127 Postgrad Med J: first published as 10.1136/pgmj.26.293.127 on 1 March 1950. Downloaded from VIRAL INFECTIONS OF THE HUMAN NERVOUS SYSTEM* Classification and General Considerations By ALBERT B. SABIN, M.D. Professor ofResearch Pediatrics, University of Cincinnati College ofMedicine. The Children's Hospital Research Foundation, Cincinnati, Ohio The diseases of the human nervous system for system and whose reservoir is in human beings, which a virus etiology has been definitely estab- are those of mumps (parotitis), herpes simplex lished may be classified into those which have their and lymphogranuloma venereum. basic reservoir in human beings and, therefore, Although the occurrence of mumps meningitis are world-wide in distribution, and those whose has been suspected for many years on clinical basic reservoir is extra-human, with consequent grounds, the very recent development by Enders variations in distribution in different parts of the and his associates1'2 of satisfactory serologic world (Table i). The most important disease in methods for diagnosis not only established the the first category is unquestionably poliomyelitis. truth of this suspicion, but provided unequivocal The other viruses, which affect the nervous proof that the nervous system is not infrequently TABLE I VIRAL INFECTIONS OF THE HUMAN NERVOUS SYSTEM on (Classification based information available in January '949t) Protected by copyright. A. DISEASES AND VIRUSES KNOWN Herpes zoster. i. Basic reservoir in human beings; world-wide in Australian ' X ' (may have been Japanese B). distribution. C. NEUROTROPIC (a) Sporadic and epidemic: VIRuSEs KNOWN, BUT DIsEASES OF Poliomyelitis. HUMAN NERVOUS SYSTEM UNKNOWN (b) Sporadic: Viruses discovered in: Mumps (parotitis). Africa: West Nile, Bwamba fever, Semliki Forest, Herpes simplex. Bunyamwera. Lymphogranuloma venereum. South America: Ilheus, Columbia 'mosquito' 2. Basic reservoir extra-human; few widespread, most viruses. limited in distribution. (a) Arthropod-borne encephalitides: Virus discovered in: St. Louis. North America: Califomia 'mosquito' virus Western equine. (Hammon and Reeves). Eastern equine. North America+Africa: Apparently same virus

Venezuelan equine. rediscovered several times and described under http://pmj.bmj.com/ Japanese B. names of 'Columbia SK,' MM poliomyelitis, Russian tick-borne. EMC (encephalomyocarditis), Mengo encepha- Louping Ill. lomyelitis. (b) Transmitted by animal secretions or excreta: Rabies. D. DISEASES SOMETIMES GROUPED WITH VIRUS IN- Lymphocytic choriomeningitis. FECTIONS WITHOUT ADEQUATE EVIDENCE (Pseudolymphocytic choriomeningitis?). Infectious polyneuritis (Guillain-Barre syndrome). B virus (monkey). Post-infection and post-vaccination (demyelinating) B. VIRUS ETIOLOGY POSSIBLE, BUT VIRUSES LITTLE encephalitis: Measles, varicella, rubella, vaccinia, KNOWN OR UNKNOWN variola, mumps, 'influenza,' etc. on September 25, 2021 by guest. Von Economo's encephalitis lethargica. Acute hemorrhagic encephalitis. t Since this paper was prepared for presentation at the Fourth not as yet been recovered from the human nervous system, but International Neurological Congress, it has become necessary to patients harbouring this virus have exhibited pleocytosis. The consider the inclusion of a new virus in this classification. This chief importance of this virus, thus far, is as a frequent cause of the virus has been recovered from the stools and nasopharyngeal secre- ' aseptic meningitis syndrome' occurring during the very months tions of patients with the clinical diagnosis of poliomyelitis. The of the year when it could most readily pass for non-paralytic polio- virus is characterized by its pathogenicity for suckling, but not older, myelitis. However, simple virological and serological procedures mice in which it produces a myositis resulting in paralysis; although are now available for the laboratory diagnosis of infection with this it multiplies in the brain as well as in most other tissues of the virus. There is as yet no unequivocal evidence that the new virus suckling mice, there is no histological evidence of neuronal involve- can produce paralysis in human beings (either due to muscle lesions ment. The virus is not pathogenic for monkeys and is distinct from similar to those in suckling mice or by some other mechanism). It the viruses of poliomyelitis. There are multiple immunological is possible that a patient may be infected simultaneously with both types of the new virus, and it has also been recovered from urban poliomyelitis virus and the new virus, and the ultimate pathogenic sewage and non-biting, 'filth' flies separately and in conjunction potentialities of the new virus can be elucidated only by additional with poliomyelitis virus. Whether or not the basic reservoir of this observations in human beings (58, 59, 6o, 6I and personal com- new virus is limited to human beings is not as yet known. It has munications from Dr. J. L. Melnick). * Opening paper delivered to the Fourth International Congress of Neurology in Paris, September 1949. It is reproduced here by kind permission of the Editors of the Proceedings of the Congress. 