foot was rather cold and cyanotic; the thigh was considerably swollen. The arterial pulsations in the foot were barely palpable. On the fifty-fourth day a little edema was noticed over the shin of the left leg. On the fifty-fifth day the temperature had reached a normal point, and from this time recovery was unin- terrupted. The slight edema soon disappeared and on the fifty-ninth day I made the following note: "The pulsation is returning; that in the dorsalis pedis is nearly as good on the left as on the right. The pop- liteal pulse is to be felt on the left side. The pulsation in the femoral artery in Scarpa's triangle is feeble, but better palpable than heretofore, though much less marked than on the right. No cord is to be felt in the region of the saphenous vein; none this afternoon in the popliteal space. There is no edema. The veins which some days ago appeared to be more prominent in the left leg have in great part disappeared or are visible only as on the other side." From this time there was a steady improvement and the patient left the hospital well on September 18th, the seventy-ninth day after the onset of his disease. The left leg and thigh were still slightly larger than the right, but the pulsations of the vessels were almost equal on the two sides. Case IV. Typhoid fever-tenderness and redness over brachial artery at bend of elbow, following repeated compression {estimations of blood pressure} just above -diminution in pulsations of the vessels at the 'wrist- coolness of hand. Recovery. L. G., a school teacher, aged 27, entered the Johns Hopkins Hospital on September 29, 1902, the thirteenth day of typhoid fever. On the tenth day of her disease she suffered from very profuse intestinal hemorrhage. During this day the blood pressure was taken repeatedly by Cushing's modification of the Riva-Rocci instrument, the elastic band being placed about the left arm just above the elbow. On the twenty-first day the following note was made: "The patient complains of pain in the left elbow; the entire left arm looks somewhat red; it is not tender on palpation except at the joint, and there only slightly. . . ." Twelve hours later the patient complained bitterly of this pain. On the following morning the leucocytes were 8,509 to the cubic centimeter. Any movement of the left arm was very painful and there was tenderness at the bend 9 of the elbow; the entire arm felt hotter than the right. Over the outer elbow region of the left arm there was a slightly reddened area with some edema; the tender- ness was most marked just at the bend of the elbow. On the right anterior aspect of the left forearm, just above the wrist and extending half way tip, there was a somewhat erythematous blush, and the skin was rather hot, but not tender. The pulse of the left side was smaller than on the right; the left hand was much cooler and somewhat paler than on the other side. There was no pain in the axilla. A count of the leu- cocytes in the evening showed 9,500 to the cubic milli- meter. On the following day the left arm, above the wrist, felt hot and burning, the corresponding part of the right arm comparatively cool; the left finger tips cool, the right warm. The pulse on the left side, however, had improved. On the twenty-fourth day the pulse was al- most as good on the left as upon the right, though the hand was still a little cooler. From this time on there was steady improvement, the patient making a gradual but complete recovery. Case V. Typhoid fever-pain, redness, swelling and resistance over brachial artery-disappearance of pulsa- tion in brachial and arteries at wrist-coolness, mottling and cyanosis of hand-threatened gangrene. Complete recovery, with return of pulsation in affected vessels. Through the kindness of Dr. W. R. Steiner, of Hart- ford, Conn., I am able to mention briefly a case which occurred in his practice two years ago. This case will probably be reported in full by Dr. Steiner in a subse- quent publication. The patient, a boy of 8, in the fifth week of typhoid fever, complained one day of pain in two fingers of the right hand. This was followed by pain radiating up along the course of the brachial artery: the tissues over the artery became somewhat swollen and slightly reddened, and the artery could be felt as a tender pulseless cord. The hand became cool, mottled and cyanotic, and the pulse at the wrist disappeared. Fqr a time it was though! that gangrene would surely follow, but in the course of several weeks the pulse gradually returned, the tenderness and resistance over the brachial artery disappeared and complete recovery followed. * * * Let us consider for a minute the manifesta- tions of these cases: The first was an instance of thrombosis of the middle cerebral artery coming on in a young 10 man, 22 years of age, on the ninth day of a mild typhoid fever without premonitory symptoms. The autopsy showed that there was an extensive arteritis, not wholly limited to the occluded area. The second case was one of occlusion, prob- ably thrombotic, of the left femoral artery, coming on in a girl of 16 on the fourteenth day of a severe typhoid fever, with a resultant dry gangrene of the leg. The exact manner of onset of the occlusion was difficult to determine on account of the delirious condition of the patient. In the third and fourth cases the patients, young people in the fifth and sixth weeks of typhoid fever, began to complain of pain along the course of one of the arteries of the extrem- ities. This was associated with swelling, heat, tenderness on pressure, and finally complete or almost complete disappearance of pulsation in the arteries of the affected part, coldness, and in one instance blueness and threatened gangrene of the extremity. In each case, however, there was, in the course of three or four weeks, com- plete disappearance of the symptoms with the return of pulsation in the affected vessels. In Dr. Steiner's case there was a well-marked re- sistant sensation along the course of the brachial artery. In. my own instance there was swelling, tenderness and heat along the course of the ves- sels in the thigh and later in the popliteal space. The fourth case, which was similar to the third and fifth, was extremely mild and especially interesting, in that it may possibly have been due to a traceable trauma-the estimation of the blood pressure. These clinical pictures are not new. That gangrene of the extremities might occur in the course of typhoid fever has been known for many years, having been noted as long ago as 1806 by Hildenbrand. Though in many instances due to venous thrombosis or of embolic origin, the 11 fact that it might be due to autochthonous arte- rial thrombosis was recognized by Fabre in 1851. There has, however, been considerable ques- tion as to the cause of this autochthonous throm- bosis. Fabre, to be sure, suggested that it re- sulted from chemical changes in the blood pro- duced by the disease. No sufficient exciting cause, however, was apparent. Occurring for the most part in young individuals, the chronic arterial changes so frequently regarded as the primary element in gangrene of the extremities in older individuals are not likely to be present, nor have they been found, and there is no evi- dence in the majority of cases of general circu- latory disturbances sufficient to play an impor- tant predisposing role. That the coagulability of the blood in typhoid fever tested by ordinary methods, is not increased is well known. In 1863, however, Patry de Sainte-Maure pointed out the fact that the thrombosis is in a large portion of cases preceded by severe pain and tenderness along the course of the vessel, which later, becomes occluded, while the gross pathological appearances found after amputation show evidences of arteritis and peri- arteritis. This arteritis, according to Patry and others, is the direct causal element in the arte- rial thromboses. Since this time many similar cases have appeared in literature, histological examinations showing general inflammatory infiltration of the walls of the affected vessel. The few microscopical studies that have been made have, however, been limited to the plugged area, and little definite information as to the character of the early stages of the process has been obtained. The observations of Hayem (1869), Landouzy and Sireday (1885, 1887),Rat- tone (1887), Mollard and Regaud (1899), and others, on the changes in the smaller arteries in the heart and elsewhere in typhoid fever and other infectious diseases, cannot without further 12 investigation, be applied to the process in the larger vessels. It must be said, moreover, that positive proof that some of these changes are not post, rather than pre-thrombotic is wanting. Our first case, however, affords an excellent example of an acute arteritis of typhoid origin in which the vascular changes have clearly pre- ceded the thrombosis. The early changes here, as noted by Mollard and Regaud in the small vessels of the heart muscle, would appear to chiefly affect the media; indeed, they bear a striking resemblance to the conditions described by these observers. Within the last forty years, also, there has been accumulated a mass of clinical material which leaves little room for doubt that these peripheral thromboses are pre- ceded in many instances by acute inflammatory processes in the course of the affected vessels. Taupin (1839), Patry (1863), Potain (1878, 1890), Barie (1884), Salles (1893), and others have shown that the initial symptoms common to these so-called peripheral arteritides, symptoms of pain, heat, tenderness, swelling and even resistance in the course of an artery, with diminution or disappearance of the pulsations and coldness or blueness of the extremity, may be followed in several weeks by complete recov- ery, with the disappearance of all symptoms and return of pulsation, not only in the peripheral, but in the affected vessels. This picture, which has been best described by Potain and Barie, will be recognized as ex- actly that of the last three cases which I have reported. How are we to account for the apparent dis- appearance of pulsation in these cases which are followed by complete recovery? It is, it seems to me, scarcely reasonable to assume that there has been actual thrombosis; a complete return of pulsation, together with the entire disappearance of all swelling or induration over the vessel 13 where an actual thrombosis has occurred, is hardly conceivable. What, then, causes this ap- parently complete occlusion? It has been sug- gested that the swelling of the arterial walls de- pendent upon the edema and infiltration may re- sult in so great a diminution of the lumen of the vessel as to render its pulsation practically im- palpable. In favor of this idea is an observa- tion of Tuthill (1885), who states that in a leg amputated for gangrene following post-typhoid arteritis and phlebitis, "The only artery found pervious was the posterior tibial, which emitted fine, needle-like jets, showing its caliber less- ened in proportion to the thickening of its walls." In other cases in which the pulse remains always somewhat diminished on the affected side, it is probable that a parietal thrombosis which has in time become organized and shrunken has been the cause of the occlusion. There are sev- eral cases in the literature in which there has also been slight persistent disability in the af- fected extremity-weakness and fatigue after standing or on exercise. What is the exciting cause of these arterial changes ? With regard to this question our knowledge is as yet incomplete. From analogy, however, with what has been shown to be the case in typhoid phlebitis, it is natural to suspect that they are a result of an actual localization of the B. typhosus, or of some secondary infectious agent in the walls of the vessels. Ratton*' (1887), indeed, asserts that he has demonstrated microscopically and by culture the presence of typhoid bacilli in foci of arteritis in the smaller vessels of the heart walls. Must we assume that an acute arteritis is always present in autochthonous arterial throm- bosis in typhoid fever? Such a conclusion would surely be unjustified. A large proportion of cases of typhoid arte- 14 rial thrombosis are preceded by symptoms sug- gestive of arteritis, but there are many, as in our first case, in which the onset is apparently as sudden as in the embolism; and yet in that case extensive arteritis was shown postmortem. The revelations of modern researches on immu- nity. with regard to the relations between micro- organisms, blood and tissues, may well bring ns in the near future to a more satisfactory explana- tion, not only of the increased tendency toward thrombosis which has long been known to exist in typhoid fever, but also perhaps of the occurrence of the vascular lesions themselves. Flexner* has already described thrombi, due apparently to bacterial agglutinines in dilated veins of the in- testinal submweosa near typhoid ulcers. Indeed, the relation of an arteritis when pres- ent, to the thrombosis may well vary. In the one instance the mechanical role of the anatomical changes in the vessel wall may be the determin- ing element in the development of thrombosis. In another, however, as possibly in our first case, the thrombus may be agglutinative, owing its origin to ihe absorption of agglutinines arising at a local focus of infection in or near the vascular wall-independent, however, of anatomical al- terations in the vessel. But my object to-day was more particularly to call attention to certain clinical facts: (1) That there is a well characterized com- plex of symptoms occurring occasionally in ty- phoid fever, more particularly in the later stages, indicative of inflammatory changes in the walls of one or more peripheral arteries. While the histological observations previously reported have not been very complete, yet when considered in connection with the changes found in our first case, as well as with the clinical pic- ''Remarks before the Amer. Assoc, of Pathologists and Bacteri- ologists at Cleveland March, 1902. Published since the reading of his paper, in Univ, of Pennsylvania Med. Bull., 1902, XV, 324. 15 turc, they would seem to justify the use of the term arteritis. The clinical picture consists in the appearance, usually at some period after the second week of typhoid fever, of pain and ten- derness along the course of one or more large arteries, usually in the leg or thigh. This is associated with local tenderness, swelling and redness, and slight enlargement of the member, with, however, little or no edema. At first there may be an increase in the extent of the pulsa- tions of the affected vessels (Potain, 1890) ; later there is disappearance or great diminution in the size of the pulse in the main artery, as well as in the peripheral vessels, together with cold- ness, and sometimes blueness and mottling of the extremity. These alarming symptoms may be followed by one of two results: (a) After a few days the pulsations entirely disappear, the coldness and discoloration of the extremity increase and are followed by the de- velopment of a dry gangrene which may affect only the more peripheral parts or may extend well up to the point of arterial occlusion, or (&) The symptoms may gradually diminish and end, in the course of several weeks, in com- plete recovery, without a trace of the original lesion. In some cases, however, the pulse may remain permanently less in the affected member, while some slight physical disability-undue fatigue after exercise-may persist. (2) The histological appearances in the first case justify the assumption that acute arteritis may be an early incident, perhaps the primary element in some of the interesting cases of aphasia and paralysis which are reported dur- ing the course of typhoid fever. LITERATURE. Alibert: *Recherches sur tine occlusion pen commune des vaisseaux arteriels consideree comme cause de gan- grene. Par., 4°, 1828. Allen, J. A.: Gangrene of the leg following typhoid 16 fever; amputation below the line of demarcation; re- covery. Med. Rec., N. Y., 1897, LIT, 918. Andrews, T. H.: Gangrene of foot following typhoid fever. Proc. Path. Soc. Phila. (1860-66), 1867, ii, 177. Also: Am. J. M. Sc., Phila., 1865. Bacologlu : *Le coeur dans la fievre typhoide. Paris, 8°, 1901. Barie: Contribution a 1'histoire de 1'arterite aigue consecutive a la fievre typhoide. Rev. de med. Par., 1884, IV, 1, 124. Beach : Diseases of the circulatory system occurring in connection with typhoid fever. Tr. Med. Soc., N. Y., Phila., 1889. 87-90. Beaumanoir : Fievre typhoide compliquee de gangrene des extremites inferieures. Bull. Soc. anat. de Par., 1880, LV, 555-562. Also: Progres med. Par., 1881, IX, 364-366. Benecke: Gangrcena pedis (als Folge eines nicht ausgebrochenen Nervenfiebers). Ztschr. d. Nordd. Chir.-Ver., Magdeb., 1848, II, 38. Berthoud: Etude pathogenique et clinique sar 1'ob- literation des troncs arteriels dans la fievre typhoide. 4°, Par.. 1881. Behier : Rapport stir une note ayant pour titre: Sur la gangrene des membres dans la fievre typhoide, par M. Ie docteur Bourgeois. Bull. Soc. med. d. hop. de Par. (1856-8), 1864, iii, 305-319. Bimsenstein : Observation d'un cas de gangrene seche des membres, consecutive a la fievre typhoide. Gaz. med. d'Orient, Constantinople, 1863-4, VII, 71. Bourdeau : Gangrene spontanee des extremites in- ferieures dans le cours d'une fievre typhoide; guerison. Arch. med. Beiges, Brux., 1874, 3 s., vi, 73-106. Bourdeaux : Note complementaire d'une observation de gangrene spontanee des extremites inferieures dans le cours d'une fievre typhoide. Arch. med. Beiges, Brux., 1885, 3. s. xxviii, 5-11. Bourgeois : Sur la gangrene des membres dans la fievre typhoide. Arch. gen. de med., Par., 1857, ii, 149. Bourguet : Observation de gangrene spontanee de la jambe, a forme seche, consecutive a la fievre ty- phoide; embolie de 1'artere tibiale posterieure. Gaz. hebd. de med., Par., 1861, viii, 350. Also: Gaz. de hop., Par., 1861, xxxiv, 277. Brongniart : Gangrene seche dans la fievre typhoide. Gaz. hebd. de med., Par., 1878, 2 s., xv, 120. Brouardel et Thoinot: La fievre typhoide, 8°, Par., 1895, Bailliere, p. 110. Burlureaux : Sur les gangrenes seches observees 17 dans le cours de la fievre typhoide. Gaz. hebd. de med., Par., 1878, 2 s., xv, 72. Camus, F.: Gangrene de la jambe a la suite de la fievre typhoide; amputation de la cuisse; guerison. Arch, de med. et pharm. mil., Par., 1891, xviii, 343-349. Cauvy: Fievre typhoide; gangrene de la jambe gauche; amputation de la cuisse; guerison. Gaz. hebd. de med., Par., 1878, 2, s., xv, 151. Chauffard: Myocardite typhique. Semaine med., 1891, xi, 397. Chauveau : *Essai critique sur la pathogenic des gangrenes en masse dans la fievre typhoide. 4°, Par., 1878. Clarke, W. B.: Gangrene after typhoid fever. Illust. M. News, Lond., 1889, iv, 301, 1 pl. Curschmann : Typhoid fever and typhus fever. (Nothnagel's Encyclopedia of Practical Medicine). American edition, edited by W. Osler. 8°, Phila., 1902, Saunders, pp. 107, 167. David, G.: *Quelques considerations sur la gangrene typhoide. 4°, Paris, 1883. Debierre, C. M.: *Des obliterations arterielles dans la fievre typhoide. 4°, Par., 1877. Dehu : *Le role du bacille d'Eberth dans les compli- cations de la fievre typhoide. Par., 1893. Deschamps: *De l'arterite aigue dans le cours de la fievre typhoide (arterite parietale). 4°, Par., 1886. Dezanneau : Gangrene du membre inferieur gauche a la suite d'une fievre typhoide; amputation de la jambe. Arch. med. d'Angers, 1898, ii, 23-27. Drewitt, F. G. D.: Gangrene of the leg in typhoid fever. Lancet, Lond., 1890, ii, 1023. Drewitt, F. G. D.: On gangrene of the limbs fol- lowing typhoid fever. 12°, London, 1894. Duchesne: Gangrene bilaterale des extremites dans le cours d'une fievre typhoide. Med. mod., Par., 1895 vi, 60. Durand : Fievre typhoide anormale; gangrene syme- trique des membres inferieurs; amputation des deux jambes; guerison. Arch, de med. et pharm., mil., Par., 1894, xxiv, 44-49. Fabre : Cas de gangrene et separation complete du pied dans le cours d'une fievre typhoide. Abeille med., Par., 1880, vii, 242. Also: Gaz. med. de Par., 1851, 3 s., vi, 539. Facieu : *De l'arterite des membres dans la fievre typhoide. 4°, Toulon, 1886. Ferrand, J. C. V.: *Contribution a 1'etude de la gangrene des membres pendant le cours de la fievre typhoide. 4°, Paris, 1890. 18 Forgues : Note sur un cas de gangrene seche de la jambe droite, consecutive a une obliteration de 1'aorte abdominale (par embolie) chez un convalescent de fievre typhoide. Rec. de mem. de med. mil., Par., 1880, 3 s., XXXVI, 386-392. Gascon, T.: Gangrena de los pies subsiguiente a una calentura tifoidea; amputacion por la contiguidad; curacion. Bol. de med., cirug. y farm., Madrid, 1847, 3 s., ii, 285. de Gastel, H.: Fievre typhoide; gangrene spontanee de la jambe; arterite. Bull. sec. anat. de Par., 1882, 4 s., vii, 73-75. Giard: Amputation des deux jambes, au lieu d'elec- tion par les seuls efforts de la nature a la suite d'une fievre typhoide. Gaz. med. de picardie, Amiens, 1893, xi, 449-451. Gigon, C.: Note sur le sphacele et la gangrene spon- tanee dans la fievre typhoide. Union med., Par., 1861, 2 s., xi, 577, 611. Gosse, W.: Gangrene after typhoid fever. Lancet, Lond., 1890, ii, 1267. Guillou : Fievre typhoide; phlebite de la veine fe- morale; arterite due membre inferieur; gangrene; am- putation; guerison. Gaz. med. de Nantes, 1883-4, ii, 108. Guyot : Deux cas de gangrene seche, suivie de gangrene humide. L'union med., Par., 1882, 3 s., xxxiv, 505. Haushalter: Phlegmasia alba dolens et bacille typhique dans la fievre typhoide. Mercredi med., Par., 1893, iv, 453. Hayem : Recherches sur les rapports existant entre la mort subite et les alterations vasculaires du coeur dans la fievre typhoide. Arch, de phys. norm, et path., 1869, ii, 699. Hayem : Des manifestations cardiaques de la fievre typhoide. Le progres med., Par., 1875, iii, 514; 525; 571; 589; 621; 696. Heurtaux : Gangrene des membres inferieurs dans la fievre typhoide. Bull. Soc. anat. de Nantes, 1876-8, Par., 1879, 1, 18. Hildenbrand: Uber den austeckenden Typhus, etc., 8°, Wien, 1810. Keen, W. W.: Gangrene as a complication and sequel of the continued fevers, especially of typhoid. Boston M. & S. J., 1896, cxxxv, 1, 29. Keen, W. W.: The surgical complications and sequels of typhoid fever. 8°, Phila., 1898, Saunders. Lacombe: *Localizations angiocardiaques de 1a fievre typhoide. 40 Par., 1890. Landouzy: La fievre typhoide dans ses rapports avec 19 1'appareil vasculaire et Cardiaque. Gaz. d. hop., Par. 1886, LIX, 323. Landouzy et Siredy: Contribution a 1'histoire de 1'arterite typhoidique; de ses consequences hatives (mort subite) et tardive (myocardite sclereuse) du coeur; cardiopathies typhoidiques. Rev. de med., Par., 1885, V, 843. Landouzy et Siredy : Etudes sur les localizations angiocardiaques prochains et eloignees. Rev. de med., Par., 1887, VII, 804, 919. LeClerc: De 1'arterite typhoidque obliterante chez les enfants. Normandie med., Rouen, 1900, XV, 445. Legendre : *Essai sur la pathogenic de la gangrene typhoide. 4°, Par., 1885. Lereboullet : Observations de gangrene seche survenue dans le cours d'une fievre typhoide. L'union med., Par., 1878, 25, 353. Levitski, I.: K kasuistike oslojnenii broushnago tipha omertveniem konechnostei i mosgovimi porajeni jami. (Complication with gangrene of extremities and affection of brain.) Ejened klin. gaz., St. Petersb., 1882, ii. 313-316. Lipscomb, T.: A case of typhoid fever resulting in dry gangrene of the right foot and leg; ultimately in death. South. Pract., Nashville, 1881, iii, 75-77. Loring, R. P.: An unusual sequel of typhoid fever; gangrene of the left leg extending to upper third of thigh; amputation and recovery. Boston M. & S. J., 1889, exx, 104. Masserell: Ein Fall von spontaner Gangriin nach Abdominaltyphus. Deutsches Arch. f. klin. Med. Leipz., 1869, v, 445-449. Mattocks, B.: Gangrene accompanying typhoid fever. Northwest. M. & S. J., St. Paul, Minn., 1873-4. IV, 94. Mercier, M.: De la gangrene seche des membres dans la fievre typhoide. Arch. gen. de med., Paris, 1878, exlii, 402, 676. Mettler, L. H.: Gangrene after typhoid fever. Phila. M. Times, 1886-7, xvii, 339-341. Mettler, L. H.: Arteritis complicating typhoid fever. Phila. Med. Times, 1886-7, xvii, 467-471. Millardet: *Des obliterations des arteres viscera'es dans la fievre typhoide. Par.. 8°, 1900. Mollard et Regaud: Etat des arteres du coeur dans les myocardites aigues. Congres Franq., de med., 1899, v, 280. Ollivier, A.: Gangrene des membres et infarctus du rein dans le cours de la fievre typhoide. Bull, med., Par., 1888, ii, 231-234. Osorio, N.: Observaciones sobre la gangrena espon- 20 tanea de los membros inferiores, como consecuencia de la fiebre tifoidea. Gaz. med., Bogota, 1866-7, ii, 10. P.achmayr, O. P.:Typhus: Gangraen beider Unter- schenkel; Operation; Tod. Verhandl. d. phys. med. Gesellsch. in Wurzb. (1866-8), 1869, n. F., i, 18-23. Pena, E.: Contribucion al estudio de la gangrena de los membros en la fiebre tifoidea. 8°. Buenos Aires. 1884. Petit, H. L.: Sur les affections cardiaques et 1'arte- rielles consecutives a la fievre typhoide. L'union med., Par., 1888, xlv, 609. Phillips, S.: A case of typhoid fever with occlusion of the femoral artery during convalescence and with acute maniacal attacks. Brit. M. J., Lond., 1891, I, 1176. Also: Lancet, Lond., 1891, I, 1207. Potain : De l'arterite et de la gangrene seche dans la convalescence de la fievre typhoide. Gaz. d. hop., Par., 1878, li, 537. Potain : De l'arterite transitoire des membres infe- rieurs dans la convalescence de la fievre typhoide. Bull, med., Par., 1890, iv, 845. Potain : De 1'aortite typhique. Semaine med., Par., 1894, xiv, 460. Purkhiser, W. J.: Typhoid fever; gangrene of th? foot. Progress, Louisville, 1886-7, i, 362-364. de Quervain, F.: Ein Fall von Extremitatengangran nach Abdominaltyphus. Centralbl. f. innere Med., Leipz., 1895, xvi, 793-803. Rattone: Dell 'arterite tifosa, Il Morgagni, 1887, xxix, 577; 641. Rodas, C.: Un caso de gangrena seca; complicacion de una fiebre tifoidea; intervencion quirurgica; cura- cion. Bol. de san. mil. Buenos Aires, 1891, i, 539-547. Roddick, T. G.: Embolism of both external iliac arteries during typhoid fever; gangrene; death. Canada M. & S. J., Montreal, 1879-80, viii, 1. Romberg: Uber die Erkrankungen des Herzmuskels bei Typhus abdominalis, Scharbach und Diphtheric. Deutsch. Arch. f. klin. Med. 1891, XLVI1I, 369; 1892, XLIX, 413. Salles : Note sur tin cas d'obstruction arterielle au cours d'un cas de fievre typhoide chez 1'enfant. Lyon med., 1893, Ixxvii, 77. Schon, F.: Nogle Tilfaelde af spontan gangraen i tifoid Feber. Hosp. Medd., Kjobenh., 1853, VI, 258- 278. Squintani, G.: Febbre tifoidea migliare terminata con gangrena acuta. Gazz. med. ital. lomb., Milano, 1859, 4 s„ iv, 362. Subert, J.: *De la pathogenic des gangrenes ty- 21 phiques. 8° Paris, 1899. (With extensive table of references to the literature.) Taupin : Recherches cliniques sur la fievre typhoide, observee dans 1'enfance. J. d. conn, med.-chir., Par., 1839-40, vii, pt. 1, 177; 241; pt. 2, 11. Tuthill, R. K.: Arteritis and phlebitis as a sequd of enteric fever. Tr. Med. Soc., N. Y., Syracuse, 1885, 222. Valette: De la gangrene des membres dans la fievre typhoide. Ann. Soc. de med. de Lyon, 1875, 2, s., XXIII, 318-328. Also: Lyon med., 1876, xxi, 191-236. Vulpian: Note sur deux cas d'accidents survenus pendant la convalescence, de la fievre typhoide. Rev. d. med., Par., 1883, iii, 617. Welch : Thrombosis and Embolism. Reprint from Allbutt's System of Medicine, Loud., 8°, 1899, vol. vi, p. 155. Worms : Gangrene du membre superieur par coagu- lation fibreuse dans le coeur droit au debut d'une fievre typhoide. Gaz. d. hop., Par., 1858, xxxi, 453. 406 Cathedral Street. 22 Observations on the Teach- ing of Clinical Medicine Chairman's Address before the Section on Practice of Medicine, at the Fifty-fourth Annual Session of the American Medical Association, held at New Orleans, May 5-8, 1903. WILLIAM SYDNEY THAYER, M.D. BALTIMORE Reprinted from the Journal of the American Medical Association, July 4, 1903. ' CHICAGO: PRESS OB' AMERICAN MEDICAL ASSOCIATION ONE HUNDRED AND THREE DEARBORN AVENUE 1003. OBSERVATIONS ON THE TEACHING OF CLINICAL MEDICINE. chairman's address before the section on practice OF MEDICINE AT THE FIFTY-FOURTH ANNUAL SESSION OF THE AMERICAN MEDICAL ASSOCIATION AT NEW ORLEANS, MAY 5-8, 1903. WILLIAM SYDNEY THAYER, M.D. BALTIMORE. A hundred years ago the young American republic bought from the French government that great tract of land of which the little frontier city of Nouvelle Orleans was the chief settlement. It is a happy chance that brings us together on the centennial anniversary of the Louisiana Purchase in this metropolis of the south. One hundred years-a small space of time in the world's history, and yet what events have been crowded into this little period! A hundred years ago the country west of the Mississippi was a wilderness. To-day we meet, a national body, the majority, perhaps, of our members coming from what was then forest and prairie, inhabited only by savage and wild beast. And the young democracy, then all but unknown to the powerful em- pires of the east, has become the dominating factor in the markets of the civilized world. In this amazing growth and expansion, in this tre- mendous accumulation of wealth and strength and power, it was scarcely to be expected that our contribu- tions to science would keep pace with those of the Old World, where accumulated wealth, settled conditions and well equipped institutions of learning naturally tempt the studious and contemplative mind to problems of 2 science and research. And yet, how many of the great discoveries and inventions of the century have come from this new country! In our own branch of learning the record is one of which we may well be proud. The discovery of anaesthesia, the demonstration by Holmes of the contagiousness of puerperal infection, the studies by the students of Louis on typhoid fever, the accom- plishments of Bigelow and Sims and McDowell and, lastly, the noble work of Reed, Lazear, Carroll and Agra- monte in Cuba and of those who have demonstrated to the world the practical value of their great discoveries- these are but a few examples of an honorable record. And during this period what a change has come over the condition of medical education in this country! One hundred years ago there were three schools of medicine in America: the Department of Medicine of the College of Philadelphia, the first school of medicine in the United States; the Medical School of Harvard College, and the Dartmouth Medical School of Hanover, N. H. To-day there are over one hundred and fifty. One hundred years ago only the most favored and fortunate were able to receive anything like a systematic medical training. Not that there were not educated physicians in America. There were in Carolina and New England, in New York and Virginia and Pennsyl- vania men who had profited by the inspiration and opportunities offered in the best schools of Europe. Many a young man, however, was obliged to begin his studies by "reading medicine" in the office of some older practitioner. His theoretical knowledge was gained from a few books, his main instruction came through the practical observation of disease, gained by assisting at the operations and visits of his preceptor. In some of our early medical schools the requirements were, however, such as may well surprise those of us who consider the fact that within fifteen years medical schools in this country were giving a degree of doctor of medicine for one year's study. "Although," says Thatcher in 1828 (American Med. Biography, 80, Boston, 1828) "there is no uniform standard of attain- ment established in order for graduation, in most of our schools it is required that before a student can be admitted to an examination for a degree he must have attained to the age of 21, have studied three years with some regular physician, attended two full courses of lectures on the different branches of medicine, and, if 3 he has not enjoyed the advantages of a college education, he must furnish satisfactory evidence of having made respectable classical attainments, and particularly that he has acquired a competent knowledge of the Latin and Greek languages, has studied mathematics, natural and experimental philosophy, geography and belles lettres. In several of our schools it is required that he shall have attended the clinical practice of some infirmary for a specified term. It is also required that before he can receive his degree he must pass a close examination in the different branches of medicine and write and defend a thesis on some medical subject." The first schools of medicine were, for the most part, founded in connection with hospitals, and the actual study and observation of the patient was an important part of the student's curriculum. The multiplication of medical schools, however, proceeded with great rapidity. The number of students in some of these institutions was so great as to preclude the possibility that each individual should have sufficient practical experience from the amount of clinical material at hand, while in other instances schools giving the degree of doctor of medicine were established entirely independently of hos- pitals or infirmaries. Ten years ago the requirements for admission to many of these schools were almost nil. It was not uncommon to hear that this or that good fellow whom one might have known but a day before as the driver of a horse car, had taken his degree in medicine. On investigation it might be found that for the past one or two years he had been attending evening classes, and at the end of this period had stepped from the platform of his car to the bedside of the patient with a degree attesting that he was a competent prac- titioner of medicine. Within thirteen years I remember to have heard a colleague relate with pride that he had just accomplished in one year his whole course in medicine at a university with an old and honorable name, practically without clinical advantages. This is, to say no more, far from the ideals of our ancestors. In the last few years, however, great changes have come into our methods of teaching. Four years' actual work in a medical institution are everywhere required. In our better schools anatomy, physiology, pathological anatomy, pharmacology are no longer taught as they used to be, by lectures to an untrained body of men. 4 In many instances the student begins his medical studies with a training which has already taught him to think and investigate for himself; and our duty as teachers is coming to be rather that of guides and leaders than of simple lecturers. The teacher to-day must be a student and investigator in his own line. The time is passing when the professor of anatomy or physiology can be a practitioner of medi- cine. His whole time must now be given to his studies and his teaching, and his immediate duties are not so much to lay facts before his students as to show the student how to find them out for himself. And so it is in all these branches. The student in the laboratory sees, acts, controls, verifies. While of old he was expected and required to believe what was said to him, he is to-day taught rather to doubt that for which he can not obtain proof. And in like manner throughout the greater part of the course the didactic lecture is passing-such matters the student can read- and is being replaced by practical anatomical, physiolog- ical, pathological, pharmacological, experiment and expe- rience. The same methods have come into the teaching of physical diagnosis in its restricted sense, as well as of minor surgery-lectures and demonstrations have largely given way to practical experience in small sections. In some of our schools the teaching in these branches com- pares with the best that can be found in the world. But when we arrive at the last stage, the study of pathological physiology in the individual, the observation and care and treatment of the patient, we find, strangely enough, that the advances which have been made in our methods of instruction have not kept pace with those in the other branches. If there be one opportunity in the course of the study of medicine which it would seem most necessary for us to provide for our students, it should be the privilege of watching and studying at the bedside those diseases which they are most likely to meet with in practice. It was the first necessity recognized by our ancestors; it is the first necessity that would be appre- ciated by any non-medical man; and yet I believe that any one who investigates the matter will realize that it is one of the weakest points to-day in our American system of medical education. What actual clinical experience does the average medical school of this country offer? 5 The clinical instruction offered in most of the better schools in this country consists in: 1. Exercises in physical diagnosis proper, which may include good practical work in small sections, but which commonly consist more of lectures and demonstrations than practice and experience. 2. Clinical lectures in which but few, if any, of the class approach the patient. 3. Ward visits which are too often infrequent. 4. Exercises in which students report individually on cases which have been assigned to them for study. The requirement of a continuous service of students as assistants in hospital wards is almost unknown in this country. The student who has graduated from such a school may, and often does, leave the institution with a fairly good training in methods of purely physical diagnosis. But how few of us in this room at the time we left the medical school, had ever followed a case of typhoid fever, pneumonia, measles or scarlet fever from beginning to end. And yet there is but one way by which one can learn to recognize and treat these diseases-and that is by bedside experience. Clinics, occasional visits, books and lectures, these weigh but little in the balance. If, as would seem to be the case, the medical records of our late war with Spain reveal a strange lack of familiarity on the part of many physicians with such important dis- eases as malarial and typhoid fevers, this is due largely to the failure of our medical schools to offer them the necessary bedside experience in the course of their early training. And again, how few of us as students ever had brought practically before us the vital questions of when and how to administer stimulants in acute infectious diseases; whether, in any given emergency, those drugs should be given which raise or depress the blood pres- sure. But these are matters which may mean the life or death of the patient, and it is a sad fact that nothing is more common than the administration of nitro- glycerin in conditions of profound vasomotor collapse by conscientious men who have missed in their education just that which early and well-directed clinical observa- tion and experience might have brought them. This defect in our medical teaching is further emphasized when we compare the curriculum in most of our schools with that which is required in England and France. In 6 London and Edinburgh, for instance, schools require of a student at least six months' service as a clinical clerk in the medical wards and a similar length of time as a dresser in the surgical department of the hospital. In Paris the student is required to give his whole morning to ward work of this nature for two years-one year in medicine, one in surgery. That it is desirable that we in America should offer in our schools and require for our license to practice an amount of practical experience equal to that required in Europe is obvious. Of the necessity for such requirements if we wish to keep pace with the progress of the world and properly educate our medical men there can be no question. Of their practicability there can also be no doubt when we consider that such methods have been in force for many years in a country where individual liberties are as jealously guarded as they are in England. Why is it, then, that so serious a defect exists ? The reasons are various and not altogether simple. The more important would seem to be: 1. The absence of state or national laws requiring such work. 2. The multiplicity of medical schools and the exist- ence of many such institutions unconnected with hos- pitals of sufficient size to furnish material for the in- struction of the students. 3. A wide-spread prejudice existing in many hospitals against the admission of students to the wards and against the use of patients in general for purposes of instruction. 1. The first of these reasons is, of course, the most important. Until the states require such experience for a license to practice there will always be schools which will give a degree for less work. It is for us indi- vidually as physicians and collectively as we are asso- ciated in teaching bodies to strive to raise the standard and to hasten the day when such requirements are put in force. 2. It is the absence of these requirements which is, in great part, responsible for the multiplicity and inferior quality of some of our medical schools. With proper state regulations institutions unable to offer the requisite amount of bedside experience would of necessity go out of existence. The hospital is the most important part 7 of a school of medicine, and that school which does not own or, to some extent, control a hospital sufficiently large to furnish practical experience for its students is not only incomplete, it is a pernicious and dangerous institution. It is greatly to be hoped that state or national laws, as well as the force of enlightened public opinion, may soon'remedy the evils caused by the exist- ence of such establishments. 3. As a matter of fact, however, most even of our larger and better supplied institutions do not, as they should, own or wholly control the hospitals on which they depend for clinical material, and the vague fear that the admission of students to the wards may prove prejudicial to the interests of patients or institution de- prives these schools of an enormous amount of valuable material. That this fear is wholly without foundation is a fact which is clear enough to any one who has had experience with active ward teaching. But there is another side of the question, to which attention has recently been called by Dr. Osler,* which is of very great importance to the hospitals themselves. The duties of the house physician with the recent advances in methods of precision in diagnosis and study of disease in ward and laboratory, have in latter years increased to a degree that demands outside assistance if the patient is to be properly studied, properly watched, properly treated. Much of this work can be done better by advanced students than by any other class of assistants. To as- sign three or four advanced students as clinical clerks to a ward of twenty-five or thirty patients, letting each student be responsible for the history, the examination of the secretions, the general observation of four or five patients, under the control of the ward physician, is to give the physician invaluable assistance in the keeping of records, in accuracy of observation, in the detection of many points in the progress of the disease, points which may be, and often are, of vital importance to the patient. The admission of students to the wards of hospitals in this capacity is not only without harm to the patient but is of the greatest practical value. That the careful study of each case resulting from such a system is, moreover, without annoyance to the patient I can testify from my experience of the past thirteen years in Professor Osler's wards, in which I have seen the direct transition from one system to another. To • Med. News, N. Y.. 1903, Ixxxli, 49. 8 the student this experience is invaluable, and it seems to me to be absolutely necessary, if the degree of doctor of medicine is supposed to represent a qualification for practice. Such experience, however, is of limited value unless it be associated with frequent and careful ward visits from the instructor. And these visits make considerable demands on his time. Teaching, direction of the re- search work of the department, the study of the material afforded by the clinic, these should be the main duties of the professor of medicine-duties incompatible with other than a purely consulting practice. To make this possible our universities must recognize the fact that the professorship of medicine, as well as the professor- ship of anatomy, should be properly endowed. Only by the adoption of some such system as this can we hope to bring our instruction in the practice of medicine to the level of that which is given in Europe. For proper ward teaching the clinic must be so organized that the professor shall have several regularly appointed assistants, who shall take part in the investiga- tion and instruction going on in the department. This is desirable, not only for the instruction of the students, but for the education of teachers. If we are to approach the infinite number of problems in pathological physi- ology which come before us every day in the observation of disease in anything like the manner in which such problems in normal physiology are studied in the labora- tory, we must have a regular staff of assistants. No lab- oratory of physiology, for instance, could accomplish scientific work if the entire staff consisted of the profes- sor and a number of young internes appointed annually from the graduating class. It is only through the oppor- tunities offered by such positions that younger men are enabled to acquire that experience which fits them for the task of teaching. The problems involved in the study and teaching of clinical medicine differ in no essential from those con- nected with the study and teaching of physiology, and until we recognize this fact and meet it squarely our clinics will remain unproductive and our teaching in- adequate. The most serious impediment in the way of advance in our methods of clinical study and teaching is the wide- spread institution of rotating services in our hospitals. In no service where the head of the department changes 9 every three or four months can really valuable investiga- tion be accomplished. And the best instruction can not be given to students in wards presided over only by a visiting physician and young, annually appointed, as- sistants. A permanent service, even though it be small, and a fixed staff of assistants offer incalculably greater advantages for study and research and teaching. It is, of course, evident that instruction of this sort in larger schools can not be given in one clinic or by one man. The day must come when every well equipped hospital shall be at the same time a laboratory for the study and teaching of clinical medicine, offering the clinical advantages required by the central university or by state regulation. Every physician or surgeon holding an appointment at a large hospital or out-patient department should be encouraged to teach. The hospital will gain by the supply of the best trained assistants and by the education of the staff, for there is no training so good as that of teaching, and there are no such spurs to work and progress as the questions and suggestions of the enthusiastic student. The student will gain, in a few months, experience which it might require years to accumulate after gradua- tion, and he will acquire that experience, as I have said elsewhere, at a time when he is free from the prejudices and preconceived ideas which are sure to obscure the judgment of the man who has gained his medical experi- ence second hand from books or lectures. The general public will gain the simple protection which any civilized government owes its citizens. In this very city there are opportunities such as exist in scarcely any other community of this country for the realization of our ideals in medical instruction-a city of over 300,000 inhabitants, a fine old hospital of nearly 900 beds, a single school connected with a university of honorable past and most promising future. Tulane Uni- versity has been a leader in this branch of medical edu- cation, but it can do more. The university can still offer to the hospital and the hospital to the university that which might make New Orleans the model for the rest of the country. BICHAT. By William Sydney Thayer, M. D., Associate Professor of Medicine, The Johns Hopkins University, Baltimore. From The Johns Hopkins Hospital Bulletin, Vol. XIV, No. 149, August, 1903.] BICHAT.1 By William Sydney Thayer, M. D., Associate Professor of Medicine, The Johns Hopkins University, Baltimore. It is fitting that in 1902, the one hundredth anniversary of the death of Bichat, we should contemplate for a moment the career of one of the most remarkable men of modern times. Marie Frangois Xavier Bichat was born in Thoirette in the province of Bresse, now Jura, on the 14th of November, 1771. His father was a physician and mayor of Poncin in Bugey. The early life of young Bichat appears to have been unevent- ful. It was the wish of the father that his son should follow in his footsteps, and whatever advantages one may gain from being brought up in a medical atmosphere the young man seems to have had. Bichat was brilliant from infancy and history shows that he was a striking exception to the common rule, in that this youthful precocity was in no way delusive. At school in Nantua and at the Seminary of Saint Yrenee in Lyon, he gained prizes and honors, and soon manifested a tendency toward mathematics and the natural sciences, especially physics and natural history. Beginning the study of anatomy at the hospital in Lyon under the direction of the celebrated Petit, he made good progress despite the fact that he appears at times to have allowed his exuberant energy and spirits to carry him into channels which deviated somewhat from those which ordinarily lead to a career in [197, 1 Read before the Johns Hopkins Historical Society, December 8, 1902. 1 I 197] science. As Levacher2 says, he was at this period more fitted to take a rapid bird's-eye view of all parts of the subject than to devote himself to the profound study of a single branch. But his memory and power of comprehension were remark- able, and early in his career he began to apply the accurate methods of thought and investigation which he had learned in mathematics and physics to the study of the structure and functions of man. Returning home to pursue his surgical work with his father, he was soon drawn again to Lyon and to his mathematical studies, without, however, abandoning anatomy. But in 1793, the stormy days of the Revolution closed the doors of all insti- tutions of learning at Lyon and drove Bichat forever from the scenes of his boyhood. After a short sojourn in Bourg he went to Paris to continue his studies which were to fit him for the position of surgeon in the army. Arriving in Paris without friends or letters of introduction he devoted himself especially to the clinic of the celebrated surgeon Desault, to whose atten- tion he was brought soon after his arrival, through circum- stances happily related by Buisson.3 " It was an established custom in the school of Desault that certain chosen pupils should undertake to collect in turn the public lesson and pre- pare an extract. This extract was read after the lesson of the following day; and these exercises, presided over by the associate surgeon, had the double advantage of bringing a sec- ond time before the pupils the useful precepts which they should absorb, and of making up for the sufficiently common inattention of the masses during the first lesson. One day when Desault had spoken for a long time on a fracture of the clavicle, and had demonstrated the utility of his bandage, ap- plying it at the same time to a patient, the pupil whose duty it was to collect these details happened to be absent. Bichat offered to take his place. The reading of his extract caused a real sensation. The purity of his style, the precision and (198] 1197] 2Levacher de la Feutrie, Eloge de Bichat, Mem. Soc. d'emulat, Par., 1803, v, pp. xxvii-lxiv. 3Buisson: De la division la plus naturelie des phenomenes physiolo- giques consideree chez 1'homme, avec un precis historique sur M. F. X. Bichat. 344 pp., 8°, Paris, Brosson, an. x (1802), p. 326, 1198] 2 clearness of his ideas, the scrupulous exactness of his resume were characteristic rather of the professor than the pupil. He was heard with extraordinary attention and left showered with praise and repeated applause." When informed of the incident by his associate Manoury, Desault straightway sought the acquaintance of this promising disciple, in whom he soon 1198] BICHAT. recognized a man of genius. The master not only opened his house to the pupil, but practically adopted him as a son, and throughout the remaining years of his life Bichat was associated with all the work of his teacher. This was the turning point in his life. His association with Desault 3 ri98i opened to him the opportunity for a scientific career to which his whole energy was afterwards devoted. In 1795 Desault died. Though a great sorrow to Bichat, the death of his master and benefactor in no way interrupted his career. He continued to live with Desault's widow who thenceforth regarded him as a son. From the death of Desault, Bichat gave himself up to a career of unremitting activity such as has rarely been equaled. In the very year of Desault's death he published his journal with an historical notice of his life and letters, and later edited his surgical works. But his main energies were devoted to the study of anatomy. The knowledge of anatomy he found in a condition which may justly be called chaotic. As one biog- rapher has said,4 " The general anatomy of man was un- known." Much that was taught consisted of a mass of hypo- thetical or dogmatic statements which had been handed down from master to pupil for ages. In the words of Husson,5 "Up to that time bristling with scholastic minutife, anatomy re- pelled too often by its dryness the young who were destined to the study of the healing art. We cannot even to-day " [the year of Bichat's death] " recall without a sensation of pain all those multiple divisions, those fatiguing descriptions, that conventional and often incomprehensible language which con- stituted then the science of anatomy. Bichat was the first to leave the common path; he presented anatomy in a new point of view; studied the general organization of man in the simple tissues of which he is composed, divided the living economy into various systems, and by accumulating facts, by bringing observation' to bear on experience, he broadened the limits of science and built for himself a monument which brings him lasting renown." Bichat's great work consisted in the in- troduction into anatomy and physiology of methods of accu- rate, systematic observation and experiment, methods similar to those which distinguished the later clinical schools of 4Knox: Lancet, Lond., 1854, ii, 393. 5 Notice liistorique sur la vie et les travaux de Marie-Fr.-Xav.-Bichat, in Traite des membranes &c. par X. Bichat. Nouvelle edition augmen- tee d'une notice &c. par M. Husson., Par., 8°, Ann. xi, 1802. 4 Laennec, Louis, and the physiological studies of Claude Ber- nard. "Anatomy," said he one day to his colleagues, 11 is not as they teach it to us, and physiology is a science to be made over again." 0 Bichat devoted himself literally day and night to his studies, and unmoved by the stirring and distracting incidents of this turbulent period, lived among his cadavers, writing the protocols of his observations and experiments in the small hours of the night. He soon gathered about him enthusiastic pupils and friends to whom in 1797 he gave his first course in anatomy. " From this moment," says Le- vacher,' " one must measure his success by his productions, and his years by his successes." He was one of the founders of the Societe medicale d'emu- lation, in the proceedings of which his earlier works were published: Description d'un nouveau trepan (vol. ii des Memoires de la Soc. med. d'emulation). Memoire sur la fracture de Vextremite scapulaire de la clavi- cule (Ibid.). Description d'un procede nouveau pour la ligature des polypes (Ibid.). Memoire sur la membrane synoviale des articulations (Ibid.). In this latter publication he introduces his ideas concern- ing the distinction of tissues which were afterwards elaborated in his general anatomy. Synovial membranes are described for the first time. Dissertation sur les membranes et sur leurs rapports gene- raux d'organization" (Ibid.). Next there appeared: Memoire sur les rapports qui exist- ent entre les organes a formes symetriques et ceux a forme irreguliere (Ibid.). Here he introduces his theory of the two lives, the animal and organic. In the same year, when barely twenty-nine years of age, he was appointed adjunct physician to the Hotel Dieu. [198| [199] 6Pariset: Discours a Pinauguration de la statue de Bichat a Bourg. Gaz. med. de Par., 1843, 2 s., xi, Ann. xiv, 566. 7 Loc. cit. [198] 5 [199] Finally, in 1800, he published his first great work, " Traite des membranes en general el de diverses membranes en particulier," Pai., 8°, 1800, an admirable example of accu- rate, systematic anatomical description. Here he recognized the fact that not only the organism as a whole, but individual organs are composed of various tissues which may be distinguished one from another and which have notable individual characteristics. In his own words: " Chemistry has its simple bodies which by the diverse combinations to which they are susceptible, form compound bodies ... In like manner anatomy has its simple tissues which by their combinations . . . form the organs." 8 During the same year he published what is perhaps his most celebrated work, " Recherches physiologiques sur la vie et la mart." This work consists of two parts: the first theoretical, in which he distinguishes the animal life from organic life; the second, experimental, in which he endeavors to deter- mine the role of the brain, the heart and the lungs in pro- ducing death. The book contains a mass of interesting physiological observations and theories, many of which are classical. Such, for instance are his observations on the action of red blood on the life of the brain, the action of venous blood in various functions, the functional inde- pendence of the brain and the heart. His theories, though ingenious, have in many instances suffered modifications with the lapse of years, but his observations and methods of research are models for all time. Bichat's position in the Hotel Dieu gave him increased opportunities for the study of disease in the living and for the comparison of clinical and anatomical observations. Of these opportunities he made the most, seeking every chance to add to his experience by acting as substitute for his col- leagues. In one winter he made over six hundred autopsies. In 1801 appeared his "Anatomic generate appliquee a la physiologic et d la medecine," a work memorable not only for its anatomical observations but for the remarkable applications 8Auatomie generale &c., p. Ixxix. 