scholarly journals CONTRIBUTIONS TO THE PATHOLOGY OF EXPERIMENTAL VIRUS ENCEPHALITIS

1928 ◽  
Vol 47 (1) ◽  
pp. 23-36 ◽  
Author(s):  
Simon Flexner

The guinea pig is subject to cerebral and corneal inoculation of the herpes virus. The effects of the inoculations vary with the strength or degree of virulence of the virus. Weak strains of the virus are implanted on the cerebrum with difficulty and strong strains with ease. Weak strains are quickly suppressed by the brain and strong strains may be passed indefinitely from brain to brain of the guinea pig. Strains of intermediate potency can be passed for a limited number of times only. Weak strains induce keratoconjunctivitis without brain involvement, while strong strains invade the brain from the eye and produce fatal encephalitis. In the latter case, the brain contains active virus inoculable upon the cornea and into the brain of rabbits and guinea pigs. Strains of intermediate potency produce keratoconjunctivitis accompanied by mild symptoms of encephalitis, from which recovery results. The guinea pig serves even more definitely than the rabbit to distinguish grades of virus according to strength or virulence. There is no difference of kind but only of degree of response to inoculation of herpes virus in the rabbit and the guinea pig. The etiology of epidemic encephalitis has not, therefore, been brought appreciably nearer solution by experiments with herpes virus carried out in guinea pigs.

1925 ◽  
Vol 41 (2) ◽  
pp. 215-231 ◽  
Author(s):  
Simon Flexner ◽  
Harold L. Amoss

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.


1925 ◽  
Vol 41 (3) ◽  
pp. 357-377 ◽  
Author(s):  
Simon Flexner ◽  
Harold L. Amoss

Mild strains of the virus of herpes are described the action of which tends to be confined and local. Unless, therefore, these mild strains are injected intracranially they do not tend to produce virus encephalitis in the rabbit. Recovery from infection with the mild strains confers immunity to virulent strains of the herpes and allied viruses. Long glycerolation reduces the number of viable organisms. This loss among the mild strains may reduce the virus below the strength required for an effective extracranial although not below the strength needed for an intracranial inoculation. Herpes virus carriage in man, even under highly favorable conditions, is difficult of detection by means of rabbit inoculation. The detection may be achieved by intracranial when it cannot be accomplished by intracorneal inoculation. The virus producing encephalitis in the rabbit attaches itself chiefly to and multiplies in the substance of the central nervous system. Hence its detection in the cerebrospinal fluid is rarely accomplished. When the inoculation of the virus is made intracranially and especially when the inoculum is composed of active brain tissue, the virus is discoverable in the cerebrospinal fluid by rabbit inoculation much more frequently than when the virus encephalitis follows an extracranial variety of infection. The herpes virus is capable of excretion by the kidney of the rabbit and of being detected in the urine by rabbit inoculation. Among the rarer symptoms of virus encephalitis is excessive lacrimation. While salivation is frequent, lacrimation is exceptional. A comparison of the Levaditi, Doerr, and Goodpasture strains of virus indicates the first to be of medium, the second of mild, and the third of high degree of neurotropic activity. The Doerr strain resembles the mild herpes strains described in this paper. The Goodpasture virus, while exceeding the Levaditi strain in affinity for the central nervous system, falls below the H. F. strain in this regard. Neutralization of virus by the serum of infected and recovered rabbits takes place regularly within certain quantitative limits. Neutralization with human serum is inconstant and capricious and without demonstrable relation to previous attacks of epidemic encephalitis. Comparison of the clinical types of encephalitis as presented by the epidemic variety in man and the experimental virus variety in rabbits brings out certain correspondences and certain differences. It is only in partial and essentially superficial aspects that the two diseases can be identified one with the other.