128 POSTGRADUATE MEDICAL JOURNAL March I950 Postgrad Med J: first published as 10.1136/pgmj.26.293.127 on 1 March 1950. Downloaded from attacked by the mumps virus in the absence of any I94I, when Smith, Lennette and Reames"5 clinical signs of involvement of the salivary glands demonstrated unequivocally, both by isolation of or of a history of exposure to a known case of the virus and the presence of acidophilic intra- mumps3. It has been shown very recently that nuclear inclusions in the patient's brain, that the approximately 40 per cent. of the population may virus of herpes simplex was indeed the cause of a exhibit no clinically recognizable signs of infection fatal, acute encephalitis in a four-week-old child. with the mumps virus4. It thus becomes clear Similar conclusive proof was provided in reports how it is possible to have mumps infection of the published in I94414 and I94615 on three additional nervous system which cannot be traced to a fatal cases, all of which occurred in adults aged known case of parotitis. Characteristically, in- 25 to 28 years. A nonfatal case of mild meningo- fection of the human nervous system by mumps encephalitis in a 15-year-old boy with recovery of virus is associated with only mild clinical mani- the virus from the cerebrospinal fluid and de- festations of aseptic meningitis (nuchal-spinal velopment of antibodies during convasescence was rigidity with predominantly mononuclear pleo- reported by Armstrong"' in 1943. cytosis) and only rarely, if ever, are there signs of Clinically, the proved infections of the human cerebral involvement to justify the diagnosis of nervous system by this virus were characterized encephalitis-a term which unfortunately is com- by acute illnesses of 5 to 13 days' duration, monly and loosely used. Thus far, there is not a with severe manifestations including coma, con- single fatal case in which death can be attributed to vulsions and focal muscular twitching pointing to the primary effect of mumps virus on the nervous cerebral involvement. Since the strains of virus system, and the precise pathological changes pro- recovered from all these cases were highly patho- duced by this virus in the nervous system are, genic for mice, and since mouse inoculation has therefore, unknown. In a patient with the clinical been common practice during the past 15 years in signs of aseptic meningitis, the diagnosis of many laboratories searching for etiological agentsProtected by copyright. mumps virus infection is most readily established in infections of the human nervous system, these by complement fixation tests on acute and con- few reports may perhaps indicate that, while the valescent serum specimens. The demonstration virus of herpes simplex can unquestionably be one of the mumps virus in the cerebrospinal fluid of a of the causes of sporadic, acute encephalitis in suspected case is a more laborious procedure, but man, it is perhaps not too frequent an occurrence. has been accomplished by several investigators in Nevertheless, the frequency of its detection is the last few years-on one occasion by inoculation undoubtedly dependent on one's alertness, for of the fluid through Stensen's duct into the parotid Dr. Margaret Smith of St. Louis recently in- gland of a monkey5 and, more recently with greater formed me that she has recovered this virus from regularity, in at least seven cases by inoculation two additional fatal cases of acute encephalitis in into the amniotic sac of the chick embryo6,7. It adolescents. It is noteworthy that in not a single should be pointed out here that the only way one one of the proved cases of herpes simplex en-

knows that mumps virus has beenpropagated in the cephalitis reported thus far was there any evidence http://pmj.bmj.com/ chick embryo is by demonstrating the presence of of herpetic eruption on the skin or mucous specific hemagglutinating or, better still, comple- membranes. ment-fixing antigen in the amniotic fluid or Satisfactory evidence that the virus of lympho- membrane. granuloma venereum can give rise to severe The status of the relation of the virus of herpes meningoencephalitis in man was first brought forth febrilis or simplex to infection of the human in I942 7, with the complete identification of virus nervous system has passed through at least three recovered on two occasions (four days and again phases during the past 30 years. In the decade 36 days after onset) from the cerebrospinal fluid on September 25, 2021 by guest. following I920, the occasional, admittedly rare, of the same patient. It is noteworthy that, isolation of herpes virus from the brain of ex- despite the severity and long duration of the ceptional cases of encephalitis led to the serious neurological manifestations in this patient, the consideration of this virus as the cause of von other clinical