rS^ CORNELL UNIVERSITY. ■^r\ THE GIFT OF ROSWELL P. FLOWER FOR THE USE OF THE N. Y. STATE VETERINARY COLLEGE. 1897 ^&tm?mmJl,«^ account of M. Pasteur' 3 1924 003 366 204 Cornell University Library The original of tliis bool< is in tine Cornell University Library. There are no known copyright restrictions in the United States on the use of the text. http://www.archive.org/details/cu31924003366204 HYDROPHOBIA <3LcX'buj9 PRINTFJ) ET SPOTTISWOODE AKD CO., XEW-STKEET SQTTARE LONDON HYDROPHOBIA AN ACCOUNT OF M, PASTEUR'S SYSTEM CONTAINING A TRANSLATION OF ALL HIS COMMUNICATIONS ON THE SUBJECT, THE TECHNIQUE OF HIS METHOD, AND THE LATEST STATISTICAL RESULTS RENAUD SUZOR M.B., CM. Edin. & M.D. Paris Commissioned hy the Government o/ the Colony of Manritin to study M. Pasteur's n^w Treatment in Paris WITH SEVEN ILLUSTRATIONS li'ouboit CHATTO & WINDUS, PICCADILLY 1887 [ The right of traftslation is resettled ©raicfulls l)c6icatcb TO HIS EXCELLENCY SIE JOHN POPE HENNESSY, K.C.M.G. &c. GOVEENOR OF MAURITIUS AND TO THE HON. MEMBERS OF THE LEGISLATIVE COUNCIL OF THAT COLONY. In tLeir zeal for the cause of science and of humanity, His Excellency moved, and the Members of Council unanimously voted, that a delegate should be appointed to study M. Pasteur's new treatment of Hydrophobia in Paris. May that first example set by a small Colony not remain sterile. The Delegate, THE AUTHOR Paris : July 21, 1887. CONTENTS. ciiAP'ren Pisj. I. A Short Desckiption of Hydkophobia feom the Eabliest Times down to the End of 1880 . . 1 II. JI. Pastedk's Communications on Hydrophobia . . 31 I.I. Techsiqce of the Method, etc 159 HYDROPHOBIA. CHAPTEE I. A SHORT DESCRIPTION OF HYDROPHOBIA FROM THE EARLIEST TIMES DOWN TO THE END OF 1880. Seven years ago, in 1880, rabies or hydrophobia had already been known, dreaded, and studied, in Europe, for more than 2,000 years. Countless authors had written upon it, beginning, so far as we can ascertain, with Democritus in the fifth century B.C., down to and including many living men of mark. Yet all our knowledge of it could be summarised in a very few pages. The disease, at first circumscribed, to all appearances, within a few limited geographical areas, had, with in- creasing facilities of intercommunication between nations, gradually spread to nearly every country of the globe, irrespective of latitude or longitude. It raged, with varying intensity, at all seasons of the year, and often assumed the proportions of an epidemic. It was occasionally met with in herbi- B 2 HYDROPHOBIA vorous animals : the ox, the horse, the sheep ; in swine and in birds more rarely ; commonest of all in the carnivora : the cat, the fox, the jackal, the wolf, and the dog. It always originated in the latter — in what manner, spontaneously or other- wise, was not and is not yet known — and spread from them by contact and direct inoculation, by a bite oftenest, to the herbivora and to man. The poison deposited in the wound lay incu- bative for a period varying from a few days to several months, and possibly even to several years. Then, having silently crept up and invaded the nervous centres, it suddenly broke out into a train of terrific symptoms, uniformly terminating in death about the fourth day, by asphyxia or by syn- cope, sudden stoppage of the heart. During that long and hopeless agony the patient's intellect kept clear and even brightened, and his affective senti- ments became more vivid than ever, circumstances which all tended to add to the horror of the pic- ture. Indeed, the very name of the scourge evoked in the popular mind in an unequalled de- gree the sombre image of fate, mysterious, awful, and inevitable. Not all died who had been bitten by rabid ani- mals, but only a certain varying proportion, as we A SHORT DESCRIPTION 3 shall see later on by quoting a few figures. Those who escaped death still had to live for years with a feeling as of the sword of Damocles ever hanging over their heads, an uncertainty of life which led not a few to commit suicide. As in all similar cases, everything had been thought of and used as remedial agents. In par- ticular shall we refer to blood-letting ad deliquiuvi, to exposure to a high temperature and excessive sweating, to mercury (Daniel Johnson, 1829), curare, electricity and revulsion all along the spinal column. Unfortunately, however, in the vast majority of re- ported cases of so-called cure by those or other means the diagnosis is far from unimpeachable. But on the other hand there is no doubt as to the efficiency of the preventive treatment first pro- pounded by Celsus in the first century of our era, and than which none better had been devised up to our own day. He recommended, to sum up, the use, immediately after the bite, of free suction of the wound, then its thorough cauterisation by means of the hot iron. But seldom only could this treatment, in actual practice, be applied with sufficient boldness and thoroughness, or soon enough after the accident. And thus the percent- age of deaths still ran very high. B 2 4 HYDROPHOBIA Police regulations also, by diminishing the total number of dogs in a country, and by enforcing the better supervision of those that remained, contri- buted efficiently to lessen the number of casualties, as evidenced in the cases of Germany and of the Scandinavian peninsula, where the number of deaths from hydrophobia has gradually gone down from year to year until it is at present only counted by units.' And yet, withal, small epidemics were ever and anon starting up afresh, and the malady retained intact aU its old terrors. As the late Professor Bouley justly remarked, any positive knowledge we had gained in the general study of hydrophobia was limited to its causation, morbid anatomy, and history. The therapeutic phase had not dawned yet, and many thoughtful authors considered it as lying indefinitely beyond our reach. Experimental researches into the nature, the seat, and the proper- ties of the virus of rabies had often been under- taken, but had only yielded very scanty results. Somewhere about the year 1870 they were re- sumed with increased accuracy, not uninfluenced certainly by the lessons already taught by Pasteur on the micro-organisms and their importance in ' In Norway the dog-tax is about 12s. a year in the country. It is higher still in the towns. A SHORT DESCRIPTION 5 pathology. Hallier, Klebs, and many others be- lieved they had found the microbe of rabies. More recently Pol, of Geneva, and Dowdeswell, of London, announced a similar discovery. But the question is still unsettled and the microbe to be isolated. Numerous experimenters, in every country, tried in- oculative experiments, and accumulated interesting although too often contradictory facts. Paul Bert as- certained that the substance of the salivary glands was always virulent, as also, to a high degree, the bronchial mucus. Nocard, of Alfort, dialysed the pure saliva of rabid dogs, and showed that its solid elements were always virulent and reproduced the disease when injected into healthy animals, while the liquid portion, similarly injected, remained inactive. Brown- Sequard and Duboue insisted on the importance of the nervous element in hydrophobia, and the former calls it ' an ascending neuritis.' Magendie had already discovered that dogs could be rendered refractory to rabies as produced by dog-bites. He got a first mad dog to bite a second healthy one ; this in turn when mad a third one, and so on. The periods of incubation became longer and longer, and the fourth or fifth dog failed to take the disease. That interesting fact remained useless and was soon completely forgotten. Galtier, 6 HYDROPHOBIA of Lyons, confirmed by Bouchard and others, showed that the lymphatic fluid was constantly virulent ; the blood had long before been proved to be innocuous when injected into animals. The same author reproduced the malady in rabbits by inserting small pieces of the brain and medulla of rabid dogs under their skin. He for the first time studied hydrophobia in the rabbit, and found that : ' The rabbit in which rabies is developing itself remains quiet and low-spirited, often sleepy, more rarely agitated and frightened by the slightest sound. From the very outset there is well-marked weakness, sometimes locaUsed in the first instance to the lumbar region, the hind limbs, and even the cervical region ; soon it creeps and invades the whole body, and then it is gradually replaced by paralysis. All the movements of the animal are difficult, irregular, ill-defined, and soon become quite impossible. It walks in a sort of crawling way, the fore-limbs dragging the hind ones, which have become quite helpless. After the first few hours it is almost always possible to notice a series of contractions, sudden, convulsive, and frequent, in the limbs, the trunk, the cervical region, the muscles of mastication ; in many cases there is also present an unceasing chewing movement. A SHORT DESCRIPTION 7 General sensibility is gradually dulled and is some- times quite lost, so that it becomes possible to thrust a pin into the animal without giving rise to any reaction on its part. Sight is lost or perverted, the eye becomes gradually less and less sensitive, the conjunctiva is congested, and the cornea, the . aqueous and vitreous humours, dull and cloudy. Some of the animals groan and utter loud cries of distress if suddenly displaced or taken up by the ears or legs. ' The sense of taste appears to be also perverted, for they are seen swallowing fragments of straw and of faecal matter, and to lick the floor of their cage. ' As a rule they do not try to bite. In one case, however, the animal had a tendency to do so, in particular when worried.^ There is an abundant flow of sahva. Thirst and hunger have disappeared, or, when the subject tries still to drink or to eat, there soon supervenes a moment when deglutition is quite impossible. ' The circulation of the blood is irregular and the ■pulse beats from 109 to 200 a minute. ' The urine is scanty or is only expelled at the time ' A Eussian laboratory assistant was actually bitten by a rabid rabbit. He had, however, been previously vaccinated, and re- mains well. 8 HYDROPHOBIA of death, so that the bladder is found after death to be at times full, at other times empty.' He con- cludes : ' 1 . Dog-madness can be transferred to the rabbit, which thus becomes a convenient and safe reagent enabling us to find out the virulence or non-viru- lence of various fluids taken from rabid animals. I have often used it in that capacity for the study of the different sorts of saliva (parotidean, sub- maxillary, &c.) and of a number of other Uquids taken from rabid dogs, sheep, and rabbits. ' 2. Eabbit-madness can be transferred to other animals of the same species ; but I cannot as yet say whether the rabies-virus of the rabbit is equally virulent with that of the dog. ' 3. The predominating symptoms of rabies in the rabbit are of the paralytic and convulsive types. ' 4. The rabbit can survive from a few hours to one, two, three, and even four days, after the symptoms of rabies have clearly manifested them- selves. ' 5. Not only is the rabbit susceptible of taking rabies and of surviving a certain time after the malady has broken out, but it is also a constant fact, judging from my experiments, that the period of incubation is shorter in this animal than in any A SHORT DESCRIPTION g other one ; and this, I repeat, makes of it a most valuable reagent, enabling us to ascertain the viru- lence of this or that liquid.' He then quotes twenty-five cases of experi- mental rabies in the rabbit giving an 'average in- cubation of eighteen days ; also an experiment with sahcyKc acid, proving that that substance is quite inefficient — used by the hypodermic way — in preventing the development of the disease; and finally, he states that the sahva taken from a live mad dog, and kept mixed with water, was still virulent after twenty-four, and even thirty-six hours. We may now give a skort list of the main signs by which it is possible to make the diagnosis of rabies in the dog. The disease shows itself in one of two forms : — 1. Furious or delirious madness; by far the commonest. 2. Dumb madness. In the furious form note : (a) A change in the usual ways and habits of the animal. He becomes dull and voiceless, crouches down in dark and quiet corners. He tries to sleep, but is often disturbed in his sleep as if by painful dreams and delusions ; he rises and walks about, then lies down again. He is in a continuous state lo HYDROPHOBIA of restlessness and agitation. In some cases he is not agitated, but sleepy and careless of whatever is going on near him. If disturbed, he growls and shows no inclination to stir. In either case he still obeys the voice of his master and has no tendency to bite yet. The agitation increases. In his kennel he piles up the straw, lays his chest on it, then rises in anger and scatters the litter about. In apartments he tears and tosses the cushions, carpets, &c. Oc- casionally there is a manifestation of intense and unwonted attachment to some other animal, or to the people of the household ; or he is seen constantly to lick cold objects (Delabere-Blaine). He is haunted by visions and hallucinations, he barks, snaps, and growls at imaginary beings (Touatt). But still he knows and obeys the voice of his master and has no tendency to bite him. Nevertheless, his saliva is already virulent, and his caresses dangerous. The saliva is virulent eight days, and possibly longer, before the disease is plainly evident. Often, too, even in this early stage, dogs will bite a stick thrust at them. So also will they often bite people when worried but slightly. (6) The mad dog has no horror of or repulsion for water. On the contrary, at all periods of the A SHORT DESCRIPTION ii malady he drinks eagerly or tries to drink. When he fails to swallow the water it is only owing to spasmodic contraction of his throat. The appetite may be at first and for a short time increased. But very soon it diminishes and is quite lost and replaced by marked disgust for all kinds of ordinary food and a thorough perversion of the sense of taste. He tears everything that he meets, carpets, trees, grass, and swallows fragments of anything, including his own excreta, urine, earth, bits of straw, chips of wood, anything. As a con- sequence of this there is not unfrequently present a certain quantity of blood in the vomited matter, vomiting being a common phenomenon at this stage. The saliva of the mad dog is not usually over-abun- dant, and may even be quite normal in quantity. (c) The bark of the mad dog is quite character- istic, and is never forgotten when it has been heard once. Bouley says of it : ' Instead of bursting out with its usual sonority and of being made up of a succession of notes equal in duration and in in- tensity, it is hoarse, veiled, lower in tone, and after a first full-mouthed bark there follows immediately a succession of five, six, or eight howls coming far back from the throat and during which the jaws are never completely closed, as they are ordinarily 12 HYDROPHOBIA after each bark.' It is not unlike the voice of dogs chasing a hare; it is something intermediate between a bark and a howl, made up of the two, with something more added, strange and sinister. (i) The sight of another dog at once and almost invariably puts the mad dog in a fit of passion. This is, therefore, an easy and valuable test method. The same effect is produced by the sight of a dog on all rabid animals, to whatever species they belong, including the sheep. Man alone perhaps constitutes an exception to the rule. Eenault quotes the case of a horse rendered rabid by inoculation from a sheep. This animal when shown a dog remained careless, but when a sheep — a healthy one — was brought in, he grew quite furious and tore it to pieces. This case stands solitary. This symptom has, of course, most value in the case of dogs which are naturally tame and non-aggressive in disposition. The mad dog is analgesic, i.e., his general sensi- bility is blunted to a considerable degree. He now seems to feel only the very in tensest pains. He no longer expresses pain by the usual nasal sound or the sharp cry which is so familiar. He can be beaten, pricked, and even slightly burnt, without stirring and without uttering any sound at all. If A SHORT DESCRIPTION 73 severely burnt he moves to another place, but still remains mute although the face becomes expressive of pain. This fact explains the cases in which dogs which were later on ascertained to be mad were seen to bite and tear at their own limbs and bodies. There is often present a certain degree of hyper- sesthesia at the seat of the bite, if the dog has been bitten by a rabid animal, shown by his constant rubbing, licking, or biting of the part, the leg, the ear, on which, on examination, there is found nothing capable of explaining the facts observed, except, perhaps, a smaU cicatrix. The same phenomenon is often met with in other animals and in man, shortly before the onset of the disease. The sexual instincts also are greatly excited and increased. (e) Confirmed Rabies. — In a few cases the animal remains tame and unaggressive to the end, but as a rule he is in a state of delirious rage about which there can be no mistake as to its significance. He bites and tears at everything thrown at him if he is chained or in a cage. He attacks furiously all animals that come within reach, later on man also, more rarely his own master. The pupils are dilated and the whole face bears an expression of terrible fierceness. Whilst biting and tearing he 14 HYDROPHOBIA is always silent, unlike the non-rabid dog who fights and barks all at once. He always, in preference, attacks animals rather than man. He often leaves home and wanders far away. From a distance he shows nothing peculiar, has his ordinary gait, and his tail instead of being held between the legs, as so often asserted, is kept high and wagging. Later on, when tired, he walks with a tottering gait, the head low, the tongue hanging out of the mouth, covered with blood and dust, and the tail falling helpless. His sight, as well as his other senses, is now dulled, and he is much less dangerous. Still he can bite, however, and is to be dreaded. After wandering about for a few hours, or it may be days, he often comes home again. At last, on the fifth day or thereabout, emaciated and worn out by repeated attacks of fightful fury and the want of food, paralysed in the hind-quarters, he dies from sheer exhaustion and asphyxia. Dumb-madness. — Inoculations of this form of madness often reproduce the disease in its furious form, and vice versd, showing that the two are only different manifestations of one and the same malady. The stages a, b, c, are very much the same as in the furious type, perhaps less marked. Then, {d, e), the voice is quite lost, and even in the A SHORT DESCRIPTION 15 first stages it is more exclusively a howl, with no admixture of the bark. The mouth is constantly gaping, owing to the paralysis of the lower jaw ; the eyes open, without expression, constantly fixed in the same direction. The predominant symptoms are muscular weakness and cerebral depression. The animal is constantly lying down or sleepy, has neither the wUl nor the power to bite. His sahva is quite as virulent as in the other form. In the immense majority of cases hydrophobia in the dog ends fatally ; a few exceptional cases are, however, on record when the disease, spontaneously or under the influence of medical treatment — namely, submersion in cold water until asphyxia is nearly complete, bleeding, enemata — gradually dis- appeared and a cure was effected. On post-mortem examination the main points of interest are the following : dark blue and almost black colour of the tongue and of the whole mucous membrane of the mouth. In the stomach some discoloration of the lining membrane, presence often of a black hquid, like coffee dregs ; presence also of a collection of heterogeneous materials not usually swallowed by healthy dogs : hairs, straw, wood, coal, ashes, bits of carpeting, earth, &c. Blaine, Youatt, and others note this last sign in almost 1 6 HYDROPHOBIA every case ; Bruckmiiller, of Vienna, only in fifty- four per cent, of his observations. Congestion of the lungs, of the central nervous system (BruckmuUer), extreme retraction of the bladder, are frequent but by no means constant or characteristic phenomena. The duration of incubation is less than two months in more than eighty per cent, of the cases ; very seldom longer than six months ; eleven months in one case related by Touatt. In the cat many of the symptoms of rabies forcibly recall to mind those we have already noted in the dog. It will therefore not be necessary to refer to them in detail, and it will be enough to add that this animal, like the wolf, very generally directs his attacks to the head and face. Wounds on those regions are particularly dangerous, as pointed out by all statistics. The general precautionary measures best cal- culated to diminish the number of hydrophobic animals and to increase the security of the public from that terrible disease, are thus summed up by Bouley : — 1. Declaration to the authorities, by the pro- prietor, of any distemper in his animals, which can in any way be suspected of being rabies. A SHORT DESCRIPTION 17 2. Immediate locking up of such animals, by the proprietor himself. 3. Destruction by the police of all rabid animals, and of all others bitten by such. 4. Compulsory locking up, under police super- vision, and for a period of time not less than eight months, of all animals suspected of having been bitten by a rabid animal. Immediate destruction is always to be preferred, however. 5. All dogs constantly to wear round their neck a collar with their police number and the name and address of the proprietor. 6. All dogs left free to wander about, to wear an efficient muzzle. 7. All dogs to be stopped which do not fulfil the preceding two conditions. 8. Destruction of all dogs so stopped, after the lapse of a certain time, if not claimed. Such animals ought never to be sold or bought. 9. Male animals to be taxed more heavily than females. 10. Blunting of the teeth, so as to render the bites less virulent, like those of herbivorous animals whose teeth oftenest simply crush the tissues and do not penetrate them. (Bourrel). In man hydrophobia assumes the same two c 1 8 HYDROPHOBIA forms as in the dog — viz. the delirious and the paralytic, the former being by far the commoner of the two. The delirious form can be subdivided into three stages : (a) Melancholia. — Towards the end of the period of incubation the patient, whether he is aware of the impending danger or not, child or adult, becomes sad, taciturn, shuns all society. He suffers constantly from the iatensest headache, and at night his sleep is disturbed by terrible dreams of very varied character. There are occasionally some itching or even painful sensations at the seat of the bite. This period is not always present, and seldom lasts more than four or five days. There is now also, in some cases, an irresistible impulse to walk or to run. In such exceptional cases of mus- cular excitement there is also found occasionally a state of mental irritability instead of the usual melancholy. (b) Excitement. Hydrophobia proper. — The breathing becomes difficult, laboured. Inspiration is cut up by frequent sighs. Gradually all the muscles receiving their nervous supply from the medulla oblongata (the part of the nervous axis wherein the brain and spinal cord become con- A SHORT DESCRIPTION 19 nected) become implicated, and there are produced the peculiar spasmodic contractions of the pharynx and larynx. General hypersesthesia (or increased activity) of all the senses, horror of water and of all bright objects, of the lightest draught of air, of the slightest sound or smell. Convulsive fits. On the second or third day there supervenes the frequent symptom of ' sputation,' — the mouth, at first dry, now becomes moist and watery, filled with frothy mucus. There are frequent hallucinations of sight, of hearing. The voice is hoarse, convulsive, spas- modic, and may simulate the bark or howl of a dog. During the convulsive attacks the patient often hurts and bruises himself, and has still the tendency to run away from home. These attacks may alter- nate with fits of melancholia and manifestations of great despondency. The temperature rises, as in tetanus, and may still increase for one hour after death (Peter) ; up to 43° C. (Joffroy). (c) Paralysis of all the senses, and finally of the intellect also, and death from exhaustion and paralysis of the respiratory and circulatory centres. Hydrophobia in man can be confounded with hysteria, tetanus, epilepsy, delirium tremens, and certain forms of acute mania. It has sometimes been identified with ursemia or blood-poisoning from c2 20 HYDROPHOBIA kidney disease. It will be enough, in order to avoid confusion with the last-named affection, to remember that in hydrophobia the temperature rises as death approaches ; in uraemia it always goes down below the normal. The type of the convulsions, the mental disorder, and the abnormalities of general and special sensibility, are very different in the two. The paralytic form of rabies in man is much less common than the one just described. Never- theless, in the second number of the ' Annales de I'lnstitut Pasteur,' Dr. Gamaleia, of Odessa, from whom is borrowed this description, publishes an account of about thirty such cases. He finds that they are generally the result of deep and multiple bites : ' Onset by a strong fever, general malaise and aching, headache and vomiting, as in all acute in- fectious diseases. Such an onset is very frequent also in cases of ordinary rabies. In all the patients whose temperatures were taken, there was found, at a certain period of the malady, a high degree of fever. ' Then come a train of localised pains, generally in the limbs bitten, and girdle pains at different heights of the vertebral column. These localised A SHORT DESCRIPTION 21 premonitory pains are rare in the lower limbs (Brouardel). 'Next supervene a degree of numbness of the senses, fibrillar contractions, ataxy, paresis, and then paralysis more or less complete of the muscles first implicated. General sensibility remains intact, or, if it disappear, it does so very much later. ' Then the paralysis spreads, preceded or accom- panied by sharp pain in the muscles invaded ; the remaining limbs, the trunk, the rectum, and bladder, the face, the tongue, the eyes, are all paralysed. So also, sooner or later, and more or less completely, the respiratory centre, the implication of which brings about a marked change in the inspiratory phase of the patient's breathing, and, as a corollary, some difficulty in swallowing liquids (the so-called great symptom of hydrophobia, or horror of water, being a result much more of the imagination of the patient and of the medical man, than of the rabies virus). ' When well-marked, this respiratory lesion is the cause of dyspnoeic convulsions in the muscles which are not yet paralysed. Then, frequently, return of the breathing to the normal, but spread of the paralysis to the heart and death by syncope.' This form of rabies has a duration of seven days and a half on an average. 