SOME EXPERIMENTS TO DETERMINE THE LESION IN QUININEBLINDNESS. A PRELIMINARY NOTE. BY G. E. de SCHWEINITZ, M.D., OPHTHALMIC SURGEON TO THE PHILADELPHIA AND CHILDREN'S HOSPITALS: OPHTHALMOLOGIST TO THE INFIRMARY FOR NERVOUS DISEASES. REPRINTED FROM TRANSACTIONS, 1890. SOME EXPERIMENTS TO DETERMINE THE LESION IN QUININE-BLINDNESS. A Preliminary Note. By G. E. de SCHWEINITZ, M.D., OPHTHALMIC SURGEON TO THE PHILADELPHIA AND CHILDREN'S HOSPITALS J OPHTHALMOLOGIST TO THE INFIRMARY FOR NERVOUS DISEASES. [Read November 5, 1890.] The characteristic clinical features of the cases of quinine amaurosis, summarized by Knapp {Archives of Ophthalmology, vol. x. p. 220) as total blindness subsequent to taking large quantities of quinine, pallor of the optic disks, marked dim- inution of the retinal bloodvessels in number and calibre, and contraction of the visual fields, have been especially elaborated by American ophthalmic surgeons from the time when Roosa's report appeared up to the date of the analysis by Atkinson {Journal of the American Medical Association, September 28, 1889). These features are so definite that blindness from the abuse of quinine is an established fact, and it now remains to be shown exactly what the lesion is, and what its position, which causes the loss of vision. Buller {Transactions of the American Ophthalmological Association, 1881, p. 262) believes the locus of the morbid process is to be found in one of three situations: (1) within the cranial cavity; (2) within the eye; and (3) in the course of the optic nerve between the chiasm and the eyeball. He rejects the first two of these posi- tions, and thinks that the latter affords the best explana- tion, by assuming a rapid effusion into the lymph-spaces around the nerves, too transient to cause papillitis, but sufii- 2 G. E. DE SCHWEINITZ, cient to induce oedema and blanching of the retinae and im- pediment in the blood-carrying capacity of the central arteries. Edgar A. Browne (Transactions of the Ophthalmological Society of the United Kingdom, vol. vii. p. 193) points out the resem- blance of the subjective symptoms to embolism of the central artery of the retina, but shows that such a theory is untenable. He further indicates the probable local nature of the retinal anaemia, the influence of the vasomotor system, and the absence of perineuritis,1 and suggests the possible influence of highly cinchonized blood upon a peripheral circulation, causing suffi- cient contraction to prevent the ingress of blood. It is obvious, as Buller has said, that uncomplicated cases of quinine-blind- ness are rarely encountered in human beings, because this drug is not administered to them in sufficient dose to produce amaurosis, unless some disease calling for its exhibition is present. Thus, in Browne's collection of thirteen cases, the following diseases were present: intermittent fever, pernicious fever, septicaemia, pneumonia, neuralgia, malaria, and drunken- ness. Exceptions to this are the instances when the alkaloid has been taken by mistake, one of which is given by Browne, and the case of a man described by Giacomani, who took three drachms of quinine, instead of cream of tartar, to relieve con- stipation. This example, as Dr. Gruening has pointed out, presents the value of a physiological experiment. As the opportunity for examining such cases has been rarely pre- sented, the best method of studying this problem is to induce quinine-blindness in animals, observe the early ophthalmoscopic appearances, and microscopically to study the optic nerves, chiasm, and cortical centres of vision. With this end in view, the following experiments were undertaken. In all dogs were used whose general condition was healthy, and whose fundus oculi was shown by ophthalmoscopic examination to be normal. The quinine was administered hypodermically in solutions made from the bimuriate of quinine combined with 1 Dickinson's case of tumefaction of the optic nerve, resembling " choked disk," was probably caused by some factor (possibly malaria) other than quinine. LESIONS IN QUININE-BLINDNESS. 3 carbamide of urea, or in the form of the bisulphate dissolved with the aid of tartaric acid : Experiment 1.-March 13, 4 p.m. Dog A, weight 16 pounds. Sixty grains of quinine injected beneath the skin. An hour later the dog vomited several times, and dragged its hind legs. Twelve hours later the dog was blind. 14^, 4 P. M. Dog entirely blind ; pupils widely dilated and irresponsive to light; the disk pallid and retinal vessels contracted. 15ZA, 12 M. The same state of affairs. 16^/i. Blindness continues. There is slight clouding or mellowing of edges of disks. 19^A. Dog entirely blind. Optic nerves whitish, edges clear, vessels much contracted. 29th. Sufficient recovery of sight only to keep him from walking into large objects; perhaps familiarity with room explains this. Optic nerves pale, vessels small. April 11. No further recovery of sight. Killed, and eyes, chiasm, optic tracts, and occipital lobes of brain removed and placed in Muller's fluid. Experiment 2.