manifestations of lymphogranuloma Economo's encephalitis lethargica by such re- venereum were negligible, although the same virus nowned investigators as Levaditi', Doerr9, Per- was recovered from insignificant vesicular lesions drau10, Gay"' and their associates. The in- on the penis and from a slightly enlarged inguinal adequacy of the evidence for this hypothesis was lymph node. Infection due to this virus should be so strong, howeverl2, that in the next decade it particularly suspected when the disease is drawn came to be regarded as highly improbable that the out over a period of weeks or months, and is virus of herpes simplex was ever the primary associated with persisting pleocytosis and ex- cause of severe, apparent disease of the human ceptionally high content of protein in the cerebro- nervous system. The question was reopened in spinal fluid. In the patient just mentioned, con- March 1950 SABIN: Viral Infections of the Human Nervous System 129 Postgrad Med J: first published as 10.1136/pgmj.26.293.127 on 1 March 1950. Downloaded from centrations of protein up to I,400 mg. per cent. virus of herpes zoster has as yet not been trans- were found more than two months after onset, and mitted to any experimental animal, and the prob- in another patient reported in I944, who developed lems concerning its relationship to the virus of an adhesive arachnoiditis, as much as 3,570 mg. varicella and the natural history and pathogenesis per cent. was present in the spinal fluid several of the disease have received no significant elucida- months after onset18. The Frei test was negative tion in recent years. The virus recovered from in the first few months after involvement of the Australian 'X' disease, an epidemic encephalitis nervous system"7"8, and, for diagnosis, reliance first recognized in Australia in 19I7-I9I8 and not must be placed on complement fixation tests and seen or recognized since 192624, was unfortunately isolation of the virus from the cerebrospinal fluid. lost, but its known properties correspond Although there are some who would exclude most closely to the virus of Japanese B en- lymphogranuloma venereum from the class of cephalitis. viruses, it is noteworthy that it is one of the very The next category, in which are listed at least few agents in this group which have been found eight viruses which have been reported since I940, to be favourably affected by sulphonamides and poses a special problem because while the viruses more recently by the antibiotic, aureomycin"l. are all neurotropic in experimental animals, they An interesting instance of many recurrences of have not as yet been definitely identified with any meningoencephalitis most likely due to lympho- naturally occurring disease of the nervous system granuloma venereum in a man, who was probably in human beings. Two of these viruses (West treated inadequately with sulphonamides was re- Nile25 and Bwamba Fever26) were recovered in ported20 in 1945. Africa from the blood of natives suffering from a Among the diseases caused by viruses, whose mild febrile illness, and serological surveys have basic reservoir is extra-human, is the large group suggested that infection with these viruses may not ofarthropod-borne encephalitides, recognized thus be uncommon in certain parts of Africa. TheProtected by copyright. far only in certain parts of the world, and the ' Semliki Forest '27 and ' Bunyamwera '28 viruses group of diseases, including rabies, lymphocytic were isolated from wild-caught mosquitoes in choriomeningitis, pseudolymphocytic chorio- Africa, the ' Ilheus '29 and ' Colombia Mosquito' meningitis and B virus, transmitted to man by the viruses30 from mosquitoes in South America, and secretions or excreta of the animals which harbour the ' California Mosquito' virus from mosquitoes them in nature. With regard to B virus infection in North America$'. Serological surveys have I would merely like to say that thus far yielded suggestive evidence that most of these it has been recognized only as a fatal infection viruses recovered from mosquitoes have been in two physicians who were either bitten responsible for inapparent or unrecognized in- by, or had a minor wound contaminated with fections in human beings. The latest virus to have the saliva of, apparently normal rhesus monkeys, been discovered in mosquitoes caught in the which were being used as experimental Mengo district of Uganda, Africa, and reported as animals. Early this year, for the second time since the ' Mengo encephalomyelitis ' virus32'33 has a http://pmj.bmj.com/ I932, I recovered this virus from the axillary particularly intriguing history, because (a) it has lymph node and nervous system of a young doctor recently been proved to be immunologically who died of an encephalomyelitis following con- identical with an agent, known as encephalo- tamination of a cut on his finger by the oral myocarditis or EMC virus, which was recovered secretions of rhesus monkeys with which he was in I945 from