22 HYDROPHOBIA The same author concludes that the virus, from the study of the symptoms detailed, can only spread by the nerves, from the periphery or ex- ternal surfaces to the centre. He also insists on the necessity of giving up the old notion of incura- bility of rabies when once developed, although he does not himself quote any authentic case of re- covery, his main argument being based on the fact that rabies is not so common or so severe in its symptoms in man as in the dog, and yet there are on record cases of undoubted recovery in the latter animal. The medical man ' ought to cease aiding on the virus by morphia ; he ought, on the contrary, to help the nervous system in its struggle against the all-invading virus, to assist the organism in bear- ing up against the momentary arrest of, the vital functions (e.g. by artificial respiration).' In that train of reasoning hypodermic injections of strych- nine might at any rate be tried. On post-mortem examination the lesions of main interest are found to lie in the central nervous system. The nerve-cells are cloudy and granular ; general congestion of the nerve-centres, the blood- vessels being, dilated and ruptured here and there, giving rise to small haemorrhages ; miliary abscesses throughout the substance of the medulla oblongata, A SHORT DESCRIPTION 23 more sparsely in that of the brain and cord ; foci of finely granular matter infiltrating the normal nervous element, the peri-vascular lymph spaces and the walls of the blood-vessels which are com- pressed and assume a monUiform or beaded aspect ; hyaline thrombi or blood-clots form in their interior at the level of those compressed points, the whole giving the appearance of a nodule or small tubercle in the interior of which Klebs thought he had dis- covered the specific micrococcus. Eoss, of Manchester, finds that the lesions are most marked around the central canal, but the anterior and posterior horns and the grey matter throughout is largely implicated also, mainly so perhaps. The same author draws attention to this interesting fact, that in tetanus and rabies the lesions are very similar, but that in the former case they are chiefly spinal, in the latter cerebral, in their main localisations (?). The ganglia of the sympathetic system and the nerve-roots show the same lesions as the brain and cord. The nerves, and in particular those of the part bitten, those rising from the medulla: the vagi, the glosso-pharyngeal, the hypoglossal, the spinal accessory, the phrenic, have been found red and hypersemic, swollen, and the seat of minute foci of 24 HYDROPHOBIA haemorrhage ; ' the myelin is diffluent, fragmented, and in many nerve fibres the axis cylinder has altogether disappeared. (Wagner, Krukenberg, Cheadle.) The lungs' 'are red and congested, here and there the seat of small haemorrhages, filled with frothy mucus formed at the time of death, for there were no auscultation signs of its presence during life. Very generally also some interstitial and subpleural emphysema. Those pulmonary lesions, just like the liquid venous-black state of the blood, seem to be the result of the terminal asphyxia (Brouardel). Note also in some cases : haemorrhages in the muscular tissue of the heart ; parenchymatous nephritis ; congestion and swelling of the lymphatic glands, with the terminal leucocythaemia ; softness of the spleen and liver, the latter being in a state of fatty degeneration — all those forcibly remind one of the lesions found in other well-known in- fectious diseases, variola, scarlatina, septicemia. Incubation in Ma7i. — Professor Brouardel quotes several trustworthy statistics, and in particular one in ' Portions of those nerves, inoculated, reproduce the disease. It would thus seem that the virus proceeded at first from the periphery to the centre, and secondarily from the centre to the periphery. A SHORT DESCRIPTION 25 ■which, out of 170 cases, rabies showed itself within the first three months in 147 cases ; and a second one in which 73 times out of 97 cases the disease declared itself within the same period. He con- cludes : ' Eabies supervenes ofteneSt in the course of the second month after infection ; rarely after the third month, quite exceptionally after the sixth month.' The more numerous the bites, and the greater their gravity, the earher do the symptoms appear. They manifest themselves earlier also in children than in old people. Prom statistics drawn by Tardieu, Bouley, and the French Committee of Hygiene or Board of Health, as well as those published by medical men, the same author finds that after efficient and early cauterisation the death-rate amounts to 30 per cent, of the cases, rising to 80 per cent, in the cases where there was no cauterisation at all or where it was insufficient or tardy. The actual figures are sUghtly above those here mentioned. Efficient cau- terisation is that effected by means of the hot iron, concentrated sulphuric, nitric, or carbolic acid, or the chloride of antimony and the acid nitrate of mercury, and applied less than one hour after the accident. Before applying the caustic it is often advisable to open up the wound well and 26 HYDROPHOBIA freely by means of a knife. Occasionally ampu- tation of a finger or of a limb will have to be considered. Under the age of twenty, 31 per cent, of persons bitten die of hydrophobia ; the proportion rises to 62 per cent, above that age. For wolf bites, Eenault finds that, out of 254 individuals bitten, 164 died of hydrophobia, that is, about two-thirds. Dr. du Mesnil having collected accounts of over 800 cases of bites by mad wolves, found a death-rate from hydrophobia of 65 per cent. For bites by mad dogs Eenault gives the per- centage of deaths as being one-third of the total number bitten. Statistics based on 383 cases collected by Bouley between 1862 and 1868, and by the Comite d'Hygiene from that date up to 1872 give a death-rate of 47 per cent. (180 out of 388). Faber, in the kingdom of Wurtemberg, finds only 28 deaths out of 145 people bitten — i.e. 20 per cent. Some Viennese statistics give a death-rate of 11 per cent. ; another counts 25 deaths for 125 cases. In Austria, in 1860, out of 115 persons bitten, 25 took hydrophobia— i.e. 22 per cent. Leblanc notes only five deaths out of 36 cases where the biting dogs had been diagnosed rabid at A SHORT DESCRIPTION 27 the Alfort Veterinary School — 15 per cent. In all those cases we are unfortunately not told how late after the accidents the tables were drawn up. If Bouley's figures seem to be perhaps too high, pos- sibly because certain cases not followed by death were not reported, some of the other statistics, on the other hand, seem to remain below the truth. The Comite d'Hygiene give the following figures for the years 1862-72 :— No. Deaths Percentage Bites on the face .... „ hands .... „ trunk .... „ arms .... legs .... Multiple (face, hands, &o.) Total 50 113 22 40 33 8 44 76 7 12 7 6 88 67-25 31-81 30 21-21 266 152 Those figures do not give an exact expression of facts, but' they are still of great use ia indicating very fairly in what direction the truth lies. Mr, Alfred Poland puts down the death-rate as being 1 in 4 — i.e. 25 percent. ; Dr. and Mr. Gamgee sayit varies from 5 to 55 per cent. Professor Gowers, in Quain's ' Dictionary of Medicine,' says : ' When no preventive measures are adopted, at least half. 28 HYDROPHOBIA perhaps two-thirds, of persons bitten escape. The immunity may be due partly to the bites being inflicted through clothes ; partly to individual in- susceptibility which has been found to exist in animals as well as in man.' These statements agree perfectly with those of the French authors. As to the time of the year when rabies is commonest, it is sufficiently pointed out in the following table, pubhshed by Dr. Pasca, of Milan (1865) :— June, July, August 14 March, April, May 35 December, January, February . . . .14 September, October, November . . .25 Such was the state, very briefly summarised, of our knowledge of hydrophobia, when in December 1880 M. Pasteur's attention was called by M. Lannelongue to the case of a httle girl who was dying of that disease in his ward at the Hopital Sainte-Eugenie. M. Pasteur had now for many years been devoting his whole energies to the investigation of maladies confined almost exclusively to animals, and with what extraordinary amount of success most people have heard. They formed a necessary stepping- stone to the study of the more complex problems A SHORT DESCRIPTION 29 of human diseases, for they left more scope for free experimentation and the acquisition thereby of great familiarity with such questions. The two classes of diseases, moreover, not unfrequently merge into one, being simply propagated frCm animal to man, and more or less modified in the latter. Experimentation, ingenious and critical, and an intuition of things, a manner of scientific conscience, developed to an unusual degree and suggesting the right choice out of many possible ones, added to which great perseverance and un- shaken faith in results thus patiently come to, such are the main elements of M. Pasteur's strength. A new era was now dawning in the history of hydrophobia, and more was done for it in the next few years than had been reahsed in the previous ages. Light was thrown upon many obscure points of its natural history ; but, most important of all, the possibility of its prophylactic treatment in man, based on results already secured in animals in the analogous cases of splenic fever, the fowl-cholera, the swine-plague, and other maladies, was now announced for the first time. This early announce- ment was soon justified, and shown to be not only possible but probable, from the results of numerous experiments on dogs and other animals. In 1885 30 HYDROPHOBIA it was actually applied to the human subject. But we must not anticipate. Those results were published in a series of communications made to the Academie des Sciences. They are so concise that we can do no better than translate them, only aiming in our rendering at being as faithful to the original as possible. We shall next give a detailed account of all we saw and learnt at the two laboratories of Eue d'Ulm and Eue Vauquelin, during our stay of many months at those two places, summing up with the statistics of all cases treated by the new method, and a few general remarks. 31 CHAPTEE II. M. pastede's communications on hydrophobia. I. January 24, 1881. — On a New Malady produced by the Saliva of a Child ivlio died of Rabies. Note by M. L. Pasteur, with the Collaboration of Messrs. Chamberland and Roux. This note deals with the experiments under- taken with the saliva of the child who died in Mr. Lannelongue's ward. This saliva, injected into dogs and rabbits, gave rise in them to a new and fatal disease, not to rabies. We shall, accordingly, not translate the article, although it is of great in- terest. M. Pasteur here expresses the idea that the new disease may possibly be the form assumed in animals by human rabies. A specific microbe had been, isolated and cultivated. He foresees the possibility of vaccinating dogs against hydrophobia, and thus indirectly preserving man himself. 11. May 30,1881. — The Academy may remember that we began the study of hydrophobia in the month 32 HYDROPHOBIA of December last, assisted by Messrs. Chamberland and Eoux, whom M. Thuillier kindly joined. By comparing the external symptoms of that malady with certain microscopical observations made on the brains of persons or animals who had died of hydrophobia, and by considering that it has not as yet been possible to communicate the affection by inoculation of the blood of rabid individuals, several authors were led to the belief that the central nervous system, and in particular the me- dulla oblongata, which joins the spinal cord to the brain and cerebellum, are specially interested and active in the development of the disease. This opinion was upheld with great distinction, two years ago, by Dr. Duboue. Nevertheless, the Lyons experiments leave room for much uncertainty as to the true seat of elaboration of the rabid virus. ' The rabid virus,' says the learned experimenter, ' exists in the saliva, as all know. But where does it come from ? Where is it elaborated ? . . . ' Hitherto I have only been able to detect the presence of the virus in the mad dog, in the lingual glands and in the bucco-pharyngeal mucous mem- brane. 'More than ten times, and always with the same want of- success, have I inoculated the sub- M. PASTEUR'S COMMUNICATIONS 33 stance extracted by compression from the brain, cerebellum, and medulla oblongata of mad dogs.' ' I have the satisfaction of announcing to the Academy that our experiments have proved more successful. On several occasions, and often with success, we have inoculated the medulla oblongata, portions of the frontal lobes of one of the cerebral hemispheres, and also the cerebro-spinal fluid. The hydrophobia thus produced presented the usual period of incubation. The virus of rabies is, therefore, not exclu- sively contained in the saliva. It is present also in the brain, where it is found to possess a viru- lence at the least equal to that of the saliva of rabid animals. One of the greatest difficulties of researches on hydrophobia consists on the one hand in the un- certainty of the development of the disease after inoculations and bites, and, on the other hand, in the long duration of the incubative period — that is to say, of the time which lapses between the intro- duction of the virus and the appearance of the symptoms of rabies. It is torturing to the experi- menter to have to wait whole months for the result of a single experiment when the question studied ' Galtier, Bull. Acad, de Mid., Jan. 25, 1881. D 34 ■ HYDROPHOBIA requires very many such. Members will therefore undoubtedly be interested to hear that we have discovered a method for considerably shortening the duration of incubation of rabies and also of reproducing the disease with certainty. That double result is secured by direct inocula- tion (after trephining the skull) on the surface of the brain of a healthy animal of the cerebral matter of a mad dog, taken out and inoculated in a state of purity. The dog inoculated under such conditions shows the first symptoms of rabies in the course of one or two weeks, and death supervenes before the end of the third week. I may add that not a single one of the inoculations thus performed failed. So many dogs trephined and inoculated on the brain, so many cases of confirmed and rapidly developed hydrophobia. Considering the special charac- teristics of this method, one may foresee that the result will always be the same. The rabies de- veloped has, furthermore, been sometimes dumb; at other times furious- -that is to say, rabies under one or other of its two habitual types. I conclude with this short exposition of facts, because our sole object to-day is to lay claim to the discovery of a new method of research, the M. PASTEUR'S COMMUNICATIONS 35 usefulness of which in practice all will appre- hend. III. December 11, 1882.— The study of rabies, of all diseases, seems to be the one which bristles with most difficulties. CUnical observation is powerless, and it is ever necessary to appeal to experimentation. But until yesterday the signi- ficance of the simplest experiment was wrapped up in undecipherable uncertainties. ^ The saliva was the only part where the pre- sence of the virus of rabies had been detected with certainty^' But the saliva, inoculated by a bite or by direct injection into the areolar tissue, does not constantly give rise to rabies. Furthermore, when the malady does show itself, it is only after a prolonged incubation, the duration of which is both varying and unsettled. It follows, therefore, that anyone wishing to draw conclusions from a set of experiments by inoculation, with regard to which no positive results have been come to, is always in fear of not having waited long enough for the results of his inoculation or else of having to deal with cases of absolute failure. Add to this the difficulty of procuring the virus ' See Galtier, Bull. Acad, de Mid., Jan. 25, 1881. I) 2 26 HYDROPHOBIA at will, the repulsion and danger of handling mad dogs, and it will be easily understood that the study of hydrophobia is full of mishaps. The situation is no longer the same. When I made up my mind, two years ago, to undertake a sifting study of that malady, I did not deceive myself as to the difficulties and slowness of the undertaking, , and understood that the first problem, to be solved consisted in finding a method of inoculation which would both reproduce the disease with certainty and do away with its pro- longed incubation. Such a method we have dis- covered and explained in a note, which, in my own name and in the name of my fellow-workers, I presented to this Academy on May 30, 1881. It consists, on the one hand, in this fact, that the principal seat of the virus of rabies is in the central nervous system, where it is found in great quantity and where it can be gathered in a state of perfect purity, and, on the other hand, in this consideration, that the virulent matter inoculated pure on the surface of the brain after trephining developes rabies with rapidity aid with certainty. Since then we have found it quite as advanta- geous, although producing slightly different forms of rabies, to use another method, which is still M. PASTEUR'S COMMUNICATIONS 37 more simple in its application— namely, intravenous injection of the virus. The two main obstacles to the experimental study of rabies had thus been got rid of. The new investigations which I have the honour to commutiicate to the Academy to-day are still very incomplete, and yet, such as they stand, they are pregnant with suggestions of new views and new experiments. And, besides, to quote Lavoisier, ' a man would never give anything to the public if he waited till he had reached the. goal of his under- taking, which is ever appearing close at hand and yet ever slipping farther and farther as he draws nearer.' I think that my exposition of facts will gain both in clearness and in conciseness if I confine myself to the summing up of the results of our study. All details will be left aside for the present, and added later on as documents to the present communication. 1. Dumb rabies and furious rabies, or, to speak more generally, aU forms of rabies, proceed from one and the same virus. We have, as a matter of fact, recognised that it is possible, experimentally, to produce furious rabies from dumb rabies, and inversely, dumb rabies from furious rabies. 38 HYDROPHOBIA 2. Nothing is more varied than the symptoms of rabies. Every case of rabies shows, so to speak, its own train of symptoms, and there is every reason to believe that the special characters of any one case depend on the nature of the region in the nervous system, encephalon or spinal cord, where the virus has located itself and multiplied. 3. In the saliva of rabid animals the virus is found associated with various micro-organisms, and the inoculations of this saliva can give rise to death in one of three modes : (a) By the new microbe which we have described under the name of ' the microbe of saliva.' (&) By the excessive development of pus. (c) By rabies. 4. The medulla oblongata of human beings, as also that of all animals who have died of hydro- phobia, is always virulent. 5. The virus of rabies is met with not only in the medulla oblongata, but also m every other part of the encephalon. It is also found localised in the spinal cord and, frequently, in all the parts of that organ. The virulence of the cord, whether in its superior, middle, or lumbar regions, or even quite close to the Cauda equina, is in no way inferior to the virulence M. PASTEUR'S COMMUNICATIONS 39 of the medulla or of the different parts of the ence- phalon (brain, cerebellum, medulla oblongata, pons, peduncles). The encephalon and cord continue virulent until the time when putrefaction sets in. We have been able to preserve a rabid encephalon with its virulence intact for three weeks, at a tem- perature neighbouring upon 12° C. (50° F.). 6. In order to develop rabies rapidly and with certainty, it is necessary, after trephining, to have recourse to inoculation on the surface of the brain, in the arachnoid space. It is similarly possible both to considerably shorten the period of incuba- tion and to give rise to the disease with certainty, by inoculating the pure virus into the blood stream directly. M. Eoux's co-operation for the application of those methods proved to be both active and valuable. He has acquired such skill in it that accidents after the operations have come to be exceptionally rare. By having recourse to those methods, which are so favourable to the experimental study of the disease, rabies now declares itself at the end of the sixth, eighth, or tenth day. 7. Eabies communicated by intravenous injec- tion of the virus very often exhibits characters which differ considerably from those of furious rabies 40 HYDROPHOBIA supervening upon a bite or after trephining, and it is likely that many cases of silent madness have passed unobserved. In such cases of rabies, which could be termed spinal, early paralysis is a common symptom, whilst the habitual fury and rabid barks are absent or rare ; but, on the other hand, frightful itching of the skin is at times a marked phenomenon. The details of our experiments would tend to show that after inoculation of the poison into the blood system, in the way we have indicated, the spinal marrow is the region first attacked, the virus locating itself and multiplying there before spread- ing to other parts. 8. Inoculation not followed by death, of the saliva or blood of a rabid animal into the veins of a dog, does not subsequently preserve the latter against the development of fatal rabies after a new inocula- tion of the pure virus made either on the brain after trephining or into a vein. {These results are in opposition with those announced to this Academy hy M. Galtier on August 1, 1881. His experiments had been made on sheep.) 9. We have met with cases of spontaneous cure after the first symptoms of rabies had alone ap- peared, but never after the advent of the acute symptoms. M. PASTEUR S COMMUNICATIONS 41 We have also met with similar cases in which, after an apparent cure, the disease broke out anew, with acute symptoms followed by death, as in ordinary cases. 10. In one of our experiments three dogs were inoculated, in 1881. Two of them rapidly took the disease and died. The third one exhibited the first symptoms only, and then recovered. This third dog, inoculated afresh, on the brain, and on two different occasions, in 1882, could not be made to take rabies, so that the disease, although mild in its symptoms, did not occur a second time. This observation constitutes a first step towards the discovery of the prophylaxis of rabies. 11. We at the present time have ia our posses- sion four dogs which are not susceptible of taking rabies, whatever method of inoculation be used and whatever also the virulence of the rabid material employed. AU control dogs, inoculated at the same time, took the disease and died. Those four dogs comprise the one mentioned in paragraph 10. Are the others, like that one, refrac- tory to the disease owing to a previous slight un- noticed attack, from which they recovered, or are they so by nature, if so it be that there are dogs 42 HYDROPHOBIA naturally refractory to rabies ? We shall investi- gate the hypothesis on an early occasion. One last remark. Man never contracts hydro- phobia except after the bite of some rabid animal ; in order, then, to preserve him against that terrible disease it will be enough to find out some way of preserving dogs. That result is remote still, but may we not be permitted, in the sight of the facts above referred to, to hope that it is not beyond the reach of modern science ? It was through the kindness of M. Bourel, veterinary surgeon in Paris, and a gentleman well known for his writings on hydrophobia, that we ob- tained the two first dogs which served for our first experiments, one with furious madness, the other with dumb madness (December 1880) . Since that time the disease has been kept up uninterruptedly in my laboratory. On several occasions we have been enabled to make use of dogs that had died of rabies at the Veterinary College at Alfort, owing to the zeal in helping us of Messrs. Goubeaux, the manager, and Nocard, the learned professor of that school. Quite recently, too, M. Eossignol, a veterinary surgeon in Melun, forwarded to us the head of a cow that had died of rabies after the bite of a mad dog. M. PASTEUR'S COMMUNICATIONS 43 It is interesting to learn that already all the animals (the last one only this morning) inoculated with the nervous matter of that cow's head, on November 22 last, have now died of rabies. Ino- culation was performed after trephining, and the parts used were the following : the medulla oblon- gata, the middle lobe of the cerebellum, the right sphenoidal lobe, the left frontal lobe. It is evident, therefore, that all the parts of the encephalon of the cow had proved to be favourable media for the cultivation of the virus. And yet all these parts appeared to be perfectly healthy, except the left frontal lobe, which was intensely congested, and the medulla, which was but sUghtly so. The preceding propositions are the result of inoculation-experiments on rabies numbering more than two hundred, and carried out on dogs, rabbits, and sheep. rV. February 25, 1884. — The Academy re- ceived with favour our preceding communications on rabies, incomplete though they were, justly considering that each step forward in the experi- mental study of that disease deserved to be en- couraged. The new facts which I shall have the honour to communicate to-day — in my own name and in the 44 HYDROPHOBIA name of my fellow-workers, amongst whom I ought to name ThuilKer, who worked with us before he left for Egypt' — have all been ascertained by the use of the two highly valuable methods, of inocu- lation of the virus of rabies on the surface of the brain after trephining, and of injection of the same into the blood system. The expression ' after trephining ' carries with it the notion of an opera- tion both long and unsafe in itself, and yet it is not so in reality. We have performed it many hundred times on dogs, rabbits, guinea-pigs, fowl, monkeys, sheep and other animals, and yet the failures could easily be counted on the fingers. The manual dexterity required for its application is also within the reach of most people. A young laboratory assistant was thus very rapidly taught by M. Eoux, and is now entrusted with the performance of all our trephining operations, and the operative casualties are altogether unimportant. Neither is the operation lengthy. The last monkey trephined was chloroformed, operated upon, and got over the after-effects of the anesthetic in twenty minutes. In another quarter of an hour he ' Louis Thuillier -went out to Egypt, where an epidemic of cholera was raging. His object was to study the disease from a bacteriological point of view. He took the infection and died. — Author. ■M. PASTEUR'S COMMUNICATIONS 45 was eating a fig. In order to make this paper shorter I shall content myself with giving, in the form of conclusions, the sum of the results come to. 1. In the communication of December 11, 1882, I said that the inoculation of the virus of rabies into the blood system generally gave rise to para- lytic rabies, with absence of furor and rabid voice. It seemed probable in those conditions that the virus fixed itself and multiplied, first of aU, in the spinal cord. We sacrificed several dogs on the appearance of the first symptoms of paralysis, and then, by a comparative study of the spinal cord (in the lumbar swelHng in particular) and of the medulla oblongata, we discovered that the former was occasionally virulent when the latter was not yet so. 2. It has been shown already that the virus of rabies is located in the encephalon and in the spinal cord. We have more recently looked for it in the nerves themselves, and in the saHvary glands. We have been able to reproduce the disease by means of small portions of the pneumo- gastric taken either near its origin, just outside the cranium, or at more distant points. So also with the sciatic necves, and the submaxillary, 46 HYDROPHOBIA parotid, and sublingual glands. The whole nervous system, then, from the centre to the periphery, is capable of cultivating the virus. It is thus easy to explain the nervous excitement which is so often present in rabies, and which in man gives rise to the strange symptom known as aerophobia. The saliva and salivary glands have been found virulent in dogs made mad by intra-cranial inocu- lations, by intra-venous inoculations, and in those affected with the so-called spontaneous disease. 3. We had previously ascertained that the rabies virus could retain its virulence intact for several weeks in the encephalon and cord, if the cadavers were preserved from putrefaction by keeping them at a temperature ranging from 0° to 12° C. (32° F. to 53°-60 P.) We have now found that the virus enclosed pure in glass tubes sealed with the blow-pipe could also be preserved for three weeks or one month, even at summer heat. 4. We have, again, ascertained that the rabies virus is occasionally present in the cerebro-spinal fluid, but not constantly so. In some cases that fluid, when perfectly limpid, gave rise to rabies, whilst in other cases, although perceptibly turbid and opalescent, it remained quite inert. M. PASTEUR'S COMMUNICATIONS 47 5. We have made many attempts to obtain ' cultures ' — crops— of the virus of rabies in this same cerebro-spinal fluid, in various other sub- stances, and even in the spinal cord taken out pure from animals killed whilst in a state of per- fect health. We have not hitherto been successful. ' Possibly there is no such thing as a microbe of rabies?' inquired last May our colleague, M. Bouley. ' All I can say,' answered I, ' is this, that if you were to bring me two brains, the one rabid and the other healthy, I could say from a micro- scopic examination of the two medullas, this one is rabid, that one is not. Both show an immense number of molecular granules, but those in the rabid medulla are finer, more numerous, suggesting the idea of a micro-organism of extreme tenuity, in shape neither a bacillus nor a diplococcus ; they are like simple dots.' One method alone, hitherto, has allowed us to isolate those granules from all the other elements of the nervous matter. It consists in injecting the pure virus taken from the medulla of an animal which had died from hydrophobia into the veins of a rabid animal just at the time when asphyxia is coming on. In a very few hours the blood of the animal is found to contain exclusively the infinitely 48 HYDROPHOBIA small granules we are speaking of, the normal elements of the nervous matter having either been stopped in the capillaries or having, more probably, been digested in the blood. It has also become easy, under these new conditions, to stain them with the aniline dyes.