1928 ◽  
Vol 48 (3) ◽  
pp. 379-391 ◽  
Author(s):  
Peter K. Olitsky ◽  
Perrin H. Long

A number of methods have been employed in attempts to induce encephalitis in guinea pigs with the Levaditi C strain of herpes virus. Some of these consisted of different modes of inoculation of the virus itself and others of different ways of combining it with vesicular stomatitis and neurovaccine viruses so as to obtain the concomitant effects of both. In still another test the Levaditi virus was combined with the neurovaccine in a manner calculated to bring about the maximum action of each at the same time. By all these methods, the Levaditi virus failed to evoke the characteristic encephalitis which this specimen is capable of inducing uniformly in rabbits. On the other hand, when the Levaditi herpes virus is inoculated into the brain of guinea pigs in conjunction with suitably timed corneal injections, it acquires active encephalitogenic properties. The results just noted suggest several considerations: 1. The possibility of increasing the virulence of a filtrable virus by animal passage in a special manner. It is not likely that the increase as observed was due to dosage, for after the virus acquired its encephalitogenic property for guinea pigs, the usual amounts of virus suspensions sufficed to induce, in a uniform way, typical encephalitis. 2. The opinion previously expressed by Flexner that the guinea pig serves merely to separate weak from strong strains of herpes virus is supported: for only according to the particular method described, could the encephalitogenic power of the Levaditi virus be developed and the weak be converted into a strong herpes strain. With the acquisition of this power, the Levaditi virus acted in precisely the same manner as strong herpes strains both in the guinea pig and the rabbit. Moreover, it was shown in guinea pigs that cross-immunity occurs between weak and strong strains. 3. The two samples of neurovaccine virus employed were incapable of inducing encephalitis in guinea pigs after intracutaneous, intratesticular, corneal, or intracerebral inoculation, although they were actively encephalitogenic in rabbits. In spite of the fact that the vaccine virus and herpes virus are different, as shown by the histopathology and absence of cross-immunity, they behave in the same way when injected into the brain of the guinea pig. The failure of the concomitant action of both viruses to induce encephalitis in the guinea pig suggests that the association of two viruses, under the experimental conditions outlined, is incapable of inducing encephalitis, if either, by itself, is non-encephalitogenic. 4. The serum from normal guinea pigs may neutralize a weak (Levaditi C) but not a strong (H.F.) strain of herpes virus; but the neutralizing action of the serum on Levaditi C virus is not uniform. 5. The Levaditi strain of virus can increase in quantity in the brain of the guinea pig to a degree which permits detection and yet fails to evoke any distinctive clinical picture or definite histopathological changes. 6. Repeated intraperitoneal injections of Levaditi virus in guinea pigs elicit no signs of infection, yet they induce a solid immunity to strong strains of herpes virus.


1925 ◽  
Vol 41 (2) ◽  
pp. 233-244 ◽  
Author(s):  
Simon Flexner ◽  
Harold L. Amoss