6 which Bichat makes of these observations to physiology and [199] pathology. " Pathological anatomy," says Cerise,9 " which was but a collection of isolated facts, is here raised to the rank 9Cerise: CEuvres du Docteur, Par., 1872, vol. ii, p. 403. 7 L199J of a science. . . . Medical genius has never at a single bound raised itself to so great a height." In the preface to this treat- ise he speaks of the methods of study which have led him to the results set forth in the work. How modern are his words I " Experiments on living animals, tests with various reagents on organized tissues, dissections, necropsies, observation of man in health and disease, these are the sources from which I have drawn; they are those of nature. Nor have I neglected those of the authors, especially of those for whom the science of the animal economy has been a science of facts and experi- ence." Nature was indeed his text-book, and on one occasion he is reported to have said, " If I have made such rapid headway, it is because I have read little." 10 The relations of pathological anatomy to clinical medicine have rarely been better expressed than in the following words: " We are, it seems to me, at a point where pathological anatomy must take a new flight. It is not alone the science of those changes which primarily or secondarily develop gradually in the course of chronic disease; it includes the examination of every alteration to which our parts are subject at whatsoever period of the disease. . . . Hew petty are the reasonings of a multitude of physicians great in the eye of the public, when investigated not by the light of their own writings, but in the cadaver! Medicine has been for a long time excluded from the exact sciences; it will have a right to be associated with them at least as regards the diagnosis of disease when one shall have combined everywhere with rigorous clinical observation the examination of the alterations suffered by our organs. . . . Of what value is clinical observation if one is ignorant of the seat of the evil ? You might take notes at the bedside of the sick for twenty years from morning to night on affections of the heart, of the lung, of the abdominal viscera, &c., and there will be but confusion in the symptoms, which resting upon no cer- tain base, will of necessity bring before you an incoherent se- quence of phenomena. Open a few cadavers and that obscur- (200J 10 The Practitioner, Lond., 1896, Ivi, 280. 8 ity which clinical observation alone could never have dissipated will vanish in a moment from before your eyes." 11 Realizing early the traditional, blind, therapeutic empiri- cism which then prevailed, Bichat became deeply interested in the physiological action of drugs and made many careful, systematic pharmacological experiments on animals. His power for work was little short of marvelous. He began a treatise upon descriptive and pathological anatomy, working all day and writing much of the night, but with such extraor- dinary rapidity, accuracy and clearness, that his pages are said to have gone unread and uncorrected from his pen to the printer. Young, attractive and spirited, the few moments which he snatched for the more ardent pleasures of life, came not from his hours of work, but from those which should have been devoted to rest and recuperation-and the end was the old familiar one. One day an attack of haemoptysis, the mo- ments of discouragement soon forgotten, the old manner of life renewed, several repetitions of the accident, frequent " gastric disturbances," and finally, after a hot July day spent among decomposing bodies in an atmosphere so foul that it had driven all his associates from the laboratory, an attack of syncope, a fall, followed shortly by an " ataxic fever " which proved fatal on the 14th day, the 22nd of July, 1802. He died in the arms of his master's widow, to whom he had been for seven years a devoted son. " He was," says Larrey,12 " but thirty years old, but he was already the greatest physiologist of his century, as he must have been the greatest physician had he but lived twenty years more." Bichat seems to have possessed, in addition to his genius, a character in many ways remarkable. With all his powers and his restless energy, he was a modest, affectionate and singularly lovable man, incapable of jealousy or resentment, and devoted to his friends. " If," says Pariset,13 " we may believe Fenelon, [200] 11 Bichat : Anatomie generale, &c. Nouvelle edit., Paris, 1812, Brosson et Gabon, t. 1, p. xcviii. 12 Larrey : Discours prononce a 1'inauguration de la statue de Bichat, 8°, Paris, 1843; also Gaz. med. de Par., 1843, xiv, 2 s., xi, 569. 13Loc. cit. 9 [200] few men have the strength to support the talents which they have received from heaven. I venture to assert that Bichat belonged to this small number of favored men." Roux,14 a companion and student, who for several years held most inti- mate relations with Bichat, speaks feelingly of his remarkable and genuine modesty. But now and then some slight act would reveal to his more intimate associates the consciousness of his own strength, and once, in a tete-a-tete with Roux he said, apropos of his own career: " J'irai loin, je crois." He died without leaving the wherewithal to provide for his funeral, but he was piously cared for by his friends, while all uGaz. med. de Par., 1845, 2 s., xiii, 763. 10 the professors of the faculty and 600 students followed his re- mains to the grave. His death caused profound emotion throughout the medical profession. Corvisart wrote to Napoleon, then first consul:15 " Bichat has just died at the age of 30; he has fallen upon a field of battle which, also, calls for courage, and which counts many a victim; he has broadened the science of medicine; no one at his age has done so many things and done them so well." And Napoleon, wishing to honor both Bichat and his master, wrote to the Minister of the Interior: " I beg that you will have placed in the Hotel Dieu a marble dedicated to the mem- ory of Citizens Desault and Bichat which shall attest the gratitude of their contemporaries for the service which they have rendered, one to French surgery, of which he is the re- storer, the other to medicine, which he has enriched by many useful works. Bichat would have broadened the domain of this science, so important and so dear to humanity, if pitiless death had not struck him down at the age of 30." The monu- mental stone upon the wall of the peristyle of the Hotel Dieu has for an inscription an extract from this memorable letter. Since this time the memory of Bichat has not faded. In 1833 the Societe d'emulation de Jura erected a commemora- tive stone by the house in which he was born in Thoirette. In 1837, David, charged with the duty of designing the frieze on the facade of the Pantheon upon which are inscribed the fine words, "Aux grands hommes la partie reconnaissante," repre- sents Bichat dying, his head crowned with laurels. In one hand he holds a pen, and in the other the manuscript of his work, " Sur la vie et la mort." In 1839 a monument was erected in honor of the memory of Bichat at Son-le-Saulnier, chef-lieu of the department of Jura, a column surmounted by a bronze bust by Huguenin. In 1843 a fine memorial was dedicated at Bourg en Bresse. The statue by David (d'Angers) represents Bichat in an atti- tude of meditation, his hand seeking the impulse of the heart of a child who stands by his side-at his feet a partly dissected [200] [201] 15Larrey: Inauguration de la statue de Bichat le 16 juillet, 1857, & la Faculte de Medecine de Paris. Discours de Larrey au nom de la Societe medicale d'emulation. [200] 11 12011 body and a lamp, symbolizing the light which his genius had cast upon the obscurities of life and death. In 1857 the statue, also by David, which stands in the quadrangle of the school of medicine at Paris was unveiled. In 1844 the city at last granted a fitting burial place for Bichat at Pere-La-chaise, and on the 16th of November, 1845, forty-three years after his death, his remains were solemnly exhumed before a committee of the Medical Congress of France and carried to Notre Dame, where obsequies were held; thousands marched in the funeral procession. And again last summer the Societe Frangaise d'histoire de la medecine celebrated the centennial anniversary of his death by a visit to his tomb, the placing of an inscription upon the house in which he died, and literary exercises in which ad- dresses were made by a number of distinguished members of the profession. A medal has been struck in honor of the occasion. Looking back upon the life of this truly great man one can- not but feel the inspiration of it all. And though reason re- mind us that 'tis a career rather to admire than to emulate, yet one must be stirred by the fine words of Levacher,18 ad- dressed to the members of the society which owed so much to his influence and labors: " Let Bichat be at the same time the guide and the model. He has shown what one could do in but a little while. What an example for you young men who are pursuing the same career. You are witnesses of the regret which he carries with him; of the tears which he has caused to flow, and of his tri- umphs ; take him for an example. Be as he was, active and laborious, patient and zealous, and if you need to sustain your- selves in your work pronounce the name of Bichat. Remem- ber above all that time adds nothing to glory and that with genius and work thirty years of life suffice to render one's name immortal." 16 Mem. Soc. med. d'emulat., Par., 1803, v, pp. xiv-xxvii. 12 PRELIMINARY REPORT OF The Tuberculosis Commission OF MARYLAND. TABLE OF CONTENTS, 1. GENERAL SUMMARY 5 II. NATURE OF TUBERCULOSIS 7 III. GENERAL PREVALENCE OF TUBERCULOSIS * 8 IV. GENERAL MORTALITY FROM TUBERCULOSIS 8 V. PREVALENCE OF AND MORTALITY FROM TUBERCU- LOSIS IN THE STATE OF MARYLAND AND IN THE CITY OF BALTIMORE 9 VI. ECONOMIC EFFECTS OF TUBERCULOSIS IN MARY- LAND 10 VII. PORTALS BY WHICH TUBERCLE BACILLI MAY ENTER INTO THE ORGANISM 12 (1) Inhalation • 12 (2) Ingestion 12 (3) Through the Skin 12 VIII. MANNER OF INFECTION . 13 (1) Heredity and Predisposition 13 (2) Inhalation 13 (3) Ingestion 13 (4) Cutaneous Infection 13 (5) General Conclusions 13 IX. PROPHYLAXIS 15 (1) General principles of prophylaxis 15 (2) Prophylactic measures in force in Maryland 15 (3) Prophylactic measures in force in other states 17 X. TREATMENT 19 (1) General Principles 19 (2) Sanitaria and dispensaries 19 XI. RECOMMENDATIONS AS TO FURTHER PROPHYLACTIC AND THERAPEUTIC MEASURES WHICH MAY BE UNDERTAKEN IN MARYLAND' 22 TUBERCULOSIS EXPOSITION 24 To His Excellency, JOHN WALTER SMITH, Governor of Maryland. Dear Sir :- / The Tuberculosis Commission of Maryland have the honor to present to you the following report of the results of their investiga- tions. This preliminary report will soon be followed by a more com- plete statistical statement in the preparation of which we are now engaged. Respectfully yours, W. S. THAYER, President of the Commission. December 14th, 1903. PRELIMINARY REPORT of THE TUBERCULOSIS COMMISSION OF MARYLAND. I. GENERAL SUMMARY. (1) TUBERCULOSIS IS A DISEASE DUE TO THE ENTRANCE INTO THE BODY OE A SPECIFIC MICROORGANISM-THE TUBERCLE BACILLUS. (2) IT IS PROBABLE THAT UNDER ORDINARY CONDITIONS OF CITY LIFE TURERCLE BACILLI GAIN ENTRANCE FROM TIME TO TIME INTO THE BODIES OF ALMOST EVERY INDIVIDUAL. (3) IN MOST CASES THE HUMAN ORGANISM IS ABLE TO OVER- COME AND DESTROY THE INVADING MICROORGANISMS BUT UNDER SPECIAL CONDITIONS-HEREDITARY PREDISPOSITION-UNHYGIENIC SURROUNDINGS DISEASE, DISSIPATION OVERWORK WORRY ESPECIALLY MALIGNANT FORM OF THE MICROORGANISM-THE DISEASE GAINS THE UPPER HAND. SOME INDIVIDUALS AND FAMILIES SEEM TO BE ESPECIALLY PREDISPOSED TO TUBERCULOSIS. THE NATURE OF THIS PREDISPOSITION IS NOT UNDERSTOOD. (4) TUBERCULOSIS PREVAILS ESPECIALLY DURING EARLY ADULT LIFE. (5) THE MICROORGANISM USUALLY ENTERS THE ECONOMY THROUGH THE NOSE OR MOUTH BY RESPIRATION, THROUGH INFECTED FOOD OR THROUGH WOUNDS OF THE SKIN. (6) THE BACILLI ARE SPREAD ABOUT CHIEFLY BY THE SPRAY EMITTED BY PATIENTS SUFFERING WITH THE DISEASE ON COUGHING OR SPEAKING AND BY THEIR EXPECTORATION. (7) THE MOST IMPORTANT METHOD OF DISTRIBUTION OF THE TUBERCLE BACILLI IS PROBABLY PROMISCUOUS SPITTING. (8) THERE ARE at LEAST 10,000 CASES OF TUBERCULOSIS IN MARYLAND TO-DAY. (9) DURING THE YEAR BETWEEN OCTOBER 1st, 1902, AND OC- TOBER 1st, 1903, THERE WERE IN MARYLAND 2,509 DEATHS FROM TUBERCULOSIS. 6 (10) THE AVERAGE INDIVIDUAL LOSS ENTAILED BY THE DISEASE FOR EACH WAGE-EARNING MALE DYING FROM TUBERCULOSIS IN MARY- LAND, IS $741.64. (11) THE AVERAGE POTENTIAL LOSS TO THE COMMUNITY EN- TAILED BY THE DEATH OF EACH WAGE-EARNING MALE IS $8,512.52. (11) THE TOTAL POTENTIAL LOSS TO THE STATE ENTAILED BY THE DEATHS FROM TUBERCULOSIS EACH YEAR CANNOT AT THE VERY LOWEST ESTIMATE BE LESS THAN TEN MILLION DOLLARS. (12) TUBERCULOSIS IS A PREVENTABLE DISEASE. (13) THE MOST IMPORTANT PREVENTIVE MEASURES ARE: (a) THE INSTRUCTION OF THE GENERAL PUBLIC AND OF THE SUFFERERS FROM THE DISEASE IN THE NATURE OF THE AFFECTION AND IN THE SIMPLE AND NECESSARY HYGIENIC MEASURES WHICH SHOULD BE CARRIED OUT IN THEIR ABODES, AS WELL AS THE EVENTUAL EMPOWERMENT OF THE STATE AND CITY HEALTH AUTHORITIES TO INSIST THAT THE MORE IMPORTANT OF THESE MEASURES BE CARRIED OUT. (b) THE ENACTMENT AND ENFORCEMENT OF PROPER ANTI- SPITTING ORDINANCES. . < (c) THE COMPULSORY NOTIFICATION OF THE CITY AND STATE HEALTH AUTHORITIES OF THE EXISTENCE OF EVERY CASE OF TUBER- CULOSIS. (d) the INTRODUCTION AND ENFORCEMENT OF proper meth- ods OF DISINFECTION OF PREMISES VACATED BY CONSUMPTIVES. (e) THE ESTABLISHMENT OF HOSPITALS AND SANITARIA FOR THE CARE OF ADVANCED CASES, AS WELL AS CASES WHICH FROM THEIR NATURE AND SURROUNDINGS MAY BE A SOURCE OF DANGER TO THOSE ABOUT THEM. (14) TUBERCULOSIS IS IN MANY INSTANCES A CURABLE DISEASE. (15) THE IMPORTANT ELEMENTS IN THE TREATMENT ARE: (a) REST. (b) FOOD. (c) FRESH AIR. (16) THE ESTABLISHMENT. OF PRIVATE SANITARIA HAS YIELDED MOST VALUABLE SERVICE IN THE TREATMENT OF THE DISEASE. (17) THE ESTABLISHMENT AND maintenance BY THE STATE OF PROPER SANITARIA FOR (a) THE TREATMENT OF EARLY TUBERCU- LOSIS AND (b) THE CARE OF ADVANCED CASES OF THE DISEASE WILL SAVE MANY LIVES, AND IN THE END WILL PROVE AN ACTUAL FINAN- CIAL benefit to the community. 7 II. NATURE OF THE DISEASE. Tuberculosis is an infectious disease due to the entrance into the body and growth at various points of a bacillus discovered by Koch in 1882. The name tuberculosis was given to the disease be- cause of the fact that in most instances the earliest changes consist in the development at the points where the bacilli have settled, of small nodular masses called tubercles. These little masses which grow about the tubercle bacilli probably represent efforts on the part of the organism to surround, segregate and destroy the germs. In many cases, however, the bacteria result sooner or later in the death of the surrounding tissues and the eventual breaking down and destruction of the diseased organ. In some parts as in the lungs, the condition may proceed with great rapidity and the destruction of large parts of the organ may occur before the actual formation of tubercles. The name tuberculosis, however, has become definitely associated 'with the disease. Recovery from tuberculosis may of course occur and in these cases the diseased areas become gradually replaced by permanent scar tissue. Tuberculosis may affect almost any part of the organism. By far the commonest seat of the disease is in the lungs, although it not infrequently affects bones, joints, glands, the intestinal tract, the genito-urinary tract, the brain and its membranes or the skin. Tuberculosis of the lungs is commonly known as "pulmonary consumption." As is well understood this may be an acute disease -"galloping consumption," lasting but a few weeks or months, or it may be a very chronic disease, lasting years. A number of the other forms of tuberculosis are familiar to the public unde'* various names. Tuberculosis of the intestines may cause a chronic wasting diarrhoea-"consumption of the bowels." "Hip disease," is tuberculosis of the hip joint. Curvature of the spine-that form which results in the deformity known as "hunchback" is due to tuberculosis of the spine. "White swelling of the knee" is tuberculosis of the knee joint. The "Brain fever" of children is commonly tuberculous men- ingitis. "Scrofula," "King's Evil," "Waxing kernels" in the neck are due to tuberculosis of the lymphatic glands. Not a few of the cases of dropsy with progressive wasting, especially in the young, are due to tuberculous peritonitis. 8 III. GENERAL PREVALENCE OF TUBERCULOSIS. Tuberculosis is prevalent throughout the world. It occurs, however, with far greater frequency in cities and closely settled com- munities, while it is relatively rare in those regions where people live almost entirely out of doors. In urban populations, almost every one has at some time of his life suffered from small local areas of tuberculosis. Naegeli in Professor Ribbert's laboratory having carefully studied the bodies of 500 individuals at autopsy, found that 100 per cent, of those over 18 years of age showed unmistakable evidences of pre-existing tuberculosis, thus proving the truth of the celebrated remark of an old Viennese physician "Jedermann hat am Ende ein bischen Tuberkulose." ("Every one has in the end a little tuberculosis.") In the enormous majority of instances the organism soon over- comes the few germs which have gained entrance and recovery oc- curs without the appearance of any recognizable symptoms of the disease. Despite this fact the infection gains the upper hand in a number of cases so great as to call for the most active measures, both public and private, for its prevention and cure. Tuberculosis is especially prevalent during early adult life; the greatest mortality from this disease occurs between the ages of 20 and 30. Tuberculosis is widespread among animals as well as among human beings although great differences in susceptibility to the dis- ease exist. It is especially common among cattle where its existence is generally believed to be of danger to human beings. In cattle as in man. the disease is more common in thicklv set- tled districts, and when the herd is once infected, spreads with con- siderable rapidity. Pearson and Ravenel estimated that in 1900 about 3 per cent, of the cattle in the state of Pennsylvania were tuberculous. Tn Saxony. 30 per cent, of all cattle are infected by this disease. The importance of the prevalence of tuberculosis among cattle may be realized from the conclusion of Pearson and Ravenel that "The disease causes more losses than all other infectious dis- eases of farm animals that exist in Pennsylvania at this time." IV. GENERAL MORTALITY FROy TUBERCULOSIS. Tuberculosis leads all other known diseases in the percentage of mortality which it causes. To this malady may be ascribed all the wav from one-fifth to one-tenth of the total mortality of the world. 9 The estimated mortality from pulmonary tuberculosis per thous- and living for the United States in the last census was 18.7*; for England 13.38; for Prussia 19; for Saxony 16.8. The percentage of mortality from tuberculosis as compared with the total mortality for these same countries was for the United States 10.68; for England 9.7; for Prussia 9.1. V. PREVALENCE OF AND MORTALITY FROM TUBER- CULOSIS IN THE STATE OF MARYLAND AND IN THE CITY OF BALTIMORE. (1) In the State of Maryland. Owing to the fact that no reports are required by law of exist- ing cases of tuberculosis it is impossible to obtain exact statistics as to the number of cases occurring yearly in this State. Our studies would lead us to believe that there are at the present at least 10,000 cases of tuberculosis in the State of Maryland. It is interesting to note that our reports come for the most part from the poorer and more unsanitary regions. It is true that the re- ports from these districts, from which the patients largely attend the dispensaries, are much more complete than those from other parts of the city and state. Yet the greater prevalence of tubercu- losis in these regions is unquestionable. In Baltimore during the last year there have been reported to the Boards of Health and to our Commission about 2,000 cases of tuberculosis. All statistics show the great frequency of tuberculosis in the colored race and our figures bear out these general statistics. The relation of tuberculosis to race as shown by the records of deaths from pulmonary tuberculosis for the year 1902 is as follows: Deaths in Maryland for 1902. All causes. Tuberculosis. White. Colored. White. Colored. 13,774 5,282 1,494 849 Ratio of deaths from tuberculosis to total mortality. White. Colored. 10.8 16.1 There were in 1902, 2,560 deaths from tuberculosis in all its forms in the State of Maryland. ♦These figures are based on returns from those regions only where there is reliable registration of the causes of death. These localities are for the most part thickly settled, so that the figures are undoubtedly higher than those for the whole country should be. 10 The mortality from tuberculosis in Maryland differs but little from that elsewhere in this country. Compared with the mortality of the eastern states in which there are good records, Maryland stands at about the middle of the list with an estimated mortality of about 16.94 for each 10,000 of the population. The relative proportion of deaths from tuberculosis to those from all other causes for 1900 was about 11 per cent., higher than in any other state excepting in Massachusetts, where the urban popu- lation is far greater. (2) In the City of Baltimore. There were in 1902, 1,392 deaths from tuberculosis in the City of Baltimore. The mortality from tuberculosis in Baltimore as compared with that in New York, Chicago, Philadelphia, Brooklyn, St. Louis and Boston for the decade from 1892 to 1902 is shown in the following table: Number of deaths from tuberculosis for each 10,000 of population. Year. Ba Ito. Boston. Phila. N. Y. Chicago. Brooklyn. St. Louis 1893 23.91 28.60 23.94 29.14 14.47 23.42 18.92 1894 23.90 29.27 22.05 25.74 13.75 23.55 16.20 1895 24.27 26.92 21.04 27.86 13.56 23.17 17.85 1896 23.49 25.73 21.15 26.20 14.27 21.89 18.00 1897 21.58 24.37 19.66 24.95 13.41 20.40 16.61 1898 21.53 22.90 20.88 25.08 14.64 21.96 16.07 1899 19.45 22.27 22.23 26.00 12.90 21.51 17.04 1900 20.76 22.23 21.00 25.69 15.30 20.90 17.49 1901 22.09 22.96 22.29 24.97 14.19 20.45 18.86 1902 22.06 20.65 21.07 22.87 14.04 18.78 18.21 It may be noticed here that Baltimore stands about at the middle of the list, although for the last year, 1902, the mortality is higher than that of all other cities excepting New York. On comparing the figures of Baltimore with those of New York' and Boston in which cities an active anti-tuberculosis campaign has been carried out for several years, it may be seen that the improve- ment which has occurred in these two cities in wanting with us. VI. ECONOMIC EFFECTS OF TUBERCULOSIS IN MARYLAND. In connection with the mortality and morbidity reports the Com- mission has endeavored to obtain some idea of the economical effects of tuberculosis upon the State of Maryland. 11 Excepting alone insanity, tuberculosis ranks first among all diseases in the proportion of its subjects who finally become de- pendent for assistance or support upon the state or community in which they live. The life history of a consumptive may be divided economically into three periods: (1) A period of unimpaired earning capacity preceding the onset of the disease and extending into its earliest stages. (2) A period in which the patient is capable of irregular work at reduced wages. (3) A period during which there is an entire loss of earning capacity with or without a condition of dependency. In this period the patient and his family become in a considerable proportion of cases, a source of direct loss to the community or state. In order to gain some idea of the average loss to the individual and his family in a given case of tuberculosis Dr. Price has tabulated the figures regarding 177 wage-earning males who died in Maryland during the last year. The data for these figures were acquired by inquiry into the histories of patients whose deaths were reported to the state or city authorities, without regard to their social state, and it may be assumed that they fairly represent the average condition in this state. Seventy-two or 40 per cent, of these men were in one way or another dependent upon charitable aid, while 26 or 14 per cent, died in charitable institutions. There is good reason to believe that the majority of the others received assistance at some time. Among those who finally became dependent were many receiving moderate incomes-contractors-bookkeepers-clerks-merchants. In these individuals there was computed: (1) The total individual final loss in earnings. (2) The potential loss to the community. This latter can be readily computed by determining the annual income of the individual at the time of the onset of his disease and multiplying that by the number of years of expected life as estimated by the figures of insur- ance companies. The average individual loss was found to be $741.64. The average potential loss to the community resulting from the death from tuberculosis of a wage-earning male was $8,512.52. During the year from October 1, 1902, to October 1st, 1903, there were 2,509 deaths from tuberculosis in the State of Maryland. Of these 908 were wage-earning males. From these figures it would appear that from the deaths of wage-earning males alone there re- 12 suited in one year a potential loss to the community of over $7,500,- 000, while the total potential loss from the 2,509 deaths can scarcely have been under $10,000,000. But these figures are far from showing the real effects of the disease upon the community. Indirectly the result of the death from tuberculosis of the father or main supporter of a family may be far- reaching. One of these other results which has impressed itself upon us is the fact that in many instances the death of such an in- dividual means the removal of children from school long before the proper time. The child must work to support the family, but he is thus started out in life with an education so imperfect as to per- manently impair his earning capacity and to lower materially the general standard of education in the community. These are impressive facts-facts which should move us to consider seriously what means we have to diminish the prevalence and mortality from tuberculosis. VII. PORTALS BY WHICH TUBERCLE BACILLI MAY ENTER INTO THE ORGANISM. There are a variety of ways in which tubercle bacilli may enter into the organism. (1) Inhalation of spray or dust containing tubercle bacilli. While it is known that tubercle bacilli may enter the mouth and nose in this manner the course by which they actually reach the lungs or the various organs throughout the body in which they may sub- sequently settle, is no means entirely certain. In many instances it is probable that through the tonsils and other lymphatic absorbing apparatus they enter into the lymph and blood to be distributed throughout the body, settling down eventually at the points of least resistance wherever these may be. It is possible, though not proven, that they may pass directly down the air tract into the lungs. (2) Through the eating of infected food. There is little doubt that tuberculosis may also enter the organ- ism through infected articles of food. In these cases the tubercle bacilli may and often do produce disease of the intestines or of the glands in the abdomen which are connected with the intestines. (3) Through the skin. Direct inoculation may occur through wounds or abrasions of the skin in individuals handling infected material. 13 VIII. MANNER OF INFECTION. How is tuberculosis usually acquired? (1) Heredity and predisposition. There are probably some who still believe that tuberculosis de- veloping some years after birth has actually been inherited; that the child is born with the bacteria in his organism. While such a condition might theoretically exist it is certainly so excessively rare that actual inheritance of tuberculosis may be left out of considera- tion. There can be little doubt that in many families an hereditary predisposition to tuberculosis exists. The importance of this here- ditary predisposition is, however, sometimes over-estimated. The dangers incident to such hereditary tendencies may often be obvi- ated by a proper manner of life. On the other hand, it is unques- tionable that the resistance of the organism to tuberculosis may be greatly reduced by an improper manner of life-overwork-worry -dissipation-lack of proper food-indoor life-close and ill-venti- lated dwellings. (2) Inhalation. As has been said tubercle bacilli often enter the human organism by inhalation. How may this occur? (a) Spray. One of the commonest methods by which trans- ference of the disease occurs is through the inhalation of the spray emitted by infected individuals who frequently cough in a careless way without covering the mouth. Each cough throws into the air a fine spray which often contains bacilli that are readily inhaled by individuals who are in close proximity to the cougher. Infected spray may also be emitted in the simple act of talking. That this is a real danger has been shown by the experiments of Flugge, Hey- mann and others. (b) Dust. Sputa or discharges or the infected tissues of ani- mals or human beings allowed to remain in exposed positions soon dry and the bacilli are easily spread about in the form of dust. Happily, the effect of sunlight in the open, soon destroys the micro- organisms, but in dwellings.and factories and cars, the inhalation of dust containing tubercle bacilli is probably a fruitful source of infec- tion. Dust containing tubercle bacilli may be brought into clean houses upon the boots or clothes of uninfected individuals who have walked upon soiled streets or floors. The dusting and cleaning of these garments will set free the bacilli which may become sources of fatal infection. Professor Strauss some years ago demonstrated 14 the presence of tubercle bacilli on cotton wads placed in the noses of attendants in the wards of a Parisian hospital. (3) Eating of infected food. (a) Intrinsic infection. Food, especially milk, butter, cheese and meat may be infected from the beginning with the bovine tubercle bacilli. This is especially common in the case of the milk of tuber- culous cows which may contain large number of bacilli. That the ingestion of such products may cause human tuberculosis has been disputed by so distinguished an observer as Koch but there is evi- dence which may be considered as positive that the disease may be acquired in this way. Strong support of this idea is afforded by the relatively greater frequency of intestinal tuberculosis in infants fed upon cow's milk. (b) Infection of food with human bacilli. It is not only food containing bovine tubercle bacilli which may cause the disease. The spray spread about by coughing or infected dust may and probably often does, result in the deposition of bacilli upon milk and other varieties of food which do not kill the germs. Flies and other insects doubtless spread bacilli in a like manner. No one who has observed the conditions of an ill kept hospital or almshouse in the summer time can fail to appreciate the possible im- portance of the role played by flies. As has been mentioned in connection with inhalation, the bacilli may be introduced into food through the hands and clothes of tuberculous patients as well as through the dusting of skirts or trousers or boots of individuals who have walked upon soiled streets or pavements or floors. (4) Cutaneous infection. Skin tuberculosis may be acquired by individuals who clean receptacles or floors or clothes containing tubercle bacilli; it is especially common in physicians who perform many autopsies. While areas of skin tuberculosis thus arising may usually be perma- nently removed by excision, a fatal spread of the process has been known to follow. (5) General Conclusions. IN CONCLUSION IT MAY BE ASSERTED THAT WHATEVER DIFFERENCES OF OPINION THERE MAY BE AS TO THE COMMONEST METHOD OF EN- TRANCE OF THE BACILLUS OF TUBERCULOSIS INTO THE ORGANISM THERE IS NO DOUBT IN THE MINDS OF ALL COMPETENT OBSERVERS THAT TIIE ENTRANCE OF THE TUBERCLE BACILLUS INTO THE HUMAN BODY IS THE PRIMARY CAUSE OF THE DISEASE AND THAT ANY METHOD 15 BY WHICH THE BACILLUS IS SPREAD ABOUT IS A SOURCE OF DANGER TO THE COMMUNITY. IT IS ALSO GENERALLY RECOGNIZED AND ACKNOWLEDGED THAT THE SPRAY FROM THE MOUTHS OF TUBERCULOUS PATIENTS AND THE GENERAL DISTRIBUTION OF THE SPUTA OF INDIVIDUALS AFFECTED WITH THIS MALADY ARE THE MOST IMPORTANT CAUSES OF THE SPREAD OF THE DISEASE. IX. PROPHYLAXIS. How can we best prevent the spread of tuberculosis ? (1) General principles of prophylaxis. / THERE IS EVERY REASON TO BELIEVE THAT THOUGH TUBERCLE BACILLI MAY LIVE FOR CERTAIN LENGTHS OF TIME OUTSIDE OF THE ANIMAL BODY AND MAY BE CULTIVATED ON SPECIALLY PREPARED MEDIA THEY FLOURISH ONLY IN THE LIVING BODY AND THAT IF DIS- SEMINATION OF THE BACILLI FROM DISEASED ANIMALS AND HUMAN BEINGS COULD BE PREVENTED THE MALADY COULD BE ARRESTED. TUBERCULOSIS IS A PREVENTABLE DISEASE. What steps should we take to prevent its spread? The proper course to pursue is clear, the sputa, dejecta, DISCHARGES AND DEAD BODIES OF ALL ANIMALS AND HUMAN BEINGS SHOULD BE DISPOSED OF IN SUCH A MANNER THAT THEY ARE NO LONGER OBJECTS OF DANGER TO THE COMMUNITY.. .THOSE SUFFERING FROM TUBERCULOSIS AND THEIR FRIENDS SHOULD BE TAUGHT THOSE SIMPLE MEASURES WHICH RENDER THE PATIENT NO LONGER A DANGER TO THOSE WHO SURROUND HIM. (2) Prophylactic measures in force in Maryland. What are we doing here in Maryland? (a) Laws with regard to animals. There are no laws with regard to animals. (b) Measures with regard to human beings. (1) STATE MEASURES. (a) Anti-spitting ordinance. There is a law forbidding spit- ting on the floors, steps and platforms of any railroad or railway pas- senger car in this state under penalty of three dollars and costs or, 16 in default of payment of fine and costs, five days in jail (Act of the Legislature for 1902, chapter 581, p. 834.) (b) Free Examintion of Sputa. The State Board of Health examines free of charge for any physician in the state, specimens of suspected sputa. (21 CITY MEASURES. (a) Anti-spitting ordinance. There is an ordinance forbidding spitting on the floor of public buildings or upon the floors of street cars or public conveyances under the penalty of a fine of one dollar and costs. (Ordinance No. 16, 1898.) (b) Morbidity Reports. The physicians throughout the city are requested to report to the Board of Health cases of pulmonary tuberculosis in their practice (Ordinance No. 75, add. sec. 164 a, B. C. C. 1893.) (c) Examination of Sputa. The City Department of Health ex- amines free of charge for any physician in the city of Baltimore specimens of suspected sputa. (d) Disinfection. The Dept, of Health on the request of any physician, will disinfect rooms or houses previously occupied by tuberculous individuals. These are the measures at present existing in Maryland. The state law relating to the spitting upon the floors of steam railway cars has, so far as we know, been absolutely without effect. The city ordinance while it has been of considerable value in reducing the amount of promiscuous spitting, is far from being prop- erly enforced. It is a striking fact that, at the present moment at all events, the officials and employees of the railway companies, the police force and the general public have but little appreciation of the importance of this matter. It is within the knowledge of the Commission that a well known citizen has within the last year remonstrated with a high official of one of the important railways leading out of Baltimore upon the subject of promiscuous spitting in the cars. The reply was that the official did not desire to have notice posted in the cars; while a further request that an order be issued to the employees to prevent the violation of the ordinance by them received a non-committal an- swer showing clearly the disinclination on the part of the railway official to carry out or draw any attention to this law. The streets and sidewalks are covered with tuberculous sputa which dries and is distributed in the dust. Patients with tuberculosis are in all occupations and in few are arrangements made for the reception of sputa. 17 The conditions existing in many houses and factories, especially in many sweat shops, are dreadful as a result of the ignorance and negligence of employers and employees as to the steps which should be taken. (3) Prophylactic Measures in Force in other States and Cities. What is being done elsewhere? (a) State measures. The only state measure of prophylaxis which has been adopted elsewhere consists in the free examination by the State Health De- partments of specimens of sputa. This measure which as has been said, is in force in Maryland is of great value in allowing of the early and certain recognition of the disease. (b) Municipal Measures. By far the most important prophylactic measures against tuber- culosis are those which have been initiated in New York and Boston. Those in New York may be considered as the best that have yet been devised. In brief these consist of: (1) An anti-spitting ordinance. This ordinance forbids spit- ting upon the floors of public buildings, upon the surface and ele- vated cars, in railway stations and on steps, and on the pavements of streets within the curb stone. Notices are posted in the street cars in elevated stations and in other public buildings. The ordinance allows of a fine not larger than five hundred dollars or imprisonment for one year. This law has been actively enforced, several plain clothes men being sent out about every month to observe the viola- tions of the law and cause arrests. As a rule, magistrates impose a fine of about two dollars and costs. (2) Compulsory notification of the Health Department of the existence of cases of tuberculosis. Every physician is obliged by law to report to the Health Department all cases of tuberculosis oc- curring in his practice as in the case of other infectious diseases. This law which was opposed at first by many physicians through fear that their practice might be interfered with and that patients might be unnecessarily annoyed, has proved of so great benefit to the community that it is now generally observed, and Dr. Biggs esti- mates that 85 per cent, of the cases of tuberculosis in New York are reported to the Health Department. This information is confidential and the patient and family are never approached other than through the physician in charge. (3) Personal surveillance. Most cases of tuberculosis treated by charity, all of those living in boarding houses, hotels and tene- ments, are personally visited by a special corps of medical inspectors 18 who are assigned to various parts of the city. On request of the attending physician these inspectors will visit patients under private medical treatment. The department is informed by these officers as to the condition of the patient's surroundings, family and so forth. According to these conditions they may recommend (1) removal of the patient to the hospital; (2) renovation of the premises; (3) fumigation; (4) disinfection; (5) that no action be taken. Further information is obtained as to the financial state of the family; as to whether assistance is necessary. Moreover, the hy- gienic factors demanded by the tenement house law are considered. The family is given a pamphlet issued by the Health Department printed in their native language. The pamphlet gives the necessary advice to the family and patient concerning his condition. The patient is expected to give the department notice if he changes his abode. If the inspector finds cases among the poor which have not been treated at the dispensaries he advises them to put themselves under the care, if not of hospitals or dispensaries, then of the Charity Organization Society. (4) House disinfection. If the premises have been vacated by death or removal of a tuberculous patient, a paster is usually placed upon the door giving notice that the room has been occupied by a consumptive and forbidding its further occupancy until reno- vation or disinfection has been carried out. Disinfection is carried out by the Board and if renovation be necessary the Board of Health has authority to demand it of the owner of the building. These measures have resulted in the fact that much better care is taken of tenements than has previously been the case. (5) Hospitals for advanced cases. A limited number of ad- vanced cases of tuberculosis are taken -care of at the pavilion on North Brother Island and in the Consumptive Pavilion attached *o the Municipal Hospital on Blackwell's Island. Apart from the value of treatment to the patient himself, hospital advantages for cases of advanced tuberculosis are of great importance to the com- munity in removing from the families of the ignorant and indigent the most dangerous source of infection. In some cases the depart- ment has ordered the removal to the consumptive pavilion on North Brother Island of individuals who had refused to take the simple precautions ordered by the Board of Health and were owing to the existing conditions, dangerous to those about them. (6) Educational measures. By lectures, circulars, publica- tions in the daily papers and personal visiting, the Charity Organiza- tion Society in New York is doing a great service to the community. 19 Indeed, it is not improbable that systematic educational measures arc likely to prove of more lasting value to the community than any other step which has been taken. X. TREATMENT. Tuberculosis is in many instances a curable disease. (1) General principles of treatment. What are the essential principles in its treatment? There is no specific for tuberculosis. If, however, the disease be recognized at a sufficiently early period it may in many cases be entirely arrested. And the successful treatment of tuberculosis de- pends upon several perfectly simple principles. (1) General hygiene. Under this heading is included rest, mental and physical, free- dom from care, cleanliness and proper care of the person. (2) Food. The diet should be simple but abundant. The patient should be given systematically as much nourishing food as he can possibly absorb. (3) Fresh air. It is of especial importance that patients with tuberculosis should live and sleep as far as possible in the open air. These principles of treatment have been recognized by wise ob- servers for centuries but their advantages have been brought forth within a comparatively few years by the striking results which have been achieved in well ordered sanitaria. (2) Dispensaries. Private sanitaria. The most successful sanitaria have been those established in the open country, usually at some altitude. Here the patients are kept at rest and are obliged to remain out of doors during the entire day and to sleep at night, either out of doors or with the windows wide open. An abundance of simple nourishing food is supplied. This is administered systematically so that the patient is really under a regime of what is sometimes called "forced feeding." With im- provement an increase in the amount of exercise is gradually allowed until finally the patient in favourable cases is discharged with the disease arrested. It may well be asked: "Why may not the same results be ob- tained in any private house?" They may. But the great advan- tages of sanitaria for tuberculous patients consist in: 20 (1) The medical supervision by which the patient is properly controlled and taught the proper manner of life. (2) The freedom from care and the temptation to work which can rarely be obtained at home. (3) The advantages of society and companionship and example offered by the other patients; for the mental attitude of the sufferer has a great effect upon the course of the disease. One of the greatest advantages of sanitaria is that the patient is taught the proper manner of life which he is able Ipter to carry on at home and to inculcate in those about him. What have sanitaria accomplished? The good that sanitaria have done may be demonstrated by two simple statements. The Adirondack Cottage Sanitarium. In the first place, the remarkable statistics of the Adirondack Cottage Sanitarium recently published by Brown. Out of 1066 cases whose history has subse- quently been followed, treated at this sanitarium during a period from 18 up to 2 years ago, 31 per cent, are well. Out of 258 cases which were classed as "incipient" at the time of admission 66 per cent, are well. Out of 563 cases which were classed as "advanced," 28.6 per cent, are to-day well. Sanitaria of German Insurance Companies. Impressive testimony as to the value of sanitaria is afforded by the fact that the insurance companies of Germany have within the two years, 1897 and 1898 spent over $1,000,000 for the establishment and mainten- ance of sanitaria for the treatment of cases of tuberculosis previously insured by them. Public dispensaries and sanitaria. While the physician in his private practice and sanitaria con- trolled by private individuals may successfully manage many cases of tuberculosis they fail to reach the great mass of the community of but limited means or indeed, dependent upon charity; these people must be provided for in another manner. This leads us to the ques- tion of public measures. Dispensaries. Much good may be done by the establishment of special sec- tions for tuberculosis in the Out-Patient departments of hospitals and free dispensaries in cities and town. In these dispensaries the care- ful examination of the patient results often in the detection of the disease at a period sufficiently early to save the patient's life, while in the more advanced cases advice may be given him and his family 21 which not only may prolong his life but may save those about him from contamination. The model institution of this class is the Phipps Institute of Philadelphia. Public Sanitaria. (1) State sanitaria. The Massachusetts sanitarium may be taken as a model for what may be accomplished in this line. This sanitarium, built in 1896 at a cost of $150,000, was last year enlarged at an -expense of $127,000. It is conducted at an annual expense of between ninety and one hundred thousand dollars. The hospital is situated on high land at Rutland, fifty miles west of Bos- ton, with beautiful country surroundings. It is designed for the treatment and cure of tuberculosis. It is therefore intended only for early cases, those in whom there is a good probability of securing a permanent arrest of the disease. Each patient pays a minimum charge of four dollars a week. This charge is universal; it is, how- ever, often paid for the individual by cities or towns or charitable societies. The total weekly cost per individual for 1902 was $9.95, leaving a weekly cost to the state per patient of five dollars and ninety-five cents. The hospital is now capable of accommodating two hundred and fifty patients and is always full. The' results obtained by this institution in the few years of its existence have been most gratifying. In the year 1901-2, 78 per cent, of those cases which on admission were classed as "incipient" were discharged with the disease arrested. In a large proportion of these cases one is justified in assuming that the arrest will prove a permanent cure. The value of such an institution can scarcely be over-estimated. In Massachusetts it has been much appreciated by the public, the demand for admission being so great as to call for the enlargement of the institution two years ago. (2) City sanitaria. The city of New York has probably the best accommodations in this respect. Sanitaria for advanced cases. The most striking feature in the New York system is the existence on North Brother Island of pavil- ions for the accommodation of advanced cases of tuberculosis. This hospital does not give sanitarium treatment to early cases but does care for and segregate patients with advanced consumption, thus freeing their ■ families and the public in general from one of the gravest sources of danger. Sanitaria for the treatment of early tuberculosis. A hospital for the treatment of tuberculosis as a part of the city hospital is situated on Blackwell's Island. While the arrangements are not as 22 yet what they might be, the situation of the buildings is excellent and the care taken of the patients is rapidly improving under the efforts of the admirable Health Department of New York. XI. RECOMMENDATIONS AS TO FURTHER PROPHY- LACTIC AND THERAPEUTIC MEASURES, WHICH MAY BE TAKEN IN MARYLAND. What can we do in Maryland toward the prevention and treat- ment of tuberculosis in the State and city ? (1) State measures. (a) Enforcement of anti-spitting ordinance. It is urgently recommended that an amendment be made to the present law for- bidding spitting upon the floors, seats and platforms of railroad or railway passenger cars which shall extend this law so as to cover the decks of steam boats, the floors of all public conveyances and of state buildings, and further directing that notices forbidding spitting upon the floors and calling attention to this act be posted in all public conveyances. (b) State Notification. It is advised that the act requiring notification of the State Board of Health of the existence of certain infectious diseases be amended so as to include tuberculosis in all its forms. (c) Disinfection. It is recommended that the law requiring disinfection of premises after their occupation by persons suffering from certain infectious diseases be amended so as to include tubercu- losis. (d) Sanitaria. It is believed that the establishment of state sanitaria for the care and treatment of consumptives will be of last- ing benefit to the state and to the community and that whatever ex- pense may attend the founding and maintenance of these plants will be ultimately more than repaid by the results of treatment. (2) City measures. (a) Anti-spitting ordinance. It is recommended that the anti-spitting ordinance be extended so as to include as in New York, the side walks within the curb stones, that the penalty be increased so as to read not less than two nor more than twenty dollars' fine. (b) Notification. It is recommended that notification of the Health Department by physicians of the existence of cases of tuber- culosis in their practice be required. (c) General surveillance. It is recommended that a system of personal surveillance by agents of the Health Department on a 23 plan similar to that carried out in the city of New York be introduced at the earliest practicable moment. (d) Disinfection. It is recommended that disinfection and renovation of the houses and rooms vacated by tuberculous patients be provided for and insisted upon. (e) Educational measures. It is recommended that an annual lecture or lectures be provided for by the city to be delivered to the teachers in the public schools of Baltimore upon hygiene with especial reference to tuberculosis. It is further highly desirable that active educational measures should be undertaken under private auspices similar to those which are now so admirably conducted in Boston and New York. * * * * ♦ This Commission is convinced that the establishment in Maryland of state sanitaria for the care and treatment of consumptives is much to be desired. We are indeed of the opinion that such sanitaria are urgently required as well for humanitarian reasons as for the safety and well-being of the community. We believe that the establishment of such sanitaria will, from a purely material standpoint be an eco- nomical measure. We are of the opinion, however, that the problem should be approached in a most careful and deliberate manner. We have in Maryland advantages in climate and soil and locality for the estab- lishment of sanitaria excelled in but few states in the Union. In a matter of such capital importance as this it is desirable that no false or hasty step be taken but that the most be made of our material ad- vantages as well as of the experience of those who have preceded us in similar undertakings in this and other countries. If the State of Maryland undertake to build sanitaria for the treatment of tuberculosis every step should be taken to make these sanitaria the best in existence. With these ends in view we would suggest the appointment by the Governor of Maryland of a Commission for the specific purpose of considering plans, expenses, localities and any other questions look- ing toward the establishment of: (1) A sanitarium or sanitaria for the care of cases of chronic tuberculosis. (2) A sanitarium or sanitaria for the treatment and cure of early and favourable cases of tuberculosis. 24 Such a Commission with the advice and assistance of a board of health of so high a grade of efficiency as that which now honours our state will we believe succeed in forming suitable and feasible plans. * * * . * Tuberculosis Exposition. With a view to facilitating the proper consideration of this sub- ject and with the desire to excite a more general public interest in and a wider general knowledge of the nature of tuberculosis and the measures necessary for its restriction and treatment, this Commis- sion in association with the State Board of Health and the Maryland Public Health Association, have arranged for a Tuberculosis Exposi- tion to be held in Baltimore during the week from January 25th to February 1st. The Exposition is under the immediate direction of a committee of which Dr. Henry Barton Jacobs is chairman. It will be held at McCoy Hall, the use of which has been most generously offered to us by the Trustees of the Johns Hopkins University. There will be exhibits illustrative of the history and nature of the disease. Statistics illustrating its prevalence and the resultant mortality will be graphically presented. Plans, models and statis- tics of dispensaries and sanitaria for the treatment of the disease have been promised from most of the important institutions in this country and in Europe. There will be daily lectures and demonstrations by distinguished authorities on tuberculosis upon the various phases of the problem. The plan of this exposition, the first of its kind, has excited a widespread interest; it is hoped that it may prove of real value to the state and the community. [Reprinted from Maryland Medical Journal, February, 1904.] REMARKS ON THE OCCASION OF THE OPENING OF THE TUBERCULOSIS EX- POSITION IN BALTIMORE ON THE 25TH OF JANUARY, 1904. By William Sydney Thayer, President of the Tuberculosis Commission of Maryland. Ladies and Gentlemen: N great medical classic, which marked the beginning of a new era in the world of biological science, opens with these words: "We are living in the midst of a great reform in medicine. In our day, for the first time in thousands of years, the whole area of this widespreading field of learning has been laid freely open to scientific research. Doctrines which belong to the oldest traditions of mankind are put to the test, not only of experience, but of investigation. For experience, proof is demanded; for research, reliable methods. Everywhere inquiry seeks out the most intricate conditions appreciable by the human mind; knowledge ramifies jJ*- countless minute details which disturb the sense o^unity of the human organism, and seem to many more fitted to set forth an adornment of learning than an instrument of action." Fifty years have not passed since Virchow wrote these lines, and what a change has come over the world! The spirit of investiga- tion and research, the development of exact scientific methods based upon such observations have spread through every branch of biological science, and the fruits at first appreciable only to the trained and initiated student are now apparent to all thinking man- kind. And what fruits ! To consider but one branch of learning: Diphtheria has lost its terrors, yellow fever is almost under our control, cholera and plague, but yesterday the most terrible of the invisible adversaries of man, are now vulnerable enemies in an open field. Thousands of trained and enthusiastic students in hundreds of laboratories maintained by State aid or the generosity of public-spirited citizens, are systematically approaching the prob- 2 lems of prevention and cure of diseases, the nature of which was but a few years ago unknown. There never was a time more fraught with hope for the future. But with all these advances and discoveries, there have come to us new duties and increased responsibilities. One of the greatest of modern biologists has recently said: "As we march onward toward the true goal of existence mankind will lose much of its liberty, but in return will gain a high measure of solidarity. The more exact and precise a science becomes the less freedom we have to neglect its lessons. Time was when we could freely teach that a whale was a fish, but since it has been definitely established that this animal is a mammal, the error is no longer permissible. Since medicine has become an exact science, the liberties of medical men have become materially restricted. We have already seen physi- cians legally condemned for neglecting to the rules of asepsis and antisepsis. Certain liberties, such as failure to vacci- nate against smallpox, spitting on the floor, * * * and a multitude of others, are worthy of a barbaric past, and must dis- appear with the progress of civilization." To-day we all realize and appreciate that if we knew how a terri- ble pestilence arises-and more than this, how it may be prevented -we have gained a new duty; we must each one of us do his utmost to prevent it. But we know also that individual effort, "The single deed, the private sacrifice," however unselfish and earnest and courageous, will be of little avail. It is only by com- bined and enlightened and continued labor that we can accomplish our ends. Ladies and gentlemen, we know all these things about tubercu- losis, and that is why we are here this evening, to take counsel together, to put shoulder to shoulder in the furthering of a great and noble work. A Case of Typhoid Arteritis. Dk. Walter R. Steiner. Discussion. Dr. Thayer.