^ With regard to the blood of rabid animals, we have in one instance been able to give hydrophobia to a dog by means of the blood of a rabbit which had died of that disease. We shall have occasion to refer again to this important case. One point in particular occupied our attention. It is well known that the bitten dog, if he take the disease at all, shows in the majority of cases symptoms of furious rabies with a propensity to bite and the special ' rabid voice ' (aboiement rabique). In the habitual run of our experiments, when we inoculate the rabies virus into a vein or into the subcutaneous areolar tissue, we more often give rise to the dumb or paralytic form of madness, voiceless and tame. By intra-cranial inoculation, on the other hand, the rule is that furious madness is produced. We have also ascertained that it is possible to give rise to furious madness by intra- > We are not yet absolutely certain that these granulations are actually the germs of rabies, but are busy collecting proof. M. PASTEUR'S COMMUNICATIONS 49 venous or subcutaneous inoculation, provided that very small quantities only of the virus be used. The smaller the quantity of virus, or disease mate- rial, used in the intra-venous or hypodermic inocu- lation, the more certainly is the furious form of rabies reproduced. We have found, on the other hand, that by in- oculating small quantities of virus the duration of incubation was considerably increased; and the same virus, if diluted beyond a certain limit, which is not very far, remains without effect when inoculated. The considerable interest attaching to those conclusions justifies me in giving the details of two experiments. On May 6, 1883, we inoculate into the vein of the right popUteal space (behind the knee) of three dogs portions of a rabid medulla diluted in sterilised broth. To the first dog we give half a cubic centimetre of the turbid liquid, to the second one-hundredth part of that quantity, to the third the two-hundredth part only. As early as the tenth day, the first dog begins to lose Ms appetite, and on the eighteenth day he is com- pletely paralysed ; he dies two days later without having at any time had the peculiar bark of mad dogs, or tried to bite. On the thirty- seventh day after inoculation the second dog still eats well ; on the thirty-eighth day he begins to look suspicious ; on the thirty-ninth day he has the rabid voice, and is found dead the next day. The third dog has not taken the disease at all. 50 HYDROPHOBIA Another experiment consisted in inoculating into a popliteal vein one cubic centimetre of rabid matter in sterilised broth for the first dog, one-twentieth of that quantity for a second dog, one-fiftieth for a third dog. The incubative periods were respectively seven, twenty, and twenty-five days. The two first dogs took paralytic madness, the third had the furious, barking and biting form. Whenever the small quantities injected failed to give rise to rabies, we ascertained that the animals were liable to take the disease by new and subsequent inoculations. In other words, the inoculation of small quanti- ties of the virus failed to produce immunity. 6. In my last paper on rabies I said that we had met with some dogs in whom the first symptoms of the disease subsided and disappeared, to reappear again after a tolerably long period of latency. We have since then met with similar cases in the rabbit. To quote one instance : on the thirteenth day after intra-cranial inoculation, one of our rabbits showed the first symptoms of paralysis. On the following days he got better and recovered completely, but forty-three days later the paralysis returned and he died of para- lytic rabies on the forty-sixth day. 7. Such cases are very rare in the rabbit as well M. PASTEUR'S COMMUNICATIONS 51 as in the dog, but we have very frequently noticed them in hens, in which latter animals the recur- rence of the symptoms may or may not be followed by death. We have already, in our last note, mentioned a case of such recurrence of rabies in the dog, not followed by death. I may just note here that rabies in our hens never showed any violent symptoms, but only a degree of sleepiness, loss of appetite, paralysis of the legs, and frequently a considerable degree of anaemia or bloodlessness, as shown by the blanching of the comb. 8. We were particularly careful in our control experiments as to certain recent assertions con- cerning the alleged attenuation of the rabies virus by the action of cold, and also as to the asserted passage of rabies from the mother to the unborn young. Although our experiments bearing on both of those points have been much more numerous than those which were brought forward in support of them, our results have constantly been negative. 9. The certainty of inoculation by intra-venous injection of the virus is in itself sufficient proof that the nerves are not the sole channels of propa- gation of the virus from the periphery or surface to the centre, as one theory would have it, and proof E 2 52 HYDROPHOBIA enough also, that in the majority of cases, to say the least, the absorption of the virus is effected through the blood-system. And yet, after all, this view of the case is still open to discussion. In order to inject the virus into a vein we must still make a wound, cut the skin and bare the vessel. Might it not be then that the virus, introduced at first into the blood circulation, was at once brought back by it to the seat of the wound, in contact with the nerve fibres and the lymphatic vessels which have been inevi- tably cut,i and are all ready to absorb it ? The following experiment does away completely with that objection. We have on several different occa- sions inoculated the virus into one of the veins of the ear, and then, immediately after, cut off that organ with the thermo-cautery between the point of inoculation and the head. Nevertheless, rabies showed itself in every instance, although, as all know, the thermo-cautery do,es not produce an open wound, the whole of the cut surface being burnt. But I must hasten to speak of the point of greatest interest. The discovery of the attenuation of different viruses and the application of it to the prophylaxis or prevention of several diseases have thrown full Hght upon the capital fact of the M. PASTEUR'S COMMUNICATfONS , 53 possible production, experimentally, of different states in the virulence of the same virus. Eabies is above all others a virulent disease. The mode of action and the nature of its virus are surrounded with so much mystery that it becomes very natural for one to investigate v?hether rabies virus is also capable of exhibiting varying degrees in its virulence. Experimentation has taught us that the answer must be in the affirmative. Whilst waiting for the proof afforded by other methods which are still in course of study, we have already ascertained that a given rabies virus has its viru- lence modified, more or less deeply, by passing it through different species of animals. Babbits, guinea-pigs, hens, monkeys, are all susceptible of taking rabies. By a succession of passages through animals of the same race the virus after a time reaches, so to speak, a fixed degree of virulence for that race, the degree being different for different races of animals and always perceptibly different from the fixed virulence of ordinary canine mad- ness, which has itself come to its present degree of fixity after countless transfers by bites throughout the past ages. In my idea there is no such thing as spontaneous rabies. We are in possession at the present time of a 54 HYDROPHOBIA virus which produces rabies in the rabbit in seven or eight days, and with such constancy that we can, within a few hours, foretell the duration of incu- bation as measured from the time of inoculation to the first appearance of a change in the temperature of the animal or of the first external symptoms of the disease. We have also a virus which gives rabies to guinea-pigs in five or six days, with no less cer- tainty as to the duration of the incubative period. Before it reaches the degree of fixity of which we are speaking in the different animal species, the virulence passes through a series of incessant variations. We count that the virulence is in the inverse ratio of the number of days' incubation when other circumstances remain the same, and when, in particular, the quantity of virus inoculated remains as much as possible the same for the same mode of inoculation. The incubative period is in general slightly shorter in yotmg animals than in the full-grown ones. Seeing that we know absolutely nothing regard- ing the new conditions which the rabies virus of the dog would assume by successive passages from man to man, we were led to try a succession of passages from monkey to monkey. M. PASTEUR'S COMMUNICATIONS 55 I shall later on communicate the very interesting results of those experiments, as they are not yet completed. I have already said that I have in my laboratory several dogs which are refractory to rabies, in what- ever way inoculated to them. I am in a position to add to-day that they are also refractory to all sorts or degrees of rabies viruses. Nevertheless, we had been obliged at the time of my last com- munication to the Academy, owing to the incom- pleteness of our observations at that moment, to ask ourselves whether those dogs were by nature re- fractory to rabies, or whether they had become so by reason of the operations which they had an- teriorly undergone. We are able to-day to answer those questions with more precision, although our answers must still be somewhat guarded. I believe I am authorised to assert that our dogs were not by natural disposition refractory to rabies. We have, as a matter of fact, discovered a method of rendering dogs refractory to rabies in numbers as large as it may be desired. However, if we consider that the length of incubation of rabies is uncertain, and in some cases very protracted, there must always linger some little doubt as to the 56 HYDROPHOBIA thoroughness of the proof afforded by control ex- periments, and I must needs beg of ^he Academy to give credit to this assertion yet for a little time, and to allow me, further, to restrict myself for the present to this statement, that the refractory state is obtained by a series of inoculations of viruses of different degrees. We possess at the present moment twenty-three dogs capable of bearing with- out danger the most virulent inoculations. By rendering dogs refractory to rabies we solve the question of the prophylaxis of that affection not only in the dog but also in man, seeing that man never takes rabies except after a bite the virus of which comes directly or indii'ectly from the dog. Lengthy is the incubation of rabies : will not human medicine be able, some day, taking advan- tage of that respite time, to render the bitten victim refractory before the first symptoms of the malady break out? Before that hope becomes a reality we have yet a long and weary way to travel. V. May 19, 1884. — The Attenuatwn of Rabies. — The great notions of the variabihty in the virulence of certain viruses, and of the preservation against a given virus by the inoculation of another of lower intensity, are to-day recognised scientific facts already put to practical uses. It is easy to appre- M. PASTEUR'S COMMUNICATIONS 57 hend all the interest attaching, in that line of study, to the search after methods of attenuation applicable to new viruses. I bring news to-day of one more step forward in that direction as concerns rabies. 1. The virus of rabies carried from the dog to the monkey, and subsequently from monkey to monkey, grows weaker at each passage. After the virulence has thus diminished by several passages through monkeys, if the virus be carried back to the dog or to the rabbit or to the guinea-pig, it still remains attenuated. In other words, the virulence does not at one bound go back to the degree it had in the dog ' a rage des rues ' — affected with ordinary or street madness. In those conditions a small number of passages from monkey to monkey suffice to bring down the attenuation to a point at which the virus injected hypodermically into dogs never gives rise to rabies in them. Intra-cranial inoculation itself, the never- failing means of communicating rabies, may now remain without effect, whilst, however, creating a refractory state in favour of the inoculated animal. 2. Successive passages from rabbit to rabbit and from guinea-pig to guinea-pig increase the virulence of rabies virus. This exalted virulence S8 HYDROPHOBIA comes to a fixed maximum in the rabbit. If now transferred to the dog it remains exalted, and shows itself to be much more intensely virulent than the virus of ordinary street rabies. So great is this acquired virulence, that the new virus injected into the blood-system of a dog unfailingly gives rise to mortal madness. 3. The virulence of rabies virus, as we have seen, is exalted by its passages through rabbits or through guinea-pigs, but it requires many such passages before it again reaches its maximum degree after it has been weakened in the monkey. In the same way the virus of ordinary canine madness, as I have just said, is far from possessing the maximum degree of virulence, and it requires several passages through rabbits before it reaches that maximum. A logical application of the results just indicated gives us the means of easily rendering dogs refrac- tory to rabies, for we can now prepare and keep at our disposal a set of attenuated viruses of different strength, some, not mortal, preserving the animal economy against the ill effects of more active ones, and these latter against the effects of mortal ones. Let us give an example : take a rabbit which has been inoculated on the brain, and which has died of rabies after a period of incubation longer by M. PASTEUR'S COMMUNICATIONS 59 several days than the shortest known incubation in the rabbit (this is always comprised between seven and eight days after intra-cranial inoculation of the maximum virus) . Extract the virus from this long- incubation rabbit and inject it, after trephining, into a second rabbit. Similarly inoculate a third rabbit from this second one. These viruses have grown stronger each time ; each time also that they are inoculated into a. fresh rabbit, let us inoculate them into the same dog. This dog, after the third inoculation, has become capable of bearing unhurt inoculations of a mortal virus. He has become entirely refractory to the rabies of ordinary canine madness, whether inoculated into a vein or into the arachnoid space. By inoculating the blood of rabid animals, under certain well-determined circumstances, I have been able considerably to simplify the process of vaccina- tion, whilst at the same time putting the dog in a most decidedly refractory state. I shall on an early occasion acquaint the Academy with the sum of my experiments on that point. In the meantime, and until we come to that remote epoch when vaccination shall have stamped out rabies from our midst, it would be highly advantageous to have the means of preventing the 6o HYDROPHOBIA development of that affection after the bite of mad dogs. The first attempts I have made in that du-ection inspire me with the greatest hopes of success. Owing to the long incubative period of rabies I have every reason to believe that we shall be able with certainty, after the bite, to put the patients in a refractory state before the first symptoms of the mortal malady show themselves. The first experiments testify strongly in favour of this view, but afferent proof must be collected from different animal races, and almost ad, infini- tum, before human therapeutics can make bold enough to try this mode of prophylaxis on mart himself. Notwithstanding the confidence I derive from the large number of the experiments I have made in the last four years, it is not without some excusable apprehension that I publish to-day a set of facts- which point to no less a result than the possible prophylaxis of rabies. Had I been able to dispose of the necessary materials I should have been glad before giving this communication to wait until I had begged of some of my colleagues of the Academy of Sciences and of the Academy of Medicine kindly to witness and to control the conclusions I have just brought forward. M. PASTEUR'S COMMUNICATIONS 6i In order to obey those scruples and those reasons I took the liberty of writing a few days ago to M. Fallieres, Minister of Public Instruction, requesting of him to appoint a commission before which I might bring my rabies-refractory dogs. The crucial experiment to be tried in the first instance would be the following. I should take from my kennels twenty refractory dogs, which I should place, for the sake of comparison, by the side of twenty ordinary, non-vaccinated control dogs. We should then have the forty dogs brought in with mad dogs and bitten by them. If the facts announced by me are real, not one of my twenty dogs will take rabies, whereas the twenty control animals will take it. A second experiment, no less conclusive than the first, would consist in taking forty dogs, where- of twenty should be vaccinated before the eyes of the commission and twenty shpuld remain not vaccinated. The forty animals will then be tre- panned and inoculated on the brain with the virus of ordinary street-dog rabies. The twenty vacci- nated dogs will not take rabies but the twenty others will all die of it, taking it either in its paralytic or in its furious form. The following commimication was made to the 62 HYDROPHOBIA members of the International Medical Congress sitting in Copenhagen, on August 11, 1884. Although not a communication to the Academic des Sciences, we give it here in full, because of its intrinsic interest and importance, and also because it forms an other- wise missing link between some of the other articles : ' Gentlemen, — Your Congress meetings are the place for the discussion of the gravest problems of medicine ; they serve also to point out the great landmarks of the future. Three years ago, on the eve of the London Congress, the doctrine of micro- organisms, the setiological cause of transmissible maladies, was still the subject of sharp criticisms. Certain refractory minds continued to uphold the idea that " disease is in us, from us, by us." ' It was expected that the decided supporters of the theory of the spontaneity of diseases would make a bold stand in London ; but no opposition was made to the doctrine of " exteriority," or ex- ternal causes, the first cause df contagious diseases, and those questions were not discussed at all. ' It was there seen, once again, that when aU is ready for the final triumph of truth, the united conscience of a great assembly feels it instinctively and recognises it. 'All clear-sighted minds had already foreseen that M. PASTEUR'S COMMUNICATIONS 63 the theory of the spontaneity of diseases received its death-blow on the day when it became possible reasonably to consider the spontaneous genera- tion of Inieroscopic organisms as a myth, and when, on the other hand, the life-activity of those same beings was shown to be the main cause of organic decomposition and of all fermentation. ' Prom the London Congress, also, dates the recognition of another very hopeful progress, we refer to the attenuation of different viruses, to the production of varying degrees of virulence for each virus, and their preservation by suitable methods of cultivation ; to the practical application, finally, of those new facts in animal medicine. ' New microbic prophylactic viruses have been added to those of fowl-cholera and of splenic fever. The animals saved from death by contagious dis- eases are now counted by hundreds of thousands, and the sharp opposition which those scientific novelties met with at the beginning was soon swept away by the rapidity of their onward progress. ' Will the circle of practical applications of those new notions be limited in future to the prophylaxis of animal distempers ? We must never think little of a new discovery, nor despair of its fecundity ; but more than that, in the present instance, it may 64 HYDROPHOBIA be asserted that the question is already solved in principle. Thus, splenic fever is common to animals and man, and we make bold to declare that, were it necessary to do so, nothing could be easier than to render man also proof against that affection. The process which is employed for animals might, almost without a change, be applied to him also. It would simply become advisable to act with an amount of prudence which the value of the life of an ox or a sheep does not call for. Thus, we should use three or four vaccine-viruses instead of two, of progressive intensity of virulence, and choose the first ones so weak that the patient should never be exposed to the slightest morbid complication, how- ever susceptible to the disease he might be by his constitution. ' The difficulty, then, in the case of human diseases, does not lie in the application of the new method of prophylaxis, but rather in the knowledge of the physiological properties of their viruses. All our experiments must tend to discover the proper degree of attenuation for each virus. But experi- mentation, if allowable on animals, is criminal on man. Such is the principal cause of the complica- tion of researches bearing on diseases exclusively human. Let us keep in mind, nevertheless, that M. PASTEUR'S COMMUNICATIONS 65 the studies of which we are speaking were born yesterday only, that they have already yielded valuable results, and that new ones may be fairly expected when we shall have gone deeper into the knowledge of animal maladies, and of those in particular which affect animals in common with man. ' The desire to penetrate farther forward in that double study led me to choose rabies as the subject of my researches, in spite of the darkness in which it was veiled. ' The study of rabies was begun in my labora- tory four years ago, and pursued since then without other interruption than what was inherent to the nature of the researches themselves, which present certain unfavourable conditions. The incubation of the disease is always protracted, the space dis- posed of is never sufficient, and it thus becomes impossible at a given moment to multiply the experiments as one would like. Notwithstanding those material obstacles, lessened by the interest taken by the French Government in all questions of great scientific interest, we now no longer count the experiments which we have made, my fellow- workers and myself. I shall limit myself to-day to an exposition of our latest acquisitions. F 66 HYDROPHOBIA ' The name alone of a disease, and of rabies above all others, at once suggests to the mind the notion of a remedy. ' But it will, in the majority of cases, be labour lost to aim in the first instance at discovering a mode of cure. It is, in a manner, leaving all pro- gress to chance. Far better to endeavour to ac- quaint oneself, first of all, with the nature, the cause, and the evolution of the disease, with a glimmering hope, perhaps, of finally arriving at its prophylaxis. ' To this last method we are indebted for the result that rabies is no longer to-day to be con- sidered as an insoluble riddle. ' We have found that the virus of rabies deve- lops itself invariably in; the nervous system, brain, and spinal cord, in the nerves, and in the salivary glands ; but it is not present at the same moment in every one of those parts. It may, for example, develop itself at the lower extremity of the spinal cord, and only after a time reach the brain. It may be met with at one or at several points of the encephalon whilst being absent at certain other points of the same region. ' If an animal is kUled whilst in the power of rabies, it may require a pretty long search to dis- M. PASTEUR'S COMMUNICATIONS 67 cover the presence here or there in the nervous system, or in the glands, of the virus of rabies. We have been fortunate enough to ascertain that in all cases, when death has been allowed to super- vene naturally, the swelled-out portion, or bulb, of the medulla oblongata nearest to the brain, and uniting the spinal cord with it, is always rabid. When an animal has died of rabies (and the disease always ends in death), rabid matter can with cer- tainty be obtained from its bulb, capable of repro- ducing the disease in other animals when inoculated into them, after trephining, in the arachnoid space of the cerebral meninges. ' Any street dog whatsoever, inoculated in the manner described with portions of the bulb of an animal which has died of rabies, will certainly develop the same disease. We have thus inocu- lated several hundreds of dogs brought without any choice from the pound. Never once was the inoculation a failure. Similarly also, with uniform success, several hundred guinea-pigs, and rabbits more numerous still. ' Those two great results, the constant presence of the virus in the bulb at the time of death, and the certainty of the reproduction of the disease by inoculation into the arachnoid space, stand out F 2 68 HYDROPHOBIA like experimental axioms, and their importance is paramount. Thanks to the precision of their ap- plication, and to the well-nigh daily repetition of those two criteria of our experiments, we have been able to move forward steadily and surely in that arduous study. But, however solid those experi- mental bases, they were, nevertheless, incapable in themselves of giving us the faintest notion as to some method of vaccination against rabies. In the present state of science the discovery of a method of vaccination against some virulent malady pre- supposes : ' 1. That we have to deal with a virus capable of assuming diverse intensities, of which the weaker ones can be put to vaccinal or protective uses. ' 2. That we are in possession of a method en- abling us to reproduce those diverse degrees of virulence at will. ' At the present time, however, science is ac- quainted with one sort of rabies only — viz., dog rabies. ' Eabies, whether in dog, man, horse, ox, wolf, fox, &c., comes originally from the bite of a mad dog. It is never spontaneous, neither in the dog nor in any other animal. There are none seriously authenticated among the alleged cases of so-called M. PASTEUR'S COMMUNICATIONS 69 spontaneous rabies, and I add that it is idle to argue that the first case of rabies of all must have been spontaneous. Such an argument does not solve the difficulty, and wantonly calls into question the as yet inscrutable problem of the origin of life. It would be quite as well, against the assertion that an oak-tree always proceeded from another oak- tree, to argue that the first of all oak-trees that ever grew must have been produced spontaneously. Science, which knows itself, is well aware that it would be useless for her to discuss about the origin of things ; she is aware that, for the present at any rate, that origin is placed beyond the ken of her investigations. ' In fine, then, the first question to be solved on our way towards the prophylaxis of rabies is that of knowing whether the virus of that malady is sus- ceptible of taking on varying intensities, after the manner of the virus of fowl-cholera or of splenic fever. ' But in what way shall we ascertain the pos- sible existence of varying intensities in the virus of rabies ? By what standard shall we measure the strength of a virus which either fails completely or kills ? Shall we have recourse to the visible symptoms of rabies? But those symptoms are 70 HYDROPHOBIA extremely variable, and depend essentially on the particular point of the encephalon or of the spinal cord where the virus has in the first instance fixed and developed itself. The most caressing rabies, for such do exist, may, when inoculated into