CONTRIBUTIONS TO THE PATHOLOGY OF EXPERIMENTAL VIRUS ENCEPHALITIS
Authors: Flexner Simon , Amoss Harold L. 
Published: June 2004

In this paper is given an account of an inoculable virus disease produced in the rabbit with cerebrospinal fluid taken from a case of vascular and neural syphilis.
The study which yielded the results presented was undertaken in the course of an investigation into the etiology of epidemic or lethargic encephalitis.
Twenty-seven samples of cerebrospinal fluid, derived from cases of epidemic encephalitis, were tested by us upon rabbits without positive result. The one successful instance in which an inoculable disease was produced arose from the injection of one of three specimens of the cerebrospinal fluid taken from the case of syphilis. Following this success, two subsequent injections of the fluid, taken from the same patient, were made unsuccessfully.
Although certain American and European investigators have reported securing a virus from the cerebrospinal fluid of cases of epidemic encephalitis, we have consistently failed in our endeavors to confirm their results. However, we believe that the finding of the J. B. virus may serve to clarify the obscurity and confusion now enveloping the so called virus of encephalitis.
It had previously been shown that no biological differences could be detected between the herpes and the encephalitis strains of virus. The former, as is well known, is readily secured by inoculating rabbits with the contents of herpes vesicles, while the latter has, at best, been obtained with great difficulty.
The J. B. virus agrees biologically with the herpes and encephalitis strains of virus. It is our opinion that the J. B. virus is merely a herpes virus which has gained access to the cerebrospinal fluid and, at the time of inoculation of the rabbits, was present in a concentration sufficing to induce virus encephalitis.
The fact, if fact it is proved to be, that the herpes virus may find its way into the cerebrospinal fluid opens to question all the supposed instances of successful implantation of a virus of epidemic encephalitis upon the rabbit. It is indeed highly probable that, in so far as such a virus has been found at all in the cerebrospinal fluid, it also is a specimen of the herpes virus.
Our studies lead us to suppose that at best it is an infrequent event for the herpes virus to occur in demonstrable form in the cerebrospinal fluid. Perhaps a more delicate means of detection than the rabbit inoculation would serve to reveal the presence oftener. It is known that strains of herpes virus of greater or less intensity of action for rabbits exist. It is, of course, possible that we discover, by present methods, only the highly active strains and those only when chancing to be present in a certain concentration. We inoculated 100 specimens of cerebrospinal fluid and obtained in a single instance the virus infection of the rabbit.
In all respects the J. B. virus agrees in intensity of effect, in mode of attack upon the cornea, skin, and brain, and in immunization responses, with the true strains of herpes virus and the so called strains of encephalitis virus.
If, as the above statements indicate, all the virus strains of the class considered are examples of the herpes virus, it follows that the etiology of epidemic encephalitis remains entirely unresolved. It is highly improbable that the ubiquitous herpes virus plays the kind of part in human pathology which it has been shown to play in experimental rabbit pathology. While the active strains of that virus possess a strong affinity for the brain structures of the rabbit, the virus has not in the past shown any selective affinity for the brain of man. To ascribe epidemic encephalitis in man to particular and peculiar varieties of the herpes virus is, with our present knowledge, unwarranted.20
The wide variations in histological lesions described in the brain of rabbits succumbing to herpes or virus encephalitis raise the question of the essential manner of action of the virus upon the brain tissues. Hitherto it has been the cellular infiltrative lesions which have been emphasized. We have, however, learned that very extensive infiltrations about blood vessels and in the brain substance may exist independently of even mild symptoms of disease.16 The question is propounded, therefore, whether the herpes virus does not attack nerve cells directly, affecting them quantitatively in such ways as at one time to produce stimulation and at another time paralysis. The manifold symptoms of virus encephalitis in the rabbit are open to this interpretation. In order, however, to base this notion on microscopical findings, a more subtle technique than hitherto widely employed is required. A histological restudy of the subject is being made with this view in mind.
The name virus encephalitis is proposed for the experimental disease produced in rabbits by the inoculation of the herpes and allied viruses.