-In connection with this remarkable case it will be remembered that we have had several similar instances in the hospital-cases which I brought together last year. In considering the question of the vascular complications of typhoid fever within the last year I have been impressed with their frequency and importance. Typhoid fever not only plays an important part in the production of phlebitis and arteritis in smaller vessels, but it is not improbable that it sometimes gives rise to more extensive and widespread changes in the arterial system. Some clinical studies upon our old typhoid fever patients which I have recently been making, and which I hope soon to report, indicate that typhoid fever plays a definite role in the etiology of arteriosclerosis. Potain has described acute aortitis occurring in the course of typhoid fever which he believes is susceptible to recogni- tion during life. I have never seen such a case. / On the Late Effects of Typhoid Fever on the Heart and Vessels. A Clinical Study. BY W. S. THAYER, M.D., ASSOCIATE PROFESSOR OF MEDICINE IN THE JOHNS HOPKINS UNIVERSITY. FROM THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES, March, 1904. Extracted from The American Journal of the Medical Sciences, March, 1904. ON THE LATE EFFECTS OF TYPHOID FEVER ON THE HEART AND VESSELS. A CLINICAL STUDY. By W. S. Thayer, M.D., ASSOCIATE PROFESSOR OF MEDICINE IN THE JOHNS HOPKINS UNIVERSITY. The series of observations here recorded is part of a study of the cardiac and vascular complications and sequels of the cases of typhoid fever treated in the last fourteen years in the clinic of Pro- fessor Osler, at the Johns Hopkins Hospital. Though not yet as complete as might be desired, the material already gathered seemed to me to be sufficient to justify an analysis of the results so far obtained.1 * * * The infrequency of endocarditis as a complication of typhoid fever is generally recognized. Only 11 cases were noted among the 2000 Munich necropsies, while but 3 have been observed in nearly 100 necropsies at the Johns Hopkins Hospital. The grave myocardial changes which may occur during the dis- ease are well known, thanks to the studies of a large number of observers, from Laennec,2 Louis,3 and Stokes,4 whose observations relate only to the gross appearances, down to the more minute his- tological investigations of Stein,5 Zenker,6 Hayem,7 Dejerine,8 Rom- 1 Read before the New York Academy of Medicine, October 20,1903. 3 Traits de l'auscultation, etc., Paris, 1819, 8°, vol. ii. pp. 286 et seq. 4 Anatomical, Pathological, and Therapeutic Researches upon the Disease known under the Name of GastroentCrite, etc. Translated from the original French by H. I. Bowditch, Boston, 1836, 8°, vol. 1. pp. 282 et seq. < Diseases of the Heart and the Aorta, Philadelphia, 1854, pp. 366 et seq. • Untersuchungen Uber die Myocarditis, Munchen, 1861, 8°, J. J. Lentner, p. 115. * Ueber die Veriinderungen der willkurlichen Muskeln in Typhus abdominalis, fol. Leipzig, Vogel, 1864, pp. 29 et seq. 7 Recherches sur les rapports existant entre la mort subite et les alterations vasculaires du coeur dans la flevre typho'ide, Arch, de phys., 1869, vol. ii. p. 698. Des complications cardi- aques de la flevre typho'ide, Gaz. hebd. de med., Paris, 1874, 25, vol. xi. pp. 796, 815. 8 Sur les al6rations du myocarde (desintegration granuleuse) comme cause de la mort subite dans la flevre typho'ide, Compt. rend, de la Soc. de biol., 1885, 8s., vol. ii. p. 769. 2 THAYER: EFFECTS OF TYPHOID FEVER ON THE HEART. berg,1 Landouzy and Siredey,2 Renaut,3 Mollard and Regaud,4 Giacomelli,5 and many others. The extent of their clinical signifi- cance and their relation to the cardio-vascular manifestations of typhoid fever are still, however, questions of dispute. That the cardiac lesions as such may account for sudden collapse and death is scarcely to be doubted, but the clinical discrimination between the collapse due to disease of the heart muscle and that in which the condition is rather one of vaso-motor paralysis is often a difficult and uncertain matter. The interesting studies of Passler and Rolly6 would tend to support the idea that the latter mechanism may ac- count for more instances of collapse in acute disease than has gen- erally been supposed. The part played by infectious processes in the aetiology of acute and chronic changes in the vessels is also a point toward which con- siderable attention has been directed in recent years. The relative frequency of venous thrombosis in typhoid fever is familiar enough, and the probability that this is, in many instances, associated with a phlebitis depending upon local infection would seem to result from various studies of recent years. The not infrequent arterial thromboses and acute arteritides, notably of the vessels of the extremities and of the brain, which have been studied particularly by French observers, need not be recalled. Potain7 has called attention to the occurrence of acute aortitis. The influence of infectious diseases in general on the production of the more insidious endarteritic changes in the aorta and other vessels-in other words, the relation of acute infections to the devel- opment of atheroma of the aorta and arterio-sclerosis in general- is a question of great importance, to which, it seems to me, we have scarcely directed sufficient attention. Numerous observers have noted the frequency of fresh gelatinous and fatty sclerotic plaques in the aorta and larger vessels in individuals dead of various acute 1 Ueber die Erkrankungen des Herzmuskels bei Typhus abdominalis, Scharlach und Diph- theric, Deutsch. Arch. f. klin. Med., 1891, vol. xlviii. p. 369; 1892, vol. xlix. 413. 2 Contribution a 1'histoire de I'artSrite typhoidique; de ses consequences hatives (mort- subite) et tardives (myocardite sclereuse) du coeur, Rev. de med., Paris, 1885, vol. v. p. 843. Landouzy, La fidvre typho'ide dans ses rapports avec 1'appareil vasculaire et cardiaque, Gaz. d. hop., Paris, 1886, vol. lix. p. 323. Landouzy et Siredey, Etude sur les localizations angio- cardiaques typhofdiques, leurs consequences immediates, prochaines et eioignees, Rev. de med., Paris, 1887, vol. vii. pp. 804, 919, 3 Les myocardites aigues, Congres Framjais de mddecine-V. session, Lille, 1899; Paris, 1899, t. ii. pp. 1-83. 4 Etat des arteres du coeur dans les myocardites aigues, Congres Franjais de med., 1899, vol. v. p. 280. Mollard, Les troubles cardiaques dans la convalescence de la fievre typho'ide, Presse med., Paris, 1900, vol. i. pp. 19-22. 6 II miocardio nelle infezioni, intossicazioni, avvelenamenti. Ricerche anatomo-patologiche e sperimentali, Policlinico, Roma, 1901, viii., M., pp. 145-155. 6 Experimentelle Untersuchungen uber Kreislaufstorungen bei acuten Infectionskrank- heiten, Deutsch. Arch. f. klin. Med., 1903, vol. Ixxvii. p. 1. 7 De l'aortite typhique, Semaine med., Paris, 1894, vol. xiv. p. 460. THAYER: EFFECTS OF TYPHOID FEVER ON THE HEART. 3 infectious diseases, while Gilbert and Lion,1 Crocq,2 and others have produced sclero-calcareous and fatty sclerotic changes in the aorta of rabbits by the injection of pathogenic bacteria after previously inflicting slight mechanical injury to the walls. Indeed, Gilbert and Lion have, in several instances, succeeded in producing changes which they believe to be closely analogous to those observed in human arterio-sclerosis by the intravascular injection of pathogenic organ- isms without the previous production of a point of least resistance by injury. On the other hand, Thoma3 mentions typhoid fever among the setiological elements in the production of thatangiomalacia which he believes to be the primary lesion in the development of arterio-sclerosis. In brief, there is much which goes to suggest that acute infections, and typhoid fever among them, play an important part in the aeti- ology of arterio-sclerosis. Some observers who have especially studied this question believe that after acute rheumatism typhoid fever is the infectious disease most frequently resulting in changes in the heart and vessels. The observations of Landouzy and Siredey4 are especially striking. These authors report the case of a man, aged twenty-three years, who died suddenly on the fifteenth day of typhoid fever. Two years before he had passed through a serious typhoid infection of six weeks' duration. The heart muscle showed extensive acute inflammatory and degenerative changes in association with grave older sclerotic alterations. There was nothing in the history of the patient, beyond his previous typhoid fever, to which these alterations could be ascribed. Out of 15 typhoid patients between five and forty-eight years of age, followed by Landouzy for a period of nine years, there were 3 in whom marked cardiac disturbance had persisted after recovery from the acute disease. These 3 patients, five, three, and two years after the disease, all showed a certain degree of hypertrophy, with cardiac irritability. As a result of their study, Landouzy and Siredey maintain among their conclusions that: "The secondary angio-cardiac complications of typhoid fever are more frequent than is generally believed and than has been generally acknowledged up to the present time. "After acute articular rheumatism, typhoid fever appears to give rise to more angio-cardiac complications than any of the other infec- tious diseases. "Among the most important and commonest of these complications are those which arise insidiously during the course or decline of the In brief, there is much which goes to suggest that acute infections, and typhoid fever among them, play an important part in the aeti- ology of arterio-sclerosis. Some observers who have especially studied this question believe that after acute rheumatism typhoid fever is the infectious disease most frequently resulting in changes in the heart and vessels. 1 Arterites infectieuses exp<jrimentales, Comptes rend, de la Soc. de biol., Paris, 1889, 9s., vol. 1. p. 583. 2 Contribution A, I'^tude experimentale des arterites infectieuses (abstr.), Arch, de m6d. exp. et d'anat. path., Paris, 1894, vol. vi. pp. 583-600. 3 Ueber das elastiche Gewebe der Arterienwand und die Angiomalacie, Verhandlungen des XIII. Cong. f. inn. Med., Wiesbaden, 1895, p. 465. * Op. cit., 1885. 4 THAYER: EFFECTS OF TYPHOID FEVER ON THE HEART. disease. The angio-cardiac lesions are important to recognize, less because of the prognostic reserve which they demand (luring the course of the disease itself (collapse, sudden death) than for that which they impose upon us for the future." And Lacombe,1 among the conclusions of his thesis, maintains that: " The disorders of the heart appearing some years after recovery from typhoid fever may be legitimately ascribed to this disease, if no other malady capable of compromising the integrity of the heart, either before or after the typhoid, has occurred." * * * The communications of Landouzy and Siredey especially sug- gested to me that it might be of interest to make a series of obser- vations as to the condition of the heart and vessels in a number of individuals who had had typhoid fever in the wards of the Johns Hopkins Hospital during the past fourteen years, comparing these results with the previous hospital records, which, in many instances, are fairly complete. This proceeding appealed to me the more because, so far as I know, it has never been previously attempted. With this end in view, I sent out letters to all patients who had had typhoid fever in the wards of the hospital since its opening in 1889-over 1400 in all. In the majority of instances, as might have been expected, the letters failed to reach their destination and were returned, but 183 patients presented themselves for examination. The majority of these patients were examined at the hospital be- tween 3 and 5 o'clock on Sunday afternoons. About 30 per cent, of the cases were studied in the Out-patient Department between the hours of 10 and 12 in the morning. The measurements of the heart, the record of the pulse, and the estimations of the blood pressure were made in the recumbent posture for comparison with the hospital records. Age and Date of Attack. The ages of the patients varied between three and sixty-nine years, while the periods which had elapsed between the discharge from the hospital and the subsequent examination ranged from one month to thirteen years. In all cases the patient was ques- tioned as to the maladies from which he might have suffered since his discharge from the hospital. The following table will show the period of time which had elapsed between the discharge from the hospital and the subsequent examination of the patients: Table I. Showing the length of time which had elapsed between the discharge of the patient from the hospital and his subsequent examination. Months. Years. 1-62 6-12' 1 2 3 4 5 6 7 8 9 10 11 12 13 22 26 18 20 23 21 11 13 11 8 6 2 0 1 1 = 182 1 Localizations angiocardiaques de la flevre typhoide, Paris, 1890, 4°. 2 There were but three cases seen under three months from the time of discharge. THAYER: EFFECTS OF TYPHOID FEVER ON THE HEART. 5 Pulse. (a) Rate. Most of the patients at the time of their examina- tion had already rested for some little period of time after their arrival at the hospital. In a large proportion of the cases, how- ever, there was a manifest nervousness; no more, probably, than is common on the examination of any one under similar circum- stances; perhaps a trifle less, inasmuch as the patients were for the most part old friends. The following table shows the rate of the pulse in 182 cases: Table II. Rate of the pulse per minute. 50-60 60-70 70-80 80-90 90-100 100-110 110-120 120-130 Not noted. Total. 1 17 42 50 26 23 8 8 17 182 In this table it will be seen that in 110 instances, or 60.4 per cent, of the cases, the pulse ranged between 60 and 90. In 16 instances, or 8.7 per cent., it was above 110. (6) Regularity. In 30 instances irregularity of the pulse was noted; four of these were cases in which the rate was not recorded. Of the cases in which the pulse was over 90, irregularity was noted in 18.3 per cent. Of the cases in which the pulse was under 90, irregularity was observed in 12.7 per cent. (c) Intermittence. In only 3 instances was the pulse distinctly intermittent. One of these was a well-marked case of hypertrophy with mitral insufficiency. There were 2 cases in which a strikingly collapsing character of the pulse was noted. In each of these in- stances an aortic diastolic murmur was present. Blood Pressure. In 165 of these cases the systolic blood pressure was taken by means of the Riva-Rocci apparatus. This proceeding was made the last step in the examination, in order that the patient might be in as placid a condition as possible. The estimations were repeated several times until constant readings were obtained. The band was always placed around the middle of the upper arm, right or left. The results of these estimations are indicated in the following table : Showing the averages of the systolic blood pressure in 165 old typhoids arranged by age according to decades. Table III. 1-10 10-20 20-30 30-40 40-50 50-60 60-70 112.4 mm. 135.2 mm. 153.5 mm. 161.5 mm. 170.2 mm. 179.6 mm. 215 mm. (5 cases) (39 cases) (58 cases.) (44 cases.) (15 cases.) (3 cases.) (1 case.) Struck by the high averages of the systolic blood pressure in this group of cases, I sought for statistics with which these figures might be compared, but soon found that it would be necessary, in order to reach a fair conclusion, to make myself a series of observations 6 THAYER: EFFECTS OF TYPHOID FEVER ON THE HEART. upon normal individuals under conditions as similar as might be. I have, therefore, in the last several months made 276 estimations of the blood pressure in presumably healthy individuals. These observations were made upon physicians, nurses, and employes of Showing averages of the systolic blood pressure in 165 old typhoids and in 276 HEALTHY INDIVIDUALS ARRANGED ACCORDING TO AGE BY DECADES. Chart I. 1-10 10-20 20-30 30-40 40-50 50-60 60-70 220 mm. ----I---I--- i -1--r । ■ i-।--i---i-----i - 210 mm. 200 mm. 190 mm. 180 .mm. 170 mm. 160 mm. 150 mm. 140 mm. 130 mm. 120 mm. 110 mm. 100 mm. OLD 112.4 135.2 153.5 161.5 170.2 179.6 215 TYPHOIDS (5 CASES) (39 CASES) ( 58 CASES) (44 CASES) (15 CASES) (3 CASES) (1CASE) healthy 104.6 128.7 136.9 140.8 142.2 154.8 180 INDIVIDUALS (37 CASES) (87 CASES) (S3 CASES) (37 CASES) (SO CASES) (5 CASES) (1 CASE) the hospitals, friends of patients, healthy children in several different asylums and schools, and upon various of my own friends. I did not allow myself to record the blood pressure of any patient, surgical or medical, no matter what his complaint. The records were taken THAYER: EFFECTS OF TYPHOID FEVER ON THE HEART. 7 between the hours of 3 and 5 in the afternoon or between 10 a.m. and 1 p.m. ; in other words, several hours after a meal. They were all taken in the recumbent posture, sufficient time being taken to allow the individual to recover from the preliminary nervousness; that is, under conditions similar to those employed in making the observations upon the previous group of patients. The averages of this table, which may be seen upon Chart I., show a distinctly and uniformly lower blood pressure than in the old typhoids. Table IV. Showing the averages of the systolic blood pressure in 276 healthy individuals and 165 old typhoids arranged according to age by decades. 1-10 10-20 20-30 30-40 40-50 50-60 60-70 112.4 mm. 135.2 mm. 153.5 mm. 161.5 mm. 170.2 mm. 179.6 mm. 215 mm. (5 cases.) (39 cases.) (58 cases.) (44 cases.) (15 cases.) (3 cases.) (1 case.) Old typhoids. 104.6 mm. 128.7 mm. 136.9 mm. 140.8 mm. 142.2 mm. 154 8 mm. 180 mm (37 cases.) (87 cases.) (89 cases.) (37 cases.) (20 cases.) (5 cases.) (1 case.) Healthy individuals. Inasmuch as all observers agree that the average blood pressure is slightly lower in women than in men, it may be well to note that the proportion of women was higher among the old typhoids than among the cases from which the control table was constructed, the exact figures being 38.7 per cent, for the old typhoids and 33.3 per cent, for the normal cases. On the other hand, more of the normal cases were examined dur- ing the morning hours than of the old typhoids, the percentage being 40.5 per cent, to 30.3 per cent. A closer analysis of the figures upon which these tables are based reveals the fact that among the old typhoids there were 54 cases in which the blood pressure was above 160; this group comprises over 50 per cent, of the cases over thirty years of age. In the much larger number of observations upon healthy indi- viduals there were but 10 such cases, 6 of which gave a history of preceding serious infectious disease, while in 1 there was a good suspicion of alcoholism. Of the 54 old typhoids, in but 17 was a similar history obtainable. The highest record of blood pressure among the cases in healthy individuals was 180, and that in a woman aged sixty years, while among the old typhoids there were 27 cases in which the pressure was above 180, a number of which were striking examples of hyper- tension, 10 showing a record of 200 or above. It might be objected that to ascribe this difference between the two curves to changes dependent upon the preceding typhoid fever would be a rash conclusion, inasmuch as a great number of other influences must have come into play, while the number of cases studied is too small to justify positive conclusions. In order to rule out some of these disturbing influences, I have prepared a THAYER: EFFECTS OF TYPHOID FEVER ON THE HEART. 8 table in which I have eliminated from each list all those cases in which a history of scarlet fever, diphtheria, acute rheumatism, pneumonia, erysipelas, smallpox, syphilis or alcoholic habits could Chart II. Showing the averages of the systolic blood pressure in old typhoids and in normal INDIVIDUALS FROM WHOM ALL CASES WITH A HISTORY OF SERIOUS INFECTIOUS DISEASE OR ALCOHOLIC HABITS HAVE BEEN EXCLUDED. oon™™ 140 'O'30 20-30 SO-40 40-50 50-60 60-70 mm. 1 1 1 1 1 ! 1 r--r- I । r- 210 mm. 200 mm. 190 mm. 180 mm. 170 mm. 160 mm. 150 mm. 140 mm. 130 mm. 120 mm. 110 mm. old 113.2 134.9 152.2 169.9 168.7 183.5 215 TYPHOIDS (4 CASES) (SS CASES) (32 CASES) <24 CASES) (8 CASES) (2 CASES) (1 CASE) HEALTHY 105.5 128.3 135.1 139.8 145.2 156.2 180 INDIVIDUALS (S2 CASES) (62 CASES) <52 CASES) (tS CASES) (11 CASES) <4 CASES) (1 CASE) be obtained. This table, which is represented graphically on Chai II., shows essentially the same relation between the two curves: 9 THAYER: EFFECTS OF TYPHOID FEVER ON THE HEART. Showing the averages of the blood pressure in old typhoids and normal individuals, from which all cases with a history of serious infectious disease or alcoholic habits have been excluded. Table V. Old typhoids. 1-10 10-20 20-30 30-40 40-50 50-60 60-70 113.2 mm. 131.9 mm. 152.2 mm. 169.9 mm. 168.7 mm. 183.5 mm. 215 mm. (4 cases.) (28 cases.) (32 cases.) (24 cases.) (8 cases.) (2 cases.) (1 case.) 105.5 mm. 128.3 mm. 135.1 mm. 139.8 mm. 145.2 mm. 156.4 mm. 180 mm. (32 cases.) (62 cases) (52 cases.) (19 cases.) (11 cases.) (4 cases.) (1 case.) Healthy individuals. The average of the observations upon healthy individuals is about 2 mm. less than in the uncorrected list. That of the typhoid obser- vations is practically unchanged. The alteration in the typhoid curve on the chart arranged by decades, due to the higher figures in the 30-40 column, emphasizes the fact that the number of cases is still too small to allow of the construction of final charts. Palpability of the Radial Arteries. Note was also made of the palpability of the radial arteries. In order to obviate the common confusion arising from a full vessel or engorgement of the venae comitantes, the blood was milked out of the artery and veins with the fingers of both hands, the tense tissues relaxed, while with a third finger an attempt was made to feel the empty vessel. The following table will show the results of observations on 181 old typhoids: Table VI. Showing the palpability of the radial arteries in 181 cases arranged by age according to decades. Age. Cases. Not palpable. Palpable. Per cent, of palpable vessels. 1-10 . . . . . 5 5 0 0 0-20 . . 12 30 12 28.5 0-30 . . . . . 62 29 33 53.2 0-40 . . 54 25 29 53.7 0-50 . . 14 7 7 50 0-60 . . 3 0 3 100 0-70 . . 1 1 0 0 A glance at these figures reveals the striking fact that over 50 per cent, of our cases above twenty years of age showed palpable radial arteries. In 2 instances in which the radials were not palpable, 1 the case of a man aged twenty-five years, and 1 that of a woman aged forty-seven years, one or the other of the temporal arteries was dis- tinctly thickened. In general, I have in these studies been impressed with the irregularity in the distribution of the sclerotic processes in peripheral vessels. It is by no means uncommon to find one radial or temporal distinctly thickened or tortuous, while the other is apparently unaffected. A comparison of the observations recorded in this table with those made upon the patients while in the hospital is of little value, 10 THAYER: EFFECTS OF TYPHOID FEVER ON THE HEART. in view of the fact that a definite note as to the palpability of the radials was made in but 48 cases. These figures, which were even more striking than the high averages of blood pressure, could, it seemed to me, be fairly compared only with a similar series of observations made by myself upon supposedly healthy individuals Chart III. Showing the percentages of palpability of the radial arteries in old typhoids and IN healthy individuals arranged according to age by decades. 1-10 10-20 20-30 30-40 40-50 50-60 60-70 Wi-----i-■----i- m i i i m i i r w - 80^ - 70;> - 60'S- 50^ - 40'S- 30;S~ 20^ - Wp old 0# 28.5# 53.2# 53.7# 50# 100# 0# TYPHOIDS (5 CASES) (42 CASES) (62 CASES) (54 CASES) (14 CASES) (S CASES) (1 CASE) hea-lthy o# 6.1# 20.4# 25# 22# 42.8# 80# INDIVIDUALS (ST CASES) (SS CASES) (186 CASES) (61 CASES) (27 CASES) (7 CASES) (5 CASES) who had not suffered from typhoid fever. Within the last several months, accordingly, I have examined the radials and temporals of 421 individuals who have never had typhoid fever. The accom- panying table, illustrated on Chart III., shows a comparison of the percentages of palpable radials arranged by decades in our old typhoids and in healthy individuals: THAYER: EFFECTS OF TYPHOID FEVER ON THE HEART. 11 Table VII. Showing the percentages of palpability of the radial arteries in old typhoids and in healthy individuals arranged according to age by decades.; Old typhoids. 1-10 10-20 20-30 30-40 40-50 50-60 60-70 0 # 28.5 # 53.2 # 53.7 # 50 # 100 # 0 # (5 eases.) (42 cases.) (62 cases.) (54 cases.) (14 cases.) (3 cases.) (1 case.) 0 # 6.1 # 20.4 # 25 # 22 # 42.8 # 80 # (37 cases.) (98 cases.) (86 cases.) (61 cases.) (27 cases.) (7 cases.) (5 cases.) Healthy individuals. By these figures it appears that between the ages of ten and fifty years 46.8 per cent, of the old typhoids showed palpable vessels as compared with 17.6 per cent, of the normal cases. Chart IV. Showing the percentages of palpability of the radial arteries in old typhoids and in healthy individuals after the removal from each list all cases in which there is a history of severe infectious disease or of alcoholic habits. 10001- 900- 800- 700- 600 r 500^ 400- 300- 200- r wf 1-10 10-20 20-30 30-40 40-50 50-60 60-70 old 0# 22.5# 54.2# 62.9# 57.1?6 100# 0# TYPHOIDS (4 CASES) (31 CASES) (35 CASES) (27 CASES) (7 CASES) (2 CASES) (i CASE) HEWTHY o# 4.2# " 21.3# 22.2# 18.7# 33.3# 75# INDIVIDUALS (32 CASES) (70 CASES) (103 CASES) (27 CASES) (16 CASES) (6 CASES) (4 CASES) 12 THAYEIC EFFECTS OF TYPHOID FEVER ON THE HEART. I have also prepared comparative tables, as in the case of the records of blood pressure, based upon an analysis of those cases only in which a history of serious infections or of habits which might induce arterio-sclerosis was wanting. This table is illustrated bv Chart IV. Showing the percentages of palpability of the radial arteries in old typhoids and in healthy individuals from which all cases giving a history of serious infections or alcoholism have been excluded. Table VIII. 1-10 10-20 20-30 30-40 40-50 50-60 60-70 0# 22.5# 54.2# 62.9# 57.1# 100# 0# (4 cases.) (31 cases.) (35 cases.) (27 cases.) (7 cases.) (2 cases.) (1 case.) Old typhoids. 0^ 4.2 % 21.3 £ 22.2 ft 18.7 54 33.3 5c 7554 (32 cases.) (70 cases.) (103 cases.) (27 cases.) (16 cases.) (6 cases.) (4 cases.) Healthy individuals. As in the case of the observations upon the blood pressure, the total average is slightly lower among the healthy individuals- 15.1 per cent. : 17.5 per cent. Among the typhoids the average palpability of the vessels in this list varies but little from that in the previous table-45.7 per cent. : 46.1 per cent. Heart. Position of the Apex. Measurements of the distance of the apex of the heart from the median line were made in 180 of the old typhoids. The average distance of the apex from the median line as determined by palpation, percussion, and auscultation in individuals between the ages of twenty and fifty years was 9.12 cm. Similar measurements made in 102 of these cases on admission to the hospital showed an average of 8.7 per cent. The following table shows the averages, arranged according to age by decades, of 102 cases which were examined on admission to the hospital, side by side with the records of those examined later: Table IX. Showing the average distance of the cardiac apex from the median line in 102 cases of typhoid fever on admission to the hospital, and of 180 cases examined later. Old typhoids. 1-10 10-20 20-30 30-40 40-50 50-60 60-70 6.3 cm. 7.7 cm. 8 9 cm. 9.1 cm. 9.8 cm. 9.5 cm. 12 cm. (5 cases.) (41 cases.) (63 cases.) (52 cases.) (15 cases.) (3 cases.) (1 case.) During attack. 5.7 cm. 6.6 cm. 8.5 cm. 8.5 cm. 9.6 cm. (5 cases.) (36 cases.) (38 cases.) (14 cases.) (9 cases.) It will be noted that the average measurements in the old typhoids are slightly but constantly larger than in the cases examined on admission to the hospital. Though this difference, as shown by the table, is trivial, it should, perhaps, be borne in mind that there is not infrequently in typhoid fever a slight dilatation of the heart, and that most of these examinations were made when the fever was well under way. THAYER: EFFECTS OF TYPHOID FEVER ON THE HEART. 13 Inasmuch as 46 of these cases entered the hospital when they were under twenty years of age, that is, at a time when, in many instances, they had not attained full development, it seemed wise to investigate the position of the apex in individuals over twenty years at the time of their admission, where notes had been made both in the hospital and subsequently. There were 59 such cases. At the time of admis- sion the average distance of the apex from the median line was 8.82 cm.; subsequently it was 9.14 per cent., a slight difference, but one which corresponds closely with the larger averages. Extent of the Cardiac Didness to the Right. In 158 cases ex- amined by myself a note was made as to the extent of the cardiac dulness to the right of the midsternal line. The average distance for each decade is shown in the following table: Table X. Showing the average extent of the cardiac dulness to the right of the midsternal line in 158 old typhoids arranged according to age by decades. 1-10 10-20 20-30 30-40 40-50 50-60 60-70 2.4 cm. 3.12 cm. 3.45 cm. 3.39 cm. 3.47 cm. 3.4 cm. 5 cm. (3 cases.) (36 cases.) (54 cases.) (47 cases.) (14 cases.) (3 cases.) (1 case.) The greatest extent of dulness to the right of the median line among these cases was 5 cm., in a man with dilated heart and mitral insufficiency. In but 1 case, that of a man aged thirty years, was no dulness to the right to be made out. This case accounts in great part for the slightly lower average in the fourth decade. There is nothing remarkable about these figures, which are, indeed, a trifle smaller than those given by Riess.1 Heart Sounds, In the Hospital. In 170 of these cases in which notes with regard to the condition of the heart sounds were made in the hospital, murmurs were noted in 39 instances, or 29 per cent. In 31 cases the murmur was a soft systolic blow heard at the apex, and only once was the sound transmitted to the axilla. In a number of cases this murmur was heard only on admission or at the height of the disease, disappearing with convalescence. In 5 of these 31 cases the pulse in the hospital was above 140, one case, however, being under fifteen years of age. On Later Examination. Notes on the heart sounds were made in all but 2 of the 183 old typhoids. 88, or 48.6 per cent., of these cases showed murmurs. In all of these the murmurs were systolic, although in 2 instances an aortic diastolic murmur was heard in addition, and in one case a doubtful mitral presystolic. In only 38 cases was the systolic murmur audible at the apex. In the majority the murmur was a soft blow, with its maximum in- tensity at the base of the heart, in the pulmonic or aortic area. 1 Sahli. Lehrbuch der klinischen Untersuchungsmethoden, Leipzig u. Wien, 8 Auflage, 1901, 8°, p. 165. 14 THAYER: EFFECTS OF TYPHOID FEVER ON THE HEART. In 11 cases an apex systolic murmur was transmitted to the axilla, and in 7 was audible also in the back. In 7 cases the symptoms justified the diagnosis of mitral insufficiency (Nos. 9921, 10,704, 10,714, 31,173, 17,636, 28,249, 36,210). One further case (20,507), an instance of aortic insufficiency, showed also evidences of mitral incompetency. In one case (32,037) there were signs suggesting mitral stenosis. In 2 instances aortic diastolic murmurs were heard in cases which had previously shown no evidence of cardiac trouble (39,371, 26,507). One of these individuals, who was examined nearly four months after discharge from the hospital, was seen again five months later, at which time the diastolic murmur had entirely disappeared and the size of the heart had slightly diminished. This case must prob- ably be regarded as one of functional insufficiency, due to relaxation of the aortic ring. Reduplication of the First Sound. In 14 of the old typhoids a reduplication of the first sound at the apex or tricuspid area was observed. One of these was a case of well marked hypertrophy, with mitral insufficiency; another was a case of Graves' disease, with high arterial tension. In general, it was noted that the arterial tension in cases showing reduplication of the first sound was high, the average pressure being 164.9. In 3 cases the pressure was above 200. In only one of these reduplications did it seem possible to determine the cause of the split in the first sound. In this case it was clearly due to delay in the closure of the tricuspid valve. Reduplication of the Second Sound. In 82 of the old typhoids there was a reduplication of the second sound. This, in every in- stance but one, was audible at the base and usually limited to the pulmonic area. In 73 cases the reduplication was clearly dependent upon delay in the closure of the pulmonic valves. The reduplications were usually slight and heard only at the end of inspiration-cases such as would fall into Galli's1 class of " reduplications of the first grade." In 10 cases, however, the reduplication was heard through- out the entire cycle. The proportion of reduplications is not far from that observed by Galli, who, in his 120 carbineers, found 19 per cent, of such redu- plications in the morning, 40 per cent, at noon, 56 per cent, in the afternoon. The blood pressure of these cases was slightly below the general average for the old typhoids of the same decades-148.3 : 152. Accentuation of the Second Sound. Out of 161 cases in which the relative accentuation of the aortic or pulmonic second sounds was noted, the pulmonic second was accentuated in 82, or 50.9 per cent. The following table will show the relative percentages of accentua- tion of the second aortic sound, arranged according to decade: 1 Munch, med. Wochenschr., 1902, vol. xlix. pp. 95, 1005,1049. 15 THAYER: EFFECTS OF TYPHOID FEVER ON THE HEART. Table XI. Showing the percentage of cases in each decade in which the aortic second sound was accentuated. 1-10 10-20 20-30 30-40 40-50 50-60 60-70 20 0 30.3 0 , 48.2 0 44.6 0 46.6 0 100 0 100 0 (5 cases.) (33 cases.) (58 cases.) (47 cases.) (15 cases.) (2 cases.) (1 case.) Compared with the figures of Cabot,1 the percentages in the lower decades are high, while those above the third decade are low. I do not, however, attach any great importance to these figures. In using the term "accentuated" I have intended to indicate that sound which was actually the louder of the two. In a number of instances, however, the second aortic sound, while not apparently as loud as the second pulmonic, was ringing, liquid, musical and suggestive of high tension. Again, the study of reduplications of the second sound, among other things, proves, I think, clearly that in many instances the closure of the aortic valve plays the greater part in the production of the loud sound which one hears in the pulmonic area. Summary of the General Analyses. To summarize the results of these general analyses we have found: 1. That our old typhoids show an average blood pressure higher than that observed in control tables of normal subjects of the same age and under the same conditions, while the individual records in a considerable proportion of cases exceed the figures usually regarded as normal. 2. That in these same cases the radial arteries are palpable with much greater frequency than was observed in a series of control observations in individuals who had never had the disease. 3. That there is some evidence of cardiac enlargement, as indi- cated by the results of measurements of the distance of the apex from the median line when compared with figures for the same decade resulting from observations made at the time of admission to the hospital. 4. That there were among these 182 old typhoids 10 instances of cardio-vascular lesions, which had developed following typhoid fever in the absence of the ordinarily recognized setiological elements; 7 cases of hypertrophy with mitral insufficiency (10,704, 10,714, 31,173, 17,636, 24,675, 28,249, 36,210) ;2 two of aortic insufficiency (39,371, 20,507); one of marked arterio-sclerosis with hyper-tension in a young man (17,632). In addition to these cases there was one instance of possible mitral stenosis (32,037). 1 Physical Diagnosis of Diseases of the Chest, 2d ed., 1903, 8°, p. 124. 2 In one other case (9921) it is well possible that the typhoid fever may have been the excit- ing cause of the condition. 16 THAYER: EFFECTS OF TYPHOID FEVER ON THE HEART. Are the more serious cardio-vascular manifestations during typhoid fever common precursors of permanent lesions ? Is it in cases pre- senting such symptoms that the grave, later changes develop ? Is it possible to recognize at the time of their origin the development of those processes which subsequently exert a permanent effect upon the organism ? In order to obtain some light upon these questions, it was deter- mined to examine separately into the subsequent condition of: 1. Those cases in which, during the attack, extreme rapidity of the pulse was noted. 2. Those cases where irregularity of the pulse was observed. 3. Those cases in which an apical systolic murmur was heard. 1. The Subsequent Condition of Those Cases of Typhoid Fever in Which Extreme Rapidity of the Pulse was Noted during the Attack. Rate of the Pulse: In 19 cases a pulse of 140 or above was recorded during the attack. 9 of these patients were under twenty years of age at the time of admission. The rate of the pulse in the remaining 10 cases on subsequent examination shows no great variations from the general average. In 2 instances the rate was not noted. In one, a case of Graves' disease, it was 120; in one, 104; in one, 92; and in the other 5 instances, or 50 per cent., the pulse was between 68 and 84. Systolic Blood Pressure. Of the 19 cases in which an extremely rapid pulse was observed in the hospital, 9 who were under twenty years of age have been omitted from the list; it is easily conceivable that in individuals under twenty years a pulse of 140 may not repre- sent the same conditions as a pulse of that rate at a later age. Of the remaining 10 cases, varying in age from twenty-two years to fifty-three years, the average systolic pressure was 166.8. The general average of the old typhoids for these decades was 159.2. There were among these 10 cases, 2 with a blood pressure above 200, and 5, or 50 per cent., with a pressure above 160. Palpability of the Radial Arteries. In 4, or 40 per cent, of these 10 cases, the radial artery was palpable. The general average for these decades among the old typhoids was 53.7 per cent. Position of the Apex of the Heart. In only 4 of the 10 cases were measurements made during the disease. The average distance of the apex from the median line in these cases was 7.37 cm. In 10 cases examined subsequently the average distance was 8.48 cm. In the 4 cases in which a hospital record was made the average distance of the apex from the median line in the later examinations was 8.5 cm. If we compare these figures with the average of the measurements on admission to the hospital-8.82-and the average for the old typhoids-9.14-we find that they are lower in both instances. The difference, however, between the measurements during the disease and later is greater in the smaller group. THAYER: EFFECTS OF TYPHOID FEVER ON THE HEART 17 Extent of the Cardiac Dulness to the Right. In none of these 10 cases were measurements of the cardiac dulness to the right made during the fever. The average extent of dulness to the right of the median line on subsequent examination was 3.61, or slightly more than the total average for the same decades-3.44. In review, then, we have found that in 10 cases over twenty years of age who, during their typhoid fever, showed extreme rapidity of the pulse, there was on subsequent examination, an average blood pressure somewhat higher than that observed in the mean of the whole 165 cases; the percentage of palpability of the radial arteries was less; the distance of the apex of the heart from the median line was somewhat less; while the extent of the dulness of the heart to the right of the median line was a trifle above the general average. The increase in the size of the heart during the period sub- sequent to the illness was somewhat above the general mean. Two cases showed distinct hypertrophy, with hyper-tension (11,331 and 14,675); in one of these there was evidence of mitral insuffi- ciency. 2. Subsequent Condition of Those Cases in Which Irregu- larity of the Pulse was Noted during the Attack. Rate and Rhythm of the Pulse. Irregularity of the heart's action was noted in 12 cases during the attack. In 1 of these the irregularity occurred in association with the bradycardia (46) of convalescence. In 2 cases irregularity was observed on the subsequent examination. In the remaining 10 nothing remarkable was noted as to rate or rhythm of the pulse. The Systolic Blood Pressure. In 11 of these 12 cases the average blood pressure on the later examination was 152.2 mm., as com- pared with the general average of 152 mm. 3 cases were under fifteen years of age. If we put aside these 3 cases in which the average pressure was 113.3 mm., there are left 8 cases, aged between twenty years and forty-two years, in whom the average pressure was 166.8 mm. The average pressure among the old typhoids for these decades was 158.6 mm. In 2 instances the pressure was above 200. Palpability of the Radial Arteries. The radial arteries were palpable in but 3, or 27.2 per cent., of these cases. Position of the Apex. The position of the apex was noted in the hospital in 9 of these cases. In 4, under twenty years of age, the average distance of the apex from the median line was 7.12 cm. In 5, over twenty years, the average distance was 8.2 cm. Of the 12 cases on the later examination, in 3, under twenty years of age, the average distance of the apex from the median line was 6.6 cm. In 9, over twenty years, it was 8.18 cm. In the 4 cases in which a hospital note was made the average distance of the apex from the median line on subsequent examination was 8 cm., or 0.2 cm. less than the average in the hospital. 18 THAYER: EFFECTS OF TYPHOID FEVER ON THE HEART. Extent of Dulness to the Right. In none of these cases was a measurement made in the hospital of the extent of the cardiac dul- ness to the right. In 11 instances a record was made on the later examination. In 3 cases, under twenty years of age, the average was 3 cm. In 8 cases, over twenty years, the average was 3.35 cm. Review. In the 12 cases which in the hospital showed irregularity of the pulse, as in the cases with rapid pulse, the blood pressure, on later examination, was found to be distinctly higher than the general mean of the 165 old typhoids. On the other hand, there was no evidence of cardiac enlargement; the distance of the apex from the median line was, indeed, less than in the general mean, or in the same cases on admission to the hospital. The percentage of palpability of radial arteries was also lower than the general average. 3. The Subsequent Condition of Those Cases in Which an Apical Systolic Murmur was Noted during the Attack. The Rate of the Pulse. Of the 31 patients in whom during their fever a systolic murmur was observed, in 29 the rate of the pulse was noted in the subsequent examination. Twenty-one, or 72.4 per cent, of these cases, showed a pulse between 76 and 88. In 2 instances the pulse was between 90 and 100; in 5, be- tween 100 and 110; and once only 120, a case of Graves' disease. When these figures are compared with the foregoing records for the total number of cases, it becomes evident that there is no ap- parent tendency in this group of cases to an increased rapidity of the pulse. Palpability of the Radial Arteries. In 30 of these cases in which a note as to the palpability of the radial arteries was made, the vessel was to be felt in 11, or 36.6 per cent., as compared with the general average of 46.1 per cent. The Systolic Blood Pressure. In 28 of these 31 cases the systolic blood pressure was taken in the later examination. The average of these 28 cases was 158.5 mm., against the general average for the total number of cases of 152.4. This higher average was observed in every decade excepting the first, in which there was but 1 case, and the third, in which there were but 4. In 18 cases, over the age of twenty years, the average pressure was 169.2, as compared with the general average of 159.6 for the same decades. In 5 cases the pressure was 200 mm. or above. Position of the Apex. In 22 of these cases the position of the apex was determined in the hospital, the average distance from the median line being 7.1 cm. In 30 cases a subsequent note was made, the average being 8.9 cm. The former figures are slightly lower than the general average, the latter slightly higher. If we subtract from this list of cases those who were under twenty years at the time of admission, the average becomes 8.54 cm. in 11 hospital cases, against 9.4 cm. in 19 cases examined later. If we further compare THAYER: EFFECTS OF TYPHOID FEVER ON THE HEART. 19 only the 11 cases in which notes were made both in the hospital and later, the averages are, respectively, 8.54 cm. and 9.25 cm. Comparing these figures with the general hospital averages for the same decades, 8.70 and 9.22, it is evident that this small group of cases in which systolic murmurs were heard at the apex during their attacks showed, on later examination, measurements essen- tially the same as in the general average, despite the fact that at the onset of the disease the average for these same cases was slightly below the general mean. Extent of Cardiac Dulness to the Right. In none of these cases was the dulness to the right measured while the patient was in the hospital. In the subsequent examinations a record was made in 29 cases, the average extent of dulness being 3.39 cm., as compared with the total average for all decades of 3.35. 9 of these patients who were under twenty years of age showed an average measure- ment of 3.3 cm., as against the general average of 3.08, while the 20 cases over twenty years of age showed an average measurement of 3.43, as compared with the general average of 3.44. Heart Sounds. In but 2 of the 31 cases in which a systolic apical murmur was heard in the hospital was the sound transmitted to the axilla, and in neither of these instances were the signs such as might have justified a diagnosis of organic cardiac disease. On the later examination: In 11 instances the heart sounds were clear. In 1 case there was a slight cardio-respiratory murmur at the apex. In 6 cases there was a soft systolic murmur at the base, in some instances heard also over the right ventricle. In 13 cases there was a systolic murmur at the apex of the heart. Of these 13 cases: In 5 the murmur was a soft systolic blow heard at the apex, and in 3 instances also over the rest of the cardiac area. In the 2 cases where the murmur was limited to the apex it disappeared in the erect posture. In 5 the signs justified the diagnosis of mitral insufficiency. In 1 there were signs suggestive of mitral stenosis. In 1 there was marked arterio-sclerosis, with hyper-tension, and a slight systolic murmur at the apex, tricuspid, and pulmonic areas. In 1 there was Graves' disease, with a systolic murmur all over the cardiac area. This condition was present also at the time of the fever. Review. On considering these figures, we find that the 31 cases in which systolic murmurs were observed during the fever showed, on later examination, nothing remarkable with regard to the pulse, while the palpability of the peripheral arteries was below the general average for the old typhoids. On the other hand, the blood pressure was strikingly higher than 20 THAYER: EFFECTS OF TYPHOID FEVER ON THE HEART. the general average, one-half of the cases of extreme hyper-tension (200 mm. or above) being observed in this small group. The size of the heart was also increased, as compared to the mean of our observations upon the old typhoids, while the actual increase in those cases in which measurements were made in the hospital and later was also greater than the general average. Seven or nearly one-quarter of these cases, showed, on subse- quent examination, evidence of organic cardiac lesions, while another case was a striking example of general arterio-sclerosis, with hyper- tension, in a young individual. * * * Among these 183 cases there are several which deserve special attention. Case I. Hypertrophied heart; mitral insufficiency.-Mrs. H. B. (Hospital No. 9921), aged forty years, was admitted to the hospital on April 19, 1894, where she passed through a typhoid fever of thirty days' duration, complicated with neuritis of the left ulnar nerve. The urine was free from albumin. Previously she had been a healthy woman, excepting for an attack of acute articular rheumatism at six years, and three attacks since then. In the hospital records it was noted that there was no increase in the area of cardiac dulness; that the sounds were clear at the apex. The highest recorded pulse was 116. On January 5,1903, the patient reported for examination in answer to my letter. She had had no illness since leaving the hospital. She had, however, complained of late of being somewhat short of breath on exertion. The pulse was 22 to the quarter, regular, of good size, rather long duration. The radial artery was just palpable; temporals not prominent. Systolic blood pressure, 200 mm. Heart. Point of maximum impulse in the fifth space 10 cm. from the midsternal line. Dulness extends 4 cm. to the right of the mid- sternal line. At the apex the first sound is replaced by a well-marked blowing systolic murmur; the second is clear. The murmur is heard distinctly throughout the axilla and in the back. It is audible also in the tricuspid, pulmonic, and aortic areas, over the manu- brium, and in the carotids. The aortic second sound is sharp, though scarcely as sharp as the second pulmonic, which is accentuated. There are one or two reduplications of the second sound in the pulmonic area at the end of each inspiration, the second part of the split sound being accentuated. This reduplication is occasionally heard in the aortic area, where the accented part is clearly the first. In this case it is possible that a valvular lesion, though not evident at the period when she was in the hospital, may have dated from her preceding attacks of rheumatism. THAYER: EFFECTS OF TYPHOID FEVER ON THE HEART. 21 Case II. Moderate hypertrophy of the heart; mitral insuffi- ciency.-E. T. E. (Hospital No. 10,704), aged twenty-five years, entered the hospital on August 23, 1894, where he passed through a typhoid fever of very moderate intensity and without complica- tions beyond albuminuria, with granular casts, and some epithelium. He had had measles, scarlet fever, and mumps as a child; no venereal history; used alcohol in moderation. The note on the heart states that: "The point of maximum impulse is in the fourth space, a little inside the mammillary line. Relative dulness not increased to the right. Pulse slow, of good volume and tension. Sounds clear, of normal relative intensity." No further note was made on the heart. On January 18, 1903, the patient returned for examination. He had been well since discharge. He was rather flushed and excited; pulse, 24 to the quarter, of good size, duration fair; vessel wall just palpable. Brachial pulse visible at the bend of the elbow, and tem- porals visible, but not especially thickened. Blood pressure, 180 mm. Heart. Impulse marked in the third and fourth interspaces; of maximum intensity in the fifth interspace in the mammillary line 10.5 cm. from the midsternal line. Dulness extends 3.2 cm. to the right of the midsternal line. At the apex the first sound is prolonged and followed by a soft systolic murmur, which is heard throughout the axilla; second clear. In the tricuspid area the sounds are clear and sharp. In the pul- monic area the first sound is prolonged and continued into a slight systolic murmur; the second, loud and sharp. The murmur is also heard in the aortic area, over the manubrium and in the carotids. Occasionally a very slight reduplication of the pulmonic second sound is to be heard at the end of inspiration. In the erect posture a soft systolic souffle is well heard in the left back, though audible at the apex. There may be some question as to the existence of mitral insuffi- ciency in this case, but the high tension, the rather large size of the heart, and the audibility of the murmur in the left back are sug- gestive. Case HI. Hypertrophy and dilatation of the heart; mitral insufficiency.-J. H. (Hospital No. 10,714), aged sixty-one years, was admitted to the hospital on August 24, 1894, where he passed through a typhoid fever of seventeen days' duration, of moderate severity. The urine during the attack showed a trace of albumin, hyaline and granular casts. He had had previously no serious ill- nesses; had used alcohol in moderation. The pulse was full, soft, regular in force and rhythm, 92. Tension not increased. Vessel wall not thickened. Heart. Apex-beat in the fifth space, 3 cm. inside the nipple line. The first sound at the apex was occasionally followed by a soft 22 THAYER: EFFECTS OF TYPHOID FEVER ON THE HEART. systolic puff, not transmitted (cardio-respiratory?). Sounds at the base clear, of normal relative intensity. On January 18, 1903, the patient returned to the hospital in answer to my letter. Up to a week before he had been fairly well. For a week he had been complaining of shortness of breath on exertion. He was somewhat cyanotic, the respirations labored and rather wheezing. The pulse was 22 to the quarter, of good size; dura- tion fairly good; vessel wall not palpable. Blood pressure, 215 mm. Heart. Point of maximum impulse neither visible nor palpable. By percussion and auscultation it was localized in the fifth inter- space, 12 cm. from the midsternal line. Dulness 5 cm. to the right. Sounds: first, reduplicated at the apex; second, clear. The redupli- cation was not clearly heard in the tricuspid area. At the base the sounds were clear in both the pulmonic and aortic areas, the aortic second sharply ringing, greatly accentuated. Fine rales were heard at both bases. The patient was admitted to the hospital on the following day, at which time the apex was found 1 cm. farther out, and a systolic murmur was audible at the apex, transmitted but a short distance outward. The sounds were feeble over the precordium. The second sounds were clear. After rest in bed the patient improved greatly. The fine rales cleared up, and eleven days later the patient was discharged. The apical murmur, however, persisted. The blood pressure in bed was 165 mm. The urine at first showed a trace of albumin, which disappeared later; specific gravity normal. This was a well-marked case of dilatation, with mitral insuffi- ciency. Case IV. Hypertrophy of the heart; mitral insufficiency.-A. B. (Hospital No. 31,173), a young woman aged twenty-four years, was admitted to the hospital on July 9, 1900, w'here she passed through an attack of typhoid fever of forty-six days' duration with- out serious complications. The urine was at all times free from albumin. As a child she had had measles, mumps, and scarlet fever, the latter followed by nephritis; the radial arteries were not palpable. Heart. Point of maximum impulse not palpable. Sounds best heard in the fourth space, 9 cm. from the median line. First sound rather feeble. The aortic second louder than the second pulmonic. There was no further note on the heart. On December 22, 1902, the patient returned for examination. She had been married and had had one child since discharge. Since the birth of the child she had not felt well. Pulse, slightly irregular in rhythm, 27 to the quarter, occasionally intermittent, of moderate size, and good duration. The vessel wall was not palpable. Blood pressure 170 mm. THAYER: EFFECTS OF TYPHOID FEVER ON THE HEART. 23 Heart. Apex impulse in the fourth space, 10 cm. from the median line. Dulness extended 3 cm. to the right of the median line. The impulse was strong, rather snapping, associated with and apparently preceded by a very slight thrill. " The first sound at the apex is rather sharp, followed by a slight systolic murmur. This murmur is heard in the axilla and faintly in the back; it is a little louder in the tricuspid area. In the pulmonic area there is a loud systolic murmur. The second sound is sharp and clear, relatively accent- uated, as compared with the second aortic; no reduplication. In the aortic area there is a well-marked systolic murmur transmitted upward over the manubrium and into the carotids. The second sound is clear." In this instance the enlargement of the ventricle and the slight irregularity of the pulse, as well as the transmission of the systolic murmur, all tend to suggest that a true mitral insufficiency exists. The snapping character of the first sound and the slight sug- gestion of a palpable thrill, although no corresponding murmur was to be heard, are in favor of the existence of an actual valvular lesion. Case V. Mitral stenosis and insufficiency (?).-A. S. (Hospital No. 32,037), a girl aged ten years, was admitted to the hospital on September 3, 1900, where she passed through a typhoid fever of thirty-four days' duration, complicated by cystitis. The case was of moderate severity, the pulse not particularly rapid at any time. As a child she had had measles, tonsillitis, and bronchitis at three years, and again the winter before entry. In the hospital record it was noted: " Heart. Point of maximum impulse in the fourth space, 6 cm. from the midsternal line. Both sounds well heard at the apex. Loud systolic murmur at the base. At the apex the first is accompanied by a very faint systolic murmur; the second pulmonic, not accent- uated." Later on it was again noted that there was a faint systolic murmur all over the precordium, loudest in the pulmonic area. No note was made on the heart at the time of discharge. The patient was not, however, supposed to have a cardiac lesion. On December 22, 1902, the patient returned for examination. She had been perfectly well since discharge. The pulse was regular, 25 to the quarter, of moderate size, and rather long duration. The vessel wall was not palpable. Blood pressure 135 mm. Heart. Apex visible and palpable in the fourth space, 7 cm. from the midsternal line, just inside the mammillary line. Dulness 2.25 cm. to the right of the median line. The impulse was strong, rather prolonged, preceded by a suggestion of a thrill. The first sound at the apex was prolonged and booming. There was a distinct 24 THAYER: EFFECTS OF TYPHOID FEVER ON THE HEART. echo in the latter part of diastole, which was almost loud enough to be called a true presystolic murmur, having all the characteristics of a presystolic murmur of slight degree. The first sound was suc- ceeded by a very soft, slight systolic murmur, which was heard in the axilla, but not in the back. Second sound well heard at the apex. In the tricuspid area there was a soft systolic murmur which became louder as one reached the pulmonic area. The second sound in the pulmonic area was sharp and clear. The same murmur was heard at the aortic orifice feebly, but better than in the pulmonic area; also over the manubrium and in the carotids. At the time of the examination it was noted: "It would seem that the apex murmur (presystolic) was doubtless produced at the time of entrance of blood into the ventricle from the left auricle, and, in all proba- bility, at the mitral valve. The case may be one of mitral stenosis, though it is not impossible that the heart may be quite normal." Case VI. Hypertrophy and dilatation of the heart; mitral insufficiency; hyper-tension.