another animal of the same species, give rise to furious :^abies of the intensest type. ' Might we then perhaps make use of the dura- tion of incubation as a means of estimating the intensity of our virus ? But what can be more changeful than the incubative period ? Suppose a mad dog to bite several sound dogs : one of them will take rabies in one month or six weeks, another after two or three months or more. Nothing, too, more changeful than the length of incubation ac- cording to the different modes of inoculation. Thus, other circumstances the same, after bite^ or hypo- dermic inoculation rabies occasionally develops itself, and at other times aborts completely ; but in- oculations on the brain are never sterile, and give the disease after a relatively short incubation. ' It is possible, nevertheless, to gauge with suffi- cient accuracy the degree of intensity of our virus by means of the time of incubation, on condition that we make use exclusively of the intra-cranial mode of inoculation ; and secondly, that we do away M. PASTEUR'S COMMUNICATIONS 71 with one of the great disturbing influences inherent to the results of inoculation made by bites, under the skin, or in the veins, by injecting the right proportion of material. ' The duration of incubation, as a matter of fact, may depend largely on the quantity of efficient virus — that is to say, on the quantity of virus which reaches the nervous system without diminution or modification. Although the quantity of virus ca- pable of giving rabies may be, so to speak, infinitely small, as seen in the common fact of the disease developing itself after rabid bites which, as a rule, introduce into the system a barely appreciable weight of virus, it is easy to double the length of incubation by simply changing the proportion of those very small quantities of inoculated matter. I may quote the following examples : — ' On May 10, 1882, we injected into the popliteal vein of a dog ten drops of a Uquid prepared by crushing a portion of the bulb of a dog, which had died of ordinary canine madness, in three or four times its volume of sterilised broth. ' Into a second dog we injected y^th of that quantity, into a third a^th. Eabies showed itself in the first dog on the eighteenth day after the in- jection, on the thirty-fifth day in the second dog. 72 HYDROPHOBIA whilst the third one did not take the disease at all, which means that, for that last animal, with the particular mode of inoculation employed, the quan- tity of virus injected was not sufficient to give rabies. And yet that dog, like all dogs, was sus- ceptible of taking the disease, for it actually took it twenty-two days after a second inoculation, per- formed on September 3, 1882. ' I now take another example bearing on rabbits, and by a different mode of inoculation. This time, after trephining, the bulb of a rabbit which had died of rabies after inoculation of an extremely powerful virus is triturated and mixed with two or three times its volume of sterilised broth. The mixture is allowed to stand a little, and then two drops of the supernatant liquid are injected after trephining into a first rabbit, into a second rabbit one-fourth of that quantity, and in succession into other rabbits, xV^b, -g'jth, yis^-'i' ^^<^ ts^^^ o^ *^^^ same quantity. All those rabbits died of rabies, the incubation having been eight days, nine and ten days for the third and fourth, twelve and sixteen days for the last ones. ' Those variations in the length of incubation were not the result of any weakening or diminution of the intrinsic virulence of the virus brought on M. PASTEUR'S COMMUNICATIONS 73 possibly by its dilution, for the incubation of eight days was at once recovered when the nervous matter of all those rabbits was inoculated into new animals. ' Those examples show that, whenever rabies follows upon bites or hypodermic inoculations, the differences in respect of length of incubation must be chiefly ascribed to the variations, at times with- in considerable limits, of the ever-undeterminate proportions of the inoculated viruses which reach the central nervous system. ' If, therefore, we desire to make use of the length of incubation as a measure of the inten- sity of the virulence, it will be indispensable to have recourse to inoculation on the surface of the brain, after trephining, a process the action of which is abso- lutely certain, coupled with the use of a larger quan- tity of virus than what is strictly sufficient to give rise to rabies. By those means the irregularities in the length of incubation for the same virus tend to disappear completely, because we always have the maximum effect which that virus can produce; that maximum coincides with a minimum length of incubation. ' We have thus, finally, become possessed of a method enabling us to investigate the possible exist- 74 HYDROPHOBIA ence of different degrees of virulence, and to com- pare them with one another. The whole secret of the method, I repeat, consists in inoculating on the braiu, after trephining, a quantity of virus which, although small in itself, is still greater than what is simply necessary to reproduce rabies. We thus disengage the incubation from all disturbing influences and render its duration dependent exclu- sively on the activity of the particular virus used, that activity beuag in each case estimated by the minimum incubation determined by it, ' This method was applied in the first instance to the study of canine madness, and in particular to the question of knowmg whether dog-madness was always one and the same, with perhaps the slight variations which might be due to the dif- ferences of race in diverse dogs. ' We accordingly got hold of a number of dogs affected with ordinary street rabies, at all times of the year, at all seasons of the same year or of different years, and belonging to the most dissimilar canine races. In each case the bulbar portion of the medulla oblongata was taken out from the recently dead animal, triturated and suspended in two or three times its volume of sterilised hquid, making use all along of every precaution to keep our mate- M. PASTEUR'S COMMUNICATIONS 75 rials pure, and two drops of this liquid injected after trephining into one or two rabbits. The inocu- lation is made with a Pravaz syringe, the needle of wMch, shghtly curved at its extremity, is inserted through the dura-mater into the arachnoid space. The results were as follows : all the rabbits, from whatever sort of dog inoculated, showed a period of incubation which ranged between twelve and fifteen days, without almost a single exception. Never did they show an incubation of eleven, ten, nine, or eight days, never an incubation of several weeks or of several months. ' Dog-rabies, the ordinary rabies, the only known rabies, is thus sensibly one in its virulence, and it modifications, which are very limited, appear to depend solely on the varying aptitude for rabies the different known races. But we are going now to witness a deep change in the vu-ulence of dog- rabies. 'Let us take one, any one, of our numerous rabbits, inoculated with the virus of an ordinary mad dog, and, after it has died, extract its bulb, prepare it as just described, and inject two drops of the bulb-emulsion into the arachnoid space of a second rabbit whose bulb will in turn and in time be injected into a third rabbit, the bulb of 76 HYDROPHOBIA which again will serve for a fourth rabbit, and so on. ' There will be eyidence, even from the first few passages, of a marked tendency towards a lessen- ing of the period of incubation in the succeeding rabbits. Just one example : 'Towards the end of the year 1882, fifteen cows and one buU died of rabies in a farm situated in the neighbourhood of the town of Melun. They had been bitten on October 2 by the farm-dog, which had become mad. The head of one of the cows, which had died on November 15, was sent to my laboratory by M. Kossignol, a veterinary surgeon in Melun. A number of experiments were made on dogs and on rabbits, and showed that the following parts, the only encephalic (or those pertainiag to the brain) ones tested, were rabid : the bulb, the cere- bellum, the frontal lobe, the sphenoidal lobe. The rabbits trephined and inoculated with those different parts showed the first symptoms of rabies on the seventeenth and the eighteenth days after inocu- lation. With the bulb of one of those rabbits two more were inoculated, of which one took rabies on the fifteenth day, the other on the twenty -third day. ' We may notice, once for all, that when rabies is transferred from one animal to another of a M. PASTEUR'S COMMUNICATIONS 77 different species, the period of incubation is always very irregular at first in the individuals of the second species if the virus had not yet become fixed in its maximum virulence for the first species. We have just seen an example of that phenomenon, since one of the rabbits had an incubation of fifteen days, the other of twenty- three days, both having received the same virus and all other circumstances remaining apparently the same for them. ' The bulb of the first one of those last rabbits which died was injected into two more rabbits, still after trephining. One of them took rabies on the tenth day, the other on the fourteenth day. The bulb of the first one that died was again injected into a couple of new rabbits, which developed the disease in ten days and twelve days respectively. A fifth time two new animals were inoculated from the first one that died, and they both took the disease on the eleventh day after inoculation ; similarly, a sixth passage was made, and gave an incubation of eleven days, twelve days for the seventh passage, ten and eleven for the eighth, ten days for the ninth and tenth passages, nine days for the eleventh, eight and nine days for the twelfth, and so on, with differences of twenty-four hours at the most, until we got to the twenty-first passage, when rabies de- 78 ■ HYDROPHOBIA clared itself in eight days, and subsequently to that always in eight days up to the fiftieth passage, which was only effected a few days ago. That long experimental series which is still going on was begun on November 15, 1882, and will be kept lip for the purpose of preserving in our rabies virus that maximum virulence which it has come to now for some considerable time, as it is easy to calculate. ' Allow me to caU your attention to the ease and safety of the operations for trephining and then inoculating the virus. Throughout the last twenty months we have been able without a single interruption in the course of the series to carry the one initial virus through a succession of rabbits which were all trephined and inoculated every twelfth day or so. ' Guinea-pigs reach more rapidly the maximum virulence of which they are susceptible. The period of incubation is in them also variable and irregular at the beginning of the series of successive passages, but it soon enough fixes itself at a minimum of five days. The maximum virulence in guinea-pigs is reached after seven or eight passages only. It is worth noting that the number of passages required before reaching the maximum virulence, both in M. PASTEUR'S COMMUNICATIONS 79 guinea-pigs and in rabbits, varies with the origin of the first virus with which the series is begun. ' If now this rabies with maximum virulence be transferred again into the dog from guinea-pig or rabbit, there is produced a dog-virus which in point of virulence goes far beyond that of ordinary canine madness. ' But, a natural query — of what use can be that discovery as to the existence and artificial produc- tion of diverse varieties of rabies, every one of them more violent and more rapidly fatal than the habitual madness of the dog ? The man of science is thankful for the smallest find he can make in the field of pure science, but the many, terrified at the very name of hydrophobia, claim something more than mere scientific curiosities. How much more interesting it would be ±0 become acquainted with a set of rabies viruses which should, on the contrary, be possessed of attenuated degrees of virulence ! Then, indeed, might there be some hope of creating a number of vaccinal rabies viruses such as we have done for the virus of fowl-cholera, of the microbe of saliva, of the red evil of swine (swine-plague), and even of acute septicaBmia. Unfortunately, however, the methods which had served for those different viruses showed themselves to be either inapplicable 8o HYDROPHOBIA or inefficient in the case of rabies. It, therefore, became necessary to find out new and independent methods, such, for example, as the cultivation in vitro of the mortal rabies virus. ' Jenner was the first to introduce into current science the opinion that the virus which he called the grease of the horse, and which we call now more exactly horse-pox, probably softened its viru- lence, so to speak, in passing through the cow and before it could be transferred to man without danger. It was, therefore, natural to think of a possible diminution of the virulence of rabies by a number of passages through the organisms of some animal or other, and the experiment was worth trying. A large number of attempts were made, but the majority of the animal species experimented on exalted the virulence after the manner of rabbits and guinea-pigs ; fortunately, however, it was not so with the monkey. ' On December 6, 1883, a monkey was trephined and inoculated with the bulb of a dog, which had itself been similarly inoculated from a child who had died of rabies. The monkey took rabies eleven days later, and when dead served for inoculation into a second monkey which also took the disease on the eleventh day. A third monkey, similarly M. PASTEUR'S COMMUNICATIONS 8i inoculated from the second one, showed the first symptoms on the twenty-third day, &c. The bulb of each one of the monkeys was inoculated, after trephining, into two rabbits each time. The rabbits inoculated from the first monkey developed rabies between thirteen and sixteen days, those from the second monkey between fourteen and twenty days, those from the third monkey between twenty-six and thirty days, those from the fourth monkey both of them after the twenty-eighth day, those from the fifth monkey after twenty-seven days, those from the sixth monkey after thirty days. ' It cannot be doubted after that, that successive passages through monkeys, and from the several monkeys to rabbits, do diminish the virulence of the virus for the latter animals ; they diminish it for dogs also. The dog inoculated with the bulb of the fifth monkey gave an incubation of no less than fifty-eight days, although it had been inoculated in the arachnoid space. ' The experiments were renewed with fresh sets of monkeys and led to similar results. We were, therefore, actually in possession of a method by means of which we could attenuate the virulence of rabies. Successive inoculations from monkey to monkey elaborate viruses which, when transferred 82 HYDROPHOBIA to rabbits, reproduce rabies in them, but with a progressively lengthening period of incubation. Nevertheless, if one of those rabbits be taten as the first for inoculations through a series of rabbits, the rabies thus cultivated obeys the law which we have seen before, and has its virulence increased at each passage. ' The practical apphcation of those facts gives us a method for the vaccination of dogs against rabies. As a startrog-point, make use of one of the rabbits inoculated from a monkey sufficiently re- moved from the first animal of the monkey series for the inoculation — hypodermic or intra- venous — of that rabbit's bulb not to be mortal for a new rabbit. The next vaccinal inoculations are made with the bulbs of rabbits derived by successive passages from that first rabbit. ' In the course of our experiments we made use, as a rule, for inoculation, of the virus of rabbits which had died after an incubation of four weeks, repeating three or four times each the vaccinal inoculations made with the bulbs of rabbits derived in succession from one another and from the first one of the series, itself coming directly from the monkey. I abstain from giving more details, be- cause certain experiments which are actually going M. PASTEUR'S COMMUNICATIONS 83 on allow me to expect that the process will be greatly simplified. ' You must be feeling, gentlemen, that there is a great blank in my communication ; I do not speak of the micro-organism of rabies. We have not got it. The process for isolating it is still imperfect, and the difficulties of its cultivation out- side the bodies of animals have not yet been got rid of, even by the use, as pabulum, of fresh nervous matter. The methods which we employed in our study of rabies ought all the more perhaps, on that account, to fix attention. Long still wiU the art of preventing diseases have to grapple with virulent maladies the micro-organic germs of which will escape our investigations. It is, therefore, a capital scientific fact that we should be able, after all, to discover the vaccination process for a virulent disease without yet having at our disposal its special virus and whilst yet ignorant of how to isolate or to culti- vate its microbe. ' As soon as the method for the vaccination of dogs was firmly estabUshed, and we had in our pos- session a large number of dogs which had been rendered refractory to rabies, I had the idea of submitting to a competent committee those of the facts which appeared destined in future to serve as Q 2 84 HYDROPHOBIA a basis for the vaccination of dogs against rabies. That course was suggested to me, in prevision of the later practical application of the method, by the recollection of the opposition with which Jenner's discovery met at its beginning. ' I spoke of my project to M. Fallieres, the Minister of Public Instruction, who was pleased to approve of it and gave commission to the following gentlemen to control the facts which I had sum- marily communicated to the Academy of Sciences in its sitting of May 19 last : Messrs. Beclard, Paul Bert, Bouley, Aimeraud, Villemin, Vulpian. M. Bouley was appointed president, Dr. Villemin secretary, and the commission at once set to work. I have the pleasure of informing you that it has just sent in a first report to the Minister. I was acquainted with it here, and the following are in a few words the facts related in that first report on rabies. I had given to the commission nineteen vaccinated dogs in succession — that is to say, dogs which had been rendered refractory by preventive inoculations. Thirteen only of them had after their vaccination been already submitted to the test-inoculation on the brain. ' The nineteen dogs were, for the sake of com- parison, divided into sets along with nineteen more M.- PASTEUR S COMMUNICATIONS 85 control dogs brought from the pound without any sort of selection. To begin with, two refractory dogs and two control dogs were on June 1 trephined and inoculated under the dura-mater, on the sur- face of the brain, with the bulb of a dog affected with ordinary street rabies. ' On June 3 another refractory dog and another control dog were bitten by a furious street mad dog. ' The same furious mad dog was on June 4 made to bite stUl another refractory and another control dog. On June 6 the furious dog which had been utilised on June 3 and 4 died. The bulb was taken out and inoculated, after trephining, into three refractory dogs and three control dogs. On June 10 another street mad dog, having been secured, was, by the commission, made to bite one refrac- tory and one control dog. On June 16 the com- mission have two new dogs, a refractory one and a control one, bitten by one of the control dogs of June 1, which had been seized with rabies on June 14 in consequence of the inoculation after trephin- ing which it had received on June 1. ' On June 19 the commission get three refractory and three control dogs inoculated before their own eyes in the popliteal vein with the bulb of an 86 HYDROPHOBIA ordinary street mad dog. On June 20 they have inoculated in their presence, and still in a vein, ten dogs altogether, six of them refractory and four just brought from the pound. ' On June 28, the Commission hearing that M. Paul Simon, a veterinary surgeon, had a furious biting mad dog, have four of their dogs, two refractory and two control dogs, taken to his place and bitten by the mad dog. ' The Kabies Commission have, therefore, expe- rimented on thirty-eight dogs altogether — namely, nineteen refractory dogs and nineteen control dogs susceptible of taking the disease. Those of the dogs which have not died in consequence of the operations themselves are still under observation, and will long continue to be. The commission, reporting up to the present moment on their obser- vations as to the state of the animals tried and tested by them, find that out of the nineteen control dogs six were bitten, of which six three have taken rabies: Seven received intra-venous inoculations, of which five have died of rabies. Five were trephined and inoculated on the bra.in; the five have died of rabies. ' On the other hand, not one of the nineteen vaccinated dogs has taken rabies. M. PASTEUR'S COMMUNICATIONS 87 ' In the course of the experiments, on July 13, one of the refractory dogs died in consequence of a black diarrhoea which had begun in the first days of July. In order to ascertain whether rabies had anything to do with it as the cause of death, its bulb was at once inoculated, after trephining, into three rabbits and one guinea-pig. All four animals are still to-day in perfect health, a certain proof that the dog died of some common malady, and not of rabies. ' The second report of the Commission will be concerned with the experiments made as to the refractoriness to rabies of twenty dogs to be vaccinated by the Commission themselves.' {M. Pasteur then announced that he had just received that same Tnorning the first report addressed to M. Fallieres by the Official Commission on Rabies. It states that twenty-three refractory dogs were bitten by ordinary mad dogs, and that not one of them had taken rabies. On the other hand, within two months after the bites, &&per cent, of the control dogs similarly bitten had already taken the disease.) VI. October 26, 1885.— 4 Method for the Preven- tion of Rabies after the Bite of a Rabid Animal. — The prophylaxis of rabies such as I exposed it in my own name and in the name of my fellow-workers in my 88 HYDROPHOBIA preceding notes certainly constituted a real progress in the study of that disease. But the progress rea- lised was more scientific than practical. In appli- cation it exposed to various accidents. Not more than fifteen or sixteen dogs in twenty could be made refractory to rabies with certainty. It was advisable, on the other hand, to end the treatment with a la*t and very virulent inoculation, a control inoculation, in order both to confirm and to strengthen the refractory state. Furthermore, simple prudence required that one should keep the dogs in sight for a longer period than that of the incubation of the disease as produced by the direct and isolated inoculation of this last virus, so that it was occasionally necessary to wait three or four months before gaining the assurance of having pro- duced a refractory state. Such serious exigencies would considerably limit the scope of the method in practice. Finally, it would have been difficult to put the method to emergency uses at a moment's notice, a condition required of it nevertheless, if we consider how casual and unforeseen are the bites of mad animals. It was necessary, therefore, if possible, to dis- cover a more rapid method, and one capable of M. PASTEUR'S COMMUNICATIONS 89 giving, if I may so speak, a state of perfect security in the dog. And it was impossible, too, before that desidera- tum was reahsed, to think of making any trial of the method on man. After, I might say, innumerable experiments, I have at last found a method of prophylaxis both practical and rapid, and one which has proved suc- cessful in the dog with so much constancy in such a considerable number of cases already, that I feel confident of its general applicability to all animals and to man himself. This new method rests essentially on the follow- ing facts : The rabbit, inoculated under the dura- mater, after trephining, with the spinal marrow of an ordinary mad dog, is always affected with rabies ; it takes the disease after a length of incu- bation averaging about fifteen days. If a second rabbit be inoculated from that first one, a third from the second, and so on, always by the same mode of inoculation, there is soon mani- fested in the succeeding rabbits a growing tendency towards a shorter incubation. After a number of passages through rabbits, varying from the twentieth to the twenty-fifth, the incubation falls down to eight days, which remains 90 HYDROPHOBIA the normal incubation time for the next twenty or twenty-five passages. Then it reached an incuba- tion of seven days only, and recurring with striking regularity up to at least the 90th passage, which is the point we have reached at present, and there is barely as yet a sHght tendency towards a shorter period of incubation than seven days. The series was begun in November 1882, and has now lasted three years already. It has never once been interrupted, and never has it been neces- sary to have recourse to any other than the virus of rabbits of the same series which had previously died of rabies. Nothing is easier, therefore, than to have constantly at one's disposal, for considerable lengths of time, a virus of perfect purity and always identical with itself or as nearly so as possible. Therein lies practically the whole secret of the method. The spinal marrows of the rabbits are virulent throughout the whole of their substance, with con- stancy of the virulence. If from those marrows we take portions a few centimetres long, using all pos- sible precautions to keep them pure, and then sus- pend them in a dry atmosphere, their virulence diminishes slowly until at last it is all lost. The time that the virulence takes to disappear entirely M. PASTEUR'S COMMUNICATIONS 91 varies somewhat with the thickness of the marrows, but most of all with the outside temperature. The lower the temperature, the longer is the virulence preserved. These points constitute the scientific part of the method.' After those preliminary explanations, here is the process for rendering dogs refractory to rabies in a relatively short time. In a series of flasks, the air inside which is kept dry by dropping pieces of caustic potash into it, suspend every day a portion of fresh spinal marrow taken from a rabbit which has died of rabies of seven days' incubation. Every day also inject under the skin of the dog to be made refractory a full Pravaz hypo- dermic syringe of sterilised broth in which has pre- viously been triturated a small piece of one of the drying marrows. Begin with a marrow old enough to make sure that it is not at all virulent. Previous experimentation will already have settled that point. On the succeeding days proceed in the same manner with fresher marrows, and use those of every second day, untU finally we inoculate a last and very viru- ' If the rabid marrow be put whilst still moist in an atmo- sphere of carbonic acid, its virulence can be preserved intact at least for several months, provided we keep it free from admixture with atmospheric or other germs. 