-March 17, 4 p. m. Dog B, weight 15 pounds. Hypo- dermic injection of one drachm of quinine. Previous examination showed normal pupils and fundus oculi. 18<7i. No general symptoms except great weakness when put into kennel between 6 and 7 P. M., apparently "not seeing anything well" (statement of attendant). 18tA. Dog found dead at 6 A. M. Eyes, optic chiasm, occipital lobes removed and put in Muller's fluid. Experiment 3.-March 19, 4 p. m. Dog C, weight 10 pounds. Thirty grains of quinine given hypodermically. In ten minutes the hind legs were dragged, the dog was partially paraplegic and staggered in his gait. At 4.30 P. M. the animal vomited and purged several times. At 5 P. M. he was weak, dazed, and apparently partially blind and deaf. 20th. Entirely blind at 6 a.m. At 3 P. M. clonic spasms followed by paralysis of the hind legs. The retinal veins not much changed in size ; the arteries mere threads. 21st Completely blind and paralyzed. Killed, and the usual organs removed and placed in Muller's fluid. Experiment 4 -March 22. Dog D, weight 25 pounds. Twenty-five grains of quinine given at 4 P. M. Normal fundus oculi. 24tA. Dog completely blind ; the arteries of the retina small, the disk pale, and in the right eye the upper vein just before it left the disk showed a constriction very much as if a thrombus had formed. No similar change in other eye and no hemorrhages. The dog's eyes were prominent (slight exophthalmus), and the pupils widely dilated and irresponsive. 4 G. E. DE SCHWEINITZ, 25th. Dog completely blind. In right eye the circle of veins on the disk completely obliterated, the arteries faint threads. No similar change in left eye. The dog was killed, and the usual organs removed and placed in Muller's fluid.1 Experiment 5.-March 24, 4 p. m. Dog E, weight 23 pounds. Thirty- two grains of salicylate of sodium were given hypodermically. 25th, 4 P. M. No results in any way from the salicylate of sodium. The same dog was given twenty-five grains of quinine. 26th. No effect from the quinine. This is the first dog unaffected by a similar dose. Thirty additional grains were injected. 21th. Dog completely blind. Paresis of hind legs. 2Mh. Some return of vision. Optic disks pale, and arteries small. 31s£. The apparent slight return of sight remains; fundus oculi as before. The animal was killed at 5 P. M., and the usual organs placed in Muller's fluid. Experiment 6.-April 1, 4 p. m. Dog F, weight 16 pounds. Thirty grains of quinine injected. 3d. No effect in vision or general condition. Thirty additional grains injected April 9th. Although this dog has received sixty grains there is no effect of the quinine on the vision. Thirty more grains injected. lOtA. Shortly after the injection of April 9th, tremblings and paralysis of the hind legs appeared. To-day, at 10 A. M., clonic convulsions began, and, shortly afterward, the animal died. It was difficult to decide the amount of the blindness, owing to the convulsions; this seemed complete. The eyes were removed and placed in Muller's fluid. Experiment 1.-April 5, 4 p. m. Dog G, weight 20 pounds. One drachm of quinine was injected. The next day the laboratory was closed, and on the 7th the animal was found dead. The effect of the drug upon the vision was not ascertained, and the usual organs were not removed. Experiment 8.-April 15, 4 p.m. A normal dog was killed, and the usual organs removed for microscopical examination and comparison with the portions taken from the " quinine dogs." From this record it becomes evident that when quinine is given hypodermically to dogs in quantities varying from one grain to the pound to four grains to the pound, blindness, generally accompanied by the other disturbance, is apparent in from three to fourteen hours. The exact date of the onset of the loss of vision was not determined; the earliest date of 1 This experiment is interesting in connection with the observation made by Voorhies in his case, where, one week after the poisoning, the disk was perfectly white and there was not a trace of optic-nerve vessels. LESIONS IN Q U 1 NI NE - BLIN DN E SS. 5 its appearance after injection which was noted is three hours. The blindness remained practically complete in one animal for twenty-nine days after a single injection of 3f grains to the pound; in one there was slight return of vision after thirty- six hours of blindness. The effects of the drug were more surely and quickly obtained with quin, bimur. carbamidat. than when the bisulphate was used. A dose exceeding 3| grains to the pound produced death (Experiment 2); one animal (Experiment 7) perished from a dose of 3 grains to the pound; and one dog (Experiment 6) resisted 1^ grains of quinine to the pound given on two successive days, but