-M. Z. (Hospital No. 17,636), a woman aged forty-three years, was admitted to the hospital on October 19, 1896, where she passed through a typhoid fever of sixty-four days' duration, without complications. The urine showed a trace of albumin, and once a hyaline cast. She had been previously a per- fectly healthy woman, excepting for an attack of typhoid fever seven years before and for occasional pains in her joints, unassociated with fever or swelling. She had had twelve children and two miscarriages. When in the hospital it was noted that at the apex the first sound was replaced by a soft systolic whiff, faintly transmitted to the axilla. The second sounds were clear. The heart's action was rather irregular. The murmur could be heard all over the base of the heart. The highest recorded pulse in the hospital was 120. No further note was made upon the circulatory apparatus. On dis- charge the patient was considered to have a normal heart. The patient returned to the hospital on February 16, 1903, in answer to my letter. For two months she had suffered from short- ness of breath, especially on excitement and exertion. This was also worse at night, so that at times she had to sit up in bed. On physical examination the pulse was 26 to the quarter, of fairly good size; duration long; vessel wall not palpable. The blood pressure was 200 mm. The urine was free from albumin. " Heart. Point of maximum impulse palpable in the fifth inter- space, 9.50 cm. from the median line. Dulness extends 2.75 cm. to the right of the median line. Sounds: The first at the apex is followed by a well-marked blowing systolic murmur heard faintly throughout the axilla; second clear. In the tricuspid area the murmur is less marked; the second sound clear. In the pulmonic area the first sound is represented by a slight systolic murmur; the second sharp and loud. In the aortic area the first is followed by a very soft systolic murmur heard over the manubrium, not in THAYER: EFFECTS OF TYPHOID FEVER ON THE HEART. 25 the carotids. The second pulmonic is sharper than the second aortic. No reduplication of the second sound. In the erect pos- ture the murmur persists at the apex, but is not heard in the back." Two months later the patient returned to the Out-patient Depart- ment again, complaining of shortness of breath. At this time the apex had moved outward 2 cm., while in other respects the signs were about the same. Case VII. Hypertrophy, mitral insufficiency.-B. W. (Hos- pital No. 24,675), a woman aged twenty-six years, was admitted to the hospital on September 11, 1898, where she passed through a long typhoid fever, with two relapses, complicated with arthritis of the ankles. The urine was free from albumin. The patient had always been healthy and had had previously no serious illnesses. In the hospital the following note was made on the heart: " Heart. Point of maximum impulse, fifth space, 3 cm. inside the mammillary line. At the point of maximum impulse there is a soft, blowing systolic murmur, not traceable into the axilla. Sounds at base clear; of normal relative intensity. Pulse regular; good volume; 36 to the quarter." In several notes there is no mention of palpable radials. Later it was stated that the second pulmonic was accentuated, and that the murmur was traced to the anterior axillary line. The patient was examined on March 6, 1903, five and a half years later. After leaving the hospital there was another relapse, with left-sided femoral phlebitis. For some time afterward there was oedema of the feet. Otherwise she has been quite well. The pulse was 80, regular, of fairly good size; long duration. Artery just palpable. Blood pressure 210 mm. " Heart. Apex impulse in the fifth space, 10.5 cm. from the median line. Dulness extends 3.5 cm. to the right of the midsternum. At the apex the first sound is followed by a systolic murmur, which is heard all over the cardiac area, though best at the point of maximum impulse; it is transmitted as far as the mid-axilla. In the erect posture it is still heard at the apex, though with much diminished intensity. In the back as the patient sits up, it is a question whether at times a faint suggestion of a murmur may not be heard. The second sounds are both strong; the second pulmonic is distinctly accentuated." Case VIII. Mitral insufficiency; hypertrophy of the heart.- E. R. (Hospital No. 28,249), a colored woman aged thirty-eight years, was admitted to the hospital on October 24, 1899, where she passed through a mild attack of typhoid fever of seventeen days' duration. The urine contained a trace of albumin, and hyaline and granular casts. As a child she had had measles, mumps, and chickenpox. No other serious illnesses. In the hospital it was noted that "the point of maximum impulse is in the fifth space, 8.5 cm. from the median line. Impulse punc- 26 THAYER: EFFECTS OF TYPHOID FEVER ON THE HEART. tate, rather heaving; slight suggestion of a thrill running up to the impulse. At the point of maximum impulse the first sound is re- placed by a short blow, which is preceded by a very short, indistinct rumbling. This latter is to be heard above and outside the point of maximum impulse. The systolic murmur is heard over the base. The second pulmonic is slightly accentuated and clear. The aortic second sound is clear." No note as to the palpability of the radial arteries. About two weeks before discharge it was noted that there was a systolic murmur at the apex and pulmonic areas, but on dis- charge it was stated that the heart sounds were clear. On August 12, 1903, the patient returned in answer to my letter. She had had one child since leaving the hospital. For three months she has felt rather poorly, the catamenia having been profuse and of late rather irregular-possibly menopause. The pulse was regular, excepting for occasional intercurrent beats, 17 to the quarter; of moderate size, long duration. The vessel wall was just palpable on the right side; not on the left. Temporals not sclerotic. Blood pressure 165. Heart. Point of maximum impulse visible and palpable in the fifth space, 11.5 cm. from the median line, 1 to 2 cm. outside the mammil- lary line. The dulness extended 3.7 cm. to the right. Impulse, heav- ing, stronger than usual. " The first sound at the apex is prolonged and followed by a distinct systolic murmur heard throughout the left axilla and faintly in the back. The second sounds are sharp. In the tricuspid area the murmur is not distinctly audible. The second pulmonic is fairly sharp, and is reduplicated with about two beats on inspiration. The second aortic is not as loud as the second pul- monic. The reduplication of the second sound is not heard in the aortic area, and is clearly due to pulmonic delay. In both pulmonic and aortic areas there is a slight suggestion of a systolic murmur, which is not heard in the carotids." Case IX. Hypertrophy and dilatation of the heart; mitral insufficiency.-J. F. (Hospital No. 36,210), aged eighteen years, was admitted to the hospital on September 9, 1901. He passed through a typhoid fever of very moderate intensity, the probable length of fever being only about thirteen or fourteen days. The urine showed a slight trace of albumin on entrance and a few coarsely granular casts, but both albumin and casts disappeared later. There were no complications. He had had chickenpox when young, but knew of no other serious illnesses. Is a farmer, and exposed to a good deal of bad weather. Does not drink nor use tobacco. In the hospital the pulse was 21 to the quarter; marked sclerosis of radials. " Heart sounds loud and booming. Systolic murmur in pulmonic area. Second sound clear." No further note was made on the heart. The highest recorded pulse was 112. During con- valescence the pulse was as low as 48. In September, 1903, he reported in answer to my letter, and, in THAYER: EFFECTS OF TYPHOID FEVER ON THE HEART. 27 my absence, was examined by Dr. Briggs. He had been perfectly well since leaving the hospital. " Radials much sclerosed. Brachials thickened and visibly pulsating at the elbow. Pulse 24 to the quarter, slightly irregular in force and rhythm, with rare intermissions of rather short duration; large volume; not collapsing. Blood pressure 182." Heart. Point of maximum impulse in the fourth interspace, 8 cm. from the midsternal line, though the impulse was to be felt as far out as 14 cm. from the median line in the fifth interspace, with which dulness was practically coexistent. Relative dulness extended 5 cm. to the right of the midsternal line. The systolic impulse was forcible; the shock of both sounds well felt; no thrill. At the apex both sounds were well heard, the first booming, and followed by a rather intense, blowing, systolic murmur, transmitted to the axilla, but not to the back. "In a small area upward and inward from the apex in the fourth space the second sound has at the beginning of examination a faintly rumbling echo, not running through diastole; this disap- pears on resting, reappearing after examination. In the tricuspid area and over the precordial region the systolic is well heard; the second sound is clear. In the pulmonic area the systolic is louder than over the right ventricle; not so loud as at the apex. The second pulmonic is louder than the second aortic and is reduplicated, the accent being on the second part of the reduplication, and the length of the interval being more marked during deep inspiration, though present throughout the respiratory phases. The aortic sound is clear, ringing, bell-like, and, though not so loud, is more intense than the second pulmonic. The first sound is fainter. No systolic murmur audible. There is no diastolic murmur to be heard at the base nor along the border of the sternum." Case X. Four months after discharge, aortic insufficiency which had disappeared five months later.-J. C. (Hospital No. 39,371), a man aged twenty-two years, entered the hospital on June 26, 1902. Here he passed through a typhoid fever of moderate severity, without complications, leaving the hospital on August 9, 1902. The urine showed a trace of albumin at the height of the disease. He had had measles as a child; denied venereal disease; habits good. In the hospital it was noted that the radial artery was palpable. On two occasions during the disease the blood pressure was 128. Heart. Dr. McCrae noted that the point of maximum impulse was very feeble, visible (?) in the fifth space, 10.5 cm. from the mid- sternal line. The first sound was everywhere of rather an indefinite quality, but there was no actual murmur. On November 30th, about sixteen weeks after discharge from the hospital, he reported in answer to my letter. The pulse was 27 to the quarter (the patient was rather nervous), collapsing, but of clearly high systolic pressure. Vessel wall not palpable. Blood pressure 174 mm. 28 THAYER: EFFECTS OF TYPHOID FEVER ON THE HEART. Heart. Apex in the fourth interspace, 10.5 cm. from the mid- sternal line. Sounds clear and strong at the apex. A soft systolic murmur was heard at the tricuspid area and at the aortic area trans- mitted upward over the manubrium. The second aortic sound was very loud; no murmur. Both sounds were heard in the carotids, the first prolonged as a roughened murmur. No murmur was heard in the pulmonic area. The systolic murmur was distinctly loudest at the aortic area, and was transmitted upward. There was a very soft diastolic murmur, heard along the left sternal border. This murmur was extremely slight, but was heard by Dr. Briggs, as well as by myself. Five months later, on April 21st, the patient reported at the dis- pensary. He had been complaining of a slight cough, the last stage of a cold which he had had for about a week. He was still hoarse, with a teasing cough. Had not been working regularly on account of nervousness. The lungs were clear. The pulse was regular, of good size; nothing remarkable about its quality. " Heart. Apex impulse not seen nor felt. By stethoscope and per- cussion it was localized 9.5 cm. from the median line, in the fifth space. Dulness extends 3.5 cm. to the right of the median line. At the apex and all over the cardiac area, most marked in the aortic area, there is a soft systolic murmur, which wholly disappears in the erect posture. The sounds are otherwise clear, excepting that in the pulmonic area there is a reduplication of the second sound, which occurs several times during ordinary inspiration, the delayed part being clearly the second pulmonic. This reduplication is heard at times in the aortic area. There is no diastolic murmur either in the erect or recumbent posture." The case is one of much interest. May it have been an instance of transient dilatation of the aortic ring? Case XI. Aortic insufficiency.-L. R. (Hospital No. 20,507), a man aged thirty-nine years, was admitted to the hospital on Sep- tember 4, 1897, and passed through a typhoid fever of fifty days' duration, followed by a relapse, associated with bronchitis and a pemphigoid eruption on the hands. The urine contained no albu- min, but an occasional hyaline and granular cast was found. As a child he had had scarlet fever, and almost every fall had had malarial fever. Four years before entry he had had another attack of typhoid fever; four years before, urethritis. The pulse was not remarkably rapid at any time during the course, and the only note with regard to the circulatory apparatus was "heart negative." On February 15, 1903, the patient reported in answer to my letter, and, in my absence, was examined by Dr. Briggs. The patient had been well since discharge, but had lived a life of hard work and exposure. "Pulse 82; slightly irregular in force and rhythm; THAYER: EFFECTS OF TYPHOID FEVER ON THE HEART. 29 distinctly collapsing; vessel wall moderately thickened; marked vis- ible pulsation in brachials and carotids; none in the temporals. Marked capillary pulsation. Systolic blood pressure, 185 mm. "Heart. Point of maximum impulse just visible and palpable in the fourth space, 12 cm. from the median line, in the left mammillary line. Impulse faint; no thrill. The relative dulness begins at the second left interspace and extends to the right sternal margin at the level of the fourth rib. No absolute cardiac dulness. At the apex both sounds are heard; the first rather muffled, followed by a soft systolic puff, carried to the mid-axilla, and faintly heard at the xiphoid. The second sound is sharp and clear. Just above the nipple, in a small area, there is a short, faint rumble in diastole, ending before the first sound, which is not snapping. Both sounds are heard over the right ventricle, with a systolic murmur, which becomes more marked in the second, third, and fourth left spaces, and is heard at the base, though not over the manubrium, and in the neck. The pulmonic second is louder, accentuated; occasionally a faint reduplication with inspiration. The aortic second is soft, but clear. In the second and third left interspaces close to the sternum there is a very short, faint diastolic murmur following the second sound." Case XII. Marked arteriosclerosis. C. Z. (Hospital No. 17,632), a boy aged thirteen years, was admitted to the hospital on October 19, 1896, where he passed through a typhoid fever of seventeen days' duration, without complications, being discharged on Novem- ber 19,1896. There was a trace of albumin, with hyaline and gran- ular casts, during the height of the fever. He had suffered from no previous serious infections, and, so far as could be determined, was a boy of good habits. The highest recorded pulse in the hospital was 112. A full note on the heart was made by Dr. McCrae. Pulse 21 to the quarter, soft, and easily compressible; synchronous in radials and femorals. Heart. Point of maximum impulse in fourth space, 7 cm. from the median line; wavy; no thrill. Area of cardiac dulness not in- creased. Sounds: A soft, systolic murmur was heard at the apex, not especially carried around to the axilla; best heard over the second and third left spaces. The second sound was very loud at the apex and much accentuated in the second left space. No further note as to the heart. On January 4, 1903, he returned in response to my letter. Three years ago he had had an attack of tonsillitis, after which his tonsils were removed. Beyond this he had considered himself quite well. The pulse was 25 to the quarter, showing rather marked irregu- larities in rhythm; of good size and long duration. The vessel wall was much thickened; readily rolled under the finger. The tem- porals were tortuous, prominent and somewhat thickened. The systolic pressure was 200 mm. 30 THAYER: EFFECTS OF TYPHOID FEVER ON THE HEART. Heart. The apex impulse was visible and palpable in the fifth space just inside the mammillary line, 8.7 cm. from the median line. The dulness extended 3.2 cm. to the right of the midsternal line. Sounds. The first at the apex was prolonged and booming, fol- lowed by a very slight systolic murmur, which was lost before one reached the mid-axilla. " A much more distinct, high-pitched, blow- ing systolic follows the first sound in the tricuspid area and over the right ventricle in the third and fourth spaces. It is, however, barely audible in the pulmonic area, and is not heard in the aortic area or over the manubrium. It is not affected by change of position. Sounds at the base clear. The second aortic is accentuated." At the time that this note was made the following remarks were added: " In this instance there is a distinctly hypertrophied heart, with marked sclerosis of the radials and temporals. The murmur heard in the tricuspid area is not of the ordinary character of a functional murmur, being higher pitched and having a very blowing sound." This case, it seems to me, is one of particular interest, in view of the fact that beyond the tonsillitis the only element to which one could reasonably ascribe the cardio-vascular abnormalities was the preceding typhoid fever. * * * Summary. A study of the condition of the heart and vessels in 183 indi- viduals who have passed through typhoid fever at the Johns Hopkins Hospital within the last thirteen years has revealed the following facts: 1. The average systolic blood pressure in these old typhoids was appreciably higher than in control observations upon healthy indi- viduals. 2. The higher average of the blood pressure was constant in every decade. 3. In many instances among the old typhoids the blood pressure exceeded appreciably the limits of what is usually regarded as normal. 4. The radial arteries in the old typhoids were palpable in a pro- portion nearly three times as great as that found in control observa- tions upon supposedly healthy individuals who had never had the disease. 5. The average size of the heart was greater among the old typhoids than in the same cases at the time of admission to the hospital. The difference held good also when the cases were classed according to age by decades. 6. Cardiac murmurs were heard with considerably greater fre- quency among the old typhoids and in the same cases during the attacks. THAYER: EFFECTS OF TYPHOID FEVER ON THE HEART. 31 7. In 8 cases where, on discharge from the hospital, the heart was considered normal, subsequent examination revealed hypertrophy, with mitral insufficiency. One case showed a possible mitral sten- osis; one an aortic insufficiency; one a striking general arterio- sclerosis, with hyper-tension. 8. In one case an aortic diastolic murmur was present four months after discharge, but had disappeared five months later. 9. Those patients whose pulse during the disease was remarkably rapid or irregular, showed, in general, on later examination, a blood pressure above the common average for the old typhoids. In other respects, however, their condition differed but little from the general run of cases. 10. Those cases in which a systolic murmur at the apex of the heart was observed during the attack showed later an increase in the blood pressure and in the size of the heart, as compared both with the mean of the observations made upon the same cases on admission to the hospital and with the general average for the old typhoids. Nearly one quarter of those cases in which during the attack, systolic apical murmurs were detected, showed, on later ex- amination, evidences of organic heart disease. Indeed, the majority of all the cases of organic cardiac lesions among the 183 old typhoids came from this small group of 31 cases. It is recognized that these results are based upon the analysis of a number of cases too small to justify final conclusions; the next 200 cases may considerably modify the figures. Yet the fact that these 183 old typhoids are materially older, from a point of view of their hearts and arteries, than the average individual who has not had typhoid fever, would tend to support the views of those who regard this disease as an active element in the aetiology of a considerable number of cases of cardiac hypertrophy and dilatation coming on sometimes in early life, as well as an important factor in the pro- duction of those vascular changes which Cazalis has happily called " la rouille de la vie." LEA'S PERIODICALS - The Medical News-Weekly. A weekly medical newspaper is indispensable to those who would keep always posted to date on the incessant advances of practical medicine. The News answers every need. Its many departments cover all avenues of information and present a comprehensive knowledge of progress in every line. Weekly, illustrated, 2496 quarto pages of reading matter per year. Price, $4.00. The American Journal-Monthly. 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Medicine and The American Journal " 10 00 Prog. Medicine and The Medical News " 9 00 The American Journal and The Medical News " 8 00 Progressive Medicine, The American Journal and The Medical News " 13 50 The Medical News Visiting List in combination with any of the above Periodicals 75 The Medical News Pocket Formulary in combination with any of the above Periodicals . . 75 Orders exceeding $4.00 may be paid for in convenient installments, regarding which please address the Publishers. LEA BROTHERS & CO., Publishers, 111 FIFTH AVENUE, NEW YORK. 706, 708 & 710 SANSOM ST., PHILADELPHIA OBSERVATIONS ON TWO CASES OF TUBERCU- LOUS PERICARDITIS WITH EFFUSION. By William Sydney Thayer, M. D. Associate Professor of Medicine in the Johns Hopkins University, Baltimore. [From The Johns Hopkins Hospital Bulletin, Vol. XV, No. 158, May, 1904.) OBSERVATIONS ON TWO CASES OF TUBERCU- LOUS PERICARDITIS WITH EFFUSION. By William Sydney Thayer, M. D. Associate Professor of Medicine in the Johns Hopkins University, Baltimore. Case I.-Tuberculous pericarditis. Large effusion. Paracente- sis of the pericardium in the 5th space about 4 cm- within the mamillary line. W. E. H., aged 26. Family history, in no way remarkable. Father, living and well. Six brothers and sisters, in good health. One sister died in infancy. The patient is a curtain hanger by occupation, of regular habits and good previous history. He has had none of the serious illnesses of childhood and considered himself perfectly well until the spring of 1898, when he had a left-sided pleurisy with effusion, which kept him in bed for a month. In the spring of 1901, he had a similar attack again of a month's duration. Three or four weeks ago while dressing, he leaned over to pick up one of his shoes and fell to the ground in a faint. He soon recovered consciousness but felt weak and " giddy " and sent for a doctor who advised him to stay at home. About a week later he began to suffer from shortness of breath, and gradually with increasing dyspnoea, there developed a fulness in the prsecordial region. The patient was under the charge of Dr. Fenby, who recognized the presence of a pericardial effusion and advised aspiration. On the 31st of October, 1902, I saw the patient in consultation with Dr. Fenby. He was in bed lying on the left side. There was marked dyspnoea. The expression was anxious, the lips, some- what cyanotic. The pulse was of small size and low tension, irregular and intermittent, uncountable at the wrist. By stetho- scope, about 150 beats could be made out to the minute. The res- pirations were shallow, 50 to the minute. There was a marked bulging of the whole praecordial region. The movements of the chest were rather more extensive on the [149] 1 [150] right than on the left. The cardiac impulse was inappreciable on inspection or palpation. On percussion the cardiac dulness was enormously increased, beginning above in the first space, extending outward to the nipple line on the right, and to the left away beyond the nipple into the posterior axilla. The cardiac flatness was also greatly in- creased, reaching the hepatic flatness at about the mamillary line on the right and on the left far out in the mid-axilla. On the left it began above at the second space. At the left apex the resonance was somewhat dull and tym- panitic. On the right there was also a distinct tympanitic quality, though the sound was clearer. In the back there was slight dul- ness at the left apex, while elsewhere the note was more tym- panitic than on the right side. On auscultation a few fine rales were heard at both bases, while at the left apex the respiration was enfeebled, the breezy quality of the inspiration was lost, and medium and fine, rather sticky rales were heard on inspiration. In the whole prsecordial region the heart sounds were almost absent; entirely so below the fifth rib. Above, they were so ex- tremely feeble and distant that nothing definite could be deter- mined as to their character. It was decided to aspirate immediately. The patient was placed in a chair in a semi-recumbent posture, and a point for aspiration was selected in the fifth space about two fingers' breadth inside the mamillary line. It seemed wise to aspirate at this point in order to establish better drainage than could be obtained by seeking a point nearer the sternum. The danger of striking the heart was deemed to be slight on account of the fact that careful auscultation seemed to definitely indicate that the apex was at a higher point. The history and character of the case were such as to leave little doubt that the effusion was serous, and the danger of infecting the pleura seemed relatively slight. The trocar was introduced at this point and slowly advanced obliquely backwards and toward the median line. Immediately on its introduction, the fluid spurted out with a force indicating that it was contained under considerable pressure. 1250 cc. of almost clear, yellowish, straw-colored fluid were withdrawn. At the end of this time the rate of the pulse had materially diminished al- though there were frequent intermissions. By moving the trocar upwards the heart could at times be felt and the rubbing of the end of the trocar against the visceral pericardium resulted in the withdrawal of a few drops of blood. During the aspiration the respirations gradually became quieter, the dyspnoea diminished and finally almost disappeared. At the end of aspiration the respirations were 28 to the minute, as compared with a rate of 50 at the beginning. 2 On percussion of the heart after the withdrawal of the trocar, the flatness to the right of the sternum was found to have completely disappeared, the lung having come back into place. The relative dulness, however, still preserved a somewhat tri- angular shape, the angle between the cardiac dulness and hepatic flatness on the right side remaining obtuse. On the left, the flat- ness ended at a point inside the nipple line and the cardiac im- pulse was well felt in the 4th space or about under the fifth rib, just inside the nipple. There was also visible pulsation in the third space. On auscultation, the heart sounds at the apex were loud and accompanied by a very slight to-and-fro pericardial friction which was well heard over the right ventricle, along the sternal border and at the base. The second pulmonic sound was somewhat accentuated. The pulse remained rapid, between 130 and 140, but was regular and of much better size and tension. About a month later, on the 21st of November, the patient who had steadily improved, called at my office with Dr. Fenby. At that time he looked rather pale though the mucous mem- branes were of fairly good color. The pulse was rapid, about 130 at the beginning of examination, in great part, probably, the re- sult of excitement. On physical examination the left upper chest was found to be distinctly flattened, while the motion on respiration was also slightly deficient. Heart.-There was marked pulsation in the second, third and fourth left interspaces and over the whole preecordial area. The apex impulse was in the fourth space, 10 cm. from the median line, just inside the nipple. Dulness began at about the second space and extended 5 cm. to the right of the median line. The angle between cardiac dulness on the right and the hepatic -flatness was acute, the dulness showing the normal curved outline. There was no flatness to the right of the sternum and no dulness outside of the point of maximum impulse. At the apex the im- pulse was of moderate intensity, while over the base there was a well marked diastolic shock. The first sound was clear at the apex, the second, reduplicated during inspiration. In the pul- monic area the second sound was reduplicated during the latter part of inspiration. Otherwise the sounds were clear. There was no friction murmur. Lungs.-At the apex of the lung on the left side, the note was duller than on the right; the vocal fremitus was of about equal intensity on the two sides. The respiratory murmur on the left was rather enfeebled; expiration prolonged. Numerous fine and medium moist rales were audible after cough; these were heard throughout the front. The right side was absolutely clear. In the back, the right side was clear throughout on percussion and auscultation. On the left, there was slight dulness with [150] 3 ri50] enfeebled respiration in the supra-spinous fossa where fine rales were heard on cough; elsewhere, clear. There was no Broad- bent's sign. 8-vii-1903. In response to a letter the patient called to-day. He says that he has felt rather weak but has been at work off and on since the fall, working steadily through January, Feb- ruary, May and June. In December his voice became so hoarse, that he could barely talk aloud, and his inability to work steadily has depended entirely upon this trouble, as he has been unable to make himself properly heard. He consulted Dr. Warfield, who discovered that there was paralysis of the left vocal cord. Later, another laryngologist told him that he had an ulcer upon one of his vocal cords. His appetite is good and he weighs as much as usual, 125-128 pounds. The patient looks better than when last seen, though his voice is very hoarse. The color is good; tongue, clean. Pulse, at beginning of examination, 25 to the quarter. Lungs.-Thorax, somewhat flattened in the whole upper left front above the nipple; perhaps a little so in the axilla. Expan- sion somewhat deficient on that side. Percussion note, somewhat deficient above the fourth rib on the left; clear on the right. Vocal fremitus, more marked on the right. On quiet breathing the respiration is a little puerile in the right front with slightly interrupted inspiration above the clavicle. On the left there is a tubular modification of the respiration; the inspiration is softened and less breezy than usual; expiration, prolonged. Below the fourth rib the respiration is normal. Occasional fine rilles above the right clavicle, after cough. Numerous fine and medium moist rales above the fourth rib in the left front, exploding after cough. Vocal resonance, increased. Slight dulness over the upper lobe in the left back with the same rather enfeebled and slightly modified respiration and fine rales. Otherwise the breathing is clear throughout. Heart.-There is well marked visible pulsation in the second, third and fourth left spaces, extending outwards nearly to the mamillary line. There is no retraction at the apex. On palpation the shock of the second sound in the pulmonic area is well felt. The point of outermost impulse is clearly localized, visible and palpable in the fourth space 8% cm. from the median line. The relative dulness begins in the second space and extends obliquely outward to this point. On the right it has a distinctly round out- line extending at its farthest point, at about the lower border of the fourth cartilage, 4 cm. from the median line. The cardiac flatness begins at the fourth rib, extending obliquely outward to the point of maximum impulse. On deep inspiration the lung comes down so as to almost cover the cardiac flatness. There [151] 4 is no flatness beyond the left sternal border. The cervical veins are scarcely visible; no diastolic collapse. At the apex the heart sounds are perfectly clear beyond a slight reduplication of the second sound which is heard during inspir- ation. In the tricuspid area the sounds are clear excepting for this reduplication for several beats with inspiration; the second part of the reduplication is accentuated. In the pulmonic area the sounds are clear. In the second left space the second sound is sharply accentuated. On inspiration this sound is reduplicated during several beats, the second part of the reduplication being accentuated. In the second right interspace the second sound is sharp but not nearly as much so as in the pulmonic area. The same reduplication is heard during inspiration, but the first part of the split sound is accentuated, clearly showing that the reduplication is due to pulmonic delay. There is no indication of Broadbent's sign. When the patient lies on the right side, the apex impulse remains practically in situ; the limits of dulness on the right side do not move. When the patient lies on the left side, the position of the apex impulse changes but little. The actual difference in the position of the point of maximum im- pulse with change of position, is only about 1 cm., measuring about 8 cm. when the patient lies on his right and 9 when he lies on his left side. Blood pressure (Riva Rocci) 123 mm.; tem- perature 98.7°. 9-vii-'O3. The patient called to-day on Dr. Warfield who sent me the following note. " Mr. H. called this morning and I find that his larynx has changed since I first saw him. Then the left cord was paralyzed, but now in addition, both cords are thickened and covered with fine superficial ulcers which are clearly tuberculous. The ulcers are very superficial and there is very little infiltration outside of the cord. * * * * " 27-xi-'O3. The patient called to-day in answer to a letter. He has been feeling quite well and working steadily since the last note. He has but little cough; does not know his weight. He looks like a different man. The color of the face, lips and mucous membranes is good. Tongue, clean. Pulse, regular, of good quality, 94. The size and pressure are fair; the vessel wall is not palpable. Lungs.-The thorax on inspection shows a well marked flatten- ing of the left front and also a slight retraction of the whole side, with diminished expansion, particularly in the upper part of the front. The vocal fremitus is more marked in the upper left front and there is slight dulness in the first three spaces; little or no dulness below the third rib. On quiet respiration the inspiratory murmur, on the right side, is rather harsh and slightly wavy. On the left side there is a slight tubular modification of the respiration which is enfeebled, occasional [151] 5 [151] medium moist rales being heard during inspiration. Occasional fine and medium rales are also heard throughout the front. On deep respiration and cough there are fine moist rales just above and below the right clavicle and throughout the left upper lobe, more marked at the apex. Throughout the rest of the right front and the lower lobes on both sides, the respiratory murmur is clear. Heart.-There is a wide area of cardiac impulse seen in the second, third, fourth and fifth spaces and over the fifth rib. The whole chest in the praecordial region moves. The point of maximum impulse in the apex region is to be felt, 8.7 cm. from the median line in the fourth space, dulness extending 4.7 cm. to the right. On standing, the impulse becomes distinctly more marked and clearly defined. This point is relatively fixed, being 8 cm. from the median line when the patient lies on the right, 10 when he lies on the left side. On inspiration the lung de- scends a little in the praecordial region, but scarcely more than a finger's breadth, flatness beginning at the fourth rib on expira- tion, in the fourth space on inspiration. When the hand is placed over the praecordium or the apex, two impulses are felt. At the apex the stronger, more deliberate impulse, that resembling the shock associated with the ventricular contraction, is syn- chronous with the protrusion at the point of outermost impulse. On auscultation, however, it becomes evident that this impulse is diastolic and not systolic; that the whole prcecordium is retracted with systole, rebounding with diastole in such a manner as to simulate an ordinary cardiac impulse. The first sound at the apex is of moderate intensity; the second, associated with the impulse, is slightly reduplicated. This reduplication is heard all over the cardiac area, most markedly in the pulmonic region. The separation between the two parts of the sound is increased on inspiration-clearly a reduplication due to pulmonic delay. In the tricuspid, pulmonic and aortic areas, the first sound is of moderate intensity but clear. The second pulmonic is louder than the second aortic sound. There is no trace of Broadbent's sign. The more interesting features of the case are: (1) The large amount of fluid obtained on aspiration. (2) The subsequent development of paralysis of the left vocal cord, due undoubtedly to sclerotic changes in the medi- astinum following involvement of lymphatic glands or exten- sion of the tuberculous process from the pericardium or lung. (3) The gradual development of the signs of adherent peri- cardium. 6 (4) The completeness of the recovery after so extensive an effusion. Case II.-Tuberculous pericarditis. Large effusion. Aspira- tion in the 6th left space at the sternal border and in the left costo-xyphoid angle, unsuccessful, the needle coming immediately into contact with the dilated heart. Death. On autopsy the enlarged and dilated heart was not adherent to, but contiguous with the anterior wall of the pericardial sac, the fluid, over 1200 cc., lying posteriorly and at the lateral angles. R. C. W., aged 59, a German saloon keeper, was admitted to the hospital at half past twelve o'clock on the first of September, 1903. The patient's complaint was of weakness and shortness of breath which had been coming on gradually for several years. The respiratory distress had greatly increased during the preceding few days. No previous history could be obtained. The following note was made by Dr. Cole. " Moderately well nourished, muscles flabby. At the time of examination the pa- tient is lying flat with the head slightly propped up; looks very ill; considerable cyanosis of the lips, ears and finger tips. Res- pirations, 10 to the quarter. The patient is coughing occasion- ally; frequent expiratory grunts. The pupils are small; react well to light. Tongue dry, slightly coated. * * * Veins of the neck are very full. No marked pulsation of deeper vessels. No general glandular enlargement. Chest; expansion fairly good, equal. Considerable respiratory distress. Resonance, clear through- out right front and axilla and left upper front, but note is markedly impaired in the lower left axilla and in the lower left back up to the angle of the scapula. On auscultation, on the left, the breath sounds are clear throughout the upper front and upper back except for a few rales in the interscapular space. Below, they are very distant, practically absent at the extreme base excepting just at the angle of the scapula, where they are a little harsher and the suggestion of a pleural friction is oc- casionally heard. On the right side the breath sounds are quite clear throughout, except in the lower back where there are mucous rales and the breath sounds are distant. Heart.-Point of maximum impulse is neither visible nor palpable. Over the entire prsecordium no impulse can be felt. There is a very wide area of absolute dulness. The relative cardiac dulness begins at the middle of the third rib, extending to a point 16.5 cm. to the left in the 5th interspace, when the patient lies on the right side. When on his back, however, the limits of dulness are difficult to make out as they extend well out into the axilla. On the right side the dulness extends appar- ently 7 cm. outward in the fourth interspace, the angle between the upper limit of liver dulness and the cardiac dulness being [151] [152] 7 very obtuse. There is definite prsecordial bulging, though the intercostal spaces seem no fuller than on the right. At the apex and over the entire prsecordium no impulse can be felt. At the apex and over the entire prsecordium the heart sounds are barely audible until one reaches almost the costal margin in the fourth and fifth interspaces where the sounds are faintly heard. A to- and-fro friction murmur is also audible over the sternum from the third to the fifth rib. The murmur sounds superficial, louder during expiration than inspiration; not apparently increased by pressure of the stethoscope; it sounds suspiciously pericardial in character but not definitely so. The heart's action is of almost foetal rhythm. The sounds are heard more loudly in the second interspace, neither aortic nor pulmonic being especially accentu- ated. The pulse is very small; it can hardly be counted. The abdomen is full; no movable dulness in the flanks; feet and legs markedly cedematous." At 5.45 P. M. I saw the patient with Dr. Cole. He was at that time prepared for paracentesis of the pericardium. At my sug- gestion Dr. Cole adopted the method advised by Delorme and Mignon.1 The patient was placed in a semi-recumbent position, and an incision about 2 cm. long was made at the left sternal margin at the level of the sixth interspace, ethyl chloride having been used previously to deaden sensation. A small trocar was then inserted in the angle between the ribs as close to the sternal margin as possible. This was introduced vertically to about the depth of the sternum, then tilted so as to pass under the sternum and finally inserted carefully into the pericardium, the needle pointing downward, inward and to the right. After withdrawing the rod a small amount of bloody fluid escaped. On inserting the trocar further the rubbing of the heart against the end could be distinctly felt. On withdrawing slightly a few cc. of clear fluid escaped and then the flow stopped. This proce- dure was repeated several times, each time with a similar result. A Potain aspirator was then attached to the trocar but only a few cc. of fluid were obtained, the tube soon becoming stopped. This was repeated several times, the trocar being moved in different directions but without result. The rubbing of the heart against it was often felt. An aspirating needle was then inserted upward and backward through the left costo-xyphoid angle, but again only a few cc. of fluid were obtained; not more than 40-50 cc. in all were removed. Owing to the patient's moribund condition it was thought best that no further efforts be made. I was unfortunately obliged to leave before the end of this procedure and witnessed only the first attempt at aspiration. [152] 'Rev. de chir., 1895, xv, 797; 987; 1896, xvi, 56. 8 At autopsy the pericardium was found to be markedly dis- tended. The distension, however, extended more to the left than to the right; a large sac-like projection almost filling the left axilla. There was also considerable distension to the right. The heart lay almost directly against the anterior wall at the point where the needles had been inserted. On inserting the needle of a large syringe in various directions above and to the right and left of the heart, about 800 cc. of fluid were removed, and after opening the parietal pericardium about 400 cc. more escaped. From the position of the heart at autopsy it could be seen that the aspiration had been attempted at almost the worst possible place. Dr. Cole observes in a note made after the autopsy: " The fact that the heart sounds were heard loudest over the sternum and along the left sternal margin together with the fact that the friction rub was audible here, should have led me to insert the needle either to the right of the sternum or far to the left outside of the mamillary line." The pericardium contained about 125 cc. of slightly turbid dark, thick, firm, yellow fibrinous exudate. This was rough and shaggy and in many places rounded in the form of ridges. The outer surface of the pericardium on the left, showed many small yellow tubercles, averaging about 2 mm. in diameter. The heart was greatly enlarged and rather soft, the surface, covered with a mass of fibrinous exudate similar to that seen on the parietal surface of the pericardium. The right ventricle was considerably dilated. The aortic valves were thickened and sclerotic. At their base, on the superior and inferior surfaces were numerous small tuberculated calcareous masses. The supe- rior edges of the valve were connected with the aortic ring by many firm fibrous bands. The valve must have offered obstruc- tion to the blood stream. Nothing remarkable in the other valves. The heart muscle was of a dark reddish color and very soft. The papillary muscles showed numerous fibroid patches. The coronary arteries were rather tortuous and showed many small, raised yellow plaques. The left pleura contained about 700 cc. of slightly turbid, straw yellow fluid. Both lungs contained numerous small areas of tuberculous broncho-pneumonia. The bronchial and tracheal glands were enlarged and caseous. These cases have seemed to me worth reporting for various reasons. The former ®hiefly on account of the amount of fluid obtained by aspiration, the latter because of its bearing upon the question as to the position of the point of greatest advantage for aspiration in pericardial effusions. [152J 9 U52J The Size of Pericardial Effusions. The amount of fluid which the pericardium may contain is enormous. Verney2 extracted 900 cc. of fluid from the peri- cardium of a young man of 23, on two occasions separated by an interval of three days. At autopsy, twenty-three days after the first puncture, the pericardial sac contained over 4000 cc. of yellowish fluid. It is not rare to find from 800 to 1000 cc. of fluid in the pericardium. The largest effusions are, how- ever, usually purulent, and records of the evacuation of from 1- to 2000 cc. of pus are not extremely rare. The largest amounts of which I have found record are in several Russian cases mentioned in West's interesting article.3 In three of these cases four and a half, five and five and a half pounds of blood, respectively, were removed from the pericardium. These were all cases of scorbutus which ended in recovery. In but few instances, however, has the removal intra vitam of a greater quantity of serous fluid been reported than in our first case. Indications for Paracentesis of the Pericardium. Although aspiration of the pericardium is a relatively sim- ple procedure, it is not one which is frequently demanded even in large effusions. Delorme and Mignon4 observe w'isely that " The opening of the pericardium should be reserved for those cases only where the limits of the tolerance of the heart are passed or the phe- nomena of cardiac adynamia begin to appear. . . . Great dyspnoea, irregular and rapid pulse, extensive praecordial dul- ness, difficulty in appreciating the heart sounds demand inter- vention, whatever may be the duration of the symptoms and acuteness or chronicity of the affection." Diagnosis of Pericardial Effusion. There can rarely be serious doubt as to the existence of a pericardial effusion in instances where it is large enough to [153] 2 Gaz. hebd. de m6d., Paris, 1856, iii, 793. 8 Med. Chir. Tr., Lond., 1883, Ixvi, 235. 4 Rev. de chir., Par., 1895, xv, 802. 10 produce symptoms calling for interference, and yet mistakes have been made even in such cases. Rotch 5 some years ago, demonstrated clinically and by injections of cocoa butter into the pericardium,-that the presence of fluid in the pericardial sac results early in the appearance of flatness in the fifth right intercostal space, contrary to what is usually the case in dila- tation or hypertrophy of the heart. But flatness in the fifth right space may be present under these latter circumstances. The essential point in distinguishing extensive cardiac hy- pertrophy with or without pericardial adhesions, from fluid in the pericardial sac was pointed out in 1896 by Ewart,8 who called attention to the fact that it is not the extent or shape of the area of cardiac flatness (absolute dulness) which is im- portant. This, of course, represents the amount of pericar- dium uncovered by air-containing lung, and may naturally depend upon a variety of circumstances. The important point is the shape of the area of dulness (relative dulness). The pericardial sac full of fluid always has a more or less tri- angular shape, and the area of pericardial dulness extends ob- liquely outward on the one hand to the splenic flatness or the lower limit of pulmonary resonance, and on the other to the hepatic flatness. The right side of the heart, however hyper- trophied it may be, always has a curved outline corresponding to the shape of the right auricle, and this curved outline it is possible to make out in most instances by careful percussion. The angle between the relative dulness of the heart and the line of flatness of the liver is thus an acute angle correspond- ing to the shape of the right side of the heart. If, however, there be fluid in the pericardium, the shape of the non-resonant body-the pericardium filled with fluid-which lies in part beneath the lung, is triangular, and the angle between the dulness over the pericardium and the flatness of the liver will be an obtuse angle. Careful attention to this point serves to distinguish good-sized effusions from cardiac hypertrophy where the anterior border of the right lung may be so far removed from the sternum as to cause flatness in the fifth right space. It is, moreover, especially valuable in the recog- [153] 5 Boston M. & S. J., 1878, xcix, 389; 421. ' Brit. M. J., 1896, i, 717. 11 1153] nition of very early and slight collections of fluid in the peri- cardium. A large proportion of errors in diagnosis in thoracic affec- tions depends upon lack of attention to the tedious minutiae of careful percussion of the chest. Those who, in obscure cases of thoracic trouble, take pains to mark out with a pencil the lower limits of the lungs and the outlines of cardiac dulness will often save themselves serious trouble. Accurate diagnosis in thoracic disease demands time, familiarity with theories and methods of. physical exploration and some power of rea- soning-and -I am not sure that time is not the most import- ant of these elements. Method of Procedure in Paracentesis of the Pericardium. Much has been written with regard to the point of election for aspiration of pericardial effusion, and there has been a surprising difference of opinion. On general principles it is best to aspirate at that point at which the most perfect drain- age may be obtained. There are, however, several dangers which one commonly seeks to avoid. These are: (1) Infec- tion of the pleura. (2) Injury to the internal mammary ves- sels. (3) Puncture of the heart. (1) Infection of the Pleura.-Under antiseptic precau- tions and in ordinary sero-fibrinous pericarditis there is little danger in puncturing at such a spot that the trocar or needle traverses the pleura on its way to the pericardium. This is often true even in purulent pericarditis. There are, however, cases in which puncture of a purulent pericarditis through the pleura has resulted in a serious spread of the infection. Thus in the case of Vaillard,7 in an individual with pericardial effu- sion following typhoid fever, 600 cc. of greenish brown pus was withdrawn by puncture in the fifth space about 6 cm. from the left sternal border. Two hours later there was severe pain in the lower left axilla with the rapid onset of a left-sided pleurisy which was followed by death. It may, however, be an extremely difficult matter even in ' Quoted by Delorme and Mignon, op. cit., p. 1013. 12 large pericardial effusions, to avoid the pleura, as has been demonstrated by the interesting observations of Delorme and Mignon. It is commonly assumed that the border of the left pleura passes the sternal margin at about the fourth space, and leaves a small area of pericardium uncovered at the sternal end of the fifth left interspace. Delorme and Mignon, how- ever, found the left border of the pleura to be contiguous with or beneath the sternum- In the 4th space, in 17 out of 32 cases. In the 5th space, in 12 out of 32 cases. In the 6th space, in 6 out of 26 cases, or nearly one-quarter. It is then, by no means always possible to avoid the pleura by puncturing vertically inwards at any point along the border of the sternum. (2) Injury to the Internal Mammary Vessels.-There is little danger of injuring the mammary vessels if one intro- duce the needle in any interspace at a point immediately contiguous to the sternal border or four centimetres to the left. In 30 cases Delorme and Mignon found that the distance be- tween the sternal border and these vessels varied, In the 4th space, from 3-20 mm. In the 5th space, from 2-30 mm. In the 6th space, from 3-40 mm. (3) Puncture of the Heart.-The possibility of puncturing the heart should always be seriously considered; yet the danger following this accident would appear to be slight. There is record of a considerable number of cases in which the right ventricle has been punctured without serious result. In several instances, however, death has followed, as in the case of Callender8 in which the trocar was introduced in the fourth left space. Two ounces of blood were removed; five minutes later death occurred from hemorrhage into the peri- cardium. The right ventricle had been perforated in the middle of its anterior surface. In Baizeau's ' case, which is [153] [1541 'West: Med. Chir. Tr., Lond., 1883, Ixvi, 275. 9 Gaz. hebd. de m£d., Paris, 1868, 2 s., v., 515, 562. 13 1154] usually regarded as one of puncture of the heart, the needle was introduced in the 5th space three fingers' breadth from the sternal border. Air entered the pleura, and about 400 cc. of dark blood was obtained. Death occurred two hours after- wards. At autopsy the pleura and pericardium contained blood. Baizeau, however, expressly denies that the heart was wounded. Shapojshnikov 10 mentions a case reported by Southey where death resulted from a wound of the heart in connection with puncture.11 Position of the Heart in Pericardial Effusion.-The only method by which we can be sure to avoid puncture of the heart is to insert the needle at a point below its lower border or outside of the apex. Despite much discussion, the relations of the heart to the chest wall in cases of large pericardial effusion are not entirely settled. It is probably true as pointed out by Rendu 12 and Ferrand 13 that in large pericardial effusions the heart, retained in place by the great vessels, remains practi- cally in its normal position while the diaphragm descends. A much more difficult and still unsettled point, however, is the relation of the heart to the anterior chest wall. Many, -espe- cially German observers who have followed Skoda,14 have been inclined to believe that the heart tends to fall backwards on account of its greater specific gravity. The observations of Shapojshnikov15 suggest that this is not the rule, but that in most cases, even in very large effusions, the heart remains close to the anterior wall of the pericardial sac. This Shapojshni- kov has determined to have been the case in a number of in- stances under his clinical care, while experimentally, after in- 10Russk. arch. pat. klin. med. i bakt., St. Petersburg, 1896, ii, 75. 11 The reference given by S. is " Soci6t6 royale de medecine et de chirurgie de Londres, 24 Avril, 1893." Careful search has failed to reveal the original. 12 Mem. Soc. m6d. des hop., Par., 1882, 86. 13 *Contribution a I'Gtude de la paracentese du pgricarde, 4°, Bor- deaux, 1882, 5. s, No. 3. " Abhandlung uber Perkussion und Auskultation, 8°, Wien, 1842, 2. Aufl., 295. 15 Op. cit. 14 U54] jection of the largest possible quantities of fluid, he found but a very thin layer between the heart and anterior wall of the pericardium. He especially emphasizes the fact that in very large effusions a friction rub may still be present. Our second case is a striking example in point. With over 1200 cc. of fluid, the visceral and parietal pericardium were still adjacent anteriorly. Point of Election for Aspiration.-In view of these facts what then is the best point at which to introduce the needle ? According to West,18 aspiration of the pericardium, while* sug- gested by Riolan in the 17th century, was first practised in 1819 by Romero of Barcelona, but it was not until about the middle of the last century that the operation was other than of the greatest rarity. Aran,17 one of the earliest to practice aspiration of the peri- cardium, sought the spot at which the heart sounds were least audible, in the 5th space, 2-3 cm. from the outer limit of flatness. Baizeau 18 advised aspiration in the fifth space as close as possible to the sternum, seeking thus to avoid wounding the mammary vessels and the diaphragm. He advised making a small incision at the end of the fifth space through which he introduced the trocar. While yet in the mediastinum the needle should be removed and the canula pushed inward until it is arrested by the pericardium. By the sensation communi- cated to the canula one should be able to determine whether it is resting upon the pericardial sac containing fluid or the right ventricle itself. This determined, the trocar is further ad- vanced and a puncture made. At this point, however, there is unquestionably danger of puncturing the heart. Dieulafoy19 advises another method. The patient is raised slightly in bed and the needle is introduced in the fourth or fifth space, best in the fifth, 5 or 6 cm. from the left border of the sternum. The needle, connected with a vacuum already 16 Med. Chir. Tr., Lond., 1883, Ixvi, 235. 