93 HYDROPHOBIA lent one which has been drying only one or two days. The dog has now become refractory to rabies, and will not take it anyhow inoculated, under the skin or on the surface of the brain. Making use of this method, I had already ren- dered fifty dogs of all ages and of all races refrac- tory to rabies, without having met with a single failure when, unawares, on Monday, July 6 last, three persons coming from Alsace presented them- selves at my laboratory ; they were — Theodore Vone, a grocer from Meissengott, near Schelstadt, bitten on the arm on July 4 by his own dog, which had become mad. Joseph Meister, nine years old, bitten also on July 4 at eight o'clock in the morning, and by the same dog. This child had been thrown down by the dog and had received numerous bites on the hand, the legs and thighs, some of them so deep that he could scarcely walk. The principal wounds had been cauterised with carbolic acid by Dr. Weber, of Ville, on July 4, at eight o'clock in the evening, twelve hours only after the accident. The third person was the mother of httle Joseph Meister, and had not been bitten. M PASTEUR'S COMMUNICATIONS 93 The dog had been killed by his own master, and on opening his stomach it had been found stuffed with hay, straw, and chips of wood. The animal was certainly mad. Joseph Meister had been res- cued from him all covered with saliva and blood. Mr. Vone had been severely contused on the arms, but he assured me that his shirt had not been traversed by the fangs of the dog. I told him there was nothing to fear, and that he could go home that same day, which he did. But I kept with me little Meister and his mother. The weekly meeting of the Academie des Sciences was held on that same day, July 6. I saw there our colleague Dr. Vulpian, to whom I related what had occurred. Dr. Vulpian, joined by Dr. Grancher, professor at the School of Medicine, kindly consented to come at once and see the state and the number of the wounds of little Joseph Meister. He had been bitten in fourteen different places. The advice of our learned colleague and of Dr. Grancher was, that owing to the depth and number of his wounds, Joseph Meister was exposed to almost certain death from hydrophobia. I then communicated to Drs. Vulpian and Grancher the 94 HYDROPHOBIA new results I had obtained in my studies of rabies since the time of my lecture in Copenhagen a year before. The child, being apparently doomed to inevit- able death, I resolved, not without feelings of utmost anxiety, as may well be imagined, to apply to him the method of prophylaxis which had never failed me in dogs. My set of fifty dogs, indeed, had not been bitten before they were made refractory to rabies ; but that objection had no share in my preoccupations, for I had already, in the course of other experi- ments, rendered a large number of dogs refractory after they had been bitten. I had that same year invited the members of the Commission on Eabies to witness that new and important progress. On July 6, then, at eight o'clock in the evening, sixty hours after the bites of the 4th, and in the presence of Drs. Vulpian and Grancher, we inocu- lated into the right hypochondrium of little Meister, under a fold made in his skin, the half of a Pravaz hypodqrmic syringe containing the marrow of a rabbit which had died rabid on June 21 previous. Since that date the marrow had been kept in dry air, suspended in a bottle — fifteen days altogether. M. PASTEUR'S COMMUNICATIONS 95 On the following days the inoculations were renewed, always in the hypochondria and in the manner indicated in the following table : — July 7 at 9 a.m. Marrow of June 23 i.e. 14 days old 7 „ 6 p.m. ,. 25 , 12 8 „ 9 A.M. „ 27 - 11 8 „ 6 P.M. » » 29 9 9 „ 11 A.M. July 1 8 10 „ 11 „ 3 , 7 , 11 „ 11 „ 5 6 12 „ 11 „ 7 , 5 , 13 „ 11 „ 9 , 4 , 14 „ 11 „ 11 3 15 „ 11 „ 13 ■ 2 , 16 „ 11 „ 15 1 The treatment, therefore, lasted ten days, and the total number of the inoculations was thirteen. I shall say later on that a smaller number of inocu- lations might have suf&ced, but in this first case I had necessarily to act with peculiar circumspection. Two fresh live rabbits were also inoculated on the brain with every one of the marrows used, ia order to follow their degrees of virulence. The observation of those rabbits brought out the foUowiag points : the marrows of July 6, 7, 8, 9, 10 were not virulent, for the rabbits inoculated with them did not become mad. The marrows of July 11, 12, 14, 15, 16 were all virulent, in ascend- ing progression. The rabbits inoculated from the marrows of July 15 and 16 took rabies after seven 96 HYDROPHOBIA days' incubation ; those inoculated from the marrows of the 12th and 14th after eight days ; those from July 11 after fifteen days. I had, therefore, in the last days of the treat- ment, inoculated Joseph Meister with the most powerful rabies virus — namely, the virus of the ordinary mad dog, strengthened by a large number of passages through rabbits, a virus giving rabies to rabbits after seven days' incubation, to dogs after eight or ten days only. My action was justi- fied by what I had observed in the fifty dogs of which I have spoken before. When once the state of immunity has been reached, there is no danger attaching to the inocu- lation in any quantities of the most powerful virus. It has always appeared to me that the only conse- quence of such inoculations was to consolidate the refractory state. Joseph Meister has, therefore, escaped from the hydrophobia which he might have developed in consequence of the bites he had received, and also from the hydrophobia, more powerful than the one resulting from ordinary canine madness, which I inoculated into him to test the immunity imparted by the treatment. This last highly virulent inoculation has one more advantage : it limits the period of time during M. PASTEUR'S COMMUNICATIONS 97 which fears may be entertamed as to the results of the bites. If rabies could come on at all it would undoubtedly do so quicker after this most virulent inoculation than after the bites. As early as the middle of the month of August I looked forward with confidence to the future health of Joseph Meister. To-day, three months and three weeks after the accident, his health is still perfect. "V^Tiat is the mode of action of the new method, just given, of the prophylaxis of rabies after bites ? I do not purpose to deal fully with the question to- day, but shall content myself with a few preliminary remarks, which will help to explain the meaning of the experiments which I am still carrying on for the purpose of giving us a clear idea as to the best possible interpretation. If we consider, on the one hand, the methods of progressive attenuation of mortal viruses and the prophylaxis which can be derived from them, and, on the other hand, the influence of atmospheric air on that attenuation, the first explanation which offers itself to the mind is that the continuous contact of the rabid marrows with dry air progres- sively diminishes their virulence until it is finally all lost. It would hence appear that our prophylactic g8 HYDROPHOBIA method rested on the use, first of all, of a virus without any appreciable degree of virulence, and then of viruses progressively virulent, from the lowest up to the highest. I shall show later on that the facts do not agree with that hypothesis. I shall also give proof that the delays in the incubative periods of the rabies inoculated from day to day into fresh Uve rabbits, as just indicated, and for the purpose of testing the state of the virulence of our desiccated mar- rows, are due not to a diminution in the degree of virulence of those marrows, but to a diminution in the quantity of rabies virus contained in them. Might it be, then, that the inoculation of a virus, the virulence of which should always remain identically the same, could bring on a state of re- fractoriness to rabies on condition that we proceeded in the use of it by very small but daily increasing quantities ? That would be one way of interpret- ing the facts of the new method, and a way which I am occupied in verifying experimentally. Yet one hypothesis suggests itself in explanation of the new method : a hypothesis which at first sight seems very strange, assuredly, but one never- theless worthy of all consideration, for it is in keep- ing with certain known facts of the vital pheno- M. PASTEUR'S COMMUNICATIONS Cjq mena observed in several of the lower beings, and, in particular, in certain pathogenic micro-organisms. A large number of micro-organisms apparently give rise, in the media where they grow, to substances which have thepropertyofopposingtheir own growth. As early as the year 1880 I had initiated" some researches having for their object to detect some such poison produced by the fowl-cholera micro- organism and toxic to that same micro-organism.' I have not been able, as yet, to demonstrate the presence of such a substance ; but I am of opinion to-day that those studies ought to be taken up anew, and I shall not fail to do so myself, taking care to cultivate the micro-organism in an atmo- sphere of pure carbonic acid gas. The microbe of swine-plague thrives in broths of very varying composition, but it is so rapidly stopped in its development, and the weight of it formed is so small, that it is occasionally barely possible to teU the presence of a crop of it by noticing the slender silky bands undulating in the nutrient medium. It looks as if at once had been produced a substance which had stopped the growth of the little being, whether sown in presence of air or in vacuo. ' See Comptes Bendus, t. xc. 1880. H 2 loo HYDROPHOBIA M. Eaulin, once my assistant, and now a pro- fessor in the Faculty of Lyons, showed, in the very remarkable thesis which he presented in Paris on March 22, 1870, that the Aspergillus niger deve- lops during growth a substance which stops, to some fextent, the further production of that mould whenever the nutrient medium does not contain iron salts. Might it be, then, that rabies virus was made up of two distinct substances, the one living and capable of multiplying in the nervous system, the other not living, but capable still, when in suitable proportions, of arresting the development of the first? In an early communication I shall give the experimental and critical results arrived at with regard to this third hypothesis concerning the mode of action of the prophylactic method. It is scarcely necessary in closing to remark that probably the most anxious question for the present is that of the time which may be allowed to elapse between the bite and the application of the treatment. That interval was, in the case of Joseph Meister, two days and a half, but it will certainly be considerably longer in a large number of cases. M. PASTEUR'S COMMUNICATIONS lot On Tuesday last, October 20, obligingly assisted by MM. Vulpian and Grancher, I had to begin the treatment of a young man of fifteen who had been bitten six full days previously on both hands and in circumstances of pecuHar gravity. The Academy will not listen without some emotion to the* story of the deed of bravery and of cool-miadedness done by the boy whose treatment I took in hand last Tuesday. Jean-Baptiste Jupille is a shepherd boy belonging to Villers-Farlay, in the department of Jura. Seeing a powerful dog Avith suspicious gait throwing himself upon a group of six of his comrades, all younger than himself, he seized his whip and rushed forward to meet the animal. The dog at once caught hold of Jupille by the left hand. Then followed a hand-to-hand fight, so to speak, the boy finally throwing down the animal and pinning him to the ground under his knee. Next, with his right hand he forced open the jaws of the beast, disengaged his left hand — all the while receiving new bites — and taking the thong of his whip he tied the muzzle of his enemy and with one of his wooden-shoes beat him dead. I shall make it a point to acquaint the Academy with the results of this new trial. 102 HYDROPHOBIA VII. March 1, 1886. — Results of the Applica- tion of the Method of Prophylaxis of Rabies after Bites. On October 26 last I acquainted the Academy of Sciences with a new method for the prevention of rabies after bites, and also with the details of its application to a young Alsatian boy, Joseph Meister, who had been severely bitten on July 4 preceding. The dog was manifestly rabid, and a recent inquiry conducted by the G-erman authori- ties has again shown that the animal was in a full fit of madness when he bit Meister. The boy is stiU in perfect health at the present time ; his bites date from nearly eight months ago. At the very time I was reading the note just referred to, I had under treatment the young shepherd boy Jupille, who had been bitten, more severely perhaps than Meister, on October 14. The health of this boy also remains to-day as good as can be desired. He was bitten four months and a half ago. Soon those two first and successful attempts were bruited about, and a large number of persons who had been bitten by mad dogs repaired to my laboratory asking to be treated like Meister and AT. PASTEUR'S COMMUNICATIONS 103 Jupille. This very morning — I am writing on Thursday, February 25 — assisted by Dr. Grancher, whose devotion and zeal are above all praise, we began the preventive inoculations in the three hundred and fiftieth patient. Although my laboratory, which has been given up altogether to the study of rabies for the last five years, has been a centre of information for every- thing appertaining to rabies, I confess that I shared in the general feeling of surprise at seeing such a large number of people who had been bitten by mad dogs. Our ignorance in that respect was due to more causes than one. As long as rabies had been considered an in- curable affection, people tried to keep away from the minds of those who had been bitten the very name of the malady. When a person ■ had been bitten, all at once unanimously declared that the dog was not mad, although the report of the veterinary surgeon or of the medical man should certify to the contrary, and the greatest silence was observed concerning the accident. Coupled with the desire of keeping the mind of the victim quiet there was added, amongst his relatives, the fear of doing him an injury. For people have occasionally gone so far as to refuse to employ workmen who 104 HYDROPHOBIA ■were known to have been bitten by mad dogs, believing that such persons could, all of a sudden, become dangerous ; a groundless fear, fortunately. A man affected with rabies is only to be feared in the last paroxysms of the disease. In order to carry conviction into the minds of persons who might be prejudiced against the method, or even hostile to it, I have been careful to draw up very rigid statistics, always insisting on the patients bringing with them certificates as to the rabid state of the dog, and delivered by registered veterinary surgeons or by medical men. And yet, all the same, I could not do otherwise, in a few very rare cases, but treat persons who had been bitten by dogs simply suspected of being mad, and which had afterwards disappeared and had never been heard of again. Such persons, in addition to -the real danger threatening from the bites received, would have gone on living in a state of perpetual anxiety capable in itself of impairing their health had we refused to intervene. I did not, however, treat any persons whose garments had not been visibly traversed or torn by the teeth of the animal. It is very evident that in such cases there is nothing to fear, for the virus cannot possibly have got into the system even M. PASTEUR'S COMMUNICATIONS I05 though there should be a deep and even a bleeding contused wound. In a certain number of doubtful cases the rabid state of the dog was demonstrated in my own laboratory by inoculations into rabbits and guinea-pigs of the nervous matter taken from the dead animal. I should hke now to give a sufficiently exact idea of the physiognomy of the treatment and also of the nature of the bites by quoting in chrono- logical order one of the series of persons undergoing treatment. It would be fastidious to give details concerning three hundred and fifty cases, I shall therefore make my choice more specially out of the first hundred persons bitten and treated. They comprise the period between November 1 and December 15. They are particularly interesting, for they have all at the present time got beyond the really dan- gerous period. I open my register at the chapter concerning that first hundred, and find in the space of ten days the following variety of cases : — - Etienne Roumier, forty-eight years old, belong- ing to the parish of Ourouere, department of Nievre, bitten on both hands on November 4, 1885, by a dog certified to be mad by M. Moreau, V.S. No io6 HYDROPHOBIA cauterisation or dressing of any kind for twenty- four hours. ' Chapot, forty-three years old, and his daughter, fourteen years, from Lyons, both bitten on the left hand on November 6, 1885, the girl much more severely than her father. The wounds had been washed with ammonia by a chemist. Dog certified mad by the Veterinary School of Lyons. ' Frangois Saint-Martin, from Tarbes, ten years old, bitten on the thumb of the right hand on Friday, November 7, 1885. Wound bathed with ammonia by a chemist. Dog certified rabid by M. Dupont, chief of the sanitary service for animal plagues. ' Marguerite Luzier, from Fongrave (Haute- Garonne), thirteen years old, bitten on the leg by a mad cat on November 11, 1885 ; cauterised with carbolic acid. The gravity of the bites calling for special surgical treatment, the chUd had to be sent to the Enfants-Malades (Sick Children's) Hospital. ' Corbillon, twenty-seven years old, from Neu- ville, near Clermont (Oise) , bitten on November 12, 1885. Dog certified mad by M. Chantareau, V.S. in Clermont. Cauterised with the red-hot iron eight hours after the accident. ' Bouchet, five and a half years, living near the M. PASTEUR'S COMMUNICATIONS loj 7th sluice of the Saint-Denis Canal, bitten on November 12, 1885, on the left hand and thigh. Trousers torn. Dog certified mad by M. Coret, V.S. in AubervUliers. Cauterised with the red- hot iron three quarters of an hour after the accident, by Dr. Dumontel. 'Madame Delacroix, from Lille (Nord), bitten on November 6, 1885, on the right foot. Cauterised with the red-hot iron nine hours afterwards. Dog certified mad by M. Freler, V.S. in Lille. ' Plantin, from Etrung (Nord), bitten on the right hand in the beginning of November 1885. Cauterised forty-eight hours after the accident. Dog certified mad by M. Eloire, V.S. in Capelle (Aisne) . ' Jeanne Pazat, seven years, from Mereuil (Dordogne), bitten on November 12, 1885, on the right hand, by a dog certified mad by Dr. de Pindray. The doctor saw her forty-eight hours only after the accident, and rightly judged that it was too late to cauterise. ' Madame Achard, from Saiat-Etienne, bitten on November 9, 1885, on the right foot, and again on November 12 on the right hand, by the same dog. Dog certified mad by M. Charloy, V.S. in Saint-Etienne. Not cauterised. io8 HYDROPHOBIA ' Madame Alphonsine Legrand, parish of Baune, in the department of Aisne. Bitten on the chin on November 6, 1885. Dog certified mad by M. Decarme, V.S. in Chateau-Thierry. Not cauterised. ' Antoine Cattier, forty-three years old, Kving at No. 12 rue des Hospitaheres Saint-Gervais, Paris, bitten on the hand on November 10, 1885. Cau- terised with the red-hot iron twenty hours only after the accident. Dog recognised to be mad by his own master : rabid voice, refused to take any food, all the while tearing and swallowing chips of wood and other objects. ' Ternat, Ms wife, Madame Dehors, Madame Dalibard, all four bitten on November 15, 1885, by the same dog, recognised to be mad while still alive, and then certified so after death by the well- known Saint-Ouen V.S. Sanfourche. Cauterisa- tions insignificant and tardy. ' Doctor John Hughes, from Oswestry (England), bitten on November 13, 1885. Two deep wounds in the lower lip. Not cauterised. Dog certified mad by the doctor himself. ' Widow Faure, from the village of Alma, Algeria, bitten on the leg on November 1, 1885 ; garments torn by the same dog, which bit the four children known as ' of Algeria,' of whom one died in M. PASTEUR'S COMMUNICATIONS 109 the Mustapha Hospital in Algiers two months after the accident. The rabid symptoms presented by this child were very carefully described by Dr. Moreau, of Algiers. The prophylactic treatment was applied to the three other children in the middle of November. Madame Greteau, from Bordeaux, bitten on November 14, 1885. Two bites on the ring finger of the right hand, one in the fleshy part of the last phalanx, the other on the nail, which was cut in two about its middle. Dog certified mad by Dr. Douand. Wounds bathed with ammonia and slightly cauterised. ' Voisenet {Noel), from Semur (Cote-d'Or), fifty years ; bitten on November 6, 1885, on both legs by a bitch certified mad by M. Colas, V.S. Cau- terised with the hot iron four hours only after the bites. ' Guichon, from Bordeaux, sixty-seven years, bitten on November 15, 1885, on the left hand, by the same dog which bit Madame Greteau, above mentioned. ' Halfacre {Walter), from London, twenty-eight years, bitten on the hand on November 15, 1885, and sent to us by Dr. James Paget. Not seriously cauterised. The brother of Halfacre died of hydro- 1 10 HYDROPHOBIA phobia five years ago in consequence of a bite which appeared so insignificant that it was left unnoticed. ' Calmeau, from Vassy-lez-Avallon, bitten on the night of November 15-16, 1885, on the abdomen, on the thigh, on the knee ; dress and shirt in shreds. Not cauterised at all. Bitch certified mad by M. Colas, V.S. in Semur. This is the same bitch which had bit Voisenet (Noel) above mentioned. ' Lorda (Jean), thirty-six years, from Lasse (Basses-Pyrenees) . This case is most interesting. Lorda was bitten on October 25, 1885, but only came to my laboratory on November 21, the twenty-fifth day after the accident. On the same day as him- self, and by the same dog, seven pigs and two cows were also bitten. The nine animals have died of rabies, the pigs after a short incubation of from fifteen to twenty-one days. It was only after the death from rabies of the pigs that Lorda took fright and left for Paris. ' The first cow died thirty-four days after she had been bitten, the second one fifty-two days after. I am indebted for the details of these curious facts to M. Inda, the able V.S. of Saint-Palais. One observation of his report is specially worth noting : the two cows had been thoroughly cauterised with the red-hot iron immediately after the accident ; he M, PASTEUR'S COMMUNICATIONS in underlines that particular point. I have had suffi- ciently numerous proofs of the inefficiency of cauterisation in certain cases, even though made with the hot iron and immediately after the bite. The health of Lorda is still keeping excellent. His treatment was finished on November 28 last.' Such is the enumeration, in the chronological order of their arrival at my laboratory, of twenty- five bitten persons comprised in a period of ten days. All other periods of ten days would offer sets of cases the enumeration of which would not teach us more than the last one, although in each one we might meet with one or more cases of bites no less interesting than that of Lorda. But I shall make short, and cite just one more of those cases because it was the cause of great anxiety to me. It is that of a young boy called JuUion, living at Charonne, rue des VignoUes, No. 6, and bitten on November 30. This chUd, seeing the dog come up to him, began to cry. At this very moment the dog thrust his lower jaw into the open mouth of the child. One of the fangs, cutting the upper lip, penetrated deeply into the hard palate, meanwhile one of the teeth of the upper jaw which had remained outside the child's mouth tearing in between the right eye and the nose. It was here 112 HYDROPHOBIA impossible to cauterise. This dog was certified mad by M. GuUlemard, V.S., rue de Citeaux, Paris. In one case alone has the treatment failed : that of the young girl Louise Pelletier, who died of rabies after she had been treated. This child, ten years old, had been bitten on October 3, 1885, at la Varenne-Saint-Hilaire by a large mountain dog, and brought to me on November 9 foUowiag, thirty- seven days only after the accident, the bites being deep and situated in the pit of the axilla and on the head. The bite on the head was so serious and so extensive that on November 9 it was still discharg- ing pus and blood, although the child had all the time been under medical care. It measured 12 centi- metres by 15 (a centimetre is 0"39370 of an English inch) and at one place the skin was still hanging loose. This wound made me feel very anxious, and I asked Dr. Vulpian to come and examine it. In the scientific interest of the method I ought to have refused to treat that child who had come so late and in circumstances of such exceptional gravity ; but I should not have forgiven myself had I not tried ever3rthuig, and I yielded to a feeling of humanity, moved also by the anguish and entreaties of the parents. Premonitory symptoms of hydrophobia showed M PASTEUR'S COMMUNICATIONS 113 themselves on November 27, eleven days only after the end of the treatment ; they became more marked on the morning of December 1, and death, accompanied by the most marked symptoms of rabies, closed the scene on December 3 in the evening. Now arose an all-important question : which of the two rabies viruses had brought on death, that of the dog-bite or that of the prophylactic inocula- tions ? It was easy to know. Twenty-four hours after the death of Louise Pelletier, with the authori- sation of the parents and of the Prefet de Police, the skull was trephined in the region of the wound, and a small quantity of cerebral or brain matter was taken out and inoculated intra-cranially into two rabbits. The two rabbits were seized with paralytic rabies eighteen days afterwards, and both in the same hour. After their death, their medulla oblongata was inoculated into fresh rabbits, and these took rabies after an incubation of fifteen days. These experimental results suffice to demonstrate that the virus which proved fatal to the girl Pel- letier was the virus of the dog that had bitten her. Had death been the result of the preventive inoculations, the incubation after this second inocu- lation into rabbits would have been seven days at I 114 HYDROPHOBIA most. This is established by the explanations given in my last note to the Academy. But although the preventive treatment in 350 cases has never once given rise to untoward re- sults, not a single inflammatory swelling, not a single abscess, barely a little cedematous redness after the last inoculations, are we yet authorised in saying that it has shown itself actually efficacious in preventing the development of rabies after bites ? Considering the large number of persons treated, one eight months ago (Joseph Meister), another more than four months since, and for the majority of the 350 others we are authorised in saying ' Yes, the method has given proof of its efficacy.' This assertion is best justified by a comparison with the average number of cases of rabies deve- loped after rabid bites. Works on human and on veterinary medicine do not agree very well on that point. The discrepancy is easily understood if we consider what I said a few moments ago with re- ference to the silence so often kept by families and by medical men as to the existence of bites by rabid animals and even as to the nature (A the cause of death, designated, wittingly at times, under the name of meningitis, when it is well known to have been due to rabies. M. PASTEUR'S COMMUNICATIONS IJ5 The dif&culty of getting up trustworthy statis- tics is well exemplified by the following case : On July 14, 1885, five persons were bitten by the same mad dog on the road to Pantin. The five persons took rabies and died. Dr. Dujardin-Beaumetz was thereupon appointed by the Prefect of Police to in- vestigate the case and report to the Conseil de Salu- brite de la Seine (Board of Health of the Seine department) the names and all the circumstances concerning the bites and the death of those five per- sons. Let such a series enter into the constitution of statistics, and at once the proportion of deaths to bites wUl rise. On the contrary, let such a series, where out of five persons bitten not one had died, be included in it, and the proportion will be lowered. I would place greater confidence in the following statistics, drawn up by M. Leblanc, the learned V.S., member of the Academy of Medicine, and for a long time chief of the sanitary depart- ment at the ' Prefecture ' of Pohce. He was good enough to let me have a copy of a valuable docu- ment on the subject of which we are speaking. It is an official abstract made by himself, and based on the reports of the commissaries of police and on information supplied by veterinary surgeons managing hospitals for dogs.' It covers a space of n6 HYDROPHOBIA six years, and shows that for the department of the Seine there were — Tear Persons Bitten Deaths by Rabies 1878 .... 103 24 1879 76 12 1880 .... 68 5 1881 .... 166 23 1882 .... 67 11 1883 .... 45 6 Those numbers give on the average one death by rabies for six persons bitten^ — one in six. But one more question, no less capital than that of the average number of deaths after rabid bites, remains to be solved yet before we can rightly estimate the efficacy or otherwise of the method of prophylaxis. It is necessary, namely, to know whether the time eflapsed since the occurrence of the accident is long enough to justify us in con- sidering the persons treated as having got beyond the period when rabies may yet break out. In other words, how long after a rabid bite does hydrophobia manifest itself ? Statistics show that rabies breaks out oftenest within the first two months — that is to say, between the fortieth and sixtieth days after the bites. Now, of those persons, of all ages and of either sex, already treated by the new method, 100 had been M. PASTEUR'S COMMUNICATIONS 117 bitten before December 15, more than two months and a half since. The bites of the second hundred date farther back already than six weeks and two months. For the remaining 150 persons treated or still under treatment all is gorag on, so far, as well as for the 200 first ones. It is evident, therefore, by comparison with the most searching statistics, that a considerable number of persons have already been snatched from death. The prophylactic treatment of rabies after bites is henceforth an established fact. There is cause enough to found a special estab- lishment for vaccination against rabies. Vm. A'pril 12, \%^^.