In this paper we have sought to show that unequivocal strains of herpes virus exist in man, which, in the rabbit, exhibit a degree of encephalitogenic power not exceeded, and perhaps rarely equalled, by any strain of the so called encephalitis virus. The fact that such highly encephalitogenic strains of the herpes virus exist in nature has, at the moment, theoretical and practical importance. Until recently, the view has been accepted by certain workers in the field that two biologically distinct viruses of this class occur—one inducing epidemic encephalitis and the other febrile herpes in man. This view, is, indeed, being supplanted at the present time by the notion, advocated by Levaditi, Nicolau, and Poincloux, of a group of closely related virus organisms for which the name "herpetico-encephalitic" is proposed. Within this group they distinguish strains of virus displaying special affinities for the central nervous organs and others exhibiting equal affinities for skin and membrane (cornea) structures. The first mentioned strains are responsible, under suitable circumstances, for epidemics of encephalitis in man; the others give rise to ordinary attacks of febrile herpes. The H. F. virus described in this paper does not conform to the classification indicated. While being a true febrile herpes strain, it possesses, nevertheless) a high degree of power to attack the central nervous system as well as marked capacity to implant itself on the skin and the cornea of the rabbit. Not only does virus encephalitis follow invariably upon the intracranial injection of the H. F. virus, but as regularly upon corneal, skin, nasal, blood, and testicular modes of inoculation. The symptoms of virus encephalitis thus provoked and the character of the brain lesions induced are precisely those, in all their detail and variety, including the presence of intracellular inclusion bodies, which have been described for the so called virus of encephalitis. Moreover, the H. F. virus is durably glycerol-resistant, is filterable through Berkefeld candles, and behaves immunologically as do the usual strains of herpes and of encephalitis virus. On the basis of the experimental data presented, we conclude that any distinction made regarding, on the one hand, encephalitogenic power as a special property of a virus secured from cases of epidemic encephalitis, and, on the other hand, of ectotropic action as an equally special quality of a virus yielded by febrile herpes, is in its nature artificial and not in harmony with ascertained fact. What can, indeed, be distinguished are stronger and weaker strains of a virus) probably always herpetic in origin, as determined by the inoculation of rabbits. While a strong herpes virus is both dermatotropic and neurotropic, a weak virus tends, in its multiplication, to remain confined to the site of inoculation, to act chiefly on the tissues on which it is immediately implanted, and not to extend to distant parts. And this is equally true whether the strain of virus came originally from cases of epidemic encephalitis, or merely from cases of febrile herpes in man. Hence direct comparison cannot be made between the stronger encephalitogenic and weaker non-encephalitogenic strains, according to any specific etiological property. The viruses we are discussing do, indeed, compose one group but it is the group of febrile herpes with which epidemic encephalitis is associated accidentally, if at all. It happens, indeed, that the Levaditi strain (souche) C and the Doerr Basel strain, both supposedly originating in cases of encephalitis in man, are less encephalitogenic for the rabbit than the true herpes strains, H. F. and Goodpasture M.


1928 ◽  
Vol 48 (2) ◽  
pp. 199-205 ◽  
Author(s):  
Peter K. Olitsky ◽  
Perrin H. Long

Cultures of microorganisms similar to those described by Evans have been obtained in media inoculated with suspensions of herpes virus-infected brains prepared by grinding. But they have also been isolated from saline suspensions of uninoculated meat particles ground in a sterile mortar, and from dextrose broth treated in the same way. It is believed that these organisms are contaminants introduced during the process of grinding. Since they enter the material in no great number, one may suppose them to be suppressed by animals inoculated with the ground substance. In artificial media, on the other hand, they find favorable conditions for multiplication. In our experience, no growth of microorganisms is obtained in routine cultures of virus-infected brains, when fragments, instead of ground material, are used—a fact which may be taken to support the explanation just given. The tests of the part played by streptococci in experimental virus encephalitis failed to disclose that the microorganisms have any etiological relationship to the affection. The intracerebral injection of rabbits with the cultures procured in the course of the experiments produces a purulent type of meningoencephalitis which does not resemble virus encephalitis either in its symptom-complex or in its pathology. The same type of meningitis follows the injection of streptococci derived from ground meat particles, from "ground" broth, from normal brains, and those infected with herpes virus. Some rabbits manifested resistance to the streptococci, whereas all that have been inoculated intracerebrally with the three strains of herpes virus used in this study have proved susceptible thereto. Certain of the rabbits just mentioned which had proved resistant to streptococci inoculated into the brain or cornea were injected with herpes virus and reacted typically. Comparative tests have revealed that the streptococci are more sensitive to the destructive effect of 50 per cent glycerol than is herpes virus. From all this, it can be concluded that streptococci are not the visible form of herpes virus, nor do they produce in rabbits effects like those induced in the brain and cornea by the herpes virus.


1986 ◽  
Vol 45 (3) ◽  
pp. 329
Author(s):  
E. R. Unger ◽  
J. Towfighi ◽  
L. R. Budgeon ◽  
C. Housman ◽  
D. J. Brigati

2021 ◽  
Author(s):  
Julia Sehl‐Ewert ◽  
Theresa Schwaiger ◽  
Alexander Schäfer ◽  
Julia E. Hölper ◽  
Barbara G. Klupp ◽  
...  

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