17 Gaz. d. hop., Par., 1855, xviii, 517. 18 Gaz. hebd. de med., Par., 1868, 2 s., v, 515, 562. 18 Traits de l'asp. des liquides morb., 8°, Paris, Masson, 1873, 279. 15 1154] produced in the aspirator, is pushed very slowly upwards and inwards. After it has passed for a distance of from 3 to 6 cm., one ought to reach the pericardium or heart. As soon as the fluid begins to come the needle is swung in such a manner that it may lie in a position parallel to the ventricle. The puncture at this point has two objections: (1) danger of puncturing the heart; (2) the certainty of puncturing the pleura. Others have recommended puncturing below the seventh rib in the angle between it and the base of the ensiform car- tilage. If, however, the diaphragm be but little depressed while the dilated heart lies anteriorly, as is apparently the rule, this is by no means a favorable point for aspiration and the needle may enter the heart before any fluid is ob- tained. Rendu20 asserts that if one observes a gradual descent of the diaphragm during several successive days, he may safely punc- ture in the mamillary line about one centimetre above the lower level of flatness which may be in the 5th, 6th or 7th space. It is easy to imagine that a large liver might be a confusing element in such a case. Delorme and Mignon,21 after a careful consideration of the subject, advise the following procedure: About one finger's breadth above the lower border of the seventh car- tilage, at the sternal margin, a cutaneous incision is made of about 4 cm. in length, exposing the fifth and sixth spaces. In the sixth, unless that space be too narrow to allow the in- troduction of a needle, and if this be the case in the fifth, or very exceptionally in the lower and internal part of the fourth space, a needle, best No. 2 Dieulafoy, is introduced at the ster- nal border, and passed slowly, vertically inwards. As soon as the needle has entered to the depth of the sternum, that is, about 8 mm., it is turned obliquely inwards so that the point may follow the posterior surface of the bone. After it has entered about 1 or 2 cm. the extremity is lifted slightly and the needle introduced obliquely inwards and downwards by a [155] 20 Op. cit. 21 Op. cit. 16 slow continuous movement until fluid enters. This, the authors believe, avoids as far as possible injuries to the pleura as well as to the heart. But our second case shows how unsatisfactory this method may be, even in the presence of a very large effusion. Shapojshnikov,22 as the result of a careful series of observations and experiments, concludes that it is not always possible to determine the position of the heart before tapping. As a rule it is to be found close to the anterior wall of the pericardium; it does not fall downwards and backwards, as Skoda and others have believed. If, then, one introduce the needle in the fourth or fifth left space close to the sternum, he has chosen a position in which it will be particularly difficult to avoid the heart. In very large effusions, where the diaphragm is depressed and the semilunar space occupied by flatness, Shapojshnikov advises aspiration in the sixth left space. Where this is not the case he prefers introducing the needle in the third or fourth right space close to the sternum, provided there be flatness at that point. In all cases Shapojshnikov advises an exploratory puncture with the hypodermic needle. This procedure serves two purposes, (a) to determine the character of the effusion; (b) to ascertain the position of the heart. If the fluid be purulent, aspiration should of course be replaced by incision and free drainage. Shapojshnikov observes, with apparent reason, that with proper care there is no danger of injuring the heart by such preliminary exploration. If the physical signs be deceptive and the heart, which was supposed to lie wholly above the point selected for aspiration, be really just behind this spot, its movements will be readily felt by the hypodermic needle. Shapojshnikov has never known pleurisy to follow such an exploratory puncture, and in justification of the measure refers to the frequency and impunity with which exploratory punctures of the liver are made in cases of suspected abscess. * * * * When we consider these various methods it seems to me that the procedure advised by Shapojshnikov is the most [155] 22 Op. cit. 17 [155] rational. It is by no means always possible to escape the pleura by tapping in the fourth or fifth left space close to the sternal border, while from every other standpoint this is a most unfavorable point, especially in view of the fact that the heart is usually close to the anterior wall of the pericardial sac. The method advised by Delorme and Mignon may fail, even in very large effusions, as has been demonstrated by our second case. If, then, we abandon the attempt to avoid the pleura, the best place to aspirate should be that in which the drainage would be most perfect. In cases where the apex cannot be localized, where there is no reason to suspect that the heart extends beyond the left mamillary line, the 6th space, at about the mamillary line, would appear to be the point of greatest advantage. It would seem best not to introduce the needle too far out, in order to allow for retrac- tion of the sac. If it be definitely determined that the dilated heart extends beyond the mamillary line, one would then seek a point a little outside of the supposed position of the apex. Aspiration should always be preceded by exploratory punc- ture with a hypodermic syringe. Should the heart be found directly behind the point selected for aspiration, it may well be wise to follow Shapojshnikov's recommendation and intro- duce the needle in the 4th right space close to the sternum, provided there be flatness on percussion at that point. If the needle be introduced downwards and to the right there ought, owing to the conformation of the right auricle, to be little danger of injuring the heart. 18 THE RELATION OF ACUTE INFECTIONS TO ARTERIO- SCLEROSIS ::::::: Read at the Fifty-fifth Annual Session of the American Medical Association, in the Section on Practice of Medicine, and approved for publication by the Executive Committee: Drs. J. M. Anders, Frank Jones and W. S. Thayer. WILLIAM SYDNEY THAYER, M.D., Associate Professor of Medicine in Johns Hopkins University, AND CLINTON ETHELBERT BRUSH, Jr., M.D., Assistant Resident Physician, Johns Hopkins Hospital, Baltimore. Reprinted from The Journal of the American Medical Association, September 10, 190^. CHICAGO: PRESS OF AMERICAN MEDICAL ASSOCIATION ONE HUNDRED AND THREE DEARBORN AVENUE 1904. THE RELATION OF ACUTE INFECTIONS TO ARTERIOSCLEROSIS. WILLIAM SYDNEY THAYER, M.D. Associate Professor of Medicine in Johns Hopkins University, AND CLINTON ETHELBERT BRUSH, Jr., M.D. Assistant Resident Physician, Johns Hopkins Hospital. BALTIMORE. In a recent study in which one of us has been engaged, on the cardiac and vascular complications and sequels of typhoid fever,1 several rather suggestive facts have come to light with regard to the possible causal relation of this disease to sclerotic changes in the arteries. One hundred and eighty-nine individuals who had passed through typhoid fever under our observation were examined months and years after their infection. It was found that among these individuals: (a) The radial arteries were palpable in a surpris- ingly large proportion of cases as compared with control observations on healthy men and women who had never had typhoid fever. Between the ages of 10 and 50, 48.3 per cent, of the old typhoids showed palpable radials, as compared with 17.5 per cent, among ordinary healthy individuals. These proportions held in every decade, and were not essentially modified in tables from which all giving a 1. Thayer: On the Late Effects of Typhoid Fever on the Heart and Vessels, Am. Jour. Med. Sci., 1904, vol. cxxvli, p. 391. Thayer: On the Cardiac and Vascular Complications and Sequels of Typhoid Fever, the Jerome Cochran Lecture, Mobile Medical and Surgical Journal, 1904, vol. v, No. 1. 2 history of serious infections or alcoholic habits had been excluded. (&) The average systolic blood pressure (Riva-Rocci) was materially higher in every decade among the old typhoids than in control observations on healthy indi- viduals who had not had typhoid fever. (c) The average size of the heart was larger among the old typhoids when considered in groups arranged by age, according to decade, than in figures obtained from examination of the typhoid patients at the time of ad- mission to the hospital. Furthermore, we have been rather impressed by the frequency with which early endarteritic plaques are found in the aorta and coronary arteries of patients dy- ing of typhoid fever. Out of 95 necropsies on patients dying of typhoid notes were made on the condition of the aorta in 52. In 30 of these sclerotic changes were observed. These are described as fresh in at least 21 instances. In 62 cases the condition of the coronary arteries was noted. In 19 of these definite sclerotic changes were described, while in 4 others "yellow opacities of the in- tima" were observed. In 13 cases the changes were de- scribed as "early" and "fresh." These figures would tend to support the view that typhoid fever must be regarded as a factor in the pro- duction of arteriosclerosis. The role of infectious dis- eases in the production of acute arteritis in medium- sized and smaller vessels is undoubted. Their influ- ence, however, on the development of the more chronic changes which are included under the term arterio- sclerosis has been and still is a disputed question. It occurred to us that some light on the relative in- fluence of acute infections as compared with other, probably more important causal factors might be ob- tained by a consideration of the records of palpability of the peripheral arteries in a large number of consec- utive histories of patients in Professor Osler's wards. 3 In these histories careful inquiry is made, not only into the record of previous infectious diseases, but also into Chart 1.-Showing the percentage of cases in which the radial arteries were papable in patients giving the histories of various acute infections, alcohol and work, compared with those cases In which there was a history, no causal factors. Pr.ct.0.82 16.6 21.4 18.5 32.6 No causal Cases 121 186 167 102 52 factor. Pr. ct. 0 Cases 10 12.8 39 33.4 92 47.2 74 48.1 49 ■ Diphtheria Pr. ct. 0 15+ 30.8 46.2 60.4 Scarlet Cases 9 53 123 119 86 ' fever. Pr. ct. 9+ 25.3 40.8 53.7 62.4 Malarial Cases 11 74 252 253 213 fever. Pr. ct. 33.3 20.8 42.5 52.1 64 7 Typhoid Cases 6 48 162 142 119 fever. Pr. ct. 0 25.8 41.2 44.1 65 9 Pneumo- Cases 9 31 109 120 94 nia. Pr. ct. 12.5 13 40.6 69 3 67.8 Rheumat- Cases 8, 46 128 150 109 ism. Pr. ct. 0 24.1 60.9 61.7 70 3 Gonor- Cases 0 29 133 128 91 'rhea. Pr. ct. 0 66.6 55.8 68.1 68 0 Cases 0 6 43 66 47 Syphilis. Pr. ct. 0 43.6 59.4 64.8 70 8 -Alcohol. Cases 1 103 589 490 357 Pr. ct. 0 48.1 56.1 68.5 69 6 Work. Cases 0 83 340 312 254 the habits of the patient with regard to alcohol and heavy work. It may be well to say at the outset that these figures deal entirely with the records of palpability of the Tadial 4 arteries. It is well recognized that the palpability of a radial artery alone may bear little relation to the ex- istence of sclerotic changes in other vessels, and, in the individual case, by no means justifies the assumption that arteriosclerosis exists elsewhere. It is also recog- nized that, in thin subjects, radial arteries which are free from change may at times be rolled under the fin- ger. On the other hand, it is. common enough to find grave changes in the aorta, coronary arteries and other vessels with perfectly soft radials. Again, in the later decades, the palpability of the radials is, in a certain proportion of cases, dependent on calcification of the media, which is entirely independent of arteriosclerosis as such. Notwithstanding these considerations, we be- lieve that changes in the radial arteries sufficient to justify a note in the course of an ordinary visit are in a considerable proportion of cases associated with ar- teriosclerotic changes elsewhere, and that this propor- tion is large enough to give a certain value to a series of observations such as we wish to present. Out of 3,894 consecutive patients admitted to the medical wards of the Johns Hopkins Hospital, the ra- dial arteries were described as palpable in 1,860 in- stances, or 47.7 per cent. No note was made as to the condition of the vessel in 1,492 cases, while it is ex- pressly stated that the arteries were soft in 582 •cases. These cases were separated into groups in which a history was obtained of diphtheria, scarlet fever, ma- larial fever, typhoid fever, pneumonia, rheumatism, syphilis, gonorrhea, alcohol and heavy work. Another group consisted of those cases presenting none of these causal factors. It should be said that under alcohol are included, not alone those who used alcohol to excess, but all patients who acknowledged that they took alcohol in any form. Chart I shows the proportion of cases showing pal- pable radial arteries in each one of these groups ar- 5 ranged according to age by decades. Recognizing the fact that, above the age of 50, the proportion of cases showing calcification of the media might well be large enough to materially vitiate the results, we have consid- ered the figures for the first five decades only. It becomes evident from a glance at this chart that the statistics with regard to syphilis and gonorrhea must Chart 2.-Showing the percentage of cases in which the radial artery was palpable in 2,031 cases in which a history of the more serious infectious diseases was obtained, and 1,111 cases in which there was no such history, arranged according to age, by decades. Pr. ct. 6 8 Cases 44 24.3 255 41.8 664 52.1 619 62 1 449 ) History >of infectious ) diseases. Pr. ct. 0 8 Cases 119 20 2 252 32.0 350 43 9 241 52 3 149 ) History >of infectious ) diseases. be of little value on account of the absurdly small pro- portion of cases in which a history of venereal disease was acknowledged. The curves fall into three main groups. Those for work, alcohol and syphilis stand materially above the others. Below this group comes a second, consisting of the remaining acute infections, and lastly, toward the base line is the curve of those 6 cases in which the history of no causal factor was pres- ent. Rheumatism, typhoid and malarial fevers seem to lead in the second group. In order to gain a more definite idea of the statistics with regard to infectious diseases in general, the cases were divided into two groups according to the presence or absence of a history of the above-mentioned acute in- fections. In each of these groups the percentage of cases in which the radial arteries were palpable was estimated. This resulted in a demonstration (Chart 2) of the fact that the radials were palpable in consid- erably higher proportion in those cases giving a history of previous infectious disease. Inasmuch as in the great majority of cases each indi- vidual presented a history of multiple causal factors, it seemed to us important to prepare a third chart in which there were included only those cases where a single one of these factors was present. When considered from this standpoint, the number of cases in each group is so small that a consideration of curves by decades becomes impossible. Figure A in Chart 3, therefore, represents the pro- portion of palpable radials in the first five decades of those cases in which a history of only one of the several causal factors which we have mentioned was present. An examination of this chart reveals the fact that the figures simply emphasize those brought out by Chart 1. By far the highest percentage of palpable radials was found among the cases with a history of heavy la- bor (57.6). Next to this come the figures for the pa- tients who gave only a history of alcohol (46.8 per cent.). Among the acute infections, rheumatism, as might be expected, leads (34.6 per cent.), with typhoid fever second (26.3 per cent.), the other infections oc- cupying a subordinate position. The cases giving a history of syphilis and of gonor- rhea alone were so absurdly small in number that they have been omitted from the list. Only 12 cases under 7 Chart 3. 8 50 years of age gave a history of syphilis alone; among these were 2, 16.6 per cent., who showed palpable radials; 10 cases gave a history of gonorrhea alone; in 40 per cent, of these the radial was palpable. Chart 4 illustrates the proportion of palpable radial arteries in those cases in which there was a history of Chart 4.-Illustrating the percentage of cases showing palpable radial arteries in patients giving a history of heavy work, alcohol or infectious diseases alone, as compared with those cases in which the history of a causal factor was obtainable. Pr.ct.0.82 16.6 21.4 18 6 32.6 )No causal Cases 121 186 167 102 52 } factors. Pr. ct. 7 1 15 4 23.9 26 39 8 i Infection Cases 42 149 255 188 118 S alone. Pr. ct. .0 35.4 33 7 56 9 63.0 / Alcohol Cases 0 31 80 65 46 5 alone. Pr. ct. .0 68 0 50.0 60 0 58 3 / Work Cases 0 25 42 20 24 J alone. acute infections only, along with those presenting a history of alcohol and work alone. The lower line rep- resents the cases in which there was a history of no causal factor. The relation of the percentages of palpable radials in these several groups is brought out more clearly in Fig- 9 lire B of Chart 3. The small proportion of palpable ra- dials among the cases giving a history of acute infec- tions alone (24.3 per cent.), as compared with those giving a history of heavy work (57.6 per cent.) or alco- hol (46.8 per cent.), stands out strikingly. CONCLUSIONS. As the result of an analysis of the records of nearly 4,000 patients entering consecutively the medical wards of the hospital, we find that: 1. The percentage of palpable radial arteries is mate- rially higher among those individuals in whom there is a history of heavy physical labor and of the use of al- coholic stimulants than in the remaining cases. This percentage is appreciably higher in the cases giving a history of heavy work. 2. The percentage of palpable radial arteries is higher among those cases presenting a history of severe infec- tious diseases than among those in which this history is absent or among those in which a history of no causal factor could be obtained. The proportion is, however, far below that in the case of work or alcohol. 3. Rheumatism appears to be the acute infection after which the percentage of palpable vessels is highest, and next to rheumatism, typhoid fever. As previously stated, it is well recognized that the results of such an investigation as this justify only rather rough generalizations. Are we even warranted on a post hoc propter hoc principle, in assuming that work, alcohol and, in a sub- ordinate way, the infectious diseases are the main or important causes of the changes which result in pal- pable radial arteries? Not necessarily. It is, however, not uninteresting that the results should, so far as they go, support the generally accepted views. It seems to us there can be small doubt that the main etiologic factor in the development of the hyperplastic thickening of the intima, which constitutes so important 10 an element of arteriosclerosis, is overstrain of the vas- cular walls, continued or intermittent high tension, whatever its ultimate cause may be. Heavy physical labor is assuredly one of the most important of these causes. It is not inconceivable that the role of the acute infections may be rather in the production of those focal degenerations with secondary regenerative changes which constitute the other important element in arterio- sclerosis. ANALYSIS OF FORTY-TWO CASES OF VENOUS THROMBOSIS OCCURRING IN THE COURSE OF TYPHOID FEVER. BY W. S. THAYER, M.D., OF BALTIMORE. From the Transactions of the Association of American Physicians. 1904. Abdominal arteries in a case of double iliac thrombosis of typhoid origin. ANALYSIS OF FORTY-TWO CASES OF VENOUS THROMBOSIS OCCURRING IN THE COURSE OF TYPHOID FEVER. By W. S. THAYER, M.D., OF BALTIMORE. In connection with some studies in which we have recently been engaged concerning the cardiac and vascular complications and sequels of those cases of typhoid fever which have been observed in the last fourteen and a half years in Dr. Osler's wards at the Johns Hopkins Hospital, I have gathered together a few statistics with regard to the cases of venous thrombosis which are, it seems to me, of a certain interest. Out of 1463 cases of typhoid fever there have been 39 instances of venous thrombosis, a percentage of 2.6+ • In addition to these, two similar cases were admitted during con- valescence, while one man who had suffered from double iliac thrombosis coming on during typhoid fever, entered the hospital for treatment two years later. Mortality. In 5 of the 39 cases occurring in the hospital there was a fatal result-12.3 per cent. In 2 instances the thrombosis was the direct cause of death, once (No. 27855) through pulmon- ary embolism from a thrombus of the left axillary vein, and once (No. 28600) from the dislodging of a piece of a thrombus in the left iliac vein, with resulting embolism of the inferior cava and right auricle. Distribution of the Lesions, (a) As to Section of the Body. The seat of the thrombus was: In the lower extremities in 40 instances. In the upper extremity "1 instance. In the pulmonary artery " 1 " 2 THAYER (6) -Ts to the Side of Body. The occluded vessel was: On the left side in 26 eases. On the right side " 5 " On both sides " 9 " Imperfect records " 2 " (c) vis to the Vessel Affected. The affected vessels were: The femoral vein in 21 instances. The popliteal vein " 5 " The iliac vein " 5 " The veins of the calf alone " 5 " The internal saphenous " 3 " The pulmonary artery alone "1 instance. The pulmonary artery and common iliac .... " 1 " The axillary vein " 1 " Time of Onset of the Symptoms. In 39 cases developing in the hospital the time of onset was as follows : Weeks. 1 2 3 4 5 6 7 8 9 10 11 12 13 ? 1 1 10 953240 1 1 0 11 Symptoms. 1. Fever. In 36 of our 39 cases the development of the thrombosis was associated with fever. In 3 there was no fever. In 26 cases the fever was intercurrent, the thrombosis coming on before complete defervescence. In 13 the temperature was normal at the time of onset. 2. Chills. In 11, or 28.2 per cent., of these 39 cases the com- plication was associated with chills. In 2 instances the chills occurred just at the time of recognition of the thrombosis. In 2 cases the chills occurred before recognition; once four days and once a week before. In 6 cases the chills occurred during the complication, once during the period of subsidence, and in the other 5 instances during the height of the process. Once the chills occurred before, during and after the onset of the throm- bosis. In one of the 3 cases entering the hospital after the acute symptoms had passed a history of chills during the course of the fever was obtained, though their relation in time to the develop- ment of the thrombosis was not clear. 3. Pain. The first definite symptom of the thrombosis in every instance was pain. This varied considerably in intensity and suddenness of onset.- VENOUS THROMBOSIS OCCURRING IN TYPHOID FEVER 3 In all the cases of femoral thrombosis but one there was pain along the course of the femoral vein. In this one instance the only symptoms noted in the hospital were those of popliteal thrombosis. The subsequent history of the case, however, made it clear that there must also have been plugging of the femoral vein. ; The first localizing symptom of the process was : Pain along the course of the femoral vessels and in Scarpa's triangle in 9 cases. Pain in the calf " 5 " Pain in the popliteal region "1 case. Unsatisfactory note "3 cases. Patient to ill to localize pain "1 case. In 3 of these cases the onset of the pain was strikingly sudden. In the 5 cases of popliteal thrombosis the first localizing symp- tom in every instance was pain in the popliteal region. In the 5 cases of iliac thrombosis the onset was associated with sudden sharp abdominal pain in 4 instances. In 1 of these cases the pain was extremely severe and associated with leukocytosis. Perforation was suspected, and exploratory laparotomy was per- formed. In the 5 cases of thrombosis of deep veins of the calf the first symptom in every instance was pain in the calf. In the 3 cases of thrombosis of the internal saphenous vein alone, the first symptom in every instance was pain along the course of the vein. 4. (Edema. In all of the 39 cases there was swelling of the affected part. In most instances the temperature was raised, and in a number of cases there was redness over the affected vessel. A definite note as to the existence of oedema was unfortunately not made in all instances. (a) In 19 cases of femoral thrombosis : (Edema was noted in 11 cases. "Swelling" alone " 6 " No oedema " 2 " (6) In 5 cases of iliac thrombosis there was : (Edema in 2 instances. No oedema 4 THAYER (c) In 5 cases of popliteal thrombosis there was : CEdema in 2 instances. "Swelling" " 1 instance. No note " 1 " No oedema " 1 " (d) In 5 instances in which the deep veins of the calf were apparently alone involved there was : CEdema in 1 case. "Swelling" " 3 cases. No oedema "1 case. (e) In all 3 cases in which the internal saphenous and veins of the calf were involved there was oedema. 5. Palpability of the Thrombotic Mass. In 16 out of the 39 cases the thrombotic mass was felt as a palpable cord. 6. Leukocytosis. In 22 cases counts of the colorless corpuscles were made during the complication. The leukocytes were over 20,000 in 3 cases. " " " 15,000 to 20,000 .... " 3 " " " " 10,000 to 15,000 .... " 6 " " " " 9,000 to 10,000 . . . . " 3 " " " " 8,000 to 9,000 .... "1 case. " " " 7,000 to 8,000 . . . . " 1 " " " " 6,000 to 7,000 .... "2 cases. " " " 2,000 to 3,000 .... "1 case. It will thus be seen that in 12, or 54.5 per cent., the leukocyte count was above 10,000, while in 15, or 66.1 per cent., it was over 9000. The highest count, 24,864, occurred in a case of iliac thrombosis in the third week of typhoid fever. In this instance an exploratory laparotomy was performed in view of the possible existence of perforative peritonitis. The lowest count, 2700, occurred on the day after the onset of a thrombosis, apparently of the popliteal, which occurred in the sixth week without fever and with very slight general symptoms. In eight instances only was a count made on the day of onset of the symptoms. In these cases the leukocyte count was : Above 20,000- . . in 2 cases. Between 15,000 and 20,000 "1 case. " 10,000 and 15,000 " 1 " " 9,000 and 10,000 . " 1 " " 7,000 and 8,000 . . t . . . . . "2 cases. " 6,000 and 7,000 . . ... . " 1 case. venous thrombosis occurring in typhoid fever 5 In connection with these blood counts it should be remembered that, in every instance but one, the phlebitis came on in the third week of the disease, or later, at a period when, according to our statistics, the leukocyte count in uncomplicated cases should not be above 5500. Association with Secondary Infections. Out of our 39 cases there were 7 instances in which secondary infections had preceded or coexisted with the onset of the thrombosis. These secondary processes were : Boils in 2 cases. Well-marked bronchitis "1 case. Gangrene of the lung " 1 " Fistula in ano " 1 " Chronic otitis media . . " 1 " Amcebic dysentery with developing hepatic abscess . . " 1 " In the remaining 32 instances there was no clinical evidence of secondary infection. Postmortem Appearances. In the three instances in which bits of the clogged vein were examined histologically evidences of well-marked inflammatory changes were found in the walls of the vessels-such, however, as might well have arisen secondarily to the thrombosis. In one of these cases there was, at the point of section, an extensive endophlebitic plaque which, however, prob- ably dated from a period preceding the typhoid fever. The sec- tions examined came from a spot above the point of origin of the thrombus. There was nothing in the sections which would justify one in drawing conclusions as to the cause of the thrombosis or as to the pre-existence of a phlebitis. Cultures. In one case the bacillus typhosus was obtained in pure culture from the thrombus. In one the cultures were nega- tive. No notes were made with regard to cultures from the thrombus in the other cases which came to autopsy. After Results. Sixteen patients were seen or communicated with at periods, months or years after the onset of the complica- tion; 10 of these were cases of femoral thrombosis; 2 of double iliac thrombosis ; 2 of popliteal thrombosis ; 2 of thrombosis of the deep veins of the calf. 6 THAYER, (a) After History of Ten Cases of Femoral Thrombosis. One patient was seen two and one-half months after convalescence ; one ten days after his discharge from the hospital, while two of the others were communicated with a year after the onset by letter. The other six patients were examined at periods varying from two to twelve years after their illness. In all instances there was more or less permanent disability. In 6 cases there had been oedema, lasting; for from several weeks to two years. In 5 cases there was a complaint of cramps in the calves, espe- cially at night and after exercise. In 1 the patient complained of sharp pains running up through the leg and thigh, especially after standing. In 1 instance the patient says that when he uses his leg too much " it becomes so weak that he can hardly move it; it seems to give out." In every instance the affected leg and thigh were materially and permanently larger than the other. In all cases, excepting in the instance seen ten days after discharge, there were marked varices. These were especially extensive in the calf, the popliteal space and on the posterior and inner side of the thigh. In 6 cases, all but 1 in which the condition was looked for, there was well-marked varicosity of the veins in the hypo- gastrium. These seem to be characteristic. The dilated veins form a triangle with the apex a little below the umbilicus, the blood flowing from the affected thigh to the apex of the triangle, and then down again into the inguinal ring on the other side, passing upward, evidently through the opposite iliac vein. (6) After History of Tiro Cases of Double Iliac Thrombosis. Two patients who had had a double iliac thrombosis were seen several years after the onset of the complication. In one of these instances there was at first much oedema and persistent weakness of the legs. In the other there were few subjective symptoms, lu both cases there were most extensive varicosities on both legs and thighs extending upward over the abdomen and anastomosing with the internal mammary veins and other veins in the axilla. The plate shows the condition of the more marked of these two cases. VENOUS THROMBOSIS OCCURRING IN TYPHOID FEVER 7 (c) After History of Two Cases of Popliteal Thrombosis. Two cases of popliteal thrombosis were seen several years after the onset of the complication. One of these patients had complained of no trouble whatever. In the other the leg was somewhat weak, and toward the end of the day it became at times oedematous. In both instances the affected leg was somewhat larger than the other, but in neither were there marked varicosities. (d) After History of Two Cases of Thrombosis of the Veins of the Calf. In one case there was, after leaving the hospital, con- siderable oedema with the development of several ulcers. There is now a fairly well-marked varicosity of the veins of the inner side of the leg and in the popliteal space. The other patient was communicated with by letter. He states " that the leg from the kuee down is the source of a little continuous annoyance. It itches, and is frequently inflamed during the warm months. It often goes to sleep." The calf measures an inch and a half more than the other. Final Observations. Conclusions based upon so small a series of observations are hardly justified. There are, however, one or two points worth emphasizing : 1. In 42 cases of typhoid thrombosis the onset occurred almost invariably in the third week or later. 2. Local pain and fever were usually the first symptoms. The fever sometimes preceded the localizing symptoms. 3. In 28.2 per cent, of our venous thromboses occurring in connection with typhoid fever there were chills. In several instances the chill preceded the appearance of localizing symptoms. In the past two years I have seen in consultation 3 further cases in which otherwise unaccountable chills during convalescence from typhoid fever were followed by thrombosis. 4. Venous thrombosis in typhoid fever is usually associated with an increase in the number of leukocytes. The extent of the leukocytosis depends apparently in part, at least, upon the extent of the lesion. It may be moderate, but in other instances is of considerable extent-over 20,000. In mild cases it may be absent. 5. The thrombosis is commonest in the lower extremities, espe- 8 DISCUSSION cially on the left side. The femoral vein is involved with partic- ular frequency. 6. In the event of a sudden severe pain in the lower part of the abdomen, coming on during the latter part of typhoid fever, and associated with a leukocytosis, the possibility of iliac thrombosis should always be considered. 7. Venous thrombosis in a lower extremity is always a serious complication of typhoid fever. Although the immediate danger is not great, the after results are often grave. In thrombosis of the femoral or iliac veins the affected extremity is usually permanently and considerably enlarged, and there is usually more or less persistent disability-extensive varices often resulting in ulceration; marked weakness of the limb; frequent cramps in the muscles, especially at night and after overexertion. In thrombosis of the popliteal or deep veins of the calf alone, the permanent changes are much less severe, though the leg always remains larger than the other. 8. In thrombosis of the femoral vein a greater or less part of the blood from the affected extremity is often carried up by the iliac vein of the opposite side, the current crossing the abdomen through anastomoses in the hypogastrium, resulting in a character- istic triangular area of varicose veins. DISCUSSION. Dr. Peabody: As bearing upon the etiology of venous thrombosis follow- ing typhoid fever, I would like briefly to call attention to a paper published in the last volume of the Medico-Chirurgical Transactions by two gentlemen con- nected with the Army Medical School at Netley, in which they seem to show that it can be contributed to by an accumulation of the calcium salts in the blood. They show experimentally that an increase in the calcium salts in the blood increases the rapidity of coagulation, and draw the conclusion that in typhoid fever this may be brought about by the large amount of milk ingested. They think, also, that it can be checked by giving sodium citrate without doing any harm to the patient. Dr. Stengel: Dr. Thayer referred to one case of thrombosis of the pul- monary artery, and I presume that is the case reported in extenso by Flexner VENOUS THROMBOSIS OCCURRING IN TYPHOID FEVER 9 some years ago. In looking up the literature I found this to be the only well- reported case. I have seen two cases myself lately, and I was interested in the question as to the possibility of primary embolism from an abdominal vein or from the extremities. In my cases I concluded the process was primary throm- bosis of the pulmonary artery and in both there was terminal necrosis of the lung. In respect of the symptoms of thrombosis I have seen a number of cases in which there were general symptoms before the local symptoms, such as were referred to by Dr. Thayer. I have in mind one case in particular in which the patient was admitted with a very marked septic condition, the temperature reaching 107° F., very decided chills, and a leukocyte count of 7000, a leukocy- tosis according to the figures Dr. Thayer has given us. The appearance of the patient led to the suspicion of post-typhoidal thrombosis, and this was proven to be the condition. Dr. Welch: I think there is a good deal of evidence in these cases in sup- port of the theory that they start with a primary inflammation of the walls of the vein. Of course, this is only a recurrence to a very old notion that was supposed to have been overthrown by Virchow. Such symptoms as Dr. Thayer has drawn attention to in his paper-chills, elevation of temperature and local pain, and another symptom that might be emphasized, the disturbance of the pulse-point to an inflammation of the venous wall, a phlebitis. The French workers have brought this forward recently very forcibly. Dr. Longcope, in my laboratory, went over the pathological specimens lately, and demonstrated the presence of bacteria on over 70 per cent, of the cases. I think there is much in favor of the view that the thrombosis is due to a local- ized infection of the vein's walls, and it would be difficult to explain the sequence of phenomena otherwise than that it is a primary infection of the wall. At the same time the question is by no means settled. Dr. Prince: It may be interesting, in connection with what Dr. Welch has just said, to report a case of typhoid that began with phlebitis in the leg; as the typhoid developed its diagnosis was masked by the previously existing inflammation. For a time it seemed as if the typhoidal symptoms might be due to some septic process elsewhere, secondary to the phlebitis. It is fair to say that this case was one that had previously had a number of attacks of phlebitis, probably due to a gouty diathesis, and therefore the occurrence with typhoid might have been a coincidence. Dr. Cary: I would like to refer to the marked disproportion between the general systemic symptoms and the local condition. I recall distinctly one case where the local trouble did not seem to be very great, but where the chills were as violent as in the vicious types of malaria. There is one other point referred to by Dr. Thayer that I would like to speak of, and that is that these cases recover entirely of the local oedema. 10 VENOUS THROMBOSIS OCCURRING IN TYPHOID FEVER Dr. W. Gilman Thompson: The after-history of these cases, as pointed out by Dr. Thayer, is interesting. I have eight cases that have been under observation from six to ten years, and in not one is there anything like com- plete recovery. Every one of them, after any prolonged exertion, has to take several days' rest to overcome the oedema that results. One of these patients very closely resembles the photograph that is passing around. He came to me the other day with an attack of appendicitis and had to undergo an operation, and the thrombotic veins seriously complicated the operation. In regard to the condition of the pulse during the formation of the thrombus, it may undoubtedly be modified at that time, but it has always seemed to me that the force of the circulation has very slight effect in determining the loca- tion of the thrombus, for the reason that the thrombi occur usually during or near convalescence, when the pulse is improving and, in fact, is nearly at its best. Dr. Tyson: Dr. Thayer's paper has revived a question that has often oc- curred to me, viz., the cause of pain in vascular obstruction. It would seem that it matters not whether arteries or veins be obstructed, pain is a constant feature of such obstructions. We have one of the most striking instances in angina pectoris, it being generally conceded that the agonizing pain of this affection is due to obstructions of the coronary artery. It has occurred to me that the pain, often so extreme, accompanying ordinary cramp may be ex- plained similarly. Dr. Osler: There is an interesting difference between the phlegmasia alba dolens of the puerperium and that of typhoid fever. How rarely one sees the leg so swollen, so hard, and so painful in typhoid thrombosis as in the other? Nor is there often that extreme agonizing pain seen in postpartum cases. The usual experience is scarcely so severe in the after-effects as would appear from our reports. I have known a number of cases in which the recovery has been perfect, and I think our hospital experience is exceptional. As the attending physician is blamed for everything that happens, I always instruct my students to blame the parents of the patient if his leg remains swollen. With proper anastomosing vessels he would not have a swollen leg after a thrombosed femoral vein in typhoid fever. Dr. Thayer. It seems to me that the evidence is decidedly in favor of the idea that these cases of venous thrombosis are for the most part due to a primary phlebitis. I did not especially analyze the pulse in these cases, but in one instance the heart's action was remarkably rapid at the time of the onset of the symptoms. ON THE CARDIAC AND VASCULAR COMPLICA- TIONS AND SEQUELS OF TYPHOID FEVER. THE JEROME COCHRAN LECTURE.1 By William Sydney Thayer, M. D., Associate Professor of Medicine in the Johns Hopkins University, Baltimore. [From The Johns Hopkins Hospital Bulletin, Vol. XV, No. 163, October, 1904. j ON THE CARDIAC AND VASCULAR COMPLICA- TIONS AND SEQUELS OF TYPHOID FEVER. THE JEROME COCHRAN LECTURE.1 By William Sydney Thayer, M. D., Associate Professor of Medicine in the Johns Hopkins University, Baltimore. TABLE OF CONTENTS. Page I.-Introductory Remarks. . 1 II.-General Clinical An- alysis 6 (1) The Pulse 6 (a) Rapidity 6 (b) Bradycardia 7 (c) Arhythmia 7 (2) Heart Sounds 7 Systolic Murmurs 8 Diastolic Murmurs 11 (3) Pericarditis 12 (4) Endocarditis 13 (5) Myocarditis 17 (6) Venous Thrombosis and Phlebitis 18 (7) Arterial Thrombosis and Arteritis 23 Page [323] III.-Analysis of the Necrop- sy Records 30 Heart Muscle 30 Arteries 30 (a) Aorta 31 (b) Coronary Arteries 31 IV.-A Study of the Subse- quent Condition of 189 Old Patients 32 (1) Age and Date of Attack. . 33 (2) Pulse 33 (3) Blood Pressure 34 (4) Palpability of the Radial Arteries 36 (5) Heart 39 (6) Phlebitis and Venous Thrombosis 42 (7) Arteritis and Arterial Thrombosis 45 V.-Conclusions 46 I. Introductory Remarks. On receiving your very kind invitation to speak before you to-day, it seemed to me that the most profitable subject to discuss would be that in the study of which I was at the 1 Delivered before the Alabama State Medical Association at Mobile on April 20, 1904, and published in the Mobile Medical and Surgical Journal for July, 1904. 1 [323] moment engaged, the cardiac and vascular complications and sequels of typhoid fever. A glance at the extensive literature concerning this question cannot fail to impress one with the considerable variance of opinion existing between different observers as to the fre- quency and extent to which the heart and vessels suffer in this malady. (1) The Heart. (a) Endocarditis.-Concerning the frequency of endocar- ditis as a complication of typhoid fever there is little difference of opinion. Most observers agree in regarding it as a rare and unimportant complication. Among the 2000 Munich necrop- sies2 there were but 11 instances of endocarditis. Girode,1 Viti/ Carbone,5 and Vincent,8 have obtained typhoid bacilli from endocarditic vegetations and Lion,' has produced ex- perimentally, an endocarditis of the aortic valves in rabbits after intra-venous injection of typhoid cultures. The major- ity, however, of the cases of endocarditis which occur as com- plications of typhoid fever are probably the result of second- ary infection. (b) Pericarditis.-The same is true-to an even greater ex- tent-of pericarditis. (c) Myocarditis.-With regard to the myocardial changes, there is a most extensive literature dating from the early part of the last century. The recent investigations of Romberg,8 Landouzy and Siredey,* Renaut,10 Mollard and Regaud,1152 2Hblscher: Munchen, med. Wchnschr., 1891, XXXVIII, 43, 62. 8 Bull. m6d., 1889, III, 1392. 4Atti d. r. Accad. d. fisiocrit. di Siena, 1890, 4 S., II, 109. BGaz. med. di Torino, 1891, XLII, 122. "Mercredi mdd., 1892, III, 130. TEssai sur la nature des endocardites infectieuses. 4°, Par., 1890. 8 Uber die Erkrankungen des Herzmuskels bei Typhus abdom- inalis, Scharlach und Diphtheric. Deutsch. Arch. f. klin. Med., 1891, XLVIII, 369; 1892, XLIX, 413. 8 Contribution h 1'histoire de l'art6rite typhoidique; de ses con- sequences hatives (mort subite) et tardives (myocardite sc!6r- euse) du coeur. Rev. de m6d., Paris, 1885, V, 843. Lan- douzy: La fidvre typhoide dans ses rapports avec l'appareil [824] 2 Giacomelli13 and others have shown clearly that in some instances the changes may be sufficient to play a grave part in determining the fatal result of the disease. Moreover, the extent of these lesions is sometimes such that it can scarcely be doubted that in cases which recover, grave sequels must appear in after years. Great differences of opinion, however, exist both as to the relative frequency of acute myo- carditis, its relation to the clinical manifestations of the dis- ease and the frequency with which it results in serious perma- nent damage to the heart. What clinical symptoms justify us in assuming the exist- ence of an acute myocarditis? How often does typhoid fever result in permanent damage to the heart ? These are questions with regard to which there is the widest difference of opinion. It must be acknowledged that this disease has not, in the past, been regarded as an important agent in the production of chronic cardiac or vascular defects. A few observers, how- ever, have been outspoken in their opinion that typhoid fever has an influence of real significance in the production of acute and chronic myocarditis. Chief among these have been Lan- douzy and Siredey and Mollard and Regaud. The emphasis which the first of these observers places upon the effect of typhoid fever upon the heart and vessels is strik- ingly shown by the following words from a communication made some eighteen years ago.14 " The day when hygiene vasculaire et cardiaque. Gaz. d. hop., Paris, 1886, LIX, 323. Landouzy et Siredey: Etude sur les localizations angiocardiaques typhoidiques, leurs consequences immediates, prochaines et dloig- ndes. Rev. de med., Paris, 1887, VII, 804, 919. 10 Les myocardites aigues. CongrSs Francais de medecine. V. session, Lille, 1899; Paris, 1899, II, 1-83. 11 Etat des artSres du coeur dans les myocardites aigues. Con- grSs Franqais de mdd., 1899, V, 280. 12 Les troubles cardiaques dans la convalescence de la flSvre typhoide. Presse mdd., Paris, 1900, I, 19-22. 13 II miocardio nelle infezioni, intossicazioni, avvelenamenti. Ricerche anatomo-patologiche e sperimentali, Policlinico. Roma, 1901, VIII, M., 145-155. 14Landouzy: Op. cit., 1886. [324] 3 [3241 shall prevent typhoid fever, it will not only save from death each year more than one thousand Parisians; it will save more than a thousand individuals from disease of various systems, especially from diseases of the heart, that is, it will save each year at least a thousand invalids." These are striking words. Are they justified by fact? There are in literature few, if any, systematic clinical obser- vations with regard to the point. (2) The Arteries. A survey of the literature with regard to affections of the arteries in typhoid fever is of considerable interest. Little attention has been paid in this country to the occurrence or significance of acute arteritis in typhoid fever, to its influence upon the course of the disease or to its later sequels. The chapter on typhoid arteritis and arterial thrombosis in most text-books on typhoid fever is extremely short; yet there is a large and interesting literature upon the subject.18 Gan- grene of the extremities has long been recognized as an occasional complication of the disease and the fact that this is, in many instances, due to autochthonous thrombosis asso- ciated with an acute arteritis has also been pointed out. That acute endarteritis may occur in the aorta and smaller arteries in connection with typhoid fever as well as in other acute infections is mentioned by many observers, and yet its extent, its frequency, its possible influence in determining grave local or general disturbances in later years, have not, to my knowledge, been systematically investigated. Curschmann18 in his recent work, says: " I would em- phasize expressly that in a large number of post-mortem ex- aminations in cases of typhoid fever in which I have noted the condition of the coronary arteries I have never found these diseased "-a statement considerably at variance with our experience. 15 For references see: Thayer. On Arteritis and Arterial Throm- bosis in Typhoid Fever. The New York State Journal of Medi- cine, 1903, III, 21. 18Curschmann: Der Unterleibstyphus. 8°. Wien, 1898. 4 (3) The Veins. [324] With regard to the venous complications of typhoid fever much more has been written and much more is known. The venous thromboses so frequent especially in the lower ex- tremities, which since the time of Virchow, have been regarded as essentially marantic, are now again more generally consid- ered as secondary to an actual phlebitis due in some instances to the typhoid bacilli alone, in others to secondary, mixed infections. Haushalter,17 obtained typhoid bacilli in pure culture from the inflamed wall of the femoral vein, and was able to demonstrate them locally in the external coat of the vessel. In such cases it has been generally assumed that the exciting cause of the thrombosis was afforded by the mechan- ical effect of actual anatomical lesions in the vessel wall. That other influences than purely mechanical changes in the wall may play an important part in inducing thrombosis in both arteritis and phlebitis has been shown by Flexner18 and others and is borne out by my own observations.18 * * * In view of these facts, it occurred to me that light upon some of the unsettled points might be obtained by a study of the material which has accumulated in the last fourteen and a half years in the clinic of Professor Osler at the Johns Hopkins Hospital and in the laboratory of the Pathological Department. The plan which I laid out for myself was as follows: (1) A study of the clinical records with regard especially to the cardiac and vascular symptoms and complications. (2) A consideration of the anatomical records of those fatal cases in which necropsies were made. (3) An investigation into the condition of as many of our old patients as could be examined. [325] 17 Phlegmasia alba dolens et bacille typhique dans la fievre ty- phoide. Mercredi med., 1893, IV, 126. 18 Univ, of Pennsylvania Med. Bull., 1902, XV, 324. 18 Thayer: On Arteritis and Arterial Thrombosis in Typhoid Fever. The New York State Journal of Medicine, 1903, III, 21. 5 F325] At the outset I quite realized that the fulfilling of this whole task which should involve a careful histological study of our anatomical material, was more than could be accomp- lished in the time at my disposal. It has, however, seemed to me that an analysis of the question from a standpoint of clinical observation and a study of the gross pathological les- ions could not fail to reveal facts of value and importance. These considerations I have the honor to present to you to-day. II. General Clinical Analysis. In the period between the fifteenth of May, 1899, and the first of January, 1904, there were admitted to the Johns Hopkins Hospital, 1458 cases of typhoid fever. Of these 132 or 9.05 per cent died. This rather high percentage is due to the fact that a con- siderable number of cases were brought to the hospital in a practically moribund condition. In analyzing the clinical records of these cases, most of which I have had the good fortune to observe personally, I have selected for consideration those of the common cardio- vascular manifestations which might be regarded as possibly indicative of actual anatomical involvement of the heart or vessels, as well as the more definite vascular complications. (1) The Pulse. (a) Rapidity.-Of these 1458 cases there were 220 or 15 per cent in which the pulse was above 140. 46 of these patients were under 15 years of age. Of the 174 cases above fifteen years of age, 86 or nearly 50 per cent, resulted fatally. 77 cases showed a pulse of over 150; of these 55 or 71.4 per cent resulted fatally. In 51 cases there was a registered pulse of above 160, with a mortality of 35 or 78 per cent. In 6 cases there was a pulse above 170; two-thirds of these were fatal. In 2 instances a pulse of 180 or above was recorded; one of these recovered. In 2 instances the pulse was uncountable; both patients died. 6 (b) Bradycardia.-In 117 cases a pulse rate below 50 was noted. In all of these instances the bradycardia was a feature of convalescence. In one case only did a relapse follow. In 6 cases a pulse below 40 was noted; the lowest recorded pulse rate-observed in two cases,-was 35. All these 117 patients recovered. This circumstance when considered in connection with the fact that eight of these pa- tients examined at periods varying from five months to eight years after their illness, showed no cardio-wascular defects, justifies the conclusion that the bradycardia of convalescence is of little or no prognostic significance. (c) Arhythmia.-Irregularity,20 of the pulse was noted in 29 instances, of which 10 resulted fatally. In many of these cases the irregularity was associated with extremely rapid action of the heart and grave general symp- toms. Of 13 instances where the pulse was above 140, 9 or 69.2 per cent ended fatally. In the remaining 16 cases, the irregularity was noted in several instances at the height of the disease; one of these resulted fatally. In the majority of cases, however, it was a feature of convalescence, being associated in 4 instances with a pulse of under 50. (2) Heart Sounds. Of the 1458 cases the heart sounds were clear throughout in 1125. In 333 instances, or 22.8 per cent of the cases, cardiac murmurs were heard at one time or another. In sixteen patients the murmurs were regarded as evidence of pre-existing valvular disease of the heart. The lesions in these cases were as follows: Mitral insufficiency 10 Mitral insufficiency and adherent pericardium 1 Mitral stenosis 2 Mitral stenosis and insufficiency 1 Aortic insufficiency 2 16 [325] 20 It is evident from the remarkably low figures that only in- stances of rather striking irregularity were recorded. 7 [326] In addition to these cases there was one instance of Graves' disease with tachycardia and a systolic murmur at the apex. Of the sixteen cases of valvular disease of the heart but 2 or 12.5 per cent died. In the remaining 316 cases the murmur was systolic in 312 instances, diastolic once, while in 3 cases both systolic and diastolic murmurs were audible. Analysis of the Cases in which Systolic Murmurs Alone were Heard. Out of the 315 cases in which systolic murmurs were heard, there were two in which the record as to the localization of the murmurs was not satisfactory. In the remaining 313 cases the murmur was heard: At the apex alone in 87 cases. At all four orifices in 66 " At the apex, tricuspid and pulmonic areas in... .49 " At the pulmonic area alone in 35 " At the aortic and pulmonic areas in 21 " At the pulmonic area and apex in 20 " At the apex, pulmonic and aortic areas in 11 " At the apex and tricuspid areas in 9 " At the pulmonic and tricuspid areas in 7 " At the aortic, pulmonic and tricuspid areas in.. 4 " At the aortic area alone in 1 " At the apex and aortic areas in 1 " At the tricuspid area alone in 1 " At the apex, aortic and tricuspid areas in 1 " 313 " Cases in which the Systolic Murmur was Heard at the Apex. There were 244 cases in which the systolic murmur was heard at the apex of the heart. In 56 of these cases it was transmitted outward as far as the anterior axillary line. In but one case was it noted that the murmur was audible in the back. 8 Time at which the Systolic Murmur at the Apex was First Observed. T3261 In all of these cases the most detailed note was made usu- ally upon admission to the hospital or within the several following days. Unfortunately, in many instances, careful notes upon the heart were not made later, and only in a rather small fraction of the cases was there a final record upon the day of discharge. It is, therefore, impossible to say with accuracy at just what period in the disease the murmurs developed. As a result of the fact that the first note was usu- ally the most careful, the proportion of cases in which the murmur was audible on entrance is probably unduly high. This was the case in 199 of the 244 cases. The period of the disease at which the systolic murmur at the apex was first noted is illustrated by the following table: Table I. Illustrating the Period at which the Systolic Murmur at the Apex was First Observed. WEEKS. Prodromal period, 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, Sth, 9th, 10th, ? Total 2 78 92 38 22 4 1 2 3 0 1 1 244 The table shows, as one might expect, that apical systolic murmurs are present with the greatest frequency during the height of the disease. The following table shows the time of development of the murmur in 45 cases in which an apical systolic murmur, ab- sent on admission, appeared later in the course of the disease. Table II. Showing the Time of Development of the Apical Systolic Murmur in ^5 Cases in which, on Entrance, the Heart Sounds were Clear. WEEKS. 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th 6 11 9 11 2 1 2 2 0 1 =45 The figures in this table are closely similar to those preced- ing. The slightly greater prevalence of murmurs in the first weeks in Table I is doubtless due to the more careful initial examinations as observed above. 