— Further Results of the Method of Prophylaxis of Rabies after Bites. — On March 1 last, I acquainted the Academy with the results arrived at by the method of prophylaxis of rabies after bites of rabid animals ; it had at that date been apphed to 350 persons of all ages. To- day, April 12, the total number of such persons who have been treated or are still under treatment amounts to 726, and can be- grouped according to nationality as follows : — France 505 Algeria 40 Bussia 75 England 25 ii8 HYDROPHOBIA Italy 24 Austria-Hungary 13 Belgium 10 America (North) . 9 Finland 6 Germany 5 Portugal 5 Spain 4 Greece 3 Brazil .... .... 1 Switzerland 1 Total 726 That list is made up itself of two others which it is essential should be considered separately. The first one comprises the persons bitten by mad dogs ; the second one, those bitten by mad wolves. The number of persons treated after bites of mad dogs comes up to 688. The number of persons treated after bites of mad wolves comes up to 38. If this distinction were left out of sight, we should run the risk of passing erroneous judgment on the method of prophylaxis of rabies. The 688 persons treated who have been bitten by mad dogs are all alive and well to-day (if we still except the case of the girl Pelletier) . And yet more than one-half of them have now got beyond the dangerous stage. M. PASTEUR'S COMMUNICATIONS 119 Of the 38 Eussians who have been treated or who are still undergoing treatment and who had been bitten by mad wolves, three have died of rabies ; the others are well, so far, but it is impos- sible to foresee how they may fare ultimately, for, as a matter of fact, there are great differences as to their consequences, between the bites of dogs and the bites of wolves. Several persons have had the kindness to com- municate to me the very authentic records of cases of bites by mad wolves, and I think it may be useful to give here the conclusions of their reports. First Document. — On February 27, 1706, eight persons belonging to the parish of Saint-Julien-de- Civry, in Burgundy, were bitten by a mad wolf. One of them died the same day in consequence of the intrinsic gravity of the wounds he had received ; the remaining seven all died of rabies after incubative periods which ranged from seven- teen to sixty-eight days (17, 26, 28, 42, 44, 60, 68 days). (Borrowed from the death-register of the parish by M. Sandre, schoolmaster, the copy certified true by the mayor of the parish) . Second Document. — On December 26, 1806, in the neighbourhood of the town of Bourg, nine persons were bitten by a mad wolf ; eight of them 120 HYDROPHOBIA died of rabies. This case is reported by Dr. Lutil- Thimecour, of Lyons, who mentions the duration of incubation for one of the victims, an old woman of sixty, Claudine Tabouet, as having been twenty- four days. He adds that the others died soon after, and at short intervals.' ThirdDocument.— On October 16, 1812, nineteen persons were bitten by a mad wolf in the town of Bar-sur-Ornain. They were all treated by Doctors Champion and Moreau, who washed their wounds and cauterised them with liquid muriate of anti- mony. Eleven of those persons died of rabies after an in- cubation time which varied from seven, thirteen, and fifteen days, to sixty, sixty-nine, and seventy days. (Prom a communication made by Dr. Champion to the Institut de France on September 6, 1813.) Fourth Document. — On February 23, 1840, a shepherd of Darbois, called Dumont, aged sixty- four years, was bitten by a mad wolf. He died of rabies after an incubation of thirty-two days. (Communicated by MM. Caillebet and Mariotti.) Fifth Document. — On January 7, 1866, three ' We have taken the liberty of altering slightly the text by in- serting the information contained in the last six lines — which the Bevzie Scieniiflgue published after the date of the present communication. — Author. M. PASTEUR'S COMMUNICATIONS 121 persons belonging to the neighbouring parishes of Nant, Alques, and Saint-Jean-du-Bruel, in the de- partment of Aveyron, were bitten by a mad she- wolf. They all three took rabies and died after incu- bations of twenty-two, twenty -three, and thirty-eight days respectively. (Communicated by Dr. Bom- paire, of Millau, Aveyron.) Sixth Document. — On October 5, 1874, in the parish of Eochette, canton of La Eochefoucauld (Charente), two men were bitten by a mad wolf which had just previously thrown down and torn up a little girl. Both men took rabies and died, after incubative periods respectively of twenty-five and thirty days. The Uttle girl died of her wounds on the day she received them. (From the newspaper Le Charentais, October and November, 1874.) Seventh Document. — In a letter written on March 26 last, Dr. Kiepce, medical officer to the mineral- water station of Allevard, gave to Dr. Vulpian an account of four eases of bites by a mad wolf, in 1822. All four persons died of rabies after incu- bations of nine, thirteen, fifteen, and nineteen days. Eighth Document.— On May 11 and 12, 1811, in the neighbourhood of Avallon, a mad wolf bit several persons and a large number of cattle. 122 HYDROPHOBIA All the persons bitten took rabies, and died on the following dates, as seen in the death-register of the hospital : — In May 1811, on the 24th, 27th, 28th, 30th (two deaths), 31st ; and therefore thirteen, sixteen, seventeen, nineteen, and twenty days after the bites. (Copied from the registers of the hospital of the town of Avallon, department of Yonne.) By adding together those eight documents we get a percentage of deaths after the bites of mad wolves of eighty-two per cent. ; and, in six cases out of the total of eight, there were as many deaths as there were persons bitten. Were we to apply the same percentage of deaths to the nineteen Eussians from Smolensk whose treatment is now ended, and of whom sixteen are leaving to-day for Eussia, it is not three deaths from rabies that we should have had to deplore, but fifteen or sixteen. It is beyond doubt that the treatment must have shown itself efficacious for the majority of them. Yet more : the consensus of opinion in Eussia is that every person bitten by a mad wolf is in- evitably doomed to death by rabies. The facts just recorded show : 1. That the incubation of rabies in man, fol- lowing upon bites of mad wolves, is often very M. PASTEUR'S COMMUNICATIONS 123 short, considerably shorter than the incubation after bites of mad dogs. 2. That the death-rate after bites of mad wolves is considerable when compared with the death-rate after bites of mad dogs. Those two propositions find suf&cient explana- tion in the great number, the depth and the seat of the wounds made by the wolf, which fastens itself to its victim, often attacking him on the head and face. The necropsy of the three Eussians who succumbed at the Hotel-Dieu and the inoculation into dogs, rabbits, and guinea-pigs of the medulla oblongata of the first one of them who died, show that wolf-virus and dog-virus are sensibly of the same strength, and that the difference between wolf-rabies and dog-rabies is owing in the main to the number and nature of the bites. Those facts have induced me to investigate whether the method might not be usefully modified, after wolf-bites, by inoculating larger quantities of the vaccinating virus and at shorter intervals of time. I shall later on acquaint the Academy with results. In any case, and after wolf-bites in particular, it is well to come for prophylactic treatment as early as possible. The Smolensk Eussians were six 124 HYDROPHOBIA days on the way, and only arrived at the laboratory fourteen and fifteen days after they had been bitten. It would therefore have been possible, at a stretch, to commence their treatment eight days earlier, and it is now impossible to say what difference that might have wrought for the three who have suc- cumbed. IX. November 1, 1886. — New Communication on Rabies. — On October 26, 1885, I acquainted the Academy with a method of prophylaxis of rabies after bites. Numerous applications on dogs had justified me in trying it on man. As early as March 1, 350 persons bitten by dogs undoubtedly mad, and several more by dogs simply suspected of rabies, had already been treated at my laboratory by Dr. Grancher. And in consideration of the happy results obtained it appeared to me that it had become necessary to found an establishment for anti-rabic vaccinations. To-day, October 31, 1886, 2,490 persons have received the preventive inoculations in Paris alone. The treatment was in the first instance uniform for the great majority of the patients, notwith- standing the different conditions presented by them as to age, sex, the number of bites received, their seat, their depth, and the time which had elapsed M. PASTEUR'S COMMUNICATIONS 125 since the occurrence of the accident. It lasted ten days, the patient receiving every day an injection prepared from the spinal marrow of a rabbit, begin- ning with that of fourteen days' and ending with that of five days' desiccation. Those 2,490 cases are subdivided according to nationality in the following manner : — Bussia . Italy Spain England . Belgium . Austria . Portugal . Eoumania United States Holland . Greece . Germany Turkey . Brazil India Switzerland France and Algeria 191 165 107 80 57 52 25 22 18 14 10 9 7 3 2 2 1,726 The number of French persons has been con- siderable, amounting to 1,726, and it will be enough to confine ourselves to the category formed by them as a basis for discussing the degree of ef&cacy of the method. Out of the total 1,726 cases treated, the treat- 126 HYDROPHOBIA ment has failed ten times — namely, in the following cases : — The children : Lagut, Peytel, Clediere, Moulis, Astier, Videau. The woman : Leduc, seventy years old. The men : Marius Bouvier (thirty years), Clergot (thirty), and Norbert Magnevon (eighteen). I leave out of count two other persons, Louise Pelletier a,nd Moermann, whose deaths must be at- tributed to their tardy arrival at the laboratory, Louise Pelletier thirty-six days, and Moermann forty-three days after they had been bitten. We have therefore ten deaths for 1,726 cases, or 1 in 170 ; such are, for France and Algeria, the results of the first year's application of the method. Those statistics, taken as a whole, demonstrate the efficacy of the treatment, as proved further by the relatively large number of deaths which occurred amongst bitten persons who had not been vaccinated. We may state as a fact that of all French people bitten by mad animals in this year 1885-1886, very few were those who did not come for treatment to the laboratory of the Normal School. And yet, out of that small minority, there have been, to my own knowledge, no less than M. PASTEUR'S COMMUNICATIONS 127 seventeen deaths by rabies. I give them in a foot- note.^ ' 1. The mayor of Tourooing acquaints me with the death from rabies on December 12, 1885, of a child called Saumyn (Franpois). He was bitten on the same day and by the game dog as M6siaux (Jacques-Louis) in November 1885. Mfisianx was treated at my laboratory and is still in good health, but they had neglected to send on Saumyn. 2. Pour children belonging to the convent of Alma, near Algiers, were bitten on August 31, 1885. One of them, not treated by the inoculations, died of rabies in the civil hospital of Algiers. The remaining three were vaccinated in November 1885, and are still well. 3 & 4. The husband and father-in-law of Celine Lagaz, of the parish of Vooray (Haute-Savoie), not vaccinated, died of rabies within the same week. Celine Lagaz was vaccinated in November 1885, and is stiU well. 5. Harembure, surnamed Larralde, not vaccinated, died of rabies on January 21, 1886, at Amoratz-Laccos, in the Basses- Pyr^nSes. 6. Malandain (Ernest), from Daubeuf-Serville (Seine-Inf6- rieure), came for treatment in August 1886, after he had seen a woman belonging to the same parish, and who had been bitten by the same dog and on the same date as himself, die of rabies. The woman had not been inoculated ; he is still alive and well. 7. Henri Eiffiondi, an Italian, died of rabies last April, in the Beauj on Hospital. -In the month of February preceding he had received a slight wound from a mad dog, and, imprudently judging that he was in no danger, did not come for treatment. 8. Widow Busson, from Voujancourt (Doubs), and still alive, applied for treatment after she had on June 17 seen one of her neighbours die of rabies. 9. M. Jamin, the father, belonging to the department of La Sarthe, was bitten on June 25 ; he was not inoculated, and showed the first symptoms of rabies on August 7 following. Whereupon his son Henri Jamin, Alfred Moermann, and Marie Touohard, who had all three been bitten on the same date as Jamin the father. 128 HYDROPHOBIA The following document forms a natural appen- dix to our statistics : The number of persons who die of rabies in the Paris hospitals is very accurately known, par- ticularly so for the last five years. By order of the Prefect of Police, every case of rabies presenting itself in any one of the Paris hospitals is at once reported by the hospital man- ager to Dr. Dujardin-Baumetz, member of the Board of Hygiene and of Salubrity of the Seine, who has charge to investigate and send in a report to the Board. It is thus accurately known that in the last five years sixty persons have died of rabies in the Paris hospitals ; on an average twelve yearly. No one year has been exempt from such deaths, more or less numerous. Last year they amounted to twenty-one. Now, since November 1, left for Paris, where their treatment was begun on the forty-third day after the accident. After this tardy arrival, and in spite of the treatment, Moermann took rabies and died. In addition to those nine persons, there have also died of rabies in Marseilles, the young girl Masson ; in Paris, at the Hotel-Dieu, the man EafSn ; the policeman Carpier; Jules L'Hote ; a child from Vervins ; Mile. Ganet, who died in the train, tardily coming up to the laboratory for treatment. Drs. Tueffard and Beucher have, in addition, informed me of the death from rabies of two persons who had not undergone the preventive treatment. Total : 17 persons, not inoculated, who have died of rabies. M. PASTEUR'S COMMUNICATIONS 129 1885, when the preventive treatment began to be applied at my laboratory, only three persons have died of rabies in the Paris hospitals, of whom two had not been inoculated,' and the third who had been treated had yet not received the intensive and repeated treatments of which I shall speak in a few moments.^ On studjdng the preceding facts we find that the larger number of those who succumbed, not- withstanding that they had been treated, were young children and had been bitten on the face. They had only received the simple treatment. I have now become convinced that this treatment may occasion- ally prove insufficient, for such severe bites especi- ally. Unfortunately, such a conclusion could only be come to gradually and after a long time, pro- tracted delays being necessary before concluding, owing to the exceptionally long incubation of rabies in certain cases. The case of the Smolensk Eussians gave us a first indication. Dr. Grancher and myself were very much dis- tressed on seeing three of the nineteen Eussians who had been bitten by a mad wolf die of rabies ' Baffin (H6tel-Dieu) ; Biffiondi (Beaujon Hospital). 2 Clerjot (Tenon Hospital). 130 H YDROPHOBIA in the Hotel-Dieu, the first one while still under treatment, the two others a few days after their treatment was ended. Were, then, the remaining sixteen going to die also ? Was the method thus proving powerless against wolf -rabies ? Kemember- ing, then, that all the dogs that I had successfully vaccinated had received, as a last preserving ino- culation, the virulent marrow taken out of the rabbit on the same day, and also that the first person vaccinated, J. Meister, had completed his treatment with a marrow dating from the previous day only, we submitted the sixteen Eussians to a second and then to a third course of treatment, including each time the freshest marrows, those of four, three, and two days. It is very likely to those repetitions of the treatment that we must attribute the cure of those sixteen Eussians. This morning again I have re- ceived a telegram saying they are still in excellent health. Encouraged by those results, and also by cer- tain new experiments of which I shall give the de- tails further on, I have modified the treatment and made it more rapid and more active for aU cases, and more rapid and energetic stiU for bites on the face, and for deep and multiple bites on exposed surfaces. M. PASTEUR'S COMMUNICATIONS 131 And actually, for bites on the face or head, and deep bites on the limbs, we precipitate the inocula- tions and come promptly to the freshest marrows. Thus, on the first day, inoculate marrows of twelve, ten, and eight days at 11, 4, and 9 o'clock ; on the second day, marrows of six, four, and two days at the same hours ; on the third day, the one- day old marrow. Then begin the treatment again on the fourth day with marrows of eight, six, and four days ; on the fifth day use the marrows three and two days old ; on the sixth day, the one day old marrow again. On the seventh day again the four days old marrow; on the eighth day, the three days old marrow ; on the ninth day, the two days old mar- row ; on the tenth day, the one day old marrow. In that manner give three courses of treatment in ten days, carrying each one of them up to the freshest marrows. If the bites have not yet healed up, or if the patients have only come up tardily for treatment, we often enough, after allowing them two or more days' rest, begin anew the same courses of treat- ment until we have reached the fourth or fifth weeks, which are the dangerous period for children bitten on the face.* ' For cases in which the bites are multiple and very severe, E 2 132 HYDROPHOBIA This new mode of vaccination has been applied for the last two months in all very severe cases, and the results are so far extremely favourable. It will be sufiScient, in order to show the correctness of my assertion, to compare on the one hand the circum- stances of the bites and inoculative treatment of the six children whom the simple treatment failed to save, and on the other hand those relating to ten children who were bitten quite as severely in the month of August last, and who received the intensive treatment. The dangerous period rarely lasts beyond the fourth or sixth week for children bitten on the head and face, and I am, therefore, confident that those ten children have already got beyond the reach of the disease. This new treatment has been naturally followed by an increase of work. Dr. Terrillon, professeur agrege at the Faculty of Medicine; Dr. Eoux, sub- manager of my laboratory ; Dr. Chantemesse, hos- pital-physician, and Dr. Charrin, have all lent Dr. Grancher and myself their most zealous collabora- tion. the first treatment might be finished in a single day, and then re- peated on the following days. Experiments on dogs would justify such a practice. In Russia such exceptionally severe wounds are frequent enough, inflicted by wolves or even by dogs. M. PASTEUR'S COMMUNICATIONS 133 .9fl S ■gSs o to 3 t> r? te 0) o a «H ^ Ea 013 oTcJ >»« a a> d g o o™-, fl g Q> S > ^-^ S ftS p,a (H 2 d o 2 oj fc[ "-< rt 01 " S-3 09 O iQ Oeo ■" >> *^ ° ca ^ fig t- ►- S r to** a o n .2 3 § bo S 15 . ^ ■p ^ 13 •a g C^ C9 to O t- o 00 o o o 1 Ph -w -g "S ;l.„.l R PI fl s aSfl o .3 1 § 1-1 3 III-- ■ ^3 ^ 2g So 1 I-H CO £ CO ■s 1 ^ o si 1° 1\ o CO 1 g . = .. o s s = 2 giro's "...■°" 1 ■a 6.0 o H O O o - K Is- Eg 2^ 2 — = a a !^ ^^^ a H ■»2 <= w «o eo cq eo o O 0) OS w -* M e*5 CT fl m5 o bb5 i fl bb^-g ) >» >» >i r*< |-> t>i t>» Pv >» -W ^ ■S ■S 5 ^ W «s OS 04 cu CO CO to t« b- S p? 43 -g 4^) 4^ .-< P fi A fl A tn ;d-g„ s 1 * = t£Sw^ 003 ■^ 3 «5o -- :. -^° = = -55 - . -pfOOJsDM H^eoXMa ■* -t^COr-f'*' ^ 4^mcoton S C^ ^ «H W _*H 'J' _«H 1 '-'0 ^-S r-< fl co' CO S " * s ^ . is a * fc fl ^ gig " S> = R P = = |4| a's§ s a s a a H !^ a ■e °i 1-1 iM ^ ra ■^ S S S5 ift ^ m -5 CQ fl «H so m ec 1.1 o« i-i c£ bib bi) bio bb bS s s fl fl Fl ft <( <1 -«1 -^ ■< -ta M «H 1 i i i i i >a t^ p^ P-. >-» <» Tf< CO r«J OT M a> • : ; • « a fl -«3 ) B 'ft d 1 1 3 S ^ M J fl 136 HYDROPHOBIA It now remains for me, finally, to give to the Academy the results of certain new experiments on dogs. Some had objected to our human vaccinations after bites, as usually practised, and based in the main on the vaccination of dogs before bites, that the immunity of animals had not been sufficiently demonstrated after they had previously and with certainty been infected with the virus of rabies. The objection is sufficiently answered if we succeed in producing the refractory state in dogs after tre- phining and intra-cranial inoculation of the virus of ordinary canine madness, this being the most certain and unfailing mode of infection. My first experiments on this particular point date from the month of August 1885. Success had at that time been but partial. I resumed the expe- riments within the last few months, as soon as the organisation of the new treatment gave me the time. They prove successful on the following conditions : the vaccination must begin soon after the infective inoculation, as early as the next day, and must be carried out rapidly, giving the whole series of pro- phylactic marrows in twenty-four hours or less ; then repeat the treatment once or twice, giving one inoculation every two hours. M. PASTEUR'S COMMUNICATIONS lyj If Dr. von Frisch (of Vienna) was not successful in this order of experiments, his failures must be attributed to the fact that he used the slow process of vaccination. In order to be successful, it is ne- cessary, I repeat, to act promptly, to vaccinate the animals in a few hours and then to revaccinate them. We might formulate in the following manner the conditions of success or of failure in those expe- riments : the success of animal vaccination after their intra-cranial infection depends upon the ra- pidity and intensity of that vaccination. The immunity conferred under such conditions is the best proof of the excellence of the method. This is the last of M. Pasteur's communications to the Academy on the subject of rabies. We have, however, one more note from him published in the first number of the monthly ' Annales de I'lnstitut Pasteur,' addressed to the editor. Prof. Duclaux, and dated from Bordighera, in Italy, December 27, 1886. We shall give here a translation of those portions of the letter which refer to the mode of action of the prophylactic inoculations; the re- mainder will come more naturally under the head- ing of statistical results further on : — 138 HYDROPHOBIA What idea can we form as to the cause of the immunity conferred by the method of prophylaxis after bites? On first thought it appears very natural to suppose that the intensity of the virulence of the rabid marrows diminishes progressively, and is at last all lost by their stay in a dry atmosphere at a temperature of 23° C. to 25° C. (about 75° F.). This would then lead to the belief that the method was based on the use at first of a virus without any appreciable degree of virulence, then of one with a feeble degree of virulence, and finally stronger and stronger ones. Notwithstanding the reserves I had made in that connection in my note of October 26, 1885, to the Academy of Sciences, that explanation seems to have very generally prevailed. It has been frequently expressed. All appearances are in favour of it, I must confess, seeing that rabid marrows, dried at 23° C. to 25° C, and then inocu- lated intra-cranially into rabbits, give rise to rabies in them after periods of incubation the length of which varies directly with the time of exposure in the dry atmosphere. In the practical apphcation of the method it does seem then that the first non- virulent marrows are followed by progressively more virulent ones. But experimentation shows, I believe, that those delays in the time of incubation M. PASTEUR'S COMMUNICATIONS 139 are a result of the diminution in quantity of the rabies virus which is dying out rather than a dimi- nution in the degree of its virulence. Suppose, for instance, we take some virus from rabbits with protracted incubation periods — protracted to one month and even more — and inoculate it by tre- phining into healthy live rabbits, we in all cases at once reproduce our seven days' incubation rabies.' The rule is absolute- In practice, then, it does not seem that we have to deal with weaker and then with progressively stronger viruses, but rather with a virus of unvarying intensity, ruled indeed by the law which will have it so, that the duration of incubation varies inversely with the quantity inoculated, the ' It might be objected to the hypothesis I am propounding that the splenic fever vaccine fluid resumes all its virulence when, by accident, it causes the death of a sheep or cow. It might also be argued that the heated splenic fever germ, which becomes vaccinal at 55° C, recovers its virulence by one single culture. It will be worth while, nevertheless, to try and see if the refractory state can be produced by inoculations of very small quantities of fully virulent rabies virus, and daily increasing the dose. I may at once say, however, that this process is not vaccinal in the case of splenic fever. The sheep thus treated are not rendered refrac- tory ; they are killed, although more slowly than by inoculations of larger quantities. Let us not lose sight, finally, of the very original and very fruitful theory put forward by Mr. Metschnikoff. Does the vac- cinal matter, supposing it to exist, reside in the dead micro- 140 HYDROPHOBIA virus remaining the same. Thus, the smaller the quantity used the longer the incubation, and vice verm. The facts agree better with the notion of a vaccinal matter which we may suppose associated with the rabies microbe, the latter preserving its own virulence intact in all the drying marrows. But the process of desiccation destroys the microbe itself progressively and more rapidly than it de- stroys the vaccinal matter. This opinion is further supported by the following facts : All methods for the inoculation of rabies, with the sole exception of subdural inoculation after trephining, sometimes, we might almost say often, give rise to a rabies-refractory state without any previous apparent symptoms of an attenuated form of the disease. I could quote numberless instances, but a few will suf&ce. 1. On February 12, 1885, six healthy dogs re- ceive under the skin of the abdomen a hypodermic syringeful of sterilised broth holding in suspension portions of the triturated medulla oblongata of a dog which had recently died of rabies in the Alfort Veterinary School. On March 6 one of the six dogs takes furious rabies, with well-marked rabid bark. M. PASTEUR'S COMMUNICATIONS 141 On March 24 the remaining five dogs are still well and receive iatra-cranial inoculations of the virus of ordinary street madness. Three of the five dogs developed rabies on April 4, 5, and 10, whilst the two others remained refractory, a state for which they were owing, evidently, to the sub- cutaneous inoculations they had received on Feb- ruary 12. 2. On July 23, 1886, seven new dogs are in- oculated under the skin of the abdomen, receiving each a syringeful of the sterilised broth holding in suspension part of the medulla of a rabbit belong- ing to the forty-seventh passage through rabbits. The first rabbit of the series had been infected with the virus of a dog which had died of ordinary canme madness. On August 5 following, two of the seven dogs show symptoms of dumb-madness, and lie down without attempting to bite and voiceless. On the following day the same symptoms develop them- selves in a third dog, in a fourth one next day, in a fifth on August 10, in a sixth one on August 25. The seventh dog does not fall ill either in August or in September. In order to ascertain whether he is now refractory in consequence of the inoculation received on July 23, he is trephined and receives on 142 HYDROPHOBIA the surface of the brain a quantity of the virus of an ordinary mad dog. He does not evince any signs of uneasiness, and remains well all through the succeeding months. He is refractory. 