suc- cumbed when a third similarly proportioned dose was admin- istered. In a single experiment (Experiment 5) salicylate of soda, in the proportion of 1| grains to the pound, produced no results on vision. In these animals the ophthalmoscopic picture was similar to that seen among human beings with quinine amaurosis, and in one there was complete obliteration of the vessels on the optic disk, and in another blurring of the edges of the optic disks. In all, the pupils were immovably dilated. The specimens which were removed for microscopical ex- amination were prepared by hardening in Muller's fluid, and sectioned by the parafline method. The stains were borax carmine and indigo carmine, and degenerations were sought for by the aid of Weigert's method. All of the preparation of the sections was carefully done by Dr. William M. Gray, in the laboratory of the Army Medical Museum. In brief, it may be stated that no very gross lesions, with one exception, were present in either the cross-sections of the nerves or in the optic-nerve entrance, or the retina. The ex- ceptions were those sections taken from the right eye of dog D, Experiment 4. Here there was decided dilatation of the bloodvessels, and the central vein was plugged with a clot containing many fibrin prolongations, while in the transverse cuts of the vein white thrombi are seen (Fig. 1). Thus, micro- scopically it was demonstrated what previously had been noticed with the ophthalmoscope, namely, the appearances as 6 G. E. BE SCHWEINITZ, Optic-nerve entrance, showing clot in central vein, with its fibrin prolongations and white thrombi in smaller veins. Fig. 1. LESIONS IN QUININE-BLINDNESS. 7 if a thrombus had formed. In the other nerve-entrances there was some dilatation of the bloodvessels, but to a very much B, cross-section of optic nerve from a dog a, showing spreading apart of the individual fibrils. Fig. 2. Ai cross-section of normal optic nerve. smaller decree. The transverse cuts of the nerves did not exhibit anv marked lesion. In a few there seemed to be some 8 G. E. DE SCHWE1NITZ, slight increase of the connective tissue; in others, the nerve- bundles between the trabeculae of connective tissue were wider than those of the normal animal; or, in other words, the trabeculae themselves were less marked and the individual fibrils more spread apart, as if the tissue was cedematous and swollen out (Fig. 2). There were no discovered lesions in the retinas. Weigert's stain failed to show any such degeneration as might have been present from an atrophy; neither was there any appearance indicating neuritis. The optic chiasms were normal in every respect. In the sections taken from the cuneus, in all instances the same lesion was present, namely, a remarkable dilatation of the pericellular lymph-spaces, with degeneration of the proto- plasm of the cells. This lesion was probably most marked in the dog that had been longest blind. In presenting this fact, I do so perfectly aware that imperfections in the hardening process might be responsible for equal appearances. I simply state this as a fact, and am unprepared to support it in any way as rendering definite knowledge of the lesion in quinine- blindness. I am exactly in the position of him who has found associated with a certain disease a microorganism, but who has been unable to prove more than this association. Very many more experiments and very many more careful com- parative microscopical studies must be made to show positively that any of the various lesions which I have described exist constantly in quinine-blindness, and these few have been re- corded as results so far obtained in a research which is only in its infancy. Numerous experiments are now under way the results of which will be detailed in a future paper. So far as the microscope is concerned, it may be said that, with the single exception of the blood-clot found in the central vein, no absolutely positive microscopic lesion was made out- that is, none that might not possibly be attributed to imperfec- tions in technique. As negative evidence, however, it may be stated that even in dogs blind for nearly a month there is no atrophy of the nerve-fibres in the sense in which we ordi- narily use that word; neither is there any appearance in the LESIONS IN QUININE-BLINDNESS. 9 earliest stage of the blindness of neuritis. It is not improbable that the conjectures of those who have placed the lesion be- tween the optic nerve and the chiasm and eyeball have come near the truth, and that there is really a species of oedema. At the same time the influence of quinine upon the peripheral circulation must not be forgotten ; and the fact, as I have shown microscopically, that under its influence a clot may form in the central vessel. Probably this is an extreme case, and should such an example arise in a human being, recovery from the blindness would not be obtained.