9 [326] Of the 244 cases in which an apical systolic murmur was heard, this murmur disappeared before discharge in 107 instances; it was present upon discharge in 3121 cases; there was no note in 106 cases. Of the 45 cases in which the systolic murmur at the apex de- veloped in the hospital this murmur disappeared on or before discharge in 17 cases; it was present on discharge in 10 cases; there was no final note in 18 cases. Character of the Murmur in those Cases in which it Persisted upon Discharge from the Hospital. In the 31 cases in which an apical systolic murmur was observed during the attack persisting in some form on dis- charge the murmur remained at the apex in 28 instances; in one instance it was audible only in the pulmonic area; in one, in the aortic, and in one, at both areas at the base. In 2 of the 28 cases where the apical murmur persisted on discharge, the sound was louder at the base; in 1 instance it was louder over the right ventricle; once it was loudest in the aortic area-a clear case of aortic stenosis. Two further cases left rather early in the course of the disease on the day on which the note was made. In 3 cases the murmur on dis- charge was transmitted to the axilla. In 10 cases a systolic murmur at the apex developed after admission to the hospital and persisted in the same area at the time of discharge; in one of these instances, however, it was more marked in the pulmonic area. There can be little doubt that the cause of these apical systolic murmurs is to be sought, in the majority of cases, in the relaxation of the heart muscle with consequent dilatation of the mitral ring. But the possibility that a certain propor- tion may be instances of endocarditis must not be lost sight of. The fact which will be mentioned shortly, that out of 95 ne- cropsies there have been three instances of acute endocarditis, all unsuspected intra vitam, should be sufficient to convince one of the necessity of considering this possibility in every [327] 21 In one of these instances the patient left on the day of entrance. 10 instance where cardiac murmurs persist after recovery from typhoid fever. The recognition of this fact should suggest to the physician the wisdom of keeping old typhoid patients under observa- tion during a considerable period following the disease as in the case of maladies more commonly associated with endo- carditis. Basic Systolic Murmurs. The cause of the basic systolic murmurs can hardly be dis- cussed at length in a communication of this nature. Their frequency and slight prognostic significance are well known. One may, perhaps, recall the happy comment made, I think, by Broadbent, who after considering the anatomical and physi- ological relations of the aortic and pulmonic orifices, observed that it is not the fact that systolic murmurs are so frequently heard in these regions that is remarkable; it is rather that they are not always present. In but one case (No. 44724), was the basic systolic murmur regarded as indicative of organic lesion. This was a clear example of aortic stenosis. Diastolic Murmurs. In 4 instances (Nos. 4020, 18118, 36484 and 41270), dias- tolic murmurs were audible. Case'I (No. 4020). The first case was that of a man, 20 years of age, without history of previous illness. On entrance a faint systolic whiff was heard at the pulmonic cartilage. The case was one of considerable severity. On the 27th day of his illness a soft diastolic murmur was heard in the third left space at the sternal border. Two days later the following note was made: "The dias- tolic murmur noted the other day is very audible in the second and third interspaces, not at the aortic cartilage. There is a soft systolic just within the apex.'' The patient made a slow but com- plete recovery; unfortunately no further notes were made on his heart. It has been impossible to trace the subsequent history. Case II (No. 18118). The second case was that of a man of 19 who entered the hospital on the eighth day of a severe typhoid fever; on entrance his heart sounds were clear. On the twelfth day Dr. Osler noted that a soft bruit was heard along the left sternal border. On the 18th day, with a very rapid pulse, a soft diastolic murmur was heard at the aortic cartilage. Unfortu- [327] 11 [327] nately, no further note was made upon the heart. The patient died four days later, of perforation. At necropsy no abnormalities were noted in the aortic valves. The heart muscle was described as opaque. Case III (No. 36484). The third case was that of a young man of 22 with no history of previous illness excepting for an attack of typhoid fever five years before admission; on the eighth day of a typhoid fever of moderate intensity, a short, sharp murmur followed the second aortic sound and was transmitted downwards along the sternal margin. Five days later it was noted that the second sound was rather indefinite and " mur- murish " at the aortic area, though no positive murmur was audible. A distinct systolic murmur was heard over the body of the heart and in the pulmonic area, fainter in the second right space. The patient made an uneventful recovery. No further note was made upon the heart. Case IV (No. 41270). A man of 40, who had had rheumatism 23 years before, developed, on the 11th day of a mild typhoid fever, an apical systolic murmur, and on the 14th day, a diastolic, heard along the left sternal border, both of which cleared up before discharge. The apex, however, moved outward 2.5 cm. In a very large number of cases in which a systolic murmur at the apex was not noted it is mentioned in the history that, at the height of the disease, the first sound was " murmurish," " feeble," " blurred," " indistinct " or " indefinite." Later, however, in all of these cases in which a note was made, the condition of the heart sounds was found to be normal. In a number of instances reduplications of the first and second sounds were recorded but sufficient attention was not paid to the study of reduplications to justify any conclusions. (3) Pericarditis. There were but 2 instances of pericarditis among these 1458 cases. Case V (No. 24135). The first case was that of a man of 20 who, on the 26th day of a rather severe typhoid fever, with pro- nounced nervous symptoms-delirium, subsultus, general tremor- showed, just outside the point of maximum impulse, a very dis- tinct to-and-fro friction rub. For several days this increased in intensity and then gradually disappeared. The patient made an uneventful recovery. Case VI (No. 30666). The second case was that of a colored man 23 years of age. Early on the morning of the 25th day of his disease, after a tub, the patient began to complain of pain 12 in the prsecordial area and in the right upper chest. A well- marked pericardial friction rub was audible, though no definite endocardial murmur could be made out. The patient grew rapidly weaker; an audible and palpable friction rub developed in the lower axilla and back, death following within twenty-four hours The necropsy showed, beside the lesions of typhoid fever, a fibrino-purulent pericarditis, due to the softening of tuberculous bronchial lymph glands and perforation of the trachea, oesophagus and pericardium. The typhoid bacillus was obtained on culture from the pericardium, bile and spleen. Case VII (No. 45535). A third case of pericarditis compli- cating typhoid fever is at present in the hospital. The patient, a woman aged 29, entered the ward toward the end of the first week of the disease. Four days before she had been seized with a stabbing pain in the region of the heart and a sense of palpitation. On entrance there was a systolic murmur in the pulmonic area and a well-marked to-and-fro pericardial friction rub in the praecordial region. No pleural friction rub was audible. Several days later evidences of a patch of broncho- pneumonia were to be detected in the left axilla. The cardiac dulness increased, and the heart sounds became more muffled. Gradually, however, in the course of two weeks, the friction mur- mur entirely disappeared. The cardiac dulness diminished, the areas of pulmonary consolidation cleared up, and at the present day the patient is in full convalescence. (4) Endocarditis. Three cases of endocarditis have been discovered at ne- cropsy. None of these were recognized intra vitam. In addi- tion, there were several cases in which endocarditis has been suspected clinically. Case VIII (No. 10131). The first case has already been re- ported by Dr. Osler.22 A. C., a colored girl of 20, was admitted to the hospital on the 7th day of her disease. Just before admission the patient had had several bloody stools, and within two hours after entry there were five more which consisted almost entirely of blood. The heart's action was rapid, the sounds clear. There was a suggestion of embryocardia. The patient's condition, which was very grave on entry, did not change for the better and she died on the following afternoon. At the necropsy, beside the lesions of typhoid fever, it was noted that the heart was not enlarged. " All the valves were normal except the mitral. Along the edges of the leaflets of this [327] [328] 22 Johns Hopkins Hospital Reports, 1895, V, 467. 13 [328] valve are a number of translucent vegetations varying in size from the head of a pin to four or five times that bulk. These are comparatively recent. The heart muscle is dark, brownish-red and slightly mottled by patches of a lighter color." The aorta was normal, the coronary arteries normal. Microscopically, the heart showed diffuse, fine, fatty degenera- tion. Typhoid bacilli were cultivated from the spleen, liver and kidneys. Staphylococcus albus was obtained from the endocar- ditic vegetations. Case IX (No. 28194). M. S., a man of 18, was admitted to the hospital on the fifth day of a very severe typhoid fever. On entry the heart sounds were loud and clear. Delirium soon devel- oped and the pulse became rapid and feeble. On the following day a rather soft systolic murmur was heard at the apex, transmitted to the axilla. The second aortic sound was markedly accentuated. The patient's condition did not change essentially; the delirium and picking at the bed clothes continued. The leucocytes, which, on admission, had been 6000 to the cm., were on the 7th day, 17,000 and 28,000, and on the following day 18,600. On the evening of the 8th day the patient died. At the necropsy, which revealed characteristic typhoid lesions, the following note was made upon the heart. " Along the edges of the mitral valve there is a row of minute dew-drop-like excrescences which are less than pin-head in size. These are fairly firm, not easily scraped off. They can, however, be pulled off with forceps. Smaller similar excrescences are found on the aortic segments. Otherwise the valves are deli- cate and apparently competent. The heart muscle is rather soft, natural in color. The vegetations on the mitral valve are on the auricular side. To those on the aortic valve there is attached a soft clot." The aorta showed slight fatty degeneration of the intima. Cultures showed both the bacillus typhosus and staphylococcus aureus from the heart's blood; staphylococcus aureus from the vegetations on the aortic valve. Case X (No. 44240). The third case, C. M., a man of 25, was admitted to the hospital in the first week of a very severe typhoid fever. He had always been strong, athletic and vigorous. He had had measles in childhood and bronchial asthma off and on for eleven years. He was very ill and delirious from the onset. The heart's action was rapid, the sounds, however, always clear. Four days after entry the first sound was reduplicated at the apex, the second at the base. Eleven days after entry a phlegmon developed in the left submaxillary region. This "was opened on the following day, cultures showing staphylococcus aureus. Twelve days after entry the patient suddenly died. Necropsy showed numerous small translucent vegetations along the line of closure of the anterior segment of the mitral valve. 14 The heart muscle was rather soft, opaque and grey, with num- erous more opaque, distinct grey spots. The anterior descending branch of the coronary artery showed many yellow flakes of sclerosis varying from 1 to 2 mm. in diameter. Almost the whole intima was converted into irregular, yellow grey patches which were slightly elevated. The walls of the smaller branches were also thickened. The aorta showed only slight thickening just above the valves. In the wall of the left ventricle, near the auriculo-ventricular ring, there were a number of small patches in which the muscle was completely replaced by greyish-white, somewhat translucent fibrous tissue. Cultures from the vegeta- tions showed staphylococcus aureus and albus. It will be noted that the presence of endocarditis was unsuspected during life in all these cases. Indeed, there was nothing in the symptoms of the first or third cases which would have justified such a diagnosis. The development in the second case of the murmur, in association with a marked leucocytosis might have suggested the complication. In three cases there developed during the disease, symptoms which persisted on discharge to an extent suggestive of an actual valvular lesion. Case XI (No. 23799). The first case, a girl of 9, was admitted to the hospital on the 31st day of her disease. She had had no serious previous illnesses. The first sound on admission was nearly replaced by a soft blowing systolic murmur which was heard, though less intensely, as one passed toward the axilla; lost in the anterior axillary line. It was also audible over the base and praecordial region. The second pulmonic sound was somewhat accentuated. The apex was in the 4th left space, 6 cm. from the midsternal line. On the final note, over two months later, the point of maximum impulse was in the 4th space, 7 cm. from the median line, and the murmur, which was rough and rumbling, entirely covered and followed the first sound; it was, however, of greater intensity in the pulmonary area and was lost beyond the anterior axillary line. The leucocyte count varied between 6000 and 15,600. It is of course possible that, in this case, the lesion may have preceded the typhoid fever, although there was no history of previous infections. Case XII (No. 40588). The second case, M. S., a colored girl of 13, was admitted to the hospital on the tenth day of her disease. On entrance the heart sounds were clear at the apex and base. The leucocytes, which were 8800 on entry, varied during the next several days, between 6000 and 14,000. On the 19th day, without [328] 15 1328] apparent cause, they were 18,600; on the 23rd day, 7500. No further note as to the condition of the heart was made until the time of discharge, the 66th day of the disease, the 14th of per- fectly normal temperature. On this date there was heard, at the apex, a very faint systolic murmur, which was lost as the sternum was approached; it was, however, transmitted into the axilla as far as the mid-axillary line, and became intensified in the erect posture. The second pulmonic was accentuated. The pulse was 23 to the quarter, somewhat irregular in rhythm and volume, the irregularities mainly dependent on respiration. The development and persistence in this case, of an apical systolic murmur in association with a rather unaccountable leucocytosis may be regarded as suspicious symptoms. Case XIII (No. 44724). The third case was that of a man of 18 who had previously suffered from measles as a child and some severe illness, the nature of which he does not know, at four. He entered the hospital on the 9th day of a typhoid fever of moderate severity. On the 10th day the point of maximum cardiac Impulse was in the 4th space 7 cm. from the mid-sternal line; the sounds were loud; the first, reduplicated at the apex and over the right ventricle. A well-marked systolic murmur was audible in the second and third interspaces in both aortic and pulmonic areas. It was not transmitted to the vessels of the neck, nor was any thrill to be felt in the aortic area. The patient passed through a mild attack of typhoid fever with a ten day's relapse. The temperature, between the 40th and 60th days, was slightly irregular, occasionally rising above 99°. The color- less corpuscles, during the early part of the malady, ranged from 3 to 4000. On the 69th day the leucocytes were 3800. On the 79th day, while the temperature was subnormal, it was noted that the point of maximum impulse was 10 cm. from the mid-sternal line, 3 cm. farther out than on entry. A definite systolic thrill was felt all over the cardiac area. At the second rib on the left ster- nal margin there was a distinct systolic murmur. The leucocytes were 7800 to the cu. mm. Two days later the point of maximum impulse was in the 5th left interspace, and a blowing systolic mur- mur was audible all over the cardiac area. This was well heard in the pulmonic region but over the aortic area it had become intensified and rougher. On the following day, I found, at the base and especially in the aortic area, a very loud echoing systolic murmur. This reached its maximum in the first right space where it was harsh and rasping. It was well heard in the epi-sternal notch, slightly in the carotids. After exercising and lying down again a soft sys- tolic murmur was heard at the apex. The pulse was distinctly [329] 16 long and well sustained, the tracings showing characteristic flat- tening of the summit of the curve. This case, which was seen also a month after discharge, pre- sents evident signs of aortic stenosis. It is interesting to note that at the time when the char- acter of the murmur at the base began to change, the leuco- cytes which had been almost invariably under 4000, went up to 7800. It seems reasonable to assume that in this instance an aortic endocarditis developed during the typhoid fever. (5) Myocarditis. There were few cases in which a definite diagnosis of acute myocarditis was made intra vitam. Indeed the symptoms upon which such a diagnosis may be based are still extremely questionable. Extreme rapidity and irregularity of the heart's action, embryocardia, the development of relative mitral in- sufficiency would lead one to suspect the existence of grave acute changes in the heart muscle. All these symptoms may, however, depend upon vaso-motor paralysis, indeed, the ob- servations of Passler and Rolly,23 would tend to suggest that this is often the cause of the collapse at the height of many acute diseases, the true cardiac changes coming on in great part secondarily to and as a result of the impaired nutrition of the heart wall incident to the fall in blood pressure. The heart muscle in many of the cases dying with symp- toms of marked cardiac collapse showed the characteristic appearances described by the old observers-general flabbi- ness, a yellowish brown, dead leaf color, looseness, oedema and diminished consistency of the heart muscle and, not infre- quently, a distinct mottling suggestive of fatty change. In how far the development of systolic apical murmurs at the height of typhoid fever may be regarded as indicative of true myocarditis is a point which we must regard at present as quite unsettled. A comparison of the more minute histological changes in the heart wall with the clinical symptoms in our fatal cases [329] 23 Experimentelle Untersuchungen uber Kreislaufstbrungen bei acuten Infectionskrankheiten. Deutsch. Arch. f. klin. Med., 1903, LXXVII, 1. 17 [329] is one of the important points of this investigation which I have not as yet been able to approach. One case which must be regarded as an example of weak- ness of the heart muscle immediately subsequent to what was probably a mild typhoid fever may be of interest. Case IV24 (No. 41270). F. J., aged 40, was admitted to the hospital on the 4th day of a mild typhoid fever. He had had rheumatism 23 years previously, and chills and fever three weeks before entry. On entry the heart sounds were clear though the first was rather muffled. On the 11th day a well-marked systolic murmur was heard at the apex, almost completely replacing the first sound and propagated to the anterior axillary line. It was not heard in the tricuspid area, nor above the 4th rib. At the base, both sounds were clear. Three days later it was noted that the pulmonic second sound was accentuated, while a soft diastolic murmur was heard along the left sternal border in addition to the systolic murmur at the apex. On the 18th day the tempera- ture was subnormal, the diastolic murmur had entirely disap- peared and the systolic murmur was barely audible. On the day of discharge, the 34th, the heart sounds were clear excepting a slight reduplication of the second in the pulmonic area. The apex impulse was, however, 11 cm. from the median line, 2.5 cm. further out than on entrance. The fact that these cardiac manifestations were associated neither with fever nor with leucocytosis speaks rather against the existence of a true endocarditis and in favor of a purely myocardial weakness. (6) Venous Thrombosis and Phlebitis. Among the 1458 cases of typhoid fever there were 38 instances of venous thrombosis, a percentage of over 2.6. In addition to these cases two patients with this complica- tion were admitted during convalescence, while one man who had suffered from double iliac thrombosis complicating ty- phoid fever entered the hospital two years later on account of the resulting symptoms. Mortality.-5 or 13.1 per cent of these cases resulted fatally. In two instances the thrombosis was probably the primary cause of death, once, through pulmonary embolism from a thrombus in the left axillary artery (No. 27855), once (No. 24Vide supra, p. 327. 18 28,600), in a case of thrombosis of the left common iliac and femoral veins, through the lodging of a large embolus in the inferior cava and right auricle. Situation of the Thrombus. (a) As to section of the body. In these 41 cases the thrombosis was: In the lower extremities in 39 cases. In the upper extremity in 1 case. In the pulmonary artery in 1 case. (b) As to side. The occluded vessel was: On the left side in 26 instances. On the right side in 5 instances. On both sides in 8 instances. Imperfect record in 2 instances. (c) As to vessels. The femoral vein was occluded in 20 instances. The popliteal vein was occluded in 5 instances. The iliac vein was occluded in 5 instances. The veins of the calf were occluded in 5 instances. The internal saphenous was occluded in 3 instances. The pulmonary artery was occluded in 1 instance. The pulmonary artery and common iliac vein were occluded in 1 instance. The axillary vein was occluded in 1 instance. In six of the cases of femoral thrombosis, plugging of the internal saphenous was also noted. Symptoms. Time of onset.-The thrombosis occurred usually toward the latter part of the fever and in a number of instances after complete defervescence. The time of onset is illustrated in the following table: Table III. Illustrating the Time of Onset of 38 Cases of Venous Thrombosis. WEEKS. 1st 2nd 3rd 4th 5th 6th 7th 8th 9th 10th 11th 12th 13th ? Total Cases 11 10 85324 0 1 1 0 11= 38 [329] [330] 19 [330] Fever.-In 35 of our 38 cases the development of the thrombosis was associated with fever; in 3 there was no fever. In 25 cases the fever was intercurrent, the phlebitis coming on before complete defervescence. In 13, the temperature was normal at the time of the onset of the phlebitis. Chills.-In 11 or 28.9 per cent of these 37 cases the compli- cation was associated with chills. In 2 instances the chills occurred just at the time of recog- nition of the condition. Twice the chills occurred before recognition, once four days and once a week before. In 6 cases the chills occurred during the course of the complication, once during the period of subsidence and in the other five instances during the height of the process. Once, the chills occurred before, during and after the ap- parent onset of the thrombosis. In one of the three cases entering the hospital after the acute symptoms had passed, there was a history of chills; their exact relation, however, to the time of development of the thrombosis was not clear. Pain.-The first definite symptom of the thrombosis in every instance was pain. This varied considerably in in- tensity and suddenness of onset. (a) Character of the first symptoms in 18 cases of femoral thrombosis. In all the cases of femoral thrombosis but one there was pain along the course of the femoral vein. In this one instance the only symptoms noted in the hospital were those of pop- liteal thrombosis. The subsequent history of the case, how- ever, made it clear that there must also have been plugging of the femoral vein. The first localizing symptom of the process was: Pain along the course of the femoral vessels and in Scarpa's triangle in 9 instances. Pain in the calf in 4 instances. Pain in the popliteal region in 1 instance. No satisfactory note in 3 instances. Patient too ill to localize pain in 1 instance. 20 In 3 of these cases the onset of the pain was strikingly sudden. (b) Character of the first symptoms in 5 cases of popliteal thrombosis. In all of the cases of popliteal thrombosis the first symptom was pain in the popliteal region. (c.) Character of the first symptoms in 5 cases of iliac thrombosis. In the cases of iliac thrombosis the onset was associated with sudden sharp abdominal pain in 4 cases. In one of these instances the pain was extremely severe and associated with marked leucocytosis, the symptoms suggesting perforation. An exploratory laparotomy was performed, revealing the true nature of the lesion. In one instance in which the patient was hemiplegic and dull, there was no pain. (d) Character of the first symptoms in 5 cases of throm- bosis of deep veins of the calf. In all of these cases the first symptom was pain in the calf. (e) Character of the first symptoms in 3 cases of throm- bosis of the internal saphenous vein. In 3 cases in which there was thrombosis of the internal saphenous vein alone the first symptom was pain along the course of the vein in every instance. (f) In the one case of axillary thrombosis the first com- plaint was of pain about the bend of the elbow. (Edema.-In all of the 38 cases there was swelling of the affected part and in most instances the local temperature was raised. Often there was redness over the affected vessel. A definite note as to the existence of oedema was unfortunately not made in all cases. (a) In 18 cases of femoral thrombosis: (Edema was noted in 10 cases. " Swelling " alone, in 6 cases. There was no cedema in 2 cases. (b) In 5 cases of iliac thrombosis there was: (Edema in 2 cases. No cedema in 3 cases. [3301 21 [330] I (c) In 5 cases of popliteal thrombosis there was: (Edema in 2 cases. " Swelling " in 1 case. No note in 1 case. No oedema in 1 case. (d) In 5 cases in which the veins of the calf were apparently involved alone there was: (Edema in 1 case. " Swelling " in 3 cases. No oedema in 1 case. (e) In all 3 cases in which the internal saphenous vein and calf muscles were involved there was oedema. (f) In the case of thrombosis of the axillary artery there was oedema. Palpability of the thrombotic mass.-In 16 out of 38 cases the thrombotic mass was felt as a palpable cord. Leucocytosis.-In 21 cases counts of the colorless corpuscles were made during the complication. In 12 or 57.1 per cent the leucocytes were above 10,000. In 18 or 85.7 per cent they were above 7000. In one instance they were below 6000. The highest count, 24,864, occurred in a case of iliac thrombosis in the third week of the disease. In this instance an exploratory laparotomy was done in view of the possible existence of perforative peritonitis. The lowest count, 2700, occurred on the day after the onset of a phlebitis, apparently of the popliteal, which occurred in the sixth week without fever and with very slight general symptoms. In connection with these blood counts it should be remem- bered that, in every instance but one the phlebitis came on in the third week of the disease or later, at a period when, according to our statistics, the leucocyte count in uncompli- cated cases should not be above 5500. Association with secondary infections.-Out of our 38 cases there were 7 instances in which secondary infections pre- ceded or co-existed with the onset of the thrombosis. These secondary processes were: Boils in 2 cases. Well-marked bronchitis in 1 case. [331] 22 Gangrene of the lung in 1 case. Fistula in ano in 1 case. Chronic otitis media in 1 case. Amoebic dysentery with developing hepatic abscess in 1 case. In the remaining 31 instances there was no clinical evidence of secondary infection. Post-mortem appearances.-In the 3 cases in which bits of the clogged vein were examined histologically, evidence of well marked inflammatory changes were found in the walls of the vessels, such, however, as might well have arisen second- arily to the thrombosis. In one of these cases there was at the point of section, an extensive endophlebitic plaque which however, probably antedated the typhoid fever. But few sec- tions were examined and it is improbable that these came from the point of origin of the thrombi, so that conclusions with regard to the pre-existence of a phlebitis are not justified. Cultures.-In one case the bacillus typhosus was obtained in pure culture from the thrombus. In 1 the cultures wrere negative. No notes were made with regard to cultures from the thrombus in the other 2 cases. A consideration of the character and extent of the general symptoms in this group of cases would seem to justify the con- clusion that in most instances the thrombosis was associated with and preceded by a phlebitis. Especially interesting is the frequency of chills in associa- tion with the complication. Unaccountable chills at the height or toward the latter part of typhoid fever, should always give rise to the suspicion that a phlebitis may be developing. (7) Arterial Thrombosis and Arteritis. Five cases of arterial thrombosis or arteritis developed under our observation. Case XIV25 (No. 12616). The first case was that of a young man of 22, of excellent family and personal history, who was 1331] "Reported by Dr. Osler, Johns Hopkins Hosp. Reports, 1900, VIII, 364; and by Thayer, N. Y. State Journal of Medicine, 1903, III, 21-28. 23 [831] admitted to the hospital on the 24th of April, 1895, on the 4th day of a mild typhoid fever. On the 9th day he was seized sud- denly with violent general convulsions, the movements being rather more marked on the right side. There was conjugate deviation of the eyes upward and to the left. The convulsions recurred at short intervals for about an hour. During the par- oxysms, the patient was profoundly unconscious, though between times his mind seemed partially clear. After an intermission of about four hours the convulsions returned, recurring with great severity at intervals for six hours, when death occurred during a severe paroxysm. The necropsy performed by Dr. Flexner, showed a thrombosis associated with an acute arteritis of the ascending parietal and parieto-temporal branches of the left middle cerebral artery. The extent of the arteritis, together with the fact that it was found in branches in which there was as yet, no thrombosis, led us to regard it as having preceded the occlusion of the vessel. Case XV28 (No. 28600). The second case was that of a man of 46 who entered the Johns Hopkins Hospital on the 27th of November, 1899, on the second day of typhoid fever. He had had measles and mumps as a child and a year before a slight arteritis of the left ankle. He had had a venereal ulcer of doubt- ful character, without secondary symptoms, seven or eight years before. On the 19th day of his disease, while delirious, he grad- ually developed a complete hemiplegia of the left side. The respiration became of a Cheyne-Stokes character, which persisted during the next several days. There was no loss of consciousness. Five days later he died suddenly from embolism of the inferior cava, resulting from the breaking off of a large thrombus in the left iliac vein. The necropsy showed an area of softening in the upper part of the right internal capsule, due undoubtedly to the plugging of the branch of the artery supplying the area. The leucocytes, which on entry, were 6200, were 9250 to the cu. mm. during the onset of the symptoms of occlusion. Case XVI27 (No. 39264). The third case was that of a girl of 16 who entered the hospital on the 16th of June, 1902, on the 5th day of a severe typhoid fever. There was a marked general bronchitis, and on the 8th day of her illness, evidences of broncho- pneumonia appeared. The leucocytes at this time were, on two counts, 6000 and 5000 to the cu. mm. On the 11th day there was a slight leucocytosis. On the succeeding three days the patient seemed better until, on the 14th day, on removing her "Reported by Dr. Osler. Johns Hopkins Hosp. Reports, 1900, VIII, 368. 27 Reported by Thayer. N. Y. State Journal of Medicine, 1903, III, 21-28. 24 [331] from the tub, the right foot and leg below the knee were found to be white and cooler than on the left side. The coolness ex- tended above the knee in front. There was no swelling of the leg or foot. The femoral artery could be followed by its pulsa- tion half way down the thigh. No pulse was palpable in the popliteal or dorsalis pedis. The patient was delirious and in a condition of profound intoxication; the leucocytes were 17,000 to the cu. mm. Gradually, a line of demarkation developed about at the junction of the upper and middle thirds of the leg with dry gangrene below. The condition of the patient became gradually worse and death followed on the 22nd day. The heart's action was rapid throughout the disease, but there was no evidence of dilatation, the sounds were always clear, and there were no signs of embolism elsewhere. The case was regarded by Dr. McCrae and the writer as one of thrombosis rather than embolism. No necropsy was allowed. Case XVII28 (No. 39471). The fourth case was that of a boy of 18 who, on the 14th day of a fairly severe typhoid fever, began to complain of pain and tenderness on the inner side of the thigh along the course of the femoral vessels, extending subse- quently to Scarpa's triangle. The left thigh was warmer than the right and swollen, while the foot and leg were pale and cool. There was no oedema. The pulse in the femoral and arteries of the foot almost disappeared. The symptoms soon began to im- prove, but on the 49th day, pain and swelling appeared in the popliteal space and calf, the foot became cooler and cyanotic again, and the arterial pulse in the foot once more entirely dis- appeared. There was slight oedema about the malleoli. The oedema lasted but a few days; the pulsations in the arteries grad- ually improved, and the patient was discharged apparently well on the 71st day. Case XVIII29 (No. 40343). The fifth case was that of a woman of 27, who on the 21st day of a mild typhoid fever, began to com- plain of pain at the bend of the elbow where there was marked tenderness with slight redness and swelling. The radial pulse was diminished in size and the hand cooler and paler than the right. In the course of several days, however, the symptoms wholly cleared up. In these two latter cases it is a question whether an actual thrombosis developed or whether the symptoms may not be regarded as due to an acute arteritis alone, the interference [332] 28 Reported by Thayer. N. Y. State Journal of Medicine, 1903, III, 21-28. 29 Reported by Thayer. N. Y. State Journal of Medicine, 1903, III, 21-28. 25 [332] with the circulation following the oedema and infiltration of the walls. In addition to these cases there have been treated in the hospital 3 instances of hemiplegia in which the onset occurred during typhoid fever, while Dr. Thomas has kindly given me the notes of two further cases which he has observed in the out-patient department. Case XIX30 (No. 14083). The first case was that of a girl of 7, who entered the hospital on October 3, 1895, complaining of inability to use the right hand. On June 3, during the 9th week of a rather severe attack of typhoid fever, the child was seized with violent convulsions confined to the head, right arm and leg. On the afternoon of the day of onset the movements of the head, which the mother described as having been thrown backward, ceased. Continued movements of flexion and extension of the limbs followed for two days. When these came to an end, it was noticed that the right arm and leg were paralyzed. There was also involvement of the face and total loss of speech. Five weeks after onset spastic rigidity of the arm was noticed. Six weeks after the onset movements of the leg began to return. In the seventh week there was some return of speech. At the time the patient was in the hospital, the speech was improv- ing rapidly, though it was still very imperfect. The child recog- nized objects and looked bright and intelligent. The right leg was dragged, the foot inverted. The right arm was held semi- flexed, the wrist and hand flexed with marked spastic rigidity. She could voluntarily flex and extend the arm at the elbow and could lift the hand to the head, but the power of extension in the wrist and of the fingers and the ability to grasp objects with the hand were almost completely lost. Case XX31 (No. 14630). The second case was that of a man of 25, of excellent family history, who entered the hospital on November 30, 1895. In March, at the end of the second week of a severe attack of typhoid fever, a paralysis of the left arm and leg suddenly developed. There were no convulsions, and his physician states that there was no aggravation of the delirium during the attack. There was no difficulty in speaking and no trouble with the rectum or bladder. When in the hospital there was no trace of paralysis of the facial muscles; the left arm could be moved at the shoulder and elbow and slightly at the wrist in flexion. The hand could be extended but only slight movements 30 Reported by Blumer. Johns Hopkins Hospital Bulletin, 1896, VII, 72. 31 Reported by Dr. Osler. Johns Hopkins Hospital Reports, 1900, VIII, 367. 26 of extension of the fingers were possible. The power of pronation ( and supination was lost. The left leg could be moved freely at the thigh and flexed and extended at the knee. The reflexes on the left were everywhere increased. Wide, irregular, choreiform movements were noted when the patient attempted to move the left arm. Case XXI (No. 30540). The third case was that of a man of 34, who was admitted to the hospital on the 19th of May, 1900. In the fall of 1897 he had had a severe typhoid fever during the third week of which he became delirious. On recovering con- sciousness, in the 9th or 10th week, he found that his left arm and leg were paralyzed. Three years later, at the time he was in the hospital, he showed distinct loss of power, with spastic contractions in both extremities and athetoid movements of the hands. Case XXII (Nervous Dispensary No. 13149). The fourth case was that of a girl of 8, who entered the Nervous Department of the Dispensary on the 13th of March, 1902, complaining of weak- ness on the right side. There was nothing remarkable in her family or previous history. Four and a half years before, in October, during the third or fourth week of a typhoid fever, she developed a right-sided hemiplegia. There were no violent con- vulsions though it is stated that " she straightened out." She was unable to clearly understand what was said to her. There was loss of control of the bladder and rectum, and involvement of the facial muscles. The power of speech began to return about eight months after the onset; she was unable to walk for a year. The facial paralysis disappeared after several months and the control of the bladder and rectum after about six months. At the time when she reported at the dispensary, the right arm was wasted and shorter than the left. There was wrist drop, and the fingers were flexed; there was spastic contraction of the flexors at the elbow and stiffness on trying to extend the wrist. There was slight toe drop on the right side, though the patient walked fairly well, the right foot being dragged but little. Case XXIII (Nervous Dispensary No. 15179). The fifth case was that of a girl of 10, of good family and previous history excepting for the fact that at 2 she had had chills and fever and convulsions. At the age of 4 she had typhoid fever. After about three weeks she was so much better that she sat up in bed. This was followed by a relapse in which there developed a right-sided hemiplegia. While sleeping, she suddenly waked with a scream and fell back unconscious. There were no convulsions. She did not recognize any one for 21 days, and did not walk for a year. Speech began to return after about three months. At the time when she consulted Dr. Thomas, six years after her illness, there were contractures and athetoid movements in both arm and leg. [3321 [333] 27 1333: In this connection I may mention a very remarkable in- stance which was communicated to me a year ago by Dr. Royster of Norfolk. Case XXIV. A girl of 8, in the 4th week of a typhoid fever of moderate severity, when the temperature had nearly reached a normal point, developed a left-sided hemiplegia involving the face, arm and leg, in association with paralysis of the right third nerve-a typical Weber's syndrome. The onset was associated with convulsions. A year later the child still had at times spas- modic twitchings involving the left side and the right eye and occasional general convulsions. The lesion in this case was undoubtedly peduncular, probably thrombotic. Two cases of cerebral thrombosis with aphasia and hemi- plegia which I have previously reported,82 may be also included in this list. Both of these instances were observed in the Massachusetts General Hospital. Case XXV. The first of these cases was that of a man of 21, of good family and previous history, who on the 10th day of a fairly severe typhoid fever, developed a complete right-sided hemiplegia with aphasia. There were no convulsions; the patient was dull but not unconscious at the time of onset. About three months later he was able to walk and the power of speech was returning. There was still, however, but little return of power in the forearm and hand. Case XXVI. The second instance was that of a girl of 10, who, in the 4th week of typhoid fever, developed paralysis of the right arm with aphasia. At the time of onset the child was in a dull stupid condition but there were no convulsions and no loss of consciousness. Six weeks later, the movements of the hand and arm were almost as good as on the other side, but the child seemed mentally dull. I have also the notes of an extremely interesting case, the anatomical specimens from which were sent to me by my friend Dr. Akerman of Wilmington, North Carolina. Case XXVII. The patient, a man of 31, of good habits, with no history of previous serious illnesses, entered the James Walker Memorial Hospital on July 1, 1903, on the third or fourth day of a severe typhoid fever. At the end of the second week (13th or 14th day) there developed a complete left-sided hemiplegia. The patient was delirious at the time of onset of the paralysis but not unconscious. Two weeks later, despite the gravity of the condi- "Johns Hopkins Hosp. Bull., 1896, VII, 73. 28 tion, signs of return of power on the paralyzed side began to appear. In the beginning of the 5th week (July 25) there devel- oped a right femoral phlebitis. The patient, who was very ill throughout, gradually failed and died on the 41st day. The autopsy showed extensive infarctions of the spleen and kidneys, due apparently to autochthonous thrombosis. The heart showed nothing remarkable; the brain, which was preserved whole, was unfortunately lost on account of a mistake in the preserving fluid, so that the exact location of the lesion could not be determined. There can, however, be little doubt from the character of the case that it was an instance of thrombosis. Time of Onset of Symptoms. Considering these 14 cases together the onset of the symp- toms occurred: In the second week in 4 cases. In the third week in 4 cases. In the fourth week in 3 cases. In the third or fourth week in 1 case. In the sixth week in 1 case. In the tenth week in 1 case. Of the 8 cases in which the onset was observed, in all but one it occurred during the febrile period. The complication appeared to have slight influence on the course of the fever, excepting in the first case where the tem- perature rose up to the time of death. In none of the cases were there chills. Leucocytosis.-In the four cases in which blood counts w'ere made the leucocytes were: 17,000 13,200 9,500 9,250 Taking into consideration the clinical symptoms in con- nection with the temperature records and the microscopical observations in the first case, it would seem not improbable that in all of these cases there was a primary arteritis. Whether in cases XVIII and XIX a partial parietal thrombosis occurred or whether the symptoms are to be as- cribed to the interference with the circulation incident to the swelling of the arterial walls alone must remain an open question. [333] 29 [333] A striking point of variance between these cases and those of phlebitis is the difference in their distribution. Of the fourteen instances of arterial thrombosis but 2 occurred in the lower extremities. One developed in the arm and the remaining in the cerebral vessels. Again, among these 14 cases the distribution as to the side of the body was more nearly equal, 6 being right-sided and 8 left-sided lesions. These particular figures cannot of course be compared with the cases of phlebitis which were in such preponderance, limited to the lower extremities. The statis- tics of Keen,33 however, show that arterial thromboses are much more evenly distributed between the two sides. Acute Aortitis.-We have never observed during life symp- toms similar to those described by Potain,34 as suggestive of the existence of acute aortitis, nor have our necropsy records shown changes which could well produce such symptoms. III. Analysis of the Necropsy Records. Between the fifteenth of May, 1899, and the first of Jan- uary, 1903, there were 132 fatal cases of typhoid fever with 95 necropsies. Heart Muscle.-Upon the gross appearances of the heart muscles comment has already been made. A study of the microscopical changes with modern methods of investigation, in those cases from which tissues have been saved, and a com- parison of the results with the clinical histories is an import- ant part of this investigation which I have as yet been unable to carry out. From what observations I have made I am convinced that there is room for further study of the changes occurring in the heart muscle in typhoid fever. It is unnecessary here to refer to the fatal cases of acute endocarditis, pericarditis, phlebitis and arteritis, mention of which has already been made. The Arteries.-Of especial interest, it seems to me, is the question as to the relation of acute infections in general and typhoid fever in particular to acute and chronic changes [334] " Surgical Complications and Sequels of Typhoid Fever. Phila- delphia, 8°, 1898, 76-78. 34 De 1'aortite typhique. Semaine m6d., Par., 1894, XIV, 460. 30 in the aorta and general arterial system. The occasional existence of acute arteritis in the peripheral vessels has already been mentioned in connection with arterial throm- bosis. There is a feeling among many observers that the severe acute infections play a more or less important part in the causation of focal endarteritic changes in the aorta and other vessels which may subsequently give rise to grave func- tional disturbances, yet a really systematic research into the effects of typhoid fever upon the heart and arteries has not, so far as I know, been made. A mere survey of the -protocols of our necropsies reveals some interesting points. In a large proportion of these cases, unfortunately, little attention has been paid to the vessels, and where observations have been made, these are re- stricted almost entirely to the aorta and coronary arteries. In a considerable number of cases, however, especially in recent years, since our attention has been more particularly directed toward this point, relatively fresh sclerotic changes have been described in the intima of the aorta and coronary arteries. The Aorta.-Out of 52 cases in which notes upon the con- dition of the aorta were made, there were evidences of scler- osis in 30. These changes were apparently recent in at least 21 instances. The Coronary Arteries.-Especially interesting are the re- cords with regard to the coronary vessels. Out of 62 cases in which the condition of the coronary arteries was recorded, there were 19 in which definite sclerotic changes were noted. In four other cases yellow opacities in the intima were de- scribed. In 13 of these cases the changes were early and appar- ently recent. These observations are, it seems to me, of con- siderable significance. They are markedly at variance with the above quoted experience of Curschmann. One case, of recent occurrence, is particularly suggestive. [334] Case XXVIII (No. 40831). A strong, vigorous man of 25, of excellent history and habits, who had suffered from measles at 21, mumps at 23 and chicken pox at 24, died at the end of the third week of a very severe typhoid fever. The heart's action was rapid but there was no apparent dilatation and no cardiac murmurs. The pulse tension was remarkably low. At necropsy 31 [384] several very early patches of endarteritis were found at the root of the aorta, and one or two on the ventricular surface of the mitral valve; these were slightly raised areas, in part somewhat yellowish, in part still translucent. On opening the coronaries there were found " numerous patches of yellowish sclerosis, espec- ially in the anterior descending branch. The posterior branch also shows extensive sclerosis. The patches are small and dis- crete and in large part translucent, spotted with yellow." Sec- tions through these areas show a very early process, so much so that one may well ask whether the lesions did not originate in the course of the typhoid infection. This patient was one of the house physicians, with regard to whose habits and life we had peculiarly good information. He was a man of exemplary habits who had not been given to excesses of any sort; he had never been in the habit of taking over-violent physical exercise, and as has been said, had suf- fered only from measles, mumps and chicken-pox. The les- ions present in the coronary vessels were really extensive, and in the course of the regressive changes which must have followed had he recovered, might well have given rise to suffi- cient stenosis to result in the gravest damage to the cardiac muscle. Such a case can but impress one with the importance of more careful observations upon this point. As Brault " said some years ago, " Alterations in the arteries of patients dead of typhoid fever should be carefully looked for, as well in the arteries of the extremities as in the aorta and arteries of the base of the brain. It is the only way to settle the question as to whether arterial affections are frequent in this disease." IV. A Study of the Subsequent Condition of 189 Pa- tients WHO PASSED THROUGH THEIR TYPHOID FEVER in the Wards of the Johns Hopkins Hospital within the Past Fourteen Years. A point of fundamental importance with regard to the ques- tion of the effect of typhoid fever on the heart and vessels, would be the study of the subsequent condition of the vascular 35 Les arterites. Leur role en pathologic. Paris (not dated). Masson & Gauthier-Villars (Encyclopedic scientiflque des aide- memoire) . 32 apparatus of a sufficient number of patients at a later period. The only method of solving this question would seem to be the careful observation of a large number of individuals dur- ing months and years following their typhoid fever. This is naturally a difficult thing to do, and the results of such an in- vestigation must very naturally be affected by a variety of dis- turbing influences. Nevertheless it seemed to me that it might not be uninteresting to examine the hearts and arteries of as many of our old typhoid patients as could be reached, and especially, to observe the subsequent course pur- sued by those cases in which cardiac and vascular lesions were recognized at the time of their disease. Within the last two years I have examined 189 of our old typhoid patients. The results of these investigations, which have, in great part, been reported in the March number of the American Journal of the Medical Sciences36 I will give here in brief: (1) Age and Date of Attack. The ages of the patients varied between 3 and 69 years, while the periods which had elapsed between the discharge from the hospital and the subsequent examination ranged from one month to thirteen years. The following table will show the period of time which had elapsed between the discharge of the patient from the hospital and the subsequent examination. [334J [3351 Table IV. Showing the Length of Time which had Elapsed Between the Discharge of the Patient from the Hospital and the Subse- quent Examination. MONTHS. YEARS. 1-637 6-12. 1 2 3 4 5 6 7 8 9 10 11 12 13 Cases 22 26. 19 21 23 22 11 13 11 10 6 2 1 1 1 = 189. With regard to the rate and regularity of the pulse, nothing especially remarkable was noted. (2) Pulse. 30 On the Late Effects of Typhoid Fever on the Heart and Ves- sels. Amer. Journ. Med. Sc., 1904, CXXVII, 391. 37 There were but three cases seen under three months from the time of discharge. 33 [335] (3) Systolic Blood Pressure. Of especial interest, however, were the observations upon the systolic blood pressure. These were made by means of the Riva Rocci apparatus. The patients were always in the CHART I. recumbent posture, the estimate being made as the last step in the examination in order that psychical influences might be excluded as far as possible. The results of these estimations compared with a series of similar observations on healthy individuals who had never had typhoid fever are indicated in the following table which is graphically represented on Chart No. 1. 34 Showing the Averages of the Systolic Blood Pressure in 276 Healthy Individuals and 172 Old Typhoids, Arranged Accord- ing to Age by Decades. Table V. [335] OLD TYPHOIDS. 1-10 10-20 20-30 30-40 40-50 50-60 60-70 112.4 mm. 135.2 mm. 152.5 mm. 160.8 mm. 170.2 mm. 179.6 mm. 215 mm. (5 cases). (39 cases). (61 cases). (48 cases). (15 cases). (3 cases). (1 case). 104.6 mm. 128.7 mm. 136.9 mm. 140.8 mm. 142.2 mm. 154.8 mm. 180 mm. (37 cases). (87 cases). (89 cases). (37 cases). (20 cases). (5 cases). (1 case). HEALTHY INDIVIDUALS. This table reveals the interesting fact that the average blood pressure in the old typhoids was uniformly higher than that CHART II. in healthy individuals who had never had the disease. A 35 1335] further analysis of our records shows that a large proportion of the old typhoids showed blood pressures above what are usually regarded as the normal limits. In order to eliminate some of the numerous sources of error I prepared other tables excluding from each list all those cases in which a history of scarlet fever, diphtheria, acute rheumatism, pneumonia, erysipelas, small-pox or alcoholic habits could be obtained. Table VI. Showing the Averages of the Blood Pressure in Old Typhoids and 'Normal Individuals, from which all Cases with a History of Serious Infectious Disease or Alcoholic Habits have been Excluded. OLD TYPHOIDS. 1-10 10-20 20-30 30-40 40.50 50-60 60-70 113.2 mm. 134.9 mm. 150.3 mm. 167.6 mm. 168.7 mm. 183.5 mm. 215 mm. (4 cases). (28 cases). (34 cases). (27 cases). (8 cases). (2 cases). (1 case). HEALTHY INDIVIDUALS. [336] 105.5 mm. 128.3 mm. 135.1mm. 139.8 mm. 145.2 mm. 156.4 mm. 180 mm. (32 cases). (62 cases). (52 cases). (10 cases). (11 cases). (4 cases). (1 case). These tables illustrated by Chart II, show, as may be im- mediately observed, no essential variation from the previous curve. The alteration of the typhoid curve, due to the higher figures in the column for the thirtieth and fortieth decades, only emphasizes the fact that the number of cases was still too small to allow of the construction of final charts. (4) Palpability of the Radial Arteries. Another striking feature in the examination of our old typhoids was the remarkable frequency with which the radial arteries were palpable. The following table which is illus- trated by Chart III, shows a comparison of the figures in our old typhoids arranged according to decades, and a series of 421 healthy individuals who had never had typhoid fever. From our figures it appears that between the ages of ten and fifty years 48.3 per cent of the old typhoids showed palpable vessels, as compared with 17.5 per cent of the control cases. 36 Showing the Percentages of Palpability of the Radial Arteries in 188 Old Typhoids and in 421 Healthy Individuals ivho had Never had Typhoid Fever, Arranged According to Age by Table VII [336] OLD TYPHOIDS. 1-10 10-20 20-30 30-40 40-50 50-60 60-70 0# 28.5# 53.1^ 54.2^ 50^ 100^ 0^ (5 cases). (42 cases). (64 cases). (59 cases). (14 cases). (3 cases). (1 case). o$ 6.1$ 20.4$ 25$ 22$ 42.8$ 80$ (37 cases). (98 cases). (186 cases). (61 cases). (27 cases). (7 cases). (5 cases). HEALTHY INDIVIDUALS. CHART III. As in the case of the blood pressure I have also prepared a second table including those cases only, in which a history of alcoholic habits and the more serious acute infections were absent. These figures, illustrated by Chart IV, show little variation from those based upon a larger number of cases. 37 [336] Showing the Percentages of Palpability of the Radial Arteries in Old Typhoids and in Healthy Individuals from which All Cases giving a History of Serious Infections or Alcoholism have been Excluded. Table VIII. OLD TYPHOIDS. 1-10 10-20 20-30 30-40 40-50 50-60 60-70 o$ 22.5$ 52.6$ 63.3$ 57.1$ 100$ 0% (4 cases). (31 cases). (37 cases). (30 cases). (7 cases). (2 cases). (1 case). 0^ 4.2^ 21.3% 22.2% 18.7% 33.3% 75% (32 cases) (70 cases). (103 cases). (27 cases). (16 cases). (6 cases). (4 cases). HEALTHY INDIVIDUALS. CHART IV. Results so striking and constant as these could hardly be acci- dental, and interesting confirmation is afforded by the follow- ing observations. 38 In connection with some studies on albuminuria which are being made by Dr. Emerson, abstracts were made of 2000 con- secutive histories in the Medical Department of the Johns Hopkins Hospital. Out of these 2000 histories a definite note as to the palpability or non-palpability of the peripheral ves- sels was made in 1174 cases. In 943 cases in which the radial arteries were palpable 188 or 19.9 per cent gave a history of typhoid fever. Out of 231 cases in which the peripheral vessels were not palpable but 25 or 10.8 per cent had had the disease. The frequency of a history of typhoid fever in the two groups arranged by decade is illustrated by the following table. [336] [337] Table IX. Showing the Relative Frequency of a History of Typhoid Fever in Hilf Consecutive Cases Arranged According to Age by Decades. Cases in which the peripheral vessels were palpable: 1-10 10-20 20-30 30-40 40-50 50-60 0% 6.35% 17.28% 17.94% 24.74% 22.35% (2 cases). (63 cases). (191 cases). (223 cases). (190 cases). 60-70 70:80 80-90 24.36% 29.17% 0% (78 cases). (24 cases). (2 cases). (170 cases). Cases in which the vessel wall was not palpable: 1-10 10-20 20-30 30-40 40-50 50-60 60-70 0^ 11.76# 10.45# 8.77# 17.39# 14.28# 14.28# (11 cases). (51 cases). (67 cases). (57 cases). (23 cases). (14 cases).