3. On July 31, 1886, seven new dogs receive under the skin of the abdomen the ordinary injec- tion prepared from the meduUa of an ordinary mad dog. Five of those dogs took rabies ; the first one on August 17, biting madness, with paralysis of the hind quarters, the second one on August 19, the third, fourth, and fifth on August 28 and Septem- ber 3, aU four taking dumb-madness. The remain- ing two are stUl well at the end of September, at which date they both receive intra-cranial inocula- tions with the virus of ordinary street-dog rabies. Several months later they are stiU keeping perfectly well. They had, therefore, been rendered refractory by the inoculations made on July 31. 4. On January 23, 1885, six new dogs receive under the skin of the abdomen the half of a hypo- dermic syringeful of the broth holding in suspen- sion the triturated medulla of a rabbit belonging to the sixty-sixth passage of the rabbit series. Five of those dogs took dumb-madness on the eleventh, twelfth, and thirteenth days following. The sixth dog resisted this inoculation and subsequently M. PASTEUR'S COMMUNICATIONS 143 showed itself refractory, owing to that same inocu- lation of January 23. 5. On July 13, 1886, seven new dogs receive under the skin of the abdomen two syringes each of the virus prepared from a rabbit belonging to the 118th passage of the rabbit series. On the 20th of the same month one of them takes paralytic madness and lies down motion- less, although still trying to bite a stick thrust at Mm. The remaining six dogs resisted the infection. They were later on all six submitted to the test : subdural inoculation with the virus of ordinary dog madness. Four of them still remained refractory, an effect due to their first inoculation on July 13. The other two took paralytic rabies, but only thirty, twenty-seven, and twenty-eight days after their intra-cranial inoculation. The case of the, last two dogs shows that their inoculations of July 13 had not made them com- pletely refractory; it shows also that they were _ partially vaccinated, if we remember that intra- cranial injection of the virus of ordinary dog rabies reproduces the disease in a much shorter time than twenty-seven and twenty-eight days. I am led to the belief that they were sufficiently well vacci- 144 HYDROPHOBIA nated to escape infection after bites of ordinary mad dogs. 6. On August 28, 1886, two new dogs receive under the skin of the abdomen ten syringes each of the virus prepared from a rabbit of the 122nd pas- sage through rabbits. On the following days the two dogs give no signs of any discomfort. In order to know if they have been made refractory, they are trephined and inoculated subdurally with virus prepared from a rabbit just dead after infection from an ordinary mad dog. As a test experiment to verify the virulence of this virus, a new live rabbit is also inoculated with it at the same time as the two dogs. This control rabbit takes rabies on the sixteenth day after its inoculation, but the two dogs remain quite well and continue so for several months. I could still give a very large number of such cases of acquired immunity after subcutaneous in- jections of any sort of rabies virus. It may seem strange that rabies is not produced, in certain cases, after such inoculations, if we consider that the. quantities injected are relatively large, whilst an extremely small fraction of the same, if injected under the dura-mater, never fails to give rise to the disease. But what is much more surprising is the M. PASTEUP'S COMMUNICATIONS 145 production, in many cases, of an absolutely refrac- tory state, and that without the previous appearance of any morbid phenomenon at all. Is not this last fact better explained by the action of some sort of vaccinal matter accompanying the rabies-microbe rather than by the action of the microbe itself ? It is true that the refractory state is not brought on in every case, but it is easy to understand that, for many reasons, the vaccinal matter, granting its existence, wiU not under aU circumstances be able to produce its effects before the microbe has fixed itself iQ some point of the organism favourable to its development. How, again, can we understand, except by ad- mitting the existence of a vaccinal matter, the last experiment cited — namely, two dogs receiving under the skin ten syringes each of the very virulent virus of the 122nd passage through rabbits, and at once rendered refractory to rabies ? The large quantity of rabies microbes introduced under the skin must have reached the nervous system, and developed here and there in it, unless there was also injected at the same time some substance capable of travelling more quickly to that same nervous system, which it places in such a condition that the microbe can no longer be cultivated in it. It is easy to see, too, L 146 HYDROPHOBIA that such experiments will not always be successful, but that rabies will often declare itself. For we must grant that in many cases the microbes will be able to fix themselves in some point which had not yet been preserved by the vaccinal matter. It might be asked why intra-cranial inoculation invariably produces rabies and never the refractory state. It would not be a sufficient answer to say that by that process the virus is in all cases brought at once ia immediate contact with the encephalon. For, as a matter of fact, the massive hypodermic inoculations must in a large number of cases have, quite as directly as by the intra-cranial inoculation, conveyed the virus and its figured elements to the encephalon by the venous or lymphatic channels. The real difference between the two modes of inocu- lation appears to me to consist in this circumstance, that subdural inoculation never introduces into the system more than a very minute quantity of virus, and, therefore, also of vaccinal matter, not enough to produce the refractory state, whereas for hypo- dermic injections the quantities used have always been much more considerable. Dogs bitten by mad dogs do not always take rabies. That is a well-known fact. Such bites, like the subdural inoculation, can only introduce M. PASTEUR'S COMMUNICATIONS 147 into the system very small quantities of virus and of vaccinal matter. I have often made experiments for the purpose of ascertaining whether such bitten dogs which had not taken rabies had all the same become refractory to the disease : in every one of the cases tried the animal developed rabies when inoculated on the brain with the virus of an ordi- nary mad dog. I have also made a large number of experiments with the object of seeing whether rabies was not oftener produced after hypodermic injection of relatively small than of larger quantities of rabid medullas of rabbits belonging to a series of pas- sages. The comparison was made, as a rule, between inoculations of one-fourth, one, two, and ten Pravaz syringes. The general showing of the experiments has often been : 1, that rabies appeared to declare itself oftener after injection of one-fourth of a syringe than of one or several syringes; 2, that in those cases where rabies was not produced, the refractory state was oftener brought on by the use of large than of small quantities. The following experiment would decisively de- monstrate the existence of a vaccinal substance in the spinal marrows of rabbits which had died of rabies. One would have to prepare a set of mar- L 2 148 HYDROPHOBIA rows, by desiccation, which should be absolutely non-virulent, and yet capable still, when inoculated into dogs, guinea-pigs, and rabbits, of rendering them refractory to rabies. This could be realised on the assumption that the microbe lost all viru- lence before the vaccinal matter did its power of prophylaxis. A considerable number of experiments have already been made in that direction. Several of them did not lead to any very definite conclusions ; in several cases the marrows experimented on were still slightly virulent. In others the inoculation of marrows which had lost all virulence failed to give the desired result — namely, the refractory condition of the animals inoculated with them. But on several occasions, also, I obtained sets of marrows, any one of which could be inoculated into rabbits after trephining without giving rise to rabies, even after intervals of two and three months ; and yet those same marrows when inoculated into dogs and guinea-pigs rendered them refractory. I have since renewed those experiments, and tried new sets of marrows, but have not this time been successful ; and, being now far from my first successful results, doubts have arisen in my mind as to the accuracy of certain of my experiments M. PASTEUR'S COMMUNICATIONS 149 which I had considered as unimpeachable, and I have resolved to begin them again whenever I shall have the leisure. They are experiments of long duration, which might well be repeated by certain managers of stations for rabies-vaccination, better than myself, perhaps, able to devote to them the necessary time. Success in these experiments must consist in the use of marrows dried at a tempera- ture as near as possible to the one which does away with all virulence in the rabies microbe. If after suspension in dry air at a temperature of 25° C. (77° F.) our marrows are found to have lost all virulence, they are the proper ones to use, begin- ning the inoculations with those even of six, seven, and eight days' desiccation. The interest of possible vaccination by means of non- virulent marrows is self-evident, and need hardly be pointed out. It would both constitute a first-rate scientific fact and a priceless improvement on the present method of prophylaxis of rabies. I should like, before closing this already long letter, to speak of a last point of great importance. Certain facts indicated in my note of October 26, 1885, and also the cases of dog-inoculations which I have related in the course of the present letter, give us some idea of the profound changes ISO HYDROPHOBIA wrought in the properties of the virus of ordinary- canine madness by successive transfers a large number of times through rabbits. Those changes are evidenced in various ways ; thus we may con- sider only the duration of incubation in the rabbits successively inoculated. At the beginning, after a first passage from the ordinary mad dog to the rabbit, the average incubation is fifteen days. For this first passage into the rabbit, from any race of dog, provided only the animal has died of ordinary canine madness, I have never seen the incubation go below eleven days, and incubations of eleven and of twelve days are altogether exceptional ; but after a large number of such passages have been made from rabbit to rabbit, the incubation goes down to eleven days, then to ten, nine, and eight days in succession, remaining long enough at the last period. Long before reaching the 80th or the 100th passage, the incubation has already lowered to seven days, without ever, even as an exception, going back to eight days. It remains a long time at seven days, only going down occasion- ally to six days. It is still seven days at the present time after the 133rd passage. Can we, then, conclude that in this direction, at any rate, the virus of rabies has come to a fixed point ? Or M. PASTEUR'S COMMUNICATIONS 151 will the duration of incubation go down perma- nently to six days when the succeeding passages have reached far enough, in our races of rabbits, at least ? Experience alone can decide the question. The further we go from the initial virus of a series, and from the first serial rabbits, the less does the virus, hypodermically inoculated, become capable of reproducing the disease, especially so if large quantities are injected, whilst still, all the same, procuring the refractory state, as I have shown previously. Finally, my dear Duclaux, I may add a few words on the duration of the immunity conferred to our vaccinated dogs. As you are aware, I have at VUleneuve-rEtang a large kennel, where I have kept for two years now a considerable number of dogs which I had rendered refractory to rabies. At the end of their first year I tried on a group of them the criterion inoculation by trephining and injecting the ordinary street dog virus. Eleven of them out of fourteen resisted. This year again I tried the same experiment on six more which had been vaccinated two years previously ; four out of six came out immune, and one of the two which did take rabies must have been partially vaccinated still, for it presented an incubation of twenty-eight 152 HYDROPHOBIA days ; for the second one the incuhation was twenty- one days. Both might, perhaps, have received with impunity the bites of ordinary mad dogs. With regard to the four refractory ones, the point is undoubted, as we know. Postscriptum. — I think it will be useful to add in a postscript the following lines which I copy from a note which was recently given to me in Paris by Mr. Helmann, the present manager of the laboratory created in St. Petersburg for the treatment of rabies by the en- lightened zeal of Prince Alexander of Oldenburg. ' Thanks to the initiative of H.I.H. Prince Olden- burg,' says Mr. Helmann, ' our operations on rabies were begun in the month of November 1885 with virus taken from a mad dog which had bitten an officer, who had himself been sent to M. Pasteur in Paris, there to undergo the preventive inoculations. With the same virus I inoculated three rabbits ; two of them took furious rabies, which was again the form reproduced when new rabbits were inoculated from the first ones. It was impossible to obtain a case of paralytic rabies, whether by intra-cranial or subcutaneous inoculation, with a small or with a large quantity of virus, whatever also the race or the sex of the rabbits, whether the virus was taken from the medulla oblongata or spinal marrow. ' After the twelfth passage, however, there was occa- sionally now and then a case of paralytio^rabies, and from the twentieth passage onward, one-half of the rabbits took the paralytic form ; but it was found im- M. PASTEUR'S COMMUNICATIONS 153 possible from one of those paralytic rabbits to reproduce the furious form in rabbits. At the present moment I have reached the twenty-fifth passage, and the incu- bation is from eight to eleven days, varying with the quantity of virus inoculated. I had, as an exception, a case of prolonged incubation. A rabbit which had been inoculated on the brain on February 21, only took furious rabies on June 7 following.' A second one, inoculated on March 3, subcutaneously, fell ill on September 16. . . .' The following description of furious rabies in the rabbit is very graphic, and applies generally even to our own varieties of rabbits : ' The symptoms of furious rabies,' says Mr. Helmann, ' are sufficiently characteristic. At the beginning the rabbit hides itself, and its ears begin to tremble ; soon after it begins to plough the floor with its fore-paws and dashes itself about with so much violence that it often bruises its nose and forehead. After the period of excitement is over there comes on a stage of reaction, during which the animal remains motionless. If worried it will stiU make a few jumps, but soon go back again into its torpid rest, more especially so if the disease is near drawing to a close. When the excitement and agitation are at their highest, certain rabbits occasionally shriek. Paralysis sometimes supervenes before death, but never lasts more than a few hours. . . . ' If this inoculation, after trephining, gave this long incuba- tion of three months and a half, it must have been owing to the fact that an extremely small quantity of virus only was deposited on the surface of the brain. 154 HYDROPHOBIA ' Several rabbits which were inoculated after tre- phining in March last, with viruses dried at 35° C. (95° F.) for twenty-four hours, are still to-day in excellent health. At 35° C. the virus loses all virulence in twenty-four hours. 'In March also I inoculated four dogs with virus dried at 85° C. In June they were re-inoculated with virus dried at 23° C. (73-4° F.) Then again they re- ceived marrows of ten, nine, eight, seven, six, five, four, three, two, one day's desiccation. On July 31, two of the dogs were trephined and inoculated on the brain with fresh virus taken from an ordinary mad dog. The four dogs are still now in perfect health, and I consider them as refractory. ' In June 1886, H.I.H. Prince Alexander of Olden- burg brought back from M. Pasteur's laboratory two rabbits, belonging to the 116th and 117th passages. We at once set to work with the virus prepared from those two rabbits. ' On July 13, 1886, in presence of Messrs. Perdrix and Loir, the preventive inoculations in the human subject were begun, and on November 8 following, 118 bitten persons had already been inoculated. Out of that number one only, an old man over seventy years of age, died, after he had been submitted to the ordinary treat- ment inclusive of the third day marrow. He had re- ceived numerous and deep bites on both hands, and the period of incubation was very short, twenty days only. ' One hundred and thirteen of those 118 persons had been bitten by dogs, five by cats. . . . M. PASTEUR'S COMMUNICATIONS 155 ' In order to ascertain whether the animals which had bitten our patients were really mad, inoculation experi- ments were performed on rabbits and on guinea-pigs. Out of forty-five dogs and five cats brought to the labora- tory, some alive, some dead, forty-three dogs and two cats were found to be rabid, as verified by the successful intra-cranial inoculation of the virus taken from them into rabbits and guinea-pigs.' The next three pages are given in a foot-note to the same article : Many Eussians had come to Paris for treatment who had been bitten by mad wolves or by mad dogs. I had thus had an opportunity in their cases of seeing how desperate such bites often are in Eussia, and how short their incubation. I had accordingly written to Dr. Gamaleia, advising him, as an exception, to give all the inoculations in twenty-four hours. The following ex- periments justified me in giving such an advice : On each of the following days, August 10, 12, 14, and 20, 1886, two new dogs were vaccinated, each animal receiving the whole set of marrows in the course of twenty-four hours. Thus : On August 10 at 8 a.m. an inoculation under the skin of the abdomen of a full syringe of the fourteen days old marrow, diluted in sterilised broth. On the same date — At 10 A.M. a syringeful of the 12 days old marrow „ 12 A.M. „ „ 10 .„ „ » 2 P.M. „ „ 8 , 4 P.M. „ „ 6 „ 6 P.M. „ •„ i „ 156 HYDROPHOBIA On August 11— At 8 A.M. a syringef ul of the 2 days old marrow „ 10 a.m. „ „ „ „ (i.e. a fresh marrow.) On August 12 same series repeated on two new dogs — namely, inoculations with the marrows from 14 to days old, every two hours, at 8 a.m., 10 a.m., 12 a.m., and 2 p.m., 4 p.m., and 6 p.m. ; and on August 13, at 8 and 10 A.M. with the marrows of. 2 days and days. On August 14, repetition of same experiment on two new dogs with marrows from 14 to days, every two hours, except the two last, which were given in the fore- noon on August 16. On August 20, finally, same series tried on two new dogs in identical conditions, and ending therefore on the 21st in the forenoon. We thus had four series of two dogs each, which had all received the whole set of marrows from 14 to days in the space of eighteen hours only. The eight dogs were soon after tested as to their re- fractoriness to rabies, the two first ones as early as August 12, thirty hours only after their last inoculation ; those of August 12, 14, and 20, were tried on August 25, after thirteen, eleven, and five days. Therefore, the test experiment consisted, for every one of them, in an inoculation on the surface of the brain, after trephining, of the virus taken from an ordinary street mad dog. Four only of those mad dogs died of rabies, one of the four belonging to the set of August 12 taking the furious and biting form of rabies. Of the other three, one belonged to the set of August 10, the last two M. PASTEUR'S COMMUNICATIONS 157 were the two dogs of August 14 ; the two animals of August 20 remained well. I ought to say that the second dog of August 10 became very weak in the hind quarters on the 28th and 29th of the same month, but he finally recovered from those first symptoms of paralysis, and by September 6 ate well and was all right again. Its fellow of August 10 was very agitated and weak in the hind quarters as early as August 26, neither barking nor prone to bite. It died completely paralysed on the 30th of the month. It is probable that a second and perhaps a third set of vaccinations would have rendered all the eight dogs refractory. In any case, even that partial success, four dogs out of eight made proof against rabies by a set of vaccinations effected in eighteen hours only, demon- strates that, notwithstanding the rapidity of its applica- tion, the method is capable of very great efficiency. Another demonstration that the inoculations are capable of rendering dogs rabies-proof in a short space of time is furnished by another kind of experiment, in which we invert the order of the two operations and inoculate the iafective virus on the brain before we vaccinate. On September 8, 1886, four new dogs are trephined and inoculated on the brain with the bulb of a dog which had recently died of rabies, and which had itself been inoculated from an ordinary street mad dog. On the following day, Septemper 9, they received under the skin a full syringe of the marrows of fourteen, twelve, ten, eight, six, four, and two days ; on the 10th 158 HYDROPHOBIA they received the marrows of two and days, at eight and at ten o'clock in the morning. Two of those four dogs became mad on the four- teenth and on the twenty-ninth days after they had been trephined ; the second one had, therefore, been at least partially vaccinated. The other two remained per- fectly refractory. We may note in passing that it would be difficult to find more convincing proof of the possibility of rendering dogs refractory to rabies, and by extension man himself, than that afforded by the details we have just given con- cerning those twelve dogs ; it is well in that connection to remember that intra-cranial inoculation of the virus of rabies reproduces the disease in animals with the utmost constancy. There are no bites which, in point of gravity, can be compared with intra-cranial inoculation after trephining. 159 CHAPTEE III. TECHNIQUE OF THE METHOD, We shall now proceed to give an account of the technique of the method of preventing rabies after bites. We give it from what we have seen our self and as applied at the present day. The Mad Dog and the Mad Eabbit. Suppose a mad dog which has either been killed or which has died of the disease itself. We shall start from it in the preparation of our rabbits and then of our prophylactic viruses. The first thing is to take out the brain and the medulla oblongata of the animal, as cleanly as pos- sible. Lay them on a clean plate, with the basal surface upwards. Whatever parts have to be touched or handled should first be wrapped up in paper. The nervous matter ought only to be handled with the help of flamed steriUsed instru- ments : dissecting forceps, scalpels, curved-bladed i6o HYDROPHOBIA scissors. The free end of the medulla is grasped with the forceps and thrown over towards the frontal lobes, whilst all adhesions to neighbouring parts are divided with the scissors. The fourth ventricle is now opened up and exposed to view. From the central part of its floor, i.e. from the medulla ob- longata portion of it, is cut away a piece about the size of a small pea, and usually also another small fragment from the neighbourhood of the central Fig. 1. — Glass for preparing ■ tlie Injection-fluid. canal, the medulla having by this time been com- pletely detached from the brain. The two small segments of nervous matter are put into a small conical glass, about half an ounce in capacity, and from which the filter-paper cover is only removed at the time (fig. 1) . Glass and paper cover come from a stove where they have been sterilised by exposure for a quarter of an hour or more to a temperature of 120° 0. (248° P.). The little pieces of nervous matter are triturated in the glass by means of a stout TECHNIQUE OF THE METHOD i6i glass rod which has also been well flamed. ^Vhen all reduced into a fine jelly-like mass, sterilised veal- broth is added, at first drop by drop and then more freely, stirring all the while untU it makes up a turbid thick liquid amountiug in quantity to about half a table-spoonful. The paper cover is laid on again and the glass put by ready for further use. All the instruments are well heated in a flame after the operation is completed, just as they were at the beginniag, but this time solely for the purpose of destroying any rabid matter on them and guard- ing against accidents to servants or others. We may now pause a moment and consider a few accessory points before proceeding further. The expression ' to sterilise ' may not be quite famihar to the casual reader. It is a term of bac- teriology, the science of bacteria, micro-organisms, germs, or microbes, and describes the operation by means of which we destroy aU living germs in or upon an object or substance, generally deposited from the air, where they float as dust. There are many sterilising agents ; thus, to name a few only, sunlight, oxygen, desiccation, heat, dry or moist, so-called antiseptic substances, such as the bichlo- ride of mercury, carbolic acid, quinine, &c. Those of the instruments which come in contact M 1 62 HYDROPHOBIA with the portions of nervous matter actually used are sterilised by holding them for a few moments in the flame of a gas-burner or of a spirit-lamp and then allowed to cool down for a few seconds before they are used. This is the quickest and most efficient method of sterilisation, also preferable to all others in the present instance because it does not add any adherent antiseptic or sterilising sub- stance to our nervous matter, which it is our only aim, so far, to keep perfectly pure from any admix- ture. Atmospheric or other germs, if they gained access into our medulla and broth would, when injected under the skin of an animal or of a man, as the case might be, give rise to various accidents, local or general, inflammation, suppuration, gan- grene, and even septicaemia. The action of the rabid poison might thus at the same time be per- verted or even nullified. The broth is prepared as follows : Take equal weights of lean veal and of water, two pounds of veal and one litre (thirty-two ounces) of water, and a glassful more to make up for evaporation. Eemove all fat, bone, tendon, loose connective tissue, &c., from the veal and cut it up into small pieces. Put these in a clean vessel with the water, cold, and leave soakmg for two hours. Then put TECHNIQUE OF THE METHOD 163 the vessel on a slow fire and keep stirring until it jnst begins to boil. Eemove from the fire, neu- tralise, if need be, with a little potash, filter through ordinary filter-paper and distribute into a number of small flasks (fig. 2), each containing about three ounces. As seen in the figure, the flask has two aper- tures. The lower one is sealed with the blowpipe ; Pig. 2. — Balloon-pipette for keeping the Sterilised Broth. the broth is poured in through the upper one, which is then closed with a plug of cotton-wool. As is well known, cotton-wool allows air to filter freely through its meshes, but efficiently stops all dust suspended in it. The flasks are now put into an autoclave or stove at a temperature of 120° C. (248° F.), All germs are killed at that temperature, and in a quarter of an hour the flasks may be taken out and M 2 1 64 ■ HYDROPHOBIA stowed away on shelves; they are sterilised, i.e. will keep pure for any length of time. At the Pasteur Institute the broth is prepared once a fort- night, ten litres at a time, and serves both for the rabies and for the splenic fever departments. The same man who prepares it is the glass-blower of Fig. 3. — Drying Bottle and Marrow. the establishment and blows most of the glass apparatus used. The bottles in which the spinal marrows are desiccated are of the capacity of one litre (fig. 3). The two apertures are closed with cotton-wool pellets, and the whole put for twenty minutes in a stove at a temperature of 120° C. It is then taken out sterilised and the cotton all brown. The top plug TECHNIQUE OF THE METHOD 165 is removed and a handful of solid