Disseminated demyelinating encephalomyelitis occurs not infrequently as a sequel to, or during convalescence from, clinically apparent infection with a number of different viruses, and rarely after vaccination against smallpox, rabies, and other viral diseases. A similar pathological picture characterizes several neurological maladies, for example, multiple and diffuse sclerosis, Schilder's disease, leucoencephalitis, neuromyelitis optica, and a score of other encephalitides, each regarded by the one who first named it as a nosological entity. Several investigators, however, hold that several or all the latter demyelinating affections belong in the same groups of essentially similar histopathological processes (Ferraro (1); Putnam (2); Roizin, Helfand, and Moore (3); and others).Although the problem of the etiology of the demyelinating diseases has been studied during the past century and considerable experimental research has been carried on, there is still no solution. A new impetus, nevertheless, has been the successful experimental production in laboratory animals of neurological syndromes accompanied by histopathological changes in the central nervous system similar to those found in the acute demyelinating affections.The earliest reports of successes were those in 1933-35 of Rivers, Sprunt, and Berry (4) and Rivers and Schwentker (5) who injected monkeys repeatedly over a period of months with brain tissue obtained from apparently normal rabbits. The first paper recorded that of eight animals receiving 14 to 93 intramuscular injections thrice weekly, two reacted with demyelinating encephalomyelitis, one after the 52nd and the other after the 84th inoculation. The second report showed that of eight monkeys similarly treated 46 to 85 times, seven gave positive results. This finding was promptly confirmed by Ferraro and Jervis (6) who introduced rabbit brain into monkeys 29 to 103 times over a period of 112 to 405 days; the animals first showed neurological signs after 3 to 13 months. Ferraro (1) in 1944, concluded that the reaction in the nervous system is of an allergic nature--a view which found active support so that commonly the experimental disease, and occasionally the human acute demyellnating 213 on

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An unusual type of acquired resistance of growing animals to infection with certain neurotropic viruses was described in a previous communication (1). This resistance was associated neither with prior exposure to infection, nor with antiviral bodies in the blood. Moreover, it was demonstrable when the virus was injected by peripheral routes but not when inoculated directly into the brain. It appeared, therefore, that certain changes in the host, associated with or the result of the process of growth, could either modify or completely suppress the effects of peripherally inoculated virus. The purpose of the present investigation was to determine the mechanism of this resistance and to ascertain as far as possible the nature of the host changes responsible for it. MethodsFor an analysis of the factors underlying the resistance of older animals to peripheral inoculation of the neurotropic viruses under investigation, it was necessary to know in each instance how the virus acted in animals succumbing to infection, i.e., (a) whether or not a primary phase of systemic infection was induced; (b) from which tissues and by what routes it spread to the central nervous system (C.N.S.); and (c) what course it pursued after the latter had been * Preliminary communication presented before the Joint Meeting of the Ameri-

Peripheral inoculation of vesicular stomatitis virus is constantly followed by myelitis or encephalitis in young mice, but not in young (or old) guinea pigs. The cause of this variation was elucidated by investigating the fate of the virus after inoculation by a number of different routes. Direct intracerebral injection of minimally infective amounts of virus was found to be equally fatal for young mice and young guinea pigs, indicating that the central nervous system as a whole was as easily injured by the virus in one species as in the other. The events following nasal instillation of the virus varied in young and old guinea pigs. While there appeared to be a transitory multiplication of virus in the nasal mucosa of both young and old, the central nervous system was regularly invaded only in the young. In these, virus was first found only in the anterior rhinencephalon; later it spread to the piriform and hippocampal (olfactory regions) but not to the neopallial portions of the cortex, and the only other area to exhibit virus was the diencephalon (including the pars optica hypothalami), where its further progression was apparently arrested. Absence of central nervous system disease following inoculation into sites supplied by spinal nerves (e.g. sciatic) was found to be due to inability of the virus to invade the nerves. Since direct intrasciatic inoculation frequently led to a fatal ascending myelitis, it was evident that the central nervous system could be invaded along the spinal nerves, and that they did not constitute the main barrier. Furthermore, since multiplication of virus was demonstrated in tissues supplied by the spinal nerves, a process of elimination made it seem possible that the specialized, terminal nerve endings might be the structures which prevent the progression of the virus from the infected tissues to the axons and hence also to the central nervous system. 7 day old guinea pigs (or guinea pigs as a species) were thus found to possess much the same type of barriers to the progression of peripherally inoculated vesicular stomatitis virus as are acquired by mice at a considerably later age. In a discussion of the present data, they have been correlated with known variations in neuroinvasiveness of other viruses and their bearing on the nature of inapparent or subclinical infections of the central nervous system has been considered.

MURINE ACUTE DISSEMINATED ENCEPHALOMYELITIS 263 0.26. Metachromasia was tested with toluidine blue. None of the supernatant fluids from synovial tissue cultures and control developed metachromasia. Heparin (as little as 5 pg per ml) and other sulfonated mucopolysaccharides showed strong metachromasia with toluidine blue.Electrophoretic Studies. To further establish the nature of the mucopolysaccharides found in the supernatants, electrophoretic patterns were obtained with a Perkin-Elmer Tiselius apparatus.Supernates with negative acetic acid precipitation tests gave protein patterns with peaks characteristic of the globulins and albumin. The latter gave the highest and fastest moving peak (Fig. la). Supernates which gave a positive precipitation test showed a new peak in front of the albumin (Fig. lb). The mobility of this component was in the range of hyaluronic acid verified by the addition of purified hyaluronic acid to a negative supernatant fluid (Fig. lc). None of the supernates exhibited a peak with a faster mobility than that for hyaluronic acid. The sulfonated mucopolysaccharides such as chondroitin sulfuric acid or heparin have a faster mobility than the hyaluronic acid. This is seen in the electrophoretic pattern obtained when heparin is added to a tissue culture supernate positive for hyaluronic acid (Fig. Id).1. Growth of human and animal synovial membrane in tissue cultures showed characteristic differences from control cultures of periarticular tissues. 2. Presence of hyaluronic acid in about two-thirds of supernates of tissue cultures. from synovium was demonstrated by precipitation reactions with acetic acid, enzymatic reactions, viscosity determination, tests for metachromasia and electrophoretic patterns. 3. Quantitative determinations by a turbidimetric method yielded a concentration of hyaiuronic acid from 4 to 15 mg %. 4. Tests were negative for sulfonated mucopolysaccharides such as chondroitin sulfuric acid or heparin. 5. Control cultures of periarticular connective tissue were negative for hyaluronic acid and sulfonated mucopolysaccharides.