(7 cases). 70-80 0% (1 case). These figures can but be regarded as strongly supporting the indications resulting from our previous observations. (5) Condition of the Heart in 188 Old Typhoids. A consideration of the condition of the heart in our old cases both in the hospital and subsequently, reveals the inter- esting fact that the average size of the heart was greater among the old typhoids than in the same cases at the time of admission to the hospital, the difference holding good also when the cases were classed according to age by decade. In 12 of these cases, where, on discharge from the hospital, 39 [337] tlie heart was considered normal, subsequent examination re- vealed evidences of organic disease; in eight instances, hyper- trophy with mitral insufficiency; in one, possible mitral stenosis; in one, aortic insufficiency; in one, marked general arterio-sclerosis with hyper-tension.38 An interesting case of hypertrophy with mitral insufficiency consecutive to typhoid fever has recently come under my observation. Case XXIX. H. C. M., aged 33, a patient of Dr. Frank M. Sharpe, of Brooklyn, N. Y., consulted me on the second of March 1904. He had had measles as a child and pneumonia at the age of 4 or 5, but no other serious illnesses. His habits were ex- cellent. He had always been a strong, athletic man. Two years ago last January, he had an attack of typhoid fever, during which he was in bed three or four weeks. Ever since this illness, he has been rather nervous, so much so that he felt obliged to give up his indoor work. He has noticed also that he is losing the " strength and the go " that he used to have, and he has been conscious of shortness of breath on going up hills. A month and a half ago he had a mild attack of influenza. About a month ago, on being examined for life insurance, he was told that he had cardiac trouble. The doctor also advised him to give up base ball and other out-of-door sports. On examination, the pulse was slow, the artery of rather large size; duration moderate; slight dicrotism. Maximum pressure (Riva Rocci), 185. The radials were palpable on both sides; temporals not prominent. The point of maximum cardiac impulse was localized in the 4th space, 9.2 cm. from the median line, the dulness extending 4^ cm. to the right; the greatest diagonal dulness, right to left, was 15 cm. In the erect posture, the im- pulse, which was strong, was in the 5th space, 9% cm. from the median line-after a little exercise, 10 cm. The first sound was prolonged and followed by a very slight systolic murmur which was lost two fingers' breadths outside the point of maximum impulse; it was not heard in the tricuspid area, but was just audible in both areas at the base. In the erect posture, however, the murmur increased in intensity and was faintly heard in the axilla and back, as well as all over the cardiac area. The second sound was louder in the aortic than in the pulmonic area. After exercise (dancing on one foot), the pulse was raised to a little over 100, but soon fell. 38 The full records of these cases may be found in Amer. Journ. Med. Sc., 1904, CXXVII, 410-420. 40 A study of the subsequent condition of those eases show- ing a remarkably rapid or irregular pulse during the disease revealed little of interest excepting for the fact that the blood pressure was somewhat above the common average for the old typhoids. Subsequent History of 31 Cases of Typhoid Fever in which a Systolic Murmur at the Apex was Audible During the Attack. The patients who, during their attack, developed a systolic murmur at the apex of the heart, showed a higher average blood pressure than the general mean of the old typhoids. In 28 of these cases, where the systolic pressure was taken on later examination, the mean was 158.5 mm. against a general average for the old typhoids of 152.4. This higher average was observed in every decade excepting the first in which there was but one case, and in the third, in which there were but four. In 18 cases over 20 years of age, the average pressure was 169.2 as compared with a general average of 159.6 for the same decades. In 5 cases the pressure was above 200 mm. The average size of the heart was found to be greater than in the same cases at the time of admission to the hospital or in the old typhoids as a whole. In 11 of these instances the heart sounds were clear on the later examination. In 20, murmurs were heard. In one instance the murmur was a slight cardio-respiratory systolic sound audible at the apex only. In 6 cases there was a soft systolic murmur at the base, in some instances heard also over the right ventricle. In 13 cases there was a systolic murmur at the apex of the heart. In 5 of these cases the signs justified the diagnosis of mitral insufficiency. In one case there were signs suggestive of mitral stenosis. In one case there was a marked arterio-sclerosis with hyper- tension. One case was an instance of Graves' disease with a systolic murmur all over the cardiac area. This condition was also present at the time of the fever. [337] 41 [337. From this, the striking fact appears that over one-fifth of those cases in whom during typhoid fever, an apical systolic murmur was audible, showed on later examination evidence suggestive of organic cardiac lesion. 13 38j (6) Subsequent History of 16 Cases of Phlebitis and Venous Thrombosis. Sixteen of our patients with venous thrombosis were seen or communicated with at a period of time, months or years after the onset of the complication. Ten of these cases were instances of femoral thrombosis; two, of double iliac throm- bosis; two, of popliteal thrombosis; two, of thrombosis of the veins of the calf. After history of 10 cases of femoral thrombosis.-One of these two cases was seen two and a half months after con- valescence, one, ten days after his discharge from the hospital, while two others were communicated with years after the onset by letter. The remaining six were examined at periods vary- ing from two to twelve years after the affection. In all instances there was more or less permanent disability. In 6 cases there had been oedema lasting for from several weeks to two years. In 5 cases there was a complaint of cramps in the calves, especially at night and after exercise. In one instance the patient complained of sharp pains running up through the leg and thigh especially after standing. In one case the patient says that when he exercises his leg too much, " it becomes so weak that I can hardly use it; it seems to give out." In every instance the affected leg and thigh were materially and permanently larger than the other. In all cases, excepting in the instance seen ten days after discharge, there were marked varicosities. These were es- pecially extensive in the calf, the popliteal space and on the posterior and inner side of the thigh. In 6 cases, all but one in which the condition was looked for, there was a well marked varicosity of the veins in the hypogastrium. This picture seems to be characteristic. The varicosities usually 42 form a triangle with the apex a little below the umbilicus, the blood flowing from the affected thigh to the apex of the triangle and then down again into the opposite inguinal ring [338] Case XXX (No. 45899) of double iliac thrombosis with extensive abdominal varices. passing upwards evidently through the iliac vein of the other side. The one case in which these varicosities were missed 43 [338] was that of an ignorant colored man who was communicated with by letter. After history of two cases of double iliac thrombosis. Two cases of double iliac thrombosis were seen several years after the onset of the complication. In one of these, the first symp- toms of which had been abdominal pain with marked leuco- cytosis and the early appearance of rather prominent veins in the lower abdomen, the later, subjective symptoms were few. Extensive varicosities, however, developed in the veins of both legs and thighs, extending upwards over the abdomen and anastomosing with the internal mammary veins and other veins in the axilla. Case XXX (No. 45899). The second case was that of a young man of 22, of good family and personal history, who had a severe attack of typhoid fever at the age of 17. On the 18th or 19th day of the disease, just before the temperature reached the normal point, there was severe pain in the left groin. A few days later, the temperature being normal, the patient got out of bed and walked about, committing also various indiscretions in diet. This was followed by a relapse, immediately after the onset of which there was swelling, redness and pain in the left groin. About a week after this there was pain and marked swelling of his right leg. There was almost complete loss of power, and it was not until four months later that he was able to go back to work. He had to use crutches for a month. In the erect posture, the legs were considerably swollen; great varicosities developed, and three ulcers appeared on the left leg. Varicosities in the abdomen appeared with convalescence from his relapse. The patient en- tered the hospital on the eighth of March, 1904, complaining of swelling and ulceration of the legs and abdominal varicosities. There was great distension and tortuosity of the veins of both legs and thighs, extending up over the abdomen and anastomosing with branches of the internal mammary veins. Large tortuous veins also extended up inU the axillae. The left leg was every- where a little larger than the right. The accompanying photo- graph illustrates well the remarkable character of the varices and anastomoses. After history of two cases of popliteal thrombosis.-Two cases of popliteal thrombosis were seen several years after the onset of the complication. One of these patients had suffered no inconvenience whatever. In the other, the legs are somewhat weak and toward the end of the day, they are, 44 at times oedematous. In both instances the affected leg is somewhat larger than the other, but in neither are there marked varicosities. After history of two cases of thrombosis of the veins of the calf.-In one case, after leaving the hospital, there was con- siderable oedema with the development of several ulcers. At the present time there is a well marked varicosity of the veins of the inner side of the leg and in the popliteal space. The other patient was communicated with by letter. He states that the " leg from the knee down is the source of a little continuous annoyance; it itches and is frequently inflamed during the warm months. It often goes to sleep." The calf measures an inch and a half more than the other. (7) Subsequent History of a Case of Typhoid Arteritis with Possible Parietal Thrombosis. J. H. T. (Case XVII, page 25), whose attack of arteritis of the left femoral with possible parietal thrombosis, has been previously described, returned on the 27th of March, 1904, in answer to a letter. He considered himself in good health and looked extremely well. He had recently entered the U S. Ma- rine Corps. On inquiry, however, a history of typical inter- mittent claudication was obtained. " I am," he said, " stand- ing or walking and all of a sudden, it " (the left leg) "gives way on me and I kind of fall." Several times when he has walked too much, his left leg has suddenly given way so that he has actually fallen down. At times, when, he tries to use it, there are sudden pains which shoot upward through his leg. Once when, as a printer, he was lifting a heavy form, the leg suddenly doubled up under him and the form fell upon his toe. On examination the left thigh and leg were everywhere slightly larger than the right. The femoral pulsation ap- peared to be equal on both sides. In the popliteal, the pulsation was difficult to feel on either side. The pulsations of the dorsalis pedis were essentially equal. The posterior tibial pulsation, however, was very feeble upon the left as compared with that upon the right. [339] 45 [339] It is unnecessary here to refer again to the results of cere- bral thrombosis. V. Conclusions. In considering this series of observations what information have we gained and what conclusions are we justified in draw- ing? (1) Typhoid fever is a disease which, from a clinical stand- point, is often associated with symptoms suggestive of a grave weakening of the heart muscle. These changes, whether due primarily to direct action of the typhoid poison on the heart or to impaired nourishment from vaso-motor paralysis, result, in a considerable proportion of cases, in a temporary insufficiency of the mitral valve as indicated by the appear- ance of apical systolic murmurs which are, not infrequently, transmitted to the axilla. These murmurs develop especially at the height of the disease, during the latter part of the first and in the second, third and fourth weeks, and disappear usually with convalescence. Sometimes, however, they may persist. 12 out of 188 cases of typhoid fever who were followed from three months to fourteen years after convalescence, showed conditions suggestive of organic cardiac lesion. In the majority of these cases a systolic apical murmur had been detected during their illness. Over one-fifth of our old typhoids in whom, during their illness, a systolic apical murmur was heard, showed on subse- quent examination, evidence of organic disease. The average systolic blood pressure (Riva Rocci) was higher in every decade among our old typhoids than in healthy individuals who had never had the disease. The radial arteries were palpable with strikingly greater frequency in our old typhoids than in healthy individuals of the same age who had never had typhoid fever. (2) Endocarditis, while not a common complication of typhoid fever, is probably more frequent than generally sup- posed. It was present without being suspected, in 3 out of 95 cases coming to necropsy at the Johns Hopkins Hospital, while in 3 further cases out of the remaining 1363, the clin- ical symptoms suggested its presence. 46 In the 3 cases discovered at necropsy, the lesion was due to a secondary mixed infection; in 2 instances, staphylococcus aureus; in one staphylococcus albus. It is not impossible that endocarditis is more frequent than indicated by these figures. Out of 188 old typhoids, 8 showed mitral insuffici- ency; one aortic insufficiency; one, possible mitral stenosis. (3) Pericarditis is an unusual and unimportant complica- tion of typhoid fever. Three instances only, were noted in our 1458 cases. (4) Phlebitis and venous thrombosis is a frequent compli- cation of typhoid fever, occurring in over 2.6 per cent of our cases. The onset occurs usually in the third week or later, and is, in most cases, associated with fever, leucocytosis and local pain. Not infrequently the fever and leucocytosis may pre- cede the localizing symptoms. The complication was ushered in by or associated with chills in 28.9 per cent of our cases. Chills otherwise unexplained, occurring during the latter part of typhoid fever or in the early stages of convalescence, especially if associated with a leucocytosis, should always suggest the possibility of a developing phlebitis. The phlebitis is, in the great majority of cases, localized in vessels of the lower extremity, especially on the left side, and is particularly frequent in the femoral veins-about one- half of our cases. Thrombosis of the iliac and femoral veins is always a ser- ious complication. Although the immediate dangers-gan- grene, extension of the thrombus, pulmonary embolism-are not great, the after results are often grave. In thrombosis of the femoral or iliac vein the affected extremity is always considerably and permanently enlarged, and there is usually more or less persisting disability-ex- tensive varicosities, often resulting in ulceration; marked weakness of the limb; frequent cramps in the muscles, espe- cially at night and after over-exertion. (5) Arteritis and arterial thrombosis is a more frequent complication of typhoid fever than is generally recognized. [339] [340] 47 [340] This complication appears to be especially common in the cerebral vessels although it may occur in the extremities. The onset may occur at the height of the disease but is commoner in the third week or later. As in the case of phlebitis, the attack is often ushered in by fever and leucocy- tosis. In the extremities, arterial thrombosis is commonly followed by gangrene; in the cerebral vessels by hemiplegia. Arteritis in the extremities may be associated with partial parietal thrombosis from which nearly complete recovery may occur. In one of our instances the patient, a year and a half after his fever, showed characteristic symptoms of inter- mittent claudication. (6) A survey of our pathological material would suggest that typhoid fever may be a not infrequent cause of focal arterio-sclerotic changes. In 21 out of 52 cases in which notes upon the condition of the aorta were made there were evidences of fresh endarter- itis. In 13 out of 62 cases in which the condition of the coron- ary arteries was recorded like changes were found. This idea is further supported by the remarkable frequency with which sclerosis of the peripheral vessels was found in our old typhoids. (7) While the deleterious influence of typhoid fever upon the cardio-vascular system is not as great as that of acute rheumatism, yet through the unfortunate frequency of the disease in this country, it is probable that post-typhoid cardio- vascular defects are not uncommon. It would be wise for the practising physician to bear this in mind and wherever possible, to keep his typhoid patients under observation for several years following the disease. 48 THE PROBLEMS OF INTERNAL MEDICINE WILLIAM SYDNEY THAYER [Reprinted from Science, N. 8., Vol. XX., No. 517, Pages 706-715, November 25, 1901,.. [Reprinted from SCIENCE, N. S., Vol. XX., No. 517, Pages 706-715, November 25, 1904-] THE PROBLEMS OP INTERNAL MEDICINE.* To recognize, to prevent, to protect, to heal-these are, in the broadest sense, the tasks of internal medicine now as ever. But how different are the problems which occupy our attention to-day from those of the period commemorated by this congress. Let us for a moment glance back at the medicine of the close of the eighteenth and the beginning of the nineteenth centuries. For over two hundred years the blind and binding faith of the middle ages, the faith that had so long fettered the human mind, had been slowly giving way before the forces of reason and truth. Now and again with ever-increasing frequency, great and courageous minds had risen above the clouds of medical tradition and dogma, which had smothered the understanding and reason of mankind, as if, indeed, medi- cine were a part of the religious doctrine which ruled the world. For truly the medicine of the middle ages was largely a matter of faith, and as a matter of faith one in which reason beyond a certain point was heresy and sacrilege. Vesalius with genius and courage had begun to with- draw the veil from naked and iconoclastic truth. Harvey had made his great dis- The medicine of the end of the eighteenth cen- tury. * Address delivered before the Section for In- ternal Medicine of the International Congress of Arts and Sciences, at St. Louis, September 22, 1904. 2 covery. Glisson had demonstrated his theory of irritability. Mayow with his 'Spiritus nitro-aereus ' had anticipated the discovery of oxygen. Leeuwenhoek and Malpighi and Hooke had opened to the human eye the realm of the infinitely small. Bacon and Descartes and Newton and Locke had introduced into the world a ra- tional and natural philosophy. Locke, himself, indeed, a wise physician, had pointed clearly to the true path of med- ical progress. "Were it my business," says he, "to understand physick, -would not the safer wTay be to consult nature herself in the history of diseases and their cures, than espouse the principles of the dog- matists, methodists or chymists. ' ' But the clouds of medical tradition were slow to clear away. Gradually, however, the first 'lonely mountain peaks of mind' had been followed by an ever-increasing number of earnest and untrammeled stu- dents. In the seventeenth century the op- portunity to give one's life freely to the search for truth had become more and more open to all. The mysticism and animism of Stahl which, in the early part of the eighteenth, hung over the medical world, wTas already breaking away. The study of the natural sciences was pursued more eagerly and generally than ever before. Reaumur and Black and Haller and Spal- lanzani and Hunter and Priestley and La- voisier had lived. Morgagni, sweeping aside the dogmatism of the old schools, had demonstrated the local changes in many diseases and had opened the way for the objective pathological anatomy of Bichat. In the field of practical medicine such men as Sydenham and Morton and Torti and Locke's method. Gradual develop- ment of rational and objective methods of re- search. 3 Lancisi practised and taught much which holds good to-day. Boerhaave had intro- duced clinical instruction. Cullen and Cheyne and Huxham and Pringle and Heberden and Van Swieten and De Ilaen were all in many ways true and faithful students; yet methods and doctrines that were often strangely fantastic still held general sway-such, for instance, as the Brunonian system. A perusal of the writings of Stoll, one of the wisest prac- titioners of his day, can not fail to impress one with the meagreness of the basis of anatomy and physiology, normal and path- ological, on w'hich medicine rested, the almost entire lack of diagnostic methods, the absence of a rational therapy-how much of the conjectural, how little of the scientifically exact there was in medicine. Diagnosis, based largely upon gross clin- ical conceptions, was necessarily vague and uncertain. Prophylaxis, in the absence of any cer- tain knowledge of the causes and manner of origin of disease, was devoid of any sound basis. Treatment was almost wholly empirical, and, where it was not empirical, it was fre- quently based upon some theoretical system so arbitrary and dogmatic that the unfor- tunate sufferer was too often stimulated or purged, fed or bled, as he fell into the hands of a Brown or a Broussais rather than according to the nature of his malady. In the Dictionnaire de 1'Academic Fran- coise for 1789, a year which marks the end of an era in the world at large, one finds the following definition: "Medecine. s. f. L 'art qui enseigne les moyens de conserver la sante & de guerir les maladies (La The lack of a scientific founda- tion for medicine. Medicine in 1789, a conjectural art.' 4 medecine est un Art conjectural * * *)." Medicine, a conjectural art! Such was the estimate placed upon our profession by the French Academy a little over one hundred years ago. But the seeds of a new life had been sown and the germination had already be- gun. Even as these words were written Lavoisier, too soon to fall a victim to the premature explosion of the forces of pent- up freedom, was in the midst of his great work. In 1796 came the introduction of vaccination by Jenner, and but a few years later Bichat, with his wonderful genius, took up the thread dropped by Morgagni and placed anatomy and physiology, nor- mal and pathological, on a basis of accurate observation and experiment. Hand in hand with the introduction of exact meth- ods of anatomical and physiological ob- servation, Auenbrugger, in 1761, had dem- onstrated in his 'Inventum Novum' a method of physical investigation which, for the first time, enabled the physician to determine changes in size, shape and con- sistency of the thoracic organs. At first unnoticed by the world, this important dis- covery was destined to gain a sudden gen- eral recognition in the early days of the nineteenth century. With the spread of knowledge of the gross pathological changes in disease which followed the inspiration of Bichat, the work of Auenbrugger, ex- pounded by Corvisart, became a common possession of the medical world, and less than ten years later, Laennec, by the intro- duction of mediate auscultation, opened possibilities for accurate physical diagnosis such as had not been dreamed of in the ages which had gone before. The develop- ment of methods of physical diagno- sis. 5 With the great school of French ob- servers which followed Laennec, Andral, Chomel, Louis, Bouillaud and Trousseau, with Skoda and Schbnlein in Germany and Addison and Bright and Stokes in Eng- land, the exact association of clinical pic- tures with local anatomical changes made great advances. Typhus and typhoid fevers were distinguished; the relation be- tween albuminuria and renal disease was demonstrated; the association of endo- carditis with acute rheumatism was dis- covered ; the corner-stone of our knowledge of cerebral localization was laid. Clinical diagnosis was becoming more than a con- jectural art. In the meantime physiology was making great strides. Majendie, Bell, Johannes Muller, Beaumont and finally Claude Ber- nard and a host of their followers, were shedding light upon many obscure corners of our knowledge of the vital functions. In the hands of Muller the microscope be- gan to open up new fields of study which were destined in a few years, through the cultivation of the genius of a Virchow and a Max Schultze, to bear a noble harvest. The 'great reform in medicine' which fol- lowed the introduction of the cellular pa- thology laid solid foundations for much which is most vital in our anatomical and physiological and pathological knowledge of to-day, and the correlation of these ob- servations with the results of accurately re- corded clinical studies, the application of the microscope to the study of the urine, the sputa, the blood, to pathological neo- plasms, to exudates and transudates, soon brought new material for the rising edifice of a rational, exact diagnosis. The sphyg- Great clinicians of the early part of the nineteenth century. Advances in physiology. The microscope and instruments of precision. The cellular pa- thology. 6 mograph, the thermometer, the ophthalmo- scope, the laryngoscope, the binaural stetho- scope, the stomach tube, the various means for studying the blood pressure, all have brought their aid, while but yesterday the discovery of Roentgen gave us new and unhoped for diagnostic assistance. At the same time, physiological chem- istry which, with the work of Berzelius on the urine, had taken its place by the side of the more purely physical methods of in- vestigation, has year by year given us greater diagnostic assistance in the analysis of the different secretions and excretions of the body and in the explanation of the various metabolic processes of the economy. The development in the hands of Du- chenne and Erb and Remak of electrical diagnosis, together with the great advances in physiology and pathology of the nervous system, have afforded explanation for much that was previously incomprehensible and have given us powers of diagnosis which, a few generations ago, would have seemed almost magical. Finally Pasteur and Koch, with the in- troduction of bacteriological investigation, opened the way to the discovery of the causal agents of a large group of infectious diseases. These discoveries, followed rapid- ly by the evolution of methods allowing of the clinical demonstration of many path- ogenic micro-organisms, afforded an early, exact and positive diagnosis, on the one hand, in conditions where previously the disease was recognizable only at a stage in which it had made inroads into the system so great as to be often beyond relief, as in tuberculosis, and, on the other, in maladies the existence of which, without these mefh- Ph y 8 i o I og i cal chemistry. Neurogieal diag- nosis. Bacteriology. 7 ods, was to be definitely determined only after the onset of an epidemic, as in cholera, plague and influenza. When one thinks of what the last quarter of a century has taught us with regard to tuberculosis, anthrax, tetanus, diphtheria, typhoid fever, cholera, plague, dysentery, influenza, not to speak of the great group of wound infec- tions, we may begin to realize what bac- teriological methods have done for diagnosis -how many diseases have been cleared up -how many symptoms have been ex- plained. In like manner Laveran with the dis- covery of the parasite of malarial fever, did much to bring certainty and precision into a field in which many had gone astray, while opening the way for the important observations of Theobald Smith and all the knowledge which we have gained in recent years with regard to the haematozoa of man and animals. As a direct result of the introduction of bacteriological methods, the study of the manner of action of infectious agents and their toxic products upon the animal organ- ism, as well as of the powers of resistance of the economy against infection, has given us, with the discovery of specific agglu- tinines and precipitines, diagnostic meth- ods of the greatest value, not only for the recognition of various infectious processes, but for the identification of specific sera, affording in particular a test for human blood destined, probably, to prove, when properly applied and interpreted, of great medico-legal value. This is, indeed, a gain over our knowl- edge of one hundred years ago. In Laveran's dis- covery. Specific agglu- tinines and preci- pitines. The diagnosis of one hundred years ago and that of to-day. 8 how many fields has the conjectural given way to the exact! At the end of the eighteenth century the diagnostic ef- fort of the physician, unaided by instru- ments of precision or even by the simplest physical methods of auscultation and per- cussion, was directed toward the detection of gross anatomical changes. To-day with our increased knowledge of anatomical, physiological and pathological processes, with our growing insight into the chemical and physical features of vital activity, our duty no longer ends in the recognition of physical changes in organs, in the deter- mination of the presence of a specific lesion or infection; it is, further, our task to search for the earliest evidence of disturb- ance of function which may later lead to grosser, more evident change, to sepa rate the physiological from the patholog- ical, to estimate, as far as may be, the power of resistance of the different organs and tissues and fluids of the body to insults of varying nature, to determine the functional capacity of a given organ-its sufficiency or insufficiency. In addition to increasing opportunities in the field of pathological anatomy we find ourselves drawn further into the study of pathological physiology- and knowledge in the field of pathological physiology leads of necessity to power in functional diagnosis. It must be acknowledged that with re- gard to many organs the determination of the limits of functional power and the esti- mation of the degree of impairment in dis- ease, are matters most difficult to appre- ciate, yet with improved methods and per- sistent research progress is being made. We are, after all, but beginning to realize Functional diag- nosis. 9 a few of the possibilities before us, but even this is a step in advance which holds out no little promise for the future and offers new and tempting opportunities for study and investigation. At the end of the eighteenth century but three important, rationally conceived meas- ures of prophylaxis had been practised- the dietetic measures of protection from scurvy, the older inoculation and Jenner's great contribution of vaccination against small-pox. It was not, indeed, until the development of bacteriology that prophy- laxis took its place as a scientifically exact branch of medicine. The recognition of the specific cause of many infectious dis- eases, the knowledge of the life history of the pathogenic micro-organisms, the discov- ery of the portals through which they gain entrance to the animal economy, and the conditions under, which infection occurs, have brought to us material powers to pre- vent and protect. The first great result of this new knowledge was the development of antiseptic surgery and all that it repre- sents. But apart from this we have but to remember what has been gained by a scientifically evolved prophylaxis against tuberculosis and typhoid fever-to reflect upon how far cholera and plague have lost their terrors-to contemplate the brilliant results of the discovery by Ross and the Italian school of the life history of the malarial parasites as manifested in the anti-malarial campaigns carried on in vari- ous regions by Koch, and in Italy by the Society for the Study of Malaria, a noble institution of which our Latin brothers may well be proud, and lastly, to look upon the beneficent and far-reaching influence Prophylaxis. Influence of bac- teriology and para- sitology on preven- tive medicine. 10 of the recent work of Reed and Lazear and Carroll and Agramonte with regard to yellow fever, to realize what bacteriological and parasitological studies are doing for preventive medicine. But beyond this external prophylaxis, the studies of the problems of immunity beginning with Pasteur's inoculations against anthrax in 1881, have given us, so to speak, an internal prophylaxis, a func- tional prophylaxis if one will, in the possi- bility of producing a greater or less degree of individual immunity, such, for instance, as is now possible in diphtheria, cholera, plague, typhoid fever and dysentery. The enforcement of scientifically planned and accurately deduced prophylactic meas- ures has become to-day one of the main duties of the practitioner of medicine. It is as much the task of the physician nowa- days to guard over the disposal of the supta of his tuberculous patient, of the excreta of the sufferer from typhoid fever or cholera or dysentery, as it is to attend to the immediate wants of the invalid. How rapidly has the exact replaced the conjectural in this branch of medicine! But while diagnosis and prophylaxis were being removed from the domain of conjecture to the field of exact observation and reason and research, while the possi- bilities of surgery were rapidly widening through the discovery of anaesthesia and the introduction of antiseptic methods, medical treatment, until the last two decades, still remained largely empirical. The development of exact clinical methods of observation and the statistical tabulation of experience for which we are especially indebted to Laennec and Louis and their Immunity. Prophylaxis in general practice. „ Treatment. Empiricism of the past. 11 followers, gradually brought about, to be sure, many advances, while a large number of useful therapeutic agents introduced by the newly developed science of pharmacol- ogy, and exactly tested by improved meth- ods of physiological study added greatly to the armamentarium of the physician for the relief of symptoms. The power to combat disease specifically, however, re- mained much as it was at the beginning of the century. Mercury in syphilis, quinine in malarial fever, were the only specifics known to the medical world-and the ac- tion of these was unexplained. The introduction by George Murray, less than fifteen years ago, of the treatment of myxcedema and allied conditions by ex- tracts of the thyroid gland, was a direct application of the results of physiological observation to the treatment of disease. If this gave rise to hopes of the possibility of obtaining like results from roughly ob- tained extracts of other ductless glands, which have hardly been fulfilled, yet this discovery was the first step toward the rational scientific therapy to which we are beginning to look forward to-day. But a moment ago I spoke of the impor- tance of the influence of the discovery of the causal agents of the infectious diseases upon the development of exact diagnostic and prophylactic methods. Great and im- pressive as these have been, yet the studies which have followed as to the manner in which these agents act upon the human organism, and of the powers of resistance which the body exerts against them, the investigation of the problems of immunity, have opened out a far wider field. The early studies of Metschnikoff and Buchner Organotherapy. Antitoxinee. 12 and Nuttall were followed with rapidity by the epoch-making work of Behring and Kitasato and Roux with regard to tetanus and diphtheria. The diphtheria and te- tanus antitoxines were not chance discov- eries of empirically determined virtue, but true specific, therapeutic agents, the results of experiment scientifically planned and carefully prosecuted. Wide-spread investi- gations of the various phases of immunity, bacterial and cytotoxic, have given us in a few short years a mass of physiological knowledge, the full import of which is scarcely yet to be comprehended. Few things in modern medicine are more im- pressive than a survey of the work of the last twelve years done under the inspira- tion of Ehrlich. Beside the antitoxines of diphtheria and tetanus and the power of producing a greater or less degree of immunity, as has already been mentioned, by preventive in- oculations against cholera, plague and ty- phoid fever, we have come to possess a bactericidal serum of a certain value in combating the actual disease, plague, while the favorable influence of Shiga's anti- dysenteric serum seems to be undoubted. There is much reason to hope that the re- cently promised anti-crotalus serum of No- guchi as well as the anti-cobra serum of Calmette may prove to be real boons to humanity. But it is not alone in the pro- duction of specific anti-sera, that the thera- peutic value of the modern studies of im- munity lies. There are signs which justify us in looking forward to the possible dis- covery of an explanation of the mode of action of substances long empirically used, Specific anti- sera. 13 knowledge the value of which may be readily appreciated. When we consider these facts it is, in- deed, easy to appreciate to what an extent the exact has driven the conjectural from this last field of medicine. A hundred years ago we were depleting and purging and sweating and bleeding according to theories often strangely lacking in founda- tion, the prevalence of which depended rather upon the individual force and vigor of the expounder than upon their intrinsic merit. To-day from the study of the pa- thological physiology of bacterial and cyto- toxic intoxications, we are rapidly evolving scientific preventive and curative measures, while searching out the rationale and mode of action of our older therapeutic agents. But a few days ago, I happened to open a copy of Littre* bearing, by a curious chance, the date of 1889, and read "Mede- cine. (me-de-si-n') 1° Art qui a pour but la conservation de la sante et la guerison des maladies, et qui repose sur la science des maladies ou pathologic"-an essential modification of the definition of one hun- dred years before and indicative of the changes of a century. To meet the manifold problems of to-day the training of the physician must, of neces- sity, be very different from what it was a hundred years ago. The strong reaction which set in in the earlier part of the nine- teenth century against philosophical gen- eralization in medicine, the insistence upon a strict objectivity, all the more emphatic because of the prevalence of anatomical methods of research, have held very gen- eral sway. Medicine, no longer, resting Passing of the conjectural from the field of thera- peutics. A definition of medicine in 1889. Expansion of the academic medical training. * Dictionnaire de la langue Franeaise. 14 upon a basis of philosophical speculation, stands upon the firmer foundation of the exact natural sciences. Almost from the beginning the student of to-day is taught methods, where a hundred years ago he was taught theories. The enormous ex- pansion of the field which must be covered has led, naturally, not only to an ever-in- creasing specialism, but to the fact that the course of study which is regarded as prop- erly fitting the physician for practise is reaching backward farther and farther into the earlier years of his school training. On the other hand, in this country at all events, there is heard a common cry that the academic medical training is extending on the other side into years which should be given to practice; that the expense and duration of a medical education so-called will soon be such as to shut out from the profession many a man who might be a useful physician and perhaps a valuable contributor to the world's knowledge. To remedy this it is advised that the prospect- ive student of medicine should be led from the earliest stages of his training through the paths of exact research into the domain of the natural sciences to the greater or. less exclusion of the classics-the old-time humanities, the study of which, useful as it may be from a standpoint of general mental training, is believed by many to be time wasted in the education of the student destined for a scientific career. But there are not wanting voices which question the wisdom of the full extent of some modern tendencies. May the affecta- tion of too strict an objectivity bred though it may be of a wholesome skepticism, the more general cultivation of the natural The student to- day is taught meth- ods rather than theories. Tendency of the day to neglect the study of the hu- manities. Possible delete- rious effects of some modern ten- dencies in educa- tion. 15 sciences to the exclusion of the humanities, the search for, facts and facts alone, cir- cumscribe the powers of synthetical reason- ing without which the true meaning of many an important problem might pass unnoticed? May they, perhaps, tend to smother the development of minds capable of grasping large general problems? Do the tendencies of the times justify the epi- grammatic observation of a recent French author: "Autrefois on generalisait avec peu de faits et beaucoup d'idees; mainten- ant on generalise avec beaucoup de faits et peu d'idees"*v That the cultivation of a strict object- ivity in research has materially impaired our powers of reason-that the exact meth- ods which are largely responsible for. the enormous advances of the last fifty years in all branches of medicine have bred a paucity of ideas, I am not inclined to be- lieve, despite the seductive formula of our Gallic colleague. But that when, in the period of so-called secondary education, it is proposed to substitute the study of the natural sciences for a good training in the humanities, there is danger of drying up some of the sources from which this very scientific expansion has sprung, seems to me by no means impossible. The study of the classics, an acquaintance with the thoughts and the philosophies of past ages, gives to the student a certain breadth of conception, a stability of mind which is difficult to obtain in another way. A familiarity with Greek and Latin literature is an accomplishment which means much to the man who would devote himself to The value of classical studies. * Eymin. ' M^decins et philosophes,' 8°. Lyon, 1903-4, No. IV. 16 any branch of art or science or history. One may search long among the truly great names in medicine for one whose training has been devoid of this vital link between the far-reaching radicles of the past and what we are pleased to regard as the flower- ing branches of to-day. Greek and Latin are far from dead languages to the conti- nental student. They are dead to us be- cause they are taught us as dead. With methods of teaching in our secondary schools equal to those prevailing in Eng- land and on the continent, 'twould be an easy matter, in a materially shorter period, to give our boys an infinitely broader edu- cation than they now receive. There should be much less complaint of time wasted, much less ground for suggesting the aban- donment of the study of branches which are invaluable to any scholarly-minded man. The assertion that the time spent in the study of the humanities results, in the end, in the encroachment of the academic train- ing upon a period which should properly be given to one's life work is, it seems to me, often based on an old idea-founded all too firmly, alas, on methods that yet pre- vail in many of our medical schools-that with his degree in medicine the student has finished a theoretical education, that he must now spend five or ten years in acquir- ing experience-at the expense, incident- ally, of the public-before he can enter into his active life; that, therefore, unless some other branches of early instruction be sacrificed to courses leading more direct- ly to medicine so that he may enter upon his strictly professional education at a period considerably earlier than is now Inferior methods of teaching the classics in our schools. A good classical education need not encroach upon a medical training. 17 the case, the physician of to-morrow will become self-supporting only at a period so late in life as to render a medical career impossible to other than those well supplied with the world's goods. With proper meth- ods of instruction this is a wholly false idea. Under fitting regulation of our sys- tem of medical training, with due utiliza- tion of the advantages offered by hospitals for clinical observation, the experience necessary to render a man a safe and com- petent practitioner should be not only of- fered, but required for a license to practise; and even if the length of the strictly med- ical curriculum be extended one or two years beyond that which is at present cus- tomary, it will not be time lost. If one but look around him he will find, I fancy, that few men who have had such a training wait long before finding opportunities for the utilization of their accomplishments; the public, in most instances, soon recog- nizes the man of true experience. But there is yet another side of the ques- tion which has hardly been sufficiently em- phasized, a side of the question which must come strongly to one's mind when he con- siders the general education of many of the men who are entering even our better schools of medicine, a point of view which has been especially insisted upon by a re- cent French observer. A large part of the success and usefulness of the practitioner of medicine depends upon the influence which he exerts upon his patients-upon the confidence which he infuses-upon his power to explain, to persuade, to inspire. It can scarcely be denied that these powers are more easily wielded by the man of gen- eral culture and education than by one of Necessity for the requirement of in- creased clinical experience for a license to practice Importance of a broad general edu- cation for the prac- titioner of medi- cine. 18 uncouth manner and untrained speech however brilliant may be his accomplish- ments in the field of exact science. I can do no better than quote the words of Pro- fessor Lemoine: "C'est qu'en effet Paction morale qu'il peut exer.cer sur le malade, et qu'il exerce d'autant plus qu'il est su- perieur par son intellectualite, est un des principaux elements de guerison. On guerit par des paroles au moins autant que par des remedes, mais encore faut-il savoir dire ces paroles et presenter une autorite morale suffisante pour qu'elles en- trainent la conviction du malade et rem- plissent le role suggestif qu'on attend d'eIles. Ne fut-ce que pour cette raison, je me rangerai parmi ceux qui demandent le maintien d'etudes claissiques tres fortes eomme preparation a celles de la medecine, car le meilleur moyen de rehausser le pres- tige du medecin c'est encore de 1'elever le plus possible au dessus de ses contem- porains. "* These words express, it seems to me, a * Indeed the moral influence which he [the physician] is capable of exercising upon the patient and which he exercises to an ever increas- ing degree with his intellectual superiority, is one of the most important of therapeutic agents. One heals by words at least as much as by drugs, but one must know how to say these words and to exercise a sufficient moral authority, that they may bring conviction to the patient and carry the full weight of suggestion which is intended. Were it but for this reason I shall range myself among those who demand the maintenance of extensive classical studies as a preparation for those of medicine, for the best means to uphold the prestige of the physician is still to raise him as far as possible above his contemporaries. Congr&s Fran- caise de medecine. VI. Session. Paris, 1902, 8°, T. II., p. xli. Observations of Prof. Lemoine. 19 large measure of truth. May it not be that in the tendency to the neglect of the humanities we are taking a false step? May it not be that if, on the other hand, we teach them earlier and better, we shall find in the end that no essential time is lost, while we shall gain for medicine men not only with minds abler to grasp the larger and broader problems, but with ma- terially fuller powers for carrying on the humbler but no less important duties of the practitioner of medicine? In that which I have just said I have touched upon the necessity of the require- ment of a considerable amount of clinical experience as an essential for the license to practise medicine. To meet the enormous- ly increased demands of the present day, medical education has become, of necessity, much more comprehensive, and must there- fore extend over a longer period of time. The methods of research, anatomical, phys- ical, chemical, which the student must master, the instruments of precision with which he must familiarize himself, are al- most alarmingly multifarious; and experi- ence in the application of these methods and in the use of these instruments de- mands increased time. Many of these pro- ceedings, it is true, the physician w'ill rarely be called upon to use personally in prac- tice, for such measures must in great part be carried out by special students or in laboratories provided by the government. Nevertheless, with their significance and value he must be familiar-familiar from personal observation and experience. But after all there are few diagnostic signs in medicine and not so many of the improved methods of clinical investigation Increasing scope of modern medi- cal education. Few diagnostic signs in medicine 20 yield diagnostic results, while to familiar- ize one's self with methods and instruments of precision is a very different matter from acquiring real experience and skill as a diagnostician or a therapeutist. It is only by gathering together and carefully weigh- ing all possible information that one is enabled to gain a proper appreciation of the situation and approach a comprehen- sion of many conditions of grave import to the patient. And in forming a sound judgment with regard to these vital ques- tions, that which comes from experience in the close personal observation of the sick is far the most important element. Bedside experience constitutes to-day, as it always has, and always will, the main, essential feature in the training of the physician. But this experience, if it is to bear its full fruit, must be afforded to the student at a time when his mind is still open and receptive and free from preconceived ideas -under conditions such that he may be directed by older trained minds into proper paths of observation and study, for few things may be more fallacious than experi- ence to the prejudiced and the unenlight- ened. That such experience may be freely of- fered to the student, there is a grave neces- sity for a more general appreciation, by institutions of medical training as well as by the powers in control of public and private hospitals and infirmaries, of the mutual advantages to be gained by a cor- dial cooperation. It must be acknowledged that, in this country at least, despite the cultivation of improved methods of clinical investigation, there still prevails in the mind of the public the perverted idea that Bedside experi- ence the essential feature of medical training. Value of scien- tific clnical inves- tigation and teach- ing in hospitals to the patient, the in- stitution and the community. 21 this bedside observation, this application of new methods of research and study, are for the advantage of the student or in the interest of general science rather, than for the benefit of the sufferer himself. It must further be recognized that a wholly mis- taken conception of the true function of a hospital is widely prevalent. It is all too common to see large and ornate institutions with every arrangement for the comfort and even luxury of the patient, with a medical staff utterly insufficient in number or training to properly study the individual case, not to speak of carrying on scientific investigations-the service, usually under the direction of a busy, driven practitioner, with barely time to make a short daily visit -large wards under the direct control of one or two young men whose time is wholly occupied by routine work-every bare taken for the present comfort of the patient- little provision for enlightened study or treatment of his malady-no opportunities for a contribution on the part of the insti- tution to the scientific progress of the day. Better far for the sufferer were he in the dingy ward of an old European hospital where he might be surrounded by active inquiring minds recording the slightest changes in his symptoms, ever ready to detect and, as far as the power in them lies, to correct the earliest evidences of perver- sion of function. What our hospitals need is men, students, whether or no they have arrived at the stage in their career-which, after all, is but a landmark, not a turning point-that entitles them to the right of independent practice, the enthusiastic, de- voted student who, in watching and study- ing the patient, is contributing alike to the chief need of our hospitals, 22 interests of the sufferer, the hospital and himself. The three main functions of a hospital, the care of the sick, the education of the physician, the advancement of science, are not to be met alone by the building of laboratories and operating rooms and lec- ture halls, by the furnishing of the refine- ments of luxury to the patient, useful ad- juvants though these may be. What the hospital mainly needs is men, men to study and think and work-students of medicine. It can not be denied that in this respect we in America are behind our cousins of the old world. Despite our many honor- able achievements, the part which we are taking in the modern study of the physi- ology of disease is still not what it should be. Ere long we must come to realize that our duty to the sick man consists in some- thing more than to afford him that which most sick animals find for themselves-a comfortable corner in which he may rest and hide from the world; that our duty to the public is to give them as physicians, men of the widest possible general training, ready to enter upon independent practice with an experience sufficient to render them safe public advisers; that our duty to our- selves is to miss no opportunity for the study of pathological physiology at the bedside of the patient; that the accomplish- ment of these ends depends in great part upon the appreciation by our universities and hospitals of the mutual advantages of cooperation in affording every oppor- tunity for the scientific study of disease while offering to the patient the privileges of enlightened observation and care. The true func- tions of a hospital are best served by opening its wards to^mediea1 teach- 23 But there are everywhere signs of a future rich in achievement. An improving system of medical education, the increasing opportunities for scientific research offered as well by the generosity of private citizens as by the wisdom of state and national governments, the community of effort which results from closer fellowship among students of all nations, are omens of great promise. The remarkable developments of the last twenty years in all branches of the natural sciences have brought a rich store of suggestion and resource for application in our laboratory, which is at the bedside of the patient. Let us look to it that our clinical methods keep pace with those which are yielding so abundant a harvest in these neighboring fields of scientific research. William Sydney Thayer. 