caustic potash, broken up into fragments, thrown in, filling the bottle as high as the level of the lower aperture. The plug is put back, and the bottle is ready to receive the marrow. The same bottle can be used twice, and then the potash is thrown away and a new supply of it put in, after renewed cleaning and sterilising of the vessel. It may perhaps be worth while to remark that there is a free circulation of air in the bottle through the two cotton plugs, but the air which thus circulates is filtered, deprived of all dust and germs by the cotton-wool, as also of moisture by the hygrometric caustic potash. When, therefore, it comes in contact with the piece of fresh moist spinal marrow suspended inside the bottle, it borrows moisture from it, a moisture which it parts with in favour of the caustic potash if the current of air be from above downwards, which is lost in the general atmosphere of the room if the current be from below upwards. The bottles are labelled, mentioning the number of the passage of the rabbit whose spinal cord is drying (beginning to count from the first rabbit in- oculated from the dog), and also the date of bottling. The bottles are then arranged in order on a table in a small dark room kept at a constant temperature 1 66 HYDROPHOBIA ranging from 20° to 25° C. (68° to 77° F.) • This room is never swept, the windows are never opened, the door just gaped to let in the person who prepares the viruses for human inoculations, and nobody but him ought ever to go into it. All those precautions aim at keeping the air of the room as undisturbed as possible, so that the germs floating in it will be as few as possible, and therefore the danger of their falling into the small glasses during manipulation at the lowest. The hypodermic syringes used for the inocula- tions are the ordinary Pravaz syringes, containing one gramme of liquid when full (one cubic centi- metre). They are to be kept scrupulously clean and efficient. Whenever a set of inoculations is over, morning or evening, the syringe is broken up into its constituent parts. All the soft parts, the leather, is thrown into the fire and destroyed. The metal parts are dropped into boiling water and left in it for a few minutes, for the purpose of destroy- ing all adherent virus (the syringes are made of silver), after which the needles are sent to the in- strument maker, who sharpens them anew and polishes them. He also renews the soft parts, which are constantly kept soaking in aseptic oil. The oiled leather does not imbibe the aqueous virus. TECHNIQUE OF THE METHOD 167 By means of all those Kttle precautions the virus is inoculated as pure as possible, and the prick of the needle is made with the minimum of pain to the patient. The inoculated rabbits are kept two together in cages made of strong iron- wire netting with abun- dance of straw for their litter. The litter is changed every day. They are fed on a mixture composed of two parts bran, one part oats, one part corn, and one part buck-wheat, three handfuls a day for each cage, i.e. for two rabbits ; also one carrot or one or two leaves of lettuce per cage. Nothing more, no water. With this regime diarrhoea is avoided and the animals are kept in good health until the symptoms of rabies show themselves, somewhere between the fourteenth and twentieth days probably, in rabbits of the first passages, death occurring in three, four, or five days ; some animals, the stronger ones, resisting longer than others. Eabies always assumes the paralytic form in the rabbit, except in the first few passages from the dog, when it is often furious. The hind legs become paralysed, and the animal crawls about in its cage, dragging them, or oftener sits or lies down motionless. Gradually the paralysis ascends and the fore legs are also impHcated, and the animal lies down quite helpless, i68 HYDROPHOBIA except the jaws, which still occasionally stretch right and left in search of food. It is now necessary to look after the animal with especial care, as other- wise vermin will often attack it and interfere with the progress of the operation. Death ultimately takes place by implication of the nerves of respira- tion and asphyxia. The main naked eye post-mortem appearances are shortly dealt with, for they are summed up in one word : congestion of the nervous centres, and in particular of the medulla oblongata, where at times it goes so far as to give rise to haemorrhage by rupture of small vessels. Congestion of the lungs is not unfrequent, especially in the furious forms of rabies. Those post-mortem appearances are evidently not pathognomonic of rabies, and may be met with after death from various other causes. Gentlemen wishing to work at rabies or to apply the prophylactic treatment at home have only to bring a couple of rabbits to the laboratory and get them inoculated. If going long distances, say to South America, it will be necessary to keep in readiness a few more live rabbits, which can in turn be inoculated on the way with the medullas of the first ones, which will die on the eleventh day or there- about after inoculation. In this fashion it becomes TECHNIQUE OF THE METHOD 169 possible to have abroad a series of inoculated rabbits identical with the mother series kept at the Pasteur Institute in Paris. If travelling shorter distances, it will be enough to take with one portions of a rabid medulla and cord kept in ice, carbonic acid or glycerine at 30°. The last-named substance preserves the nervous matter with its virulence intact for a whole month. The glycerine ought to be neutral and quite pure (Eoux). We now go back to our dog- virus which we left diluted in veal-broth and all ready for further use. The next step con- sists in inoculating it into a rabbit, on the surface of the brain. The animal, full-grown, alive and healthy, is placed upon a plank, flat on its abdomen, and its four limbs stretched out and secured by strings to pegs driven in the wood (fig. 4). A double sheet of filter- paper is folded roughly into the shape of a funnel, a teaspoonful or less of chloroform poured into it, and the whole stuck firmly over the nose and mouth of the animal. It wriggles a little, and in one minute is fast asleep. The assistant holds Fio. 4.— The little star shows the place for the Trephine. 170 HYDROPHOBIA the head steady whilst the operator cuts the hair covering that part short and makes along the median line an incision one inch long and running back- ward from a point midway between the two eyes. He cuts down to the bone and inserts an ordinary eye-dila- tor or blepharostat, to keep the lips of the wound gaping. This also he entrusts to his assistant whilst he himself proceeds with the delicate operation of trephining. He uses a small trephine, with a crown about one-sixth of an inch in diameter, and such as is employed in aural sur- gery for trephining the mas- toid cells (fig. 5). He applies it in the median line, a quar- ter of an inch or so behind the line joining the two eyes. He works very gently, taking care to cut nothing but bone and not to injure the underlying meninges. The cir- cular piece of bone trephined is removed by means Fio. 5. TECHNIQUE OF THE METHOD 171 of a strong curved needle, and the cerebral mem- branes come into view. He now takes a hypo- dermic syringe with curved needle and so con- structed as to allow one to count the number of drops injected. This is filled with the dog-virus contained in the small conical glass ; the point of the needle is inserted under the cerebral membranes and two drops of the virus injected. When the needle is removed a small quantity of cerebro- spinal fluid sometimes regurgitates through the little aper- ture in the dura-mater, but there is no harm in that. The wound is bathed freely with a three per cent, solution of carbolic acid and the skin flaps sewn together by means of two or three sutures. The whole operation has only lasted three minutes. The rabbit is by this time out of chloroform, but still duUed. Soon, however, it regains conscious- ness and begins to eat as if nothing were the matter. The operation is constantly successful, the wound is healed in two days, and not more than one or two per cent, of the animals die under chloroform. If larger animals, such as dogs, are trepanned for purposes of inoculation, it is well to apply the instrument some distance right or left of the median line, not on it, in order to avoid wound- ing the longitudinal venous sinus and giving rise to 172 HYDROPHOBIA very troublesome and sometimes fatal haemorrhage. In rabbits the loss of blood is practically nil. It goes without saying that at the same sitting several rabbits may be inoculated. From this first batch of rabbits we select the one which dies first and operate as early after death as possible, in order to have it quite fresh. Proceed as in the case of the dog, extract the medulla and brain, and from the former prepare another small glass of virulent broth. This, as before, inject under the cerebral meninges of a few more fresh live rabbits. They will take the disease after a shorter time of incubation. Proceed again with the first ones that die to inoculate fresh animals, and so on until at last we come to a period of incubation of seven days' duration. As we know already, this is about the shortest incubation attain- able, for, after more than a hundred and fifty such passages or transfers through rabbits, it still remains seven days, or occasionally an hour or two less. The incubation of seven days' duration is already reached by the fiftieth passage. The rabbit taking ill on the seventh day and dying on the tenth day or later is the one used for human inoculations as well as for the purpose of perpetu- ating the disease in other rabbits. By dealing with TECHNIQUE OF THE METHOD 173 a sufficiently large number of animals it is possible to have a rabbit dying every day, and thus also to put one spinal cord in a drying bottle every day. We shall, therefore, by the fourteenth day have a set of fourteen marrows undergoing the desiccation process, and be in a position to begin our pro- phylactic inoculations. If beginning work abroad, the set of fourteen spinal marrows will be more quickly obtained by daily taking out and bottling a small piece of a spinal cord preserved in carbonic acid or otherwise, and it is well in such circum- stances to try a few test experiments on dogs, rabbits, or guinea-pigs before launching out into the treatment of human subjects. The spinal marrows of more than fourteen days are thrown away as being inert and useless. At the Pasteur Institute there are two rabbits inocu- lated, and therefore also two dying (of rabies) every day, for fear if one alone were used it might die from accident and the series be interrupted. Practically one animal is found to be quite sufficient, and the second one is only inoculated for prudence' sake. The medulla or cord of a rabbit in which the in- cubation has been seven days, when injected intra- cranially into a dog, develops rabies in the latter animal in about twelve days. The nervous matter 174 HYDROPHOBIA of this dog, inoculated back by the same process into rabbits, at once reproduces the malady after an incubation of seven days, and thus the series is recovered. On this experiment is based the test-method for ascertaining whether a person has died of inoculated rabies or not. Portions of his medulla are diluted in broth and injected intra- cranially into a number of rabbits. If the person died of rabies communicated to him by the Pastorian virus the rabbit ought to develop the disease on the seventh day after inoculation and to die some- where about the tenth or eleventh day. The rabbits commonly used in Paris are, on the average, five or six months old, weigh two kilo- grammes and a half (5 lbs.), and measure from 45 to 50 centimetres from tip of nose to root of tail. These details are worth noting, for it has been found that smaller or younger rabbits take the disease quicker and also die quicker after its onset. A lean weakly animal will also die quicker than a strong fat one of the same age. In Eussia rabbits are generally much smaller than in France, and therefore react in a way slightly different, taking ill and dying at earlier dates after inoculation. As we have already seen in the ' communica- tions,' the virus of an ordinary mad dog or of a TECHNIQUE OF THE METHOD 175 mad rabbit injected directly into the veins of a dog generally gives rise to paralytic rabies. The same virus injected upon his brain produces furious rabies. Pure water, simple sterilised broth, or the same containing a quantity of pulverised marrow of fourteen days' desiccation, the blood, the urine, of a rabid animal, injected on the brain of dog or rabbit, do not give rise to rabies. Such has been the result, at any rate in a large number of experi- ments. There was only one exception in favour of the blood, and the fourteenth day marrow, if in- jected in very large quantities, does exceptionally reproduce the disease. The bodies and all the unused parts of dead rabid animals are put in a large tub containing a four per cent, solution of sulphate of copper. Once a week the knacker comes round and carts them away. He plunges his bare arms in the liquid and deals with the carcases just as if they were common non-rabid ones. Their virulence is all destroyed.* Several guinea-pigs have been inoculated and rendered refractory, and then allowed to produce young ones for the purpose of ascertaining whether their acquired immunity is hereditarily transmitted ' Of all sterilising agents, it would seem tliat turpentine is the one which possesses the, greatest activity — in vitro — against the specific virus of hydrophobia. 176 HYDROPHOBIA to their young. But these experiments, like many- other subsidiary ones, are not yet completed. The main objection to the use of guinea-pigs in the preparation of the prophylactic virus is the small size and fragility of their spinal cord, which renders them very inconvenient practically. Occasionally a rabbit or a dog is hit upon which presents a longer period of incubation than it ought to from the strength of the virus used. Such cases remind one forcibly of analogous ones of protracted incu- bation in man after bites. The virus or seed is the same, but the patient or soil varies, is more or less fertile, and offers greater or less resistance. The Marrow. The Vaccinal Virus. The dead rabbit is taken up soon after death, when still quite fresh, and laid flat on the abdomen. It ought, like all rabid material, to be handled with the greatest care, and any part touched with the fingers ought to be wrapped in paper. The workers at the Pasteur Institute have, several of them, been vaccinated as a safeguard against accidental infec- tion from the animals they manipulate daily ; so also about twenty sound persons working in diffe- rent branch-institutes, in Eussia in particular. There never followed any untoward effects. The TECHNIQUE OF THE METHOD 177 assistant holds the cadaver steady, and the operator proceeds to slit up the skin along the dorsal median line, from the head down to a few inches from the root of the tail. It is thrown back freely right and left, and then the muscles are detached from Fig. 6. Pio. 7. the skull, the spine, and the ribs for half an inch or so on either side of the vertebral column. The spinal processes are cut away with the curved scissors and the skull cap broken off in fragments by means of Liston's bone-for(?eps (fig. 6), the left N 178 HYDROPHOBIA hand all the while holding the muzzle firmly gripped in Farabeuf's davier or crab-claw forceps (fig. 7). When the brain and medulla have been sufficiently bared, slit up the meninges covering them and re- move those two parts, which place in a clean dish with their basal surface upwards. Then, still using the same instruments, proceed to remove the vertebral laminsB with the roots of the spinal pro- cesses covering the spinal cord. Cut them right and left alternately, from above downwards, insert- ing the point of the blade of the bone-forceps into the spinal cavity, between the spinal meninges and the laminae, and taking great care not to tear the former and injure the cord. It requires a certain amount of practice to bare and extract the cord intact, in particular from the narrower parts in the neck and shoulder. It is sufficient, as a rule, to ex- pose the spinal cord for a distance of about eight or ten inches. Then divide it transversely with the scalpel, seize the lower extremity of the exposed portion with the dissecting forceps, and raise it from the spinal groove where it is lying. Successively cut all the spinal nerves which hold it down, and work up towards the head. In that way remove the cord, with its membranes, and place it in another clean dish. Cut it into segments about TECHNIQUE OF THE METHOD 179 three inches long, and tie a thread to one end of each of them. Now take a drying-bottle and insert into it one of the segments, which hold hanging by means of the thread. Whilst introducing it into the bottle take care that it does not touch the sides of the neck, and when it has got fairly in, about the centre of the vessel, put back the cotton-wool stopper so as to catch the free ends of the thread between it and the neck of the bottle ; the piece of spinal marrow will thus be kept hanging vertically over the bed of caustic potash, in the centre of the bottle. Proceed similarly with the other pieces of marrow, if more than one should be judged neces- sary. From them will be by-and-by prepared the vaccinal viruses. At the Pasteur Institute two such 3 -inch segments, daily are found to be quite suffi- cient for all purposes. Label the bottle, mention- ing the number of the passage to which the rabbit belonged, and also the date of bottling. Next put them away and keep them at a temperature ranging between 20° and 25° C, as previously mentioned. The bulb or swelled-out topmost portion of the medulla oblongata of this same rabbit is used at once for intra-cranial inoculation into two fresh live rabbits, for the purpose of perpetuating the disease and the series. The remaining portions of the V 2 i8o HYDROPHOBIA animal are thrown away into the solution of sul- phate of copper. This marrow we have just bottled could at a stretch serve on the same day or on the next, for the last inoculation, the most virulent, of a patient finishing his treatment. On the fourteenth day the same marrow, having its virulence reduced to its minimum owing to desiccation, will serve for the first inoculation of a patient just beginning treatment. The same process is repeated every day, so that, to sum up, we have daily two dead rabbits (only one of which is actually used) , two pieces of spinal marrow bottled, two fresh rabbits inoculated. We thus have, at any time after the fourteenth day, two sets of marrows drying, going from those of the fourteenth day up to and including those of the first day, the latter being the most virulent and the former the least so. If we only bottled one seg- ment of marrow, we only have one such set ; if three, three, all three identical. On drying, the marrows become crumpled up and brittle ; grey-white and streaked red by the blood-vessels when fresh, they gradually darken in colour and are uniformly dark- brown by the fourteenth day, owing apparently to the blood which was contained in their substance oozing to the surface, where it' dries up. The super- TECHNIQUE OF THE METHOD i8i ficial parts of the piece of marrow are naturally sooner dried and at any time drier than the more central parts surrounding the central canal. The attenuated and graduated viruses for human inoculation are prepared in exactly the same way that we prepared the medulla of the dog for inoculation into our first rabbits, only now we use the desiccated spinal cord instead of the fresh medidla oblongata. The reason for the preference given in this instance to the spinal cord is that it is more easily managed owing to its regular and con- venient shape. The virulence is the same in the two. The quantity of marrow used for human inocu- lations is about one millimetre for each person, judging approximately, with the naked eye. Sup- pose ten persons applying for treatment to-day, i.e. being on the first day of their treatment, ten milli- metres of the marrow which has been La the drying bottle for fourteen days are cut with flamed scissors and dropped into a sterilised conical glass just come from the stove, and from which the cover is only re- moved at the time. It is next reduced into as fine a powder as possible by trituration with a flamed glass rod. Then ten cubic centimetres of sterilised veaUbroth is added, at first drop by drop and then more freely, stirring all the while. The broth is 1 82 HYDROPHOBIA taken from one of the flasks shown on page 131 by- breaking off the tip of the lower nozzle and blowing through the upper or vertical aperture, through the cotton plugging it. The lower nozzle is then sealed with the blowpipe, and the remaining broth will still keep pure and can be used again and again. The scissors and glass rod are again passed through the flame and laid aside, and the paper cover is put back and made to fit tightly on the conical glass, which is left standing for half an hour or so. In practice use two or three more milli- metres of marrow and two or three more cubic centimetres of broth, because more patients may turn up at the last moment, and also because it is better to inject the clearer supernatant liquid than the lower strata, which are mixed up with the de- posited larger and heavier particles of marrow. The virus is now a greyish fluid, cloudy and thick from the presence of a large number of fine mole- cules of marrow held in suspension ; it is not unlike rice water in appearance. In the same manner the marrow of thirteen days' desiccation is prepared for those patients who are on the second day of their treatment, the marrow of twelve days' desiccation for those on the third day of their treatment, and so on. TECHNIQUE OF THE METHOD 183 As soon as the glasses are all ready they are labelled, mentioning (a) the age of the marrow, (&) the number of persons to be inoculated from the particular glass, as ascertained beforehand from the secretary. They are then arranged in order in a small wooden box and are ready for use. The Inoculations. These, the treatment proper, were at first car- ried out at M. Pasteur's small but historically in- teresting laboratory in the EcoleNormaleSuperieure, Eue d'Ulm. The patients soon became so nume- rous, however, that it became necessary to look for more spacious and convenient premises, and the main seat of the operations was transferred to No. 14 Eue Vauquelin. The Pasteur Institute proper will be erected later on, when the necessary funds have been collected, in Eue Dutot (Paris). The rabbits are still kept and inoculated at Eue d'Ulm, but all else belonging to rabies is done at Eue Vauquelin. Here also is prepared the vaccinal virus for splenic fever. A few mad dogs are kept at this place, but the great body of them is at Villeneuve I'Etang, a Government property in the neighbour- hood of Paris, placed at the disposal of M. Pasteur 1 84 HYDROPHOBIA in addition to a considerable annual grant allowed him in aid of his researches and experiments. The present building is essentially composed of four rooms. The largest one is the waitiag-room for the patients, with a screen behind which the women can go and bare a square inch or so of their hypo- chondria beforehand. It opens into the office, where the secretary of the establishment keeps his books and takes down the names of the patients and all particulars concerning them. The office in turn communicates with the inoculation-room, the one where the inoculations are actually made. The fourth room is the surgery, communicating with the last two. Here the bites and wounds of the patients requiring dressing are attended to under the general supervision of M. Terrillon. As a rule they heal kindly under the ordinary treat- ment of common wounds; iodoform and carbolic acid are chiefly used.' In the inoculation-room the interest centres round a small fenced-in area in the middle of the room. Within the area sits the vaccinator, Dr. Eoux, one of the gentlemen who, in 1884, went to Egypt on the cholera-mission. By his side one or ' Quite recently iodol has been substituted for iodoform. It has the advantage of being odourless. TECHNIQUE OF THE METHOD 1S5 two medical gentlemen helping him. Close by, a small table entrusted to the care of M. Viala. On this table we find our small wooden box containing the complete series of our conical virus-glasses, prepared an hour ago, two or three hypodermic syringes, and a spirit-lamp on which is kept boiling a small tin pan full of water in which has been dissolved some chloride of calcium. This addition raises considerably the boiling-point of the liquid. Plunged in the water there is an ordinary test-tube filled with ordinary sweet oil, whose temperature is soon brought in this water-bath to close upon 100° C, the boiling-point of pure water. Lastly, a sheet of paper is communicated by the secretary with a list of all the persons to be treated at the particular sitting, arranged in groups according to the day of their treatment and the particular marrow or glass from which they are to be inoculated. This, along with the previous labelling of the glasses, as we have seen it done, ensures and facilitates control. We give below the copy of one of those lists : — April 19; Eleven o'Clook. — persons Marrow of April 5 Marrow aged 14 days 7 „ 7 „ 12 8 „ 11 9 „ 10 i86 HYDROPHOBIA 4 perBons Marrow of April 10 Marrow aged 9 days 11 „ „ „ 11 .. .. 8 „ 26 „ „ „ 12 „ „ 7 „ 11 , „ „ 13 „ „ 6 „ 3 „ „ „ U „ „ 5 „ The first horizontal line refers to those persons who have just come and are receiving their first inoculation. Their number is only put down when they are, at the next sitting, receiving their second inoculation and forming the second group. The second line refers to persons receiving their thkd inoculation ; the third line to those receiving their fourth inoculation ; the ninth line to those receiving their tenth inoculation, and finishing the course of treatment. The marrow of April 4, fourteen days old, was inoculated in the morning of the 18th, i.e. on the preceding day, to the three persons in the second line ; the marrow of April 5, thirteen days old, was inoculated into them on the evening of the same day. The marrow of twelve days, which they had to receive on the morning of April 19, was that of April 7 ; hence the absence on the list of the marrow dated April 6. Thus we see that on April 19, at eleven o'clock A.M., there were n persons beginning treatment, and inoculated from the marrow which was bottled on April 5, and therefore had, on the 19th, been TECHNIQUE OF THE METHOD 187 drying fourteen days. This, as we know already, is the weakest virus used. Similarly, also, the three persons in the second line were receiving their third inoculation with the marrow of twelve days, and so on. Finally, the operation was ended at that same sitting with the last group of three persons who were receiving their tenth or last inoculation from the marrow bottled on April li, and only five days old. This is the most virulent marrow used at the present time, ia winter. In summer, during hot weather, other conditions remaining the same, it is found that the virulence of the marrows undergoing desiccation disappears more rapidly than in cold weather, and therefore the last inoculation is made with the marrow aged four days, which is the one corresponding in viru- lence with the winter marrow of five days. The patients assemble in their general waiting- room every morning at ten o'clock — one hour before the time for the inoculations to begin. The secretary or his assistant then inscribes the names of aU new-comers in a large register kept for the purpose, two pages for each person. The bites are examined, and if the skin is found to be unbroken, simply contused through the garments, or occa- sionally even less than that, the applicant is told 1 88 HYDROPHOBIA to go home and keep his mind quiet. He is in no danger. The patients who have been actually bitten are kept for treatment. We shall now give the scheme according to which the patients are examined and inscribed. The parts within brackets have been added by ourselves, and the different headings'sufficiently ex- plain themselves. Under ' Eemarks ' are noted par- ticularly whether the patient is of alcoholic habits, of the neurotic disposition, subject to epileptic fits, syphilitic, &c. All the patients are inoculated with the same syringe, except the syphilitic ones, who have a special syringe put apart for them. 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