406 Cathedral St., Baltimore. ^Promise for the OPENING OF THE SURGICAL BUILDING AND NEW CLINICAL AMPHITHEATRE OF THE JOHNS HOPKINS HOSPITAL. [From The Johns Hopkins Hospital Bulletin, Vol. XV, No. 165, December, 1904.1 OPENING OF THE SURGICAL BUILDING AND NEW CLINICAL AMPHITHEATRE OF THE JOHNS HOPKINS HOSPITAL. A large audience, composed largely of members of the medical profession from Baltimore, the State of Maryland, Washington, Philadelphia, New York, Boston and other cities, was present at the opening of the surgical building and clini- cal amphitheatre upon Wednesday, October 5, 1904, at 11 A. M. Dr. W. H. Welch presided and introduced Hon. H. D. Harlan, the President of the Board of Trustees of the Hos- pital, who spoke as follows: It is my pleasant duty on behalf of the Trustees to welcome you to the simple ceremonies attendant upon the formal open- ing of this new building, devoted to clinical medicine and surgery. We are much gratified at the number of our friends who have assembled. We make our special acknowledgments to the distinguished physicians and surgeons, pathologists, and other masters in the world of medical science, who have jour- neyed from afar, and particularly to those who have consented to deliver addresses on this occasion. That so many have done us the honor to accept our invitation is evidence (if any be needed), that the work of the Johns Hopkins Hospital and Medical School is not unknown or unappreciated either at home or abroad. At the time of the death of Johns Hopkins, on Christmas Eve, 1873, there was no Johns Hopkins Hospital, although there was a corporation which Mr. Hopkins had caused to be formed during his life, and a board of trustees carefully selected by him, who were engaged in gathering information [379] 1 L3791 and in making plans not only for the buildings which were to be erected on this site, but also for the organization of a medical staff and the equipment and operation of the institu- tion they were to bring into existence. The task which was set for these trustees was one of great responsibility; and, while a large latitude of discretion was vested in them, they were not left wholly without guidance as to the intentions of the founder. In a letter of instructions written in 1873, he had, among other things, said, (1) "that they were to provide for a Hospital, which, in construction and arrangement, should compare favorably with any other institution of like character in this country or in Europe," and (2) " that it should be their special duty to secure, for the service of the Hospital, surgeons and physicians of the highest character and greatest skill." These directions have ever been borne in mind by the Trus- tees. We may speak to-day of the wisdom and forethought, the sagacity and prudence, of the charter Trustees and their successors during the formative age of the Hospital without any self-glorification, because not one of the original Trustees still lives, the two last survivors having died in quick suc- cession during the past summer-much beloved and much regretted by their associates ; and because, with the single exception of Mr. George W. Corner, to whom all honor is due for his long and faithful service, extending over more than twenty-nine years, not one of the present Board was in office when the Hospital was dedicated in 1889, and only one when the Medical School was opened in 1893. How well the earlier Trustees fulfilled the trust reposed in them with reference to the construction of the Hospital is indi- cated " by the international reputation of the Hospital as a model of hygienic construction, by the influence it has had upon the building of later hospitals, and by the conspicuous place which the plans of the Hospital occupy in recent treatises devoted to the discussion of the methods and problems of hos- pital construction." How successful they were in their plan for the organization of the medical staff of the Hospital and the selection of its members the brilliant record of the work of this staff during [380] 2 the past fifteen years will attest. These years have been years of marvellous advance in medical science and research every- where ; and that the members of the staff of the Johns Hopkins Hospital and Medical School have contributed, to speak with moderation, in a marked degree to this advance is universally admitted. If proof were required of the proud position they occupy, it could be furnished by the action of that venerable seat of learning, Oxford University, in coming to the Johns Hopkins Hospital to take away, much to our regret, our Dr. Osler to make him its Regius Professor of Medicine. One cannot contemplate the growth of this institution, its far-reaching influence, the results accomplished in the brief space of thirty years since Mr. Hopkins died, without a kind- ling of the soul and without being profoundly impressed with the thought that he was right in his belief that his wealth was given to him for a great purpose, and that this purpose he discovered, and that it is being grandly accomplished. The relation of the Johns Hopkins Hospital to the Medical School was determined by the founder of both in these words: " In all your arrangements in relation to this Hospital you will bear constantly in mind that it is my wish and purpose that the institution shall ultimately form a part of the Medical School of that University for which I have made ample pro- vision by my will." The Trustees have sedulously endeavored to follow this injunction. They have kept it in mind in the construction of the Hospital, designing it with special reference to its uses for higher medical education and research; in the organiza- tion of the medical staff, making the professors and teachers in the Medical School their chief officers and advisers; in the liberal policy they have adopted in supplying means for origi- nal investigation, and in supporting the Hospital publications for the dissemination of the knowledge here gained. This building is the latest product of the recognition by the Trustees of the obligation imposed upon them by the founder towards the Medical School and medical education. The growth of the classes in medicine and surgery demanded en- larged clinical accommodations, and for some time the neces- sity of securing better facilities for the surgical work of the [3801 3 [380] Hospital has been brought to the attention of the Trustees. This building is intended to furnish these accommodations and to provide all the facilities necessary for the most modern surgical work. I beg that, as you examine it, you will note how much of it is devoted to teaching purposes. The plans were prepared by an accomplished architect of our city, Mr. George Archer, who has had a large experience in hospital construction, under the direction of the Superintendent and Mr. Charles F. Mayer, the Chairman of the Building Committee, and with many consul- tations with the chief of every department for whose use it was intended. We believe the result obtained will be highly satisfactory, and, like the other buildings at the time of their construction, it will, as the founder wished, compare favorably with any other of like character in this country or in Europe. It is cause for sincere regret that Mr. Mayer, who gave to the details of the plan so much of his time and who was so deeply interested in its construction, has not lived to see its comple- tion. We hope that this building will mark a new era in the advance and work of the Hospital. The present year has been full of vicissitudes in the affairs of this institution. Five of its oldest, most active and useful Trustees have been removed by death. In the early part of January, we were shocked by the sudden death of Mr. John E. Hurst, long a member of the Finance Committee of the Board. The embers of the great fire had scarcely ceased to smolder when the unexpected death of Mr. Mayer, the Chairman of the Building Committee, occurred, at a time when we most needed his services. In August, the sad news came from the North, where he was recuperating, of the death of Mr. William T. Dixon, who had held the position of President of this Board for a period of eleven years, and had only retired from it, as we hoped, temporarily until his health should be restored. He had hardly been laid in his grave when an end came to the life of Mr. Lewis N. Hopkins, who had served the University and the Hospital as Secretary of their respective Boards for many years; and early in September, Mr. Francis White, a member of every important committee of the Board, the trusted friend of Johns Hopkins, and the last survivor of the 4 Trustees selected by him, expired. All of these were deeply interested in the Hospital's welfare and gave of their time and experience to its service without stint and with the most self- sacrificing devotion. Their fidelity to the duty they had undertaken is an inspiring example to their successors. Our fiscal year had hardly opened when the great conflagra- tion which devastated the business center of the city destroyed sixty-four warehouses, stores and office buildings belonging to the Hospital, and we were suddenly brought face to face with a loss of income of sixty thousand dollars a year, arising from the cutting off of the rentals of these properties, and a loss of endowment of about three hundred and eighty thousand dollars. Great anxiety was felt lest it should become necessary to curtail the work of the Hospital. No note of encouragement came to us which touched us more deeply than offers from members of the medical staff and nurses to remit their salaries. Fortunately our anxiety was relieved by the liber- ality of Mr. John D. Rockefeller, who, after having thoroughly familiarized himself with the work and manage- ment of this institution, placed at the disposal of the Trustees five hundred thousand dollars to repair the fire losses and to enable them to go on with its work without diminution. We were and are profoundly grateful for this timely aid. The State also came to our assistance in this time of distress, and the legislature appropriated twenty thousand dollars a year for two years as an offset to our loss of income. With this help the work of the Hospital has gone steadily forward and the Trustees have taken resolute hold of the situ- ation arising out of its properties in the burned district. Already buildings are in course of construction, some ap- proaching completion, or plans are prepared for rebuilding, on more than half of its sixty-four lots. Some have been disposed of to advantage, and we trust that, as a result of the liberality of Mr. Rockefeller and the generosity of the State, the fire may prove after all not to have been a misfortune. The Trustees have many problems to face. Not the least difficult of these is the necessity for an increase in the endow- ment of the Hospital to enable it to grow and develop and [380] [381] 5 [381] occupy the field that lies open to hand. Additional wards are needed to accommodate a larger number of poor patients and to afford greater clinical facilities for the Medical School. A new Children's Ward is required. The Nurses' Home should be enlarged to provide quarters for the increase of nurses made necessary by the growth of the Hospital. The pathological laboratories must be increased in size to meet the increase of students in that important department. The investments of the Hospital's endowment have been watched with the greatest care, and, while there has been some shifting of values, the net result is, that the endowment, received from the executors of Johns Hopkins' will, remains unimpaired, but rates of interest are diminishing, and the growth of the work in every department has been so phenom- enal that the expenses of the Hospital are constantly increasing. How are we to meet them? This will soon become a press- ing question. But we face the future with good courage, confident that this great charity, this Hospital, with its glorious past history, its present opportunities and future prospects, will not be allowed to languish; and as lately in our hour of need a benefactor was found, so in the days that are fast approaching, others, who are seeking to employ well the wealth with which they have been blessed for the largest benefit of mankind, will recognize ihe claims of the Johns Hopkins Hospital and the Atedical School. Dr. W. S. Halsted was introduced and gave a brief account of the educational aims of the building and dwelt especially upon the facilities which it would afford for the teaching of surgery. Dr. Lewis A. Stimson, of New York, Professor of Surgery in Cornell University, then delivered the following address: It is a great privilege to be permitted to take part in the opening of this building, a building devoted to the surgical relief of suffering and to the advancement of the art and science of that relief. In that collocation of terms, sanctioned and sanctified by 6 long usage, the art is named first, and with good reason. The science long had scant title to be named. We have the authority of no less a master of science and the scientific method than Huxley for the statement that they are practi- cally the product of the century that has just ended; and what is true of science in general is much more true of the science of surgery. That has been created within our own times. Half of the men now living and practicing surgery have seen its birth and all its growth. In that creation the men connected with this University have borne a worthy part, and to its advancement a notable part of this building is devoted, a signal recognition not only of the importance of that scientific work, but also of the labors and successes of those who have here done it in the past, and who in doing it have added so much to the honor and the renown of the University. Heretofore that work has been carried on without a specific equipment for the purpose, and this building is a recognition by the Hospital Trustees of the value and importance of the work, of their confidence in those who have carried it on, and of the need of observation, experience, and experiment for the proper advance of the science and the improvement and extension of the art. It must be gratifying to those under whose direction this great University has won so pre-eminent a place to reflect that its surgical division, so widely known and so highly honored as it is, is in fact its own child, that its personnel is of its own upbringing and development, that its reputation and its honor are the crown of its own methods and labors. Before the medical department was established he who is now the head of the surgical division was studying and working in the patho- logical laboratory which so wisely had been made the founda- tion-stone of the complete structure which was to follow. And when a head was sought for the new division, a surgeon for the Hospital and an incumbent for the new chair of surgery, he was found within your own walls, trained in your own methods, imbued with your own ideas, working in full harmony with his associates. His success was immediate and has been continuous. Into the details of Professor Halsted's [381] 7 [381] work and success the time is not now ours to enter, great as they have been, interesting and stimulating as the story would be. It must suffice, here and now, to say that his work has been characterized by industry, thoroughness, an accurate scientific method, and great originality. In everything he has wrought he has stepped out from the beaten path and opened new lines. Uncontrolled by tradition and established practice he has not been content to perfect accepted methods, but he has gone back to underlying principles, and upon that sure foundation has developed ideas and procedures which have been illuminating in their effect upon practice. He has shown the courage of conviction based upon thorough investi- gation, and in the carrying out of his ideas he has protected his patients by an accurate and exhaustive technique to which his own contributions have been most valuable and are now universally accepted. And under him has appeared here, presumably as the result of his influence and example, a corps of junior officers whose work is everywhere acknowledged to be of the greatest value in itself and of rich promise for the future. Although in the world of science all men are kin, and the teaching ranks of one university freely draw upon and are in turn drawn upon by others as the need of enlargement or re- pair arises, yet the possession of such an adjuvant and reserve force as you have here created gives a most comforting assur- ance of your ability to carry on your work not only with unbroken continuity but also almost unchecked even by such a grievous loss as the one you have just sustained and in which we all share. Surely it will be permitted to me to pause for a moment to speak just one word in recognition of all that has been done by him who is leaving you, for medical science and the renown of your University and in appreciation of the personal qualities which have so endeared him to all, and to wish the fullest measure of opportunity and happiness in his new field to your departing colleague, Professor Osler. The revolution effected in the practice of surgery in the last three decades is known to everyone. It has been coincident with and dependent upon the creation and development of a new science, that of bacteriology, and it has been carried to [382] 8 such perfection in detail and technique that it would hardly be thought unreasonable to say that so far as regards the treatment of the wound made by the surgeons no important additional advance is to be anticipated. The surgeon to-day divides almost any tissue, opens any cavity, exposes any region of the body with the confident anticipation that the injury he inflicts will be promptly repaired without danger or perma- nent loss to his patient. This has, of course, enormously extended the field of opera- tive surgery, has brought within the range of relief and cure conditions before which our art formerly stood helpless, and by substituting early inspection during life for tardy inspec- tion after death, it has taught us to recognize disease while still it is relievable, to anticipate and prevent disaster, and to write the natural history of processes of which formerly we knew only the ultimate term. The story is too familiar to permit more than a reference to it in this gathering. Our minds turn instead to the future. We ask in what directions will this laboratory increase our knowledge, and what errors, what exaggerations, if any, what defects of their qualities have grown out of our past progress to interfere with the welfare of those who are to occupy these wards. Some of these problems of the future are concerned with the incompleteness, the occasional failures, of the knowledge already acquired and the methods already established. Others deal with new material. Among the latter the most prominent perhaps is that of the origin and nature of the malignant neoplasms, of cancer, in a word. After making all allowance for possible error by defective records or faulty diagnosis, it seems unquestionable that the importance of this subject is daily increasing through increasing frequency of occurrence and through the gradual extension of the disease to periods of life which have hereto- fore appeared almost immune. The deaths by cancer, in its various forms, now constitute one of the largest groups in our mortality records. We have indeed made some gain in its treatment. We remove it earlier and we remove it more thoroughly; and we can show not only a delay in recurrence, [382] 9 [382] but also a much greater escape from it. And for this, in one of the most prevalent forms of the disease, and voicing, I am sure, the opinion of the whole profession, we have to thank the clear insight, the courage, and the technical skill of Pro- fessor Halsted. But we still remain ignorant of the nature and the cause of this disease, powerless to prevent its appear- ance or to arrest its development, able only somewhat better to do for it what has been done for centuries. And this although many observers have long been actively engaged in its investigation. That its origin in a germ should be suspected was of course inevitable, and not only because of the extent to which the germ theory of disease has occupied our minds and the many cases in which it has been proved, but also because of prominent features in the life history of the disease which seemed to show a close analogy with other diseases in which such causation was fully recog- nized, and of the prospect of gain to the sufferer which such a discovery would open. But the search has thus far been inconclusive, and at present the line of investigation which seems to hold out the best promise is that of physiological chemistry, in the hope that it may disclose some quality in the growth utilizable in the treatment, or in the nature of a toxin produced by it, the effects of which may be successfully combated. Thus far we can say little more than that differ- ences from the normal in the proteids of the growth, and from inflammation in the form of cell-division (Farmer) have been demonstrated. The extension of the study to tumors in the lower animals, notably by the English observers and by Moran and Jensen, together with the success of attempts to trans- plant, justifies the expectation that a much more thorough investigation by experiment is possible, and the hope that our knowledge of the essential nature of the cell-process may thereby be increased. The value of the X-rays in treatment, too, is yet to be measured; meanwhile they have shown that the vital resist- ance of the morbid cells to them is less than that of the normal cells, and thus is suggested a possibly fruitful line of investigation. The remaining problems in wound-infection and sepsis, 10 notwithstanding the enormous gains that have been made, are still of very great importance and complexity. Speaking broadly, we may say that our technique in the treatment of fresh wounds is established and that our success in the pre- vention of their infection is assured. But yet we still have our failures, even our disasters, therein; and in the wide field of wounds infected before they come to us, of patients already septic through one cause or another, our power to save is still sadly restricted. So long as the fight against the bacillus can be waged outside the body it can be won; but when once a lodgment within the body has been effected the bactericidal agents upon which we elsewhere rely with so much confidence cannot always be effectively employed. The natural history of the micro-organisms has long been studied ardently and successfully, and our knowledge of them is now sufficient to make us their master under ordinary con- ditions, and our technique competent to protect our wounds. We do not, and cannot, prevent all access of bacteria, but we can and habitually do limit the number of those which enter to an amount with which the tissues of our patients are usually able successfully to deal. What we do not know, and what we gravely need to know, are those conditions in our patient which nullify the bactericidal power of his tissues and transform them into a soil favorable to the rapid growth and multiplication of specific micro-organisms, to recognize such conditions beforehand if possible, and to combat them success- fully. When the infection is comparatively mild, when it remains for a time measurably local, we can usually overcome it by measures analogous to those which we employ to prevent infection; but when it is violent, when the entire organism is acutely involved, we are comparatively helpless. Serum therapy, which has done so much good in allied con- ditions, has proved ineffectual here. The bacilli of septic infection differ greatly from those others in the products they form, in their action upon the tissues, and in their reaction to remedial agents. The diphtheria bacillus, for example, kills by a toxin which it produces in a localized growth. Under cultivation outside the body it produces an abundant diffus- ible toxin which in turn when introduced into an animal pro- [382] [383] 11 [383] duces an abundant antitoxin, and that antitoxin introduced into the patient neutralizes the toxin there produced by the bacillus and thus saves the patient's life; and as this neutral- ization is effected, so the bacilli cease to multiply and soon disappear. In septicaemia, on the other hand, the micro-organisms rapidly invade all parts of the body and kill not solely by a poison of their own production but by one which results from the combined action of the bacterial and tissue cells. To arrest this process it is not sufficient, so far as we know, to neutralize the poison; the bacilli themselves must first be destroyed. In some allied infections this destruction of the micro-organism can be accomplished by an antitoxin obtained from the blood of an immunized animal aided by a comple- mentary body normally found in the blood of the patient. But the animal immunized against the streptococcus produces the corresponding antitoxin in only very scant quantities, and it finds the necessary complementary body only in the blood of animals of the same species. 'The serum of the immunized rabbit will protect or cure another rabbit; it is practically powerless in man. Even the complementary body found normally in man diminishes in sepsis almost to the point of disappearance, and thus is created another gap in the neces- sary chain. Furthermore, the toxic effect of the streptococcus varies within so wide limits for the same culture that we must infer an explanatory difference in the resistance of the tissues of the individual, a difference the cause of which is only in part known or conjectured. Under the term " resistance " is of course to be included the capacity of the organism promptly and effectively to rid itself of the poisons manufactured within it by the bacilli, or possibly by the tissue cells under influences which bring about a perversion of metabolism. Illustrative examples can be found by every surgeon in his own experience. A simple, almost minor, operation which suggests no thought of danger is followed by the rapid de- velopment of a high temperature and early death with no evidence of more infection than would ordinarily be easily overcome. Or in another, less simple, less free from infection, 12 a general condition promptly supervenes which indicates a fatal arrest of the eliminatory, or a grave alteration of some intermediate function. The habitual gravity of puerperal sepsis can hardly be fairly attributed to the virulence of the infecting streptococcus; it suggests rather a change in the soil, a change presumably dependent upon the entrance of the organism upon the function of gestation; and the grave modi- fication or the arrest of the function of the liver or the kidney under the action of agents that can affect it only mediately through the nervous system shows a delicacy of balance which should impose upon us a watchful reserve in those classes of cases in which interference has shown itself most likely to affect it. And how shall we explain, and how guard our patients against those overwhelming intoxications which occur so promptly when tissues have been half killed, when the circu- lation still goes on through them? Studies of cell ferments show the possibility of sudden and complete inhibition or reversal of function of the ferments in the internal organs, and the detailed study of the nitrogenous excretion may reasonably be expected to lead to a clearer understanding of the cases and possibly to prevention or cure. Such cases can be thoroughly worked up only by the col- laboration of experts in several branches. They need not only the clinician and the pathologist, but also the bacteriologist and the physiological chemist; and such collaboration can hardly be provided by a hospital which is not connected with a well-equipped institution of learning. It is, however, prac- ticable here, and such is now your opportunity. The work that has been so well done in the past is a guarantee that your enlarged opportunities will be appreciated and utilized. In these instances of problems awaiting solution which have been mentioned the functions of the laboratory are mainly concerned, and it is but natural that so marked a step for the advancement of our science, so notable a provision for the sound establishment and furtherance of our art as its creation should attract attention. But we do not forget that it has been created and that it will be maintained by you for the benefit of suffering humanity, and that in the adjoining [383] 13 [383] I wards, in the work of the clinician, is to be found the reason for the existence of the laboratory, the end and the object of the work to be done in it. The observation which does not lead to the reduction of physical ill, the promotion of health, the relief of suffering, has no right to be deemed a part of medical science. The laboratory is the handmaiden of the ward, and its achievements must be controlled and tested by the clinician and must derive their final crown of honor from the use which he can make of them. And while it is his correlative duty to suggest lines of investigation and to familiarize himself with what is there gained, he remembers that this is but one of the many sources from which he must draw aid and information, one of the many fields which his vision must survey, and that he himself must supply much of the material for and indicate many of the lines of investigation. And rich and brilliant as the clinical record of the past is in advances made and obstacles overcome by the aid of the laboratory, it contains also many an equally notable one accomplished entirely within its own field, many a valuable addition or supplement to the results of laboratory research, or explanation of what there remained obscure. Let me briefly recall in illustration the work done by one man in one disease. Is there any disease to-day more widely known, more banal, than appendicitis? Its occurrence is so frequent, its recogni- tion is so easy, its treatment is so successful that the concep- tion of its danger has slipped into the background, and the surgeon's interest in it has even become a part of the stock in trade of the professional humorist. And yet, less than two decades ago it was known clinically as a disease that was generally fatal, and known pathologically only in its late, its most advanced form, and even there but incompletely known and with no conception, clinical or pathological, of the common mode of origin and of the means of recognition in the stage in which it is now habitually met and overcome. The profession spoke of, and the books described as separate and distinct affections, typhlitis or caecitis, caecal retention, perityphlitis, paratyphlitis, gangrene or perforation of the appendix, acute idiopathic peritonitis, and intestinal obstruc- [384] 14 tion, with no grasp, without even a suspicion of the causal relation which makes them all parts of one nosological entity, and they disputed only from time to time whether the peri- typhlitic abscess was extra- or intra-peritoneal. The treat- ment was limited to opium and expectation, to be followed, if the patient survived long enough, by a surgical evacuation of the abscess if that could be accomplished without an ex- posure of the peritoneum to what was deemed an inevitably fatal contact with its contents. In the remarkable paper read by Dr. Reginald Fitz before the Association of American Physicians in 1886, in which the word appendicitis was, I believe, first spoken and which did so much not only to call attention to the subject but also to clear the way to a full understanding and a rational and successful treatment, conditions of the appendix which we now know to be the consequences of the disease were spoken of as causal conditions, and in the discussion which followed he said " So impressed have I been with the obscurity of the signs of incipient inflammation of the appendix that no attempt has been made to consider the process until there was evidence that perforation had taken place." Too much praise, too hearty a recognition cannot be given to this paper which deserves always to hold a high place in our grateful remembrance. It was written by a physician for physicians, but it clearly showed the surgical need and opportunity and commanded the surgical attention which so promptly followed and which furnished the information needed to complete our knowledge and to establish a success- ful method of treatment, and which, it should also be noted, added so much to the development of the surgery of the abdomen and to our understanding of the pathology of in- flammations of the peritoneal cavity. About a year after the publication of Dr. Fitz's paper, Dr. Sands did the first operation for the prompt relief of a per- foration of the appendix into the abdominal cavity and re- ported it in a paper which, while containing some current erroneous conceptions, pointed out in the clear and trenchant manner so characteristic of that great surgeon the surgical 1884] 15 [384] need and opportunity in that class of cases and the manner in which they could be properly met. In the few months of life which remained to him Dr. Sands actively pursued the study of the subject in conjunction with Dr. McBurney, wrho immediately succeeded him as surgeon of Roosevelt Hospital, a position which during his incumbency became the most influential center of surgical teaching in New York. His clinics were frequented by men already in practice, and this added largely in the rapid spread of his opinions through the medical community. Opportunity mul- tiplied rapidly and its first fruit appeared in a paper read by Dr. McBurney before the New York Surgical Society in November, 1889 (N. Y. Medical Journal, December 21, 1889), followed a year later by another on the " Indications for Early Laparotomy in Appendicitis " read before the Medical Society of the State of New York in February, 1891. In these papers, based wholly on clinical experience, Dr. McBurney gave what was essentially a complete picture of the disease in its pathology, course, symptoms, and treatment. Synthesis was substituted for differentiation, and the widely different conditions previously subjected to separate consider- ation were brought together under one rubric and shown to be diverging developments of processes originating in a common cause. The great frequency of this initiatory condition was demonstrated, and the means by which it could be readily and surely recognized and safely and efficiently treated before it had progressed to those perilous conditions in which alone it had previously been recognized, were described in detail with the support of a large and successful experience. He showed not only that the means of recognition of the early condition were so accurate as fully to justify anticipation of its rapid and dangerous progress and to demand active treatment, but a]so that the treatment recommended, the immediate removal of the affected organ, was vastly safer than expectation, even if the comparison included the mild cases which recover unaided within a few days. It was shown also that the same plan of treatment, inci- sion directly into the abdominal cavity, was also the best for the later and the intermediate stages, that even as a means [385] 16 of exploration to determine the presence or absence of pus, upon which operative interference had previously stood wait- ing on the brink, it was safer than the exploratory needle puncture which had previously been employed, and that it also offered the safest means of treating the abscess if one should be found. His cases showed that pus could be safely evacuated across the peritoneal cavity, that its contact with the peritoneum was less dangerous than the prolongation of its retention beside it while awaiting its progress toward the surface or its spontaneous opening into the bowel, and that, finally, in the latest stages, the same free incision held out the best chance of recovery by the drainage and the relief of tension which it supplied. A little later he devised a method of operating which pre- served the full strength of the abdominal wall and thus removed an objection to the early and possibly avoidable operation which had been urged with some persistence and force. It is not easy for one who did not work in the antecedent period to appreciate the vast relief that came from this sim- plification of the problem, from the easy and early recogni- tion of the disease and from the removal of the doubts and hesitation which embarrassed treatment. The relief was immediate and widespread and was felt even more by the physician than by the surgeon. It has wrought inestimable good, and the story, which well deserves to be told at much greater length than is here permissible, is a constant stimulus to thorough, intelligent, and conscientious labor. Finally, in the future, it seems to me, the part of opera- tive surgery will be somewTiat lessened, at least relatively. 1 trust it will not be misunderstood if I say that in some respects we might be compared to one whose position has been changed by an unexpected inheritance from poverty to affluence, and who does not at first fully grasp the limitations or the responsibilities of wealth. We suddenly found our- selves able to do with great safety things which previously had carried great risk, a risk which often was prohibitive. It was natural, and proper, that that gain in our resources should be pushed to the utmost, that we should enjoy all that [385J 17 1385] it could properly give, and that its limitations should be established by experience. To that first exuberance, to the feeling that any operation might properly be undertaken be- cause the wound would heal kindly, is succeeding a more reserved attitude. We appreciate that even if a wound heals well, the tissue that has been repaired after our cutting is not always as sound as if it had not been put in need of repair. To the hopeful expansion of the frontiers of our operative interference is succeeding the less dramatic but equally useful elaboration and perfectioning of what has been acquired, and the recognition of the conditions and limita- tions of the advance. We hear less often the argument " He will surely die if we do nothing; let us therefore operate." We appreciate that of two evils it is a less one that our patient should die of his disease than that he should die of our attempt to cure him. Our exploratory work, too, is more closely restricted to obtaining only such information as can be utilized in treatment, and less is done which though harm- less is also without benefit. There is so much necessary and legitimate operating to be done that we are freed from the insidious temptation to add to our numerical record and spurred to improve our results. The future is rich in promise that is almost within our grasp, promise of advance in our science and promise of help to those who are in need of our art. And to you who have builded and to you who are to make use of what has been built, I wish a hearty Godspeed in the illustrious and benefi- cent work which lies before you and of which your past offers so sound a guarantee. Dr. T. Clifford Allbutt, Regius Professor of Physic at the University of Cambridge, England, after congratulating the Hospital upon the erection of a building which promised to do much to advance clinical teaching, spoke briefly of the relations of medicine and surgery. Dr. A. Jacobi, of New York, spoke as follows: I am not here to sail under a false flag. Dr. Welch has just said that I have been a teacher of his, but. for two dozen 18 years at least he has been so to me, as well as to the profes- sion of the United States and of Europe. Now, statistics prove that provincials have a tendency to crowd into centers. No wonder then that I, like the wise men of the East, come at this time to the shrine of Johns Hopkins. In appreciation ■of that fact your good and great men have consented to give me an opportunity to prove that I am not a good extempora- neous speaker. Indeed words fail me to express my feeling at such an occasion as this. There is no necessity for me to repeat what the new buildings that have been inaugurated to-day stand for. They will do a great deal for medicine, a great deal for Johns Hopkins, and a great deal for the world of science through the Johns Hopkins. Through the Johns Hopkins I say, for in the last quarter of a century, indeed even in less time, Johns Hopkins has succeeded in proving itself one of the head centers of the world and of science. It has largely contributed to the rapid changes that have taken place in medicine. Up to half a century ago it was an art only. It has since developed into art and science, and grown not only in its theories, but also in practice and usefulness. That is what Cicero meant when he said that all our glory was of no use unless what we did was useful, and also our own Benjamin Franklin, who claimed that all philosophy was useless unless it could be put to some use in the interest of mankind. That was the way Rudolph Virchow looked at medicine and at science in general. Many of you were present thirteen years ago when his seventieth birthday was celebrated in this very Johns Hop- kins. At that time we learned a great deal about that great man whom some of us had not known. He was really a greater man than Aristotle for Aristotle with all his gifts and accomplishments, was only a great naturalist. He was a greater man than was von Haller, for Haller knowing everything knowable did not have the immense horizon of Virchow. I like to speak of Virchow, because he has been my example and he has been that example to all those who now live and those that will come after us as one of the greatest men, not only in medicine, but in man's history. He saw, like Sokrates and Kant, the future welfare of man- |385] [386] 19 1386] kind in medicine. He created the best in general and special science that Johns Hopkins stands for. As a pathologist he elucidated the cause and seat of illness. As a therapeutist, acknowledging that we arc in a new era of therapy, he believed in drugs, but more in schools, education, culture, good roads, industry, and all the demands and bless- ings of democracy. He was the apostle of sanitation and prevention, and promoted the hygiene, physical, moral and mental-of the individual, the city, the state and mankind. As a humanitarian he claimed that the physician was the attorney of the rich and poor alike, and the guardian of all social problems. As a statesman he found no trifle too small, no great aim inaccessible. To him it was as important a law to help, as to fight one another. We cannot all be Virchows. But next to accomplishing a great goal, comes the earnest wish to accomplish it. The best the young medical men of the nation can do is attempt it. There is much to do in every direction. Do not forget illness is not confined to individuals; human society is still abnormal and diseased. There must be remedies for them all. Though the best of us be more or less impotent, we should be aware that there must be means to reach every reasonable end. Cure and prevention are required for the individual and for mankind. There is no better way to them than through medicine. That is what I wish I could impress upon the minds of you, the young men to whom the future belongs with all its privileges and responsibilities. And I know of no better way to medicine than through Johns Hopkins. I am glad to be here to participate in these exercises, as a deeply interested listener, to congratulate the teachers upon having greater facilities to instruct, the students upon their improved opportunities to learn, and the city of Baltimore upon the new glory in store for it. With all that, I have to thank those who have established these institutions for this new foundation by which they have added new accommoda- tions for the sick, rich and poor, and a benefaction to man- kind. 20 Dr. D. C. Gilman, ex-President of the Johns Hopkins Uni- versity, was introduced by Prof. Welch as the first Director ■of the Hospital, he having held that position upon the organi- zation and opening of the Hospital in May, 1889. Dr. Gilman humorously acknowledged the introductory remarks of Dr. Welch, and then called attention to three points which might be emphasized at the close of this hour: First, we should remember that it was the munificence of one person, a lady now present, which enabled the Johns Hopkins authorities to establish this Medical School. After years of waiting for the lack of sufficient funds, she made possible what many had hoped for. In her presence I will not venture to say all that would be appropriate under other circumstances, but I am sure you will gladly be reminded that it was a great, untrammeled and generous gift from Miss Mary E. Garrett, which initiated this school of medi- cine and prepared the way for the rich fruits of medical skill and knowledge which have been rehearsed by the speakers before me. (Applause.) Next, let me remind you that the good results which have here been attained, results that are good not only for the suf- ferers here relieved, but for suffering humanity everywhere, these results have been reached by the harmonious co-opera- tion of three institutions, the University, the Hospital, and the Medical School. I do not know where you can find an exact parallel to this union. The University from its inception laid its plans for the encouragement of those branches of natural science, physics, chemistry and biology which underlie the science of medicine and in other ways it upheld the ideal of broad liberal culture. Then came the Hospital so finely endowed, so admirably arranged, so well administered, and so well manned by dis- tinguished physicians and surgeons. Then came the Medical School. These three sisters may be likened to the ancient statue with which you are familiar, three Graces with arms intertwined and hands locked. Neither one without the other could accomplish so much. [386] 21 Third, after all the key to the success of this institution, has been the maintenance of lofty ideals from the very begin- ning. When Dr. Welch was here alone, when he was joined by Dr. Osler and Dr. Halsted, and soon afterward by Dr. Kelly, all the way through, the loftiest ideals have been up- held. 1 believe they always will be while the spirit of Dr. Hurd and President Remsen pervades these institutions. Look at Boston, New York, Philadelphia, Cleveland, Chicago, California, and other centers of medical science and hospital practice, and you will find in all these places young men trained under the teachers here assembled. Their knowledge has gone out to all the world. Even the University of Oxford comes to Baltimore for a torch-bearer. Finally, let me remind you that it is the individual student who goes out from among us who shows what this institution is. We are soon to unveil a memorial to Lazear, dear Lazear, who sacrificed his life for the good of mankind, and not long hence, in Washington, another Johns Hopkins man is to be honored by a great memorial, Major Walter Reed. If this University, if this Medical School, if this Hospital had pro- duced these two men only it would be worth all the cost. Young men, emulate their examples. Live up to the lofty ideals brought before you by your teachers, the great and the wise, the learned and the skillful. After an inspection of the buildings a luncheon was served at 1.30 P. M. in the Administration Building, and at 3 P. M. the audience reassembled in the clinical amphitheatre to wit- ness the unveiling of a tablet to Dr. Jesse W. Lazear, a former officer of the Johns Hopkins Hospital, who died in Cuba of yellow fever in 1900. Dr. William Osler presided and spoke as follows: It has been well said that Milton's poem Lycidas touches the high-water mark of English poetry; I do not know but that it may be said the high-water mark of all poetry. This is true not only because the poem appeals to us by its intrinsic merit and worth, but because it touches that chord in each one [386] [387] 22 of us which responds at the personal loss of some young man to whom we had become attached. Those of us who have got on in years mourn many young fellows whom we have seen stricken by our sides. We have had in this Hospital fortunately only a few such losses. We have lost on the medical side Meredith Reese, Oppenheimer and Ochsner, and we have also lost a man of rare worth, in whose memory we meet to-day, whose story will be told you by Or. Carroll and Dr. Thayer, Jesse William Lazear, a Baltimore boy, a Hop- kins graduate of the Academic Department, a graduate of Columbia University in Medicine and a resident physician of this Hospital, the first man to take charge of our clinical laboratory, who, in Cuba, sacrificed his life in the cause of humanity. Assistant Surgeon James Carroll, representing the United States Army Medical Corps, was then introduced and spoke as follows: As a member of the Army Medical Department and a former associate of Dr. Jesse W. Lazear, I am proud to join you in honoring the memory of one to whom the State of Maryland, the Johns Hopkins University and the United States Army may point with genuine pride and affection. Acting Assistant Surgeon Lazear was the first person to pro- duce an undoubted case of experimental yellow fever with the mosquito and it was he who first worked out the key to our present knowledge that we can control this devastating disease which has been justly designated the plague of the American continent. Because of his previous experience while working with Dr. William Sidney Thayer, in the study of malaria-transmitting mosquitoes, Dr. Lazear was chosen to conduct the first mosquito experiments of the Army Yellow Fever Board, and as the result of his own individual work he enjoyed the satis- faction of producing the two first authentic cases of experi- mental yellow fever on record. Then with a full knowledge of the power of the insect to convey the disease, he afterwards calmly permitted a stray mosquito that had alighted upon his hand in a yellow fever ward, to take its fill, and inject into [387] 23 [387] his system the virus that twelve clays later robbed him of his life. About a month prior to this he had deliberately applied to his person with negative result another mosquito of the genus Stegomyia that had bitten a yellow fever patient ten days before. It is true that in the present instance he did not think the insect belonged to the genus that had been shown to convey the disease, but who could say at that time that more than one genus would not convey it? He made no attempt to capture or preserve the mosquito nor did he make any record of the fact that he was bitten, nevertheless the fact remains that he deliberately submitted to the bite, and accepted all the chances that went with it, whether of infec- tion with yellow fever, filariasis or what not. As soon, how- ever, as the nature of his infection was established he at once appreciated the significance of the bite to which he had submitted; he then related the circumstance to me, emphasiz- ing his belief that the insect was not a Culex fasciatus, but, as he expressed it, " a common ordinary brown mosquito," in which the hospital at that time abounded. This statement is not so surprising if we remember that the markings of different Stegomyias of the same species may vary greatly in their distinctness, and that some of the wards of Las Animas Hospital were heavily shaded by foliage and were very dark, especially in the corners, where some of the beds were located. Under such conditions the markings of an old insect might readily escape observation. It is very sad for those who knew Dr. Lazear to contem- plate the loss to his family and to the profession, of one so true, so energetic, so gifted, so well equipped and so ambi- tious, but thanks to the efforts of his friends in this Univer- sity his memory will be preserved by the handsome and fitting memorial dedicated to him to-day and his achievement will stand as a monumental stimulus to other young men, who will have imbibed their hunger for knowledge from the same fount as he, and who will go forth imbued with the same intense desire to relieve suffering and to acquire further knowledge for the benefit of the human race. The value to the United States alone of the work that he began can be estimated in millions and I hope the time is not far distant 24 when the beautiful city of Havana will display a suitable monument to him who accomplished the first step in proving Dr. Finlay's theory of the transmission of yellow fever by the mosquito, and who laid down his life in the actual prosecu- tion of that work. At the time the Army Board met on the 26th of June, 1900, Dr. Lazear had been on the Island several months, and during that time he had fearlessly visited and studied a number of cases of yellow fever both during life and after death, not in the army alone, but among the civil population as well. He had taken many cultures at autopsies and had studied many films of blood, stained and unstained, so that he was already able to say with confidence that cultures and blood examinations promised nothing of unusual interest. Dr. Lazear was indefatigable and his labors were fre- quently prolonged into the night in the little cottage where he lived alone in happy anticipation of a visit from his beloved wife and family. Owing to the strict quarantine that was maintained, there w'ere but few cases of yellow fever at Columbia Barracks and it was necessary for him to visit Las Animas Hospital, about five miles distant, in the suburbs of the city of Havana. It was here, while applying mosquitoes to a patient, that he received the fatal bite on September 13, 1900. Five days later on the evening of September 18, at eight and eleven o'clock P. M., he suffered two chills and was found in bed with fever next morning. I examined his blood for malarial parasites twice on the 18th and again on the morning of the 19th, each time with negative result. This, together with the clinical symptoms, made the diagnosing fairly conclusive, and in accordance with the custom he was then removed to the yellow fever isolation camp. Before his removal he turned over to me his notes covering all the attempts at mosquito inoculation and told me of his own experience of which he had made no record. For three days he barely held his own, then the gravity of his symptoms increased, black vomit supervened, he became delirious, and death closed the scene one week from the day of onset. Thus ended a life of brilliant promise at the early age of [387] [388] 25 [388] thirty-four. Dr. Lazear died in order that his fellow-men might live in happiness and comfort. We know that only last year, when one thousand cases of yellow fever occurred in Texas, the scenes of 1878 would have been repeated in the South but for the work that was begun by him. It is no exaggeration to say that hundreds, nay perhaps thousands, in the southern states to-day unconsciously owe their lives, cer- tainly their prosperity, to the results of the work in which he was engaged and for which he and his family have paid such a fearful penalty. The world lost in him a benefactor; the profession a man of high attainments, noble character and lovable disposition; words cannot measure the loss to his widow and orphans, the younger of whom he had never seen. This grand University will always be proud of Lazear, whose name will forever be associated with that of Reed in the history of the transmission of yellow fever. Dr. William S. Thayer then said: As we meet to-day to dedicate this plate to the memory of our dear colleague, it seems but yesterday that Lazear told me of his desire to make use of the advantages which service in Cuba offered for the study of malaria and other tropical diseases and of the opportunities which had been held out to him by authorities of the army. It was, indeed, but five years ago. But in another sense how far away that time seems. For, as it ever is with truly great discoveries, the blessings of which are immediately appreciated by all mankind, certainty and enlightenment soon dull the memory of the groping past and we almost forget that the time ever was when this knowl- edge was not ours. And if we estimate the length of his life by the results which he helped to achieve, the day that Lazear left for Cuba was, truly, long ago, and the few months which remained for him to live, measure up to a riper lifetime than that which lies before many of us more fortunate to-day in the eyes of the world. Of the four names connected with the noble work of the Yellow Fever Commission, two were of men who were 26 students, associates or comrades of those of us who remember the Johns Hopkins Hospital fourteen years ago. Alas, neither is with us to-day! Both Reed and Lazear worked in these laboratories and wards, walked these corridors and lived under this roof, and both were deservedly loved by their col- leagues and friends. It is not for me to-day to speak of Reed, of whose simple, noble, upright character, of whose fine quali- ties and achievements you all know, but I would say a few words of Lazear as a man and a friend. Born near Balti- more, where his mother still lives, Lazear graduated from the Academic Department of the Johns Hopkins University. Studying medicine at Columbia, he afterwards served two years at the Bellevue Hospital in New York. After the term of his hospital service he spent a year in Europe, in part at the Pasteur Institute in Paris, after which he served a year as bacteriologist to the medical staff of this Hospital. In 1896 he married and began the practice of medicine in Baltimore. Holding the position of assistant in clinical microscopy in the University, much of his time was spent in research work in the clinical laboratory. During his interne- ship he had succeeded, for the first time, in isolating the diplococcus of Neisser in pure culture from the circulating blood in a case of ulcerative endocarditis. The three years which followed were devoted mainly to the study of questions concerning the malarial parasites. Lazear was the first in this country to confirm and elaborate the studies of Roman- ovsky and others concerning the intimate structure of the luematozoaof malaria, the work appearing unfortunately some time after its accomplishment and, indeed, after his death. He was, with W oolley and myself, the first in this country to partly confirm the work of Ross and the Italians on the mosquito cycle of the malarial parasites. These studies in particular fitted him for the work which the Yellow Fever Commission was to undertake in Cuba, and the part which he played in that work was essential and important. But of this Dr. Carroll has already spoken. I wish, especially for the younger men here, that I might be able to picture to you Lazear as a man and a companion. [388 27 [388] Quiet, retiring and modest, almost to a fault, he was yet essentially a manly man with a good, vigorous temper, well controlled, and rare physical courage. He was one who made his own plans and worked out his own problems; with a deep love of his profession and an ardent desire to make adequate contributions to its advance. He always seemed to me a man of promise, and but a few weeks before his death, I had warmly recommended him for the vacant chair of medicine in a northern university. When the news of his cruel death became known, there were those who blamed what they regarded as unjustified temerity, who felt that such risks were not for married men. With this I cannot agree. No man loved his family more than Lazear; but he was engaged in a great work-and he knew it-in a work where at the moment no substitute could take his place. Lazear saw his duty clearly and where he saw his duty fear and doubt could not enter in. A few well-known lines of Emerson tell the whole story: " Though love repine, and reason chafe, There came a voice without reply, ' 'Tis man's perdition to be safe, When for the truth he ought to die.' " It was that voice which guided Lazear as it has guided in the past and will guide in the future many a good and brave man. (The tablet was then unveiled.) 1 may add a few words about the history of this plate. Shortly after Hr. Lazear's death many of his friends wished to have a fitting memorial for him in some way connected with this Hospital with which he had been identified, and subscriptions were asked for a fund. We had no thought of collecting a large sum of money but in a very short time nearly twenty-five hundred dollars were subscribed. With a small part of this sum this plate has been secured while the rest constitutes a fund for the benefit of the children of Dr. Lazear. Foremost in the movement for collecting this fund [389] 28 was Dr. Stewart Paton, who regrets, I know, very deeply that [389] he may not be here to-day. The inscription upon this plate wTas written by President Eliot of Harvard University. • « Ik Memory of Jesse William Lazear Born 2 May u«e at Baltimore Graduated in arts at the Johns Hopkins University in wbs ano in Medicine at Columbia University in wsr In I8SS-S6 assistant Resident physician in the Johns Hopkins Hospital Member of theYellovi Fever commission in isoo with the rank of Acting Assistant Surgeon re died of yellow fever at quemados Cuba ss September isoo. With more than rue courmcf and bewwr w the SOLPIER HE RISKED AND LOST HIS LIFE TO SHOW ROW A. FEARFUL PESniENrB IS CWMONICATEP AKO HOW ITS , RAVAVES MAY BE PREVENTED. , 29