chimpanzees in Florida and also working. Our present data suggest that the B virus with the so-called ' MM ' and Columbia ' SK ' is carried by monkeys much as the virus of herpes viruses which have been erroneously called polio- simplex, to which, it is related antigenically, is myelitis viruses34; (b) recent serological surveys on September 25, 2021 by guest. carried by human beings 21,22,23 by Warren36 have shown that this virus is in- This completes the list of viral infections of the digenous to rats in certain parts of the United human nervous system in which the diseases are States; (c) the Mengo virus was the cause of an known and the viruses have been isolated and illness which may have been encephalitis in one studied. In the next category we deal with known of the laboratory workers engaged in its investiga- clinical entities, for which the viruses are either tion32, and (d) although preliminary serological unknown or ill-defined, although a virus etiology surveys in the United States and Africa indicated is most likely on the basis of the pathological that this virus is not ordinarily disseminated manifestations. In the case of von Economo's among humar) beings, suggestive serological encephalitis lethargica, no etiological agent was evidence was nevertheless obtained that it might established during the years when the disease was have been the cause of an acute, short, febrile, prevalent, and its relative rarity during the past non-fatal illness associated with signs of aseptic 20 years has precluded any further work. The meningitis and occasionally coma in a small group 130 POSTGRADUATE MEDICAL JOURNAL March 1950 Postgrad Med J: first published as 10.1136/pgmj.26.293.127 on 1 March 1950. Downloaded from of American soldiers in the Philippine Islands in acute and convalescent serum specimens now pro-. I94636. It seems to me that it is important for us vides the simplest laboratory procedure for the to keep in mind two possibilities with regard to routine, specific diagnosis not only of all the this new group of viruses. One is that their arthropod-borne virus encephalitides, but also of marked neurotropic property in experimental the infections caused by the viruses of mumps, animals does not necessarily mean that they are lymphogranuloma venereum and lymphocytic predominantly neurotropic in man; in support of choriomeningitis. Infection of the nervous system this possibility might be mentioned the fact that by the virus of herpes simplex can be established yellow fever virus is almost strictly neurotropic in in the surviving patient only when recovery of the the mouse and that recent work has shown that the virus from the cerebrospinal fluid can be associated virus of dengue fever is strictly neuronotropic in with the demonstrations that neutralizing anti- the mouse37 and predominantly so in the rhesus bodies for the virus either appeared or markedly monkey38. Furthermore, 139 have recently found increased in concentration during convalescence. that the yellow fever and dengue viruses, which are The only known viruses which one may expect to so predominantly viscerotropic in man, are anti- recover with regularity from the cerebrospinal fluid genically related not only to the West Nile virus of infected persons are those of mumps, herpes which is a member of this new group, but also to simplex, lymphogranuloma venereum and lympho- Japanese B encephalitis virus which has been the cytic choriomeningitis. cause of so many epidemics of encephalitis in The pathways by which viruses invade the human beings in Japan. The other possibility to central nervous system and spread within it have keep in mind is that at least some of this new group received extensive experimental investigation in of viruses may one day prove to be the cause of an the attempt to elucidate the pathogenesis of the extensive epidemic of encephalitis in human diseases resulting from such invasion. The results beings. It may be worth remembering that if by available thus far, which are much too extensiveProtected by copyright. chance the virus of Western equine encephalo- for detailed review in this communication, indicate myelitis had been discovered in mosquitoes 20 to that the cellular affinities of a given virus and the 30 years ago, we would have been in a similar level of multiplication it may attain in certain quandary then; for, as it happened, although this susceptible cells can determine not only the path- virus was first recovered from horses in California ways of invasion, but also the extent of its spread in I930, it was not until I94I that it caused the -and accordingly can vary not only in different first recognized epidemic affecting over 3,000 species of animals, but also in the same species people in West North-Central United States and depending on age, nutrition or genetic constitution the adjacent regions of Canada40,4". of the host42. The property which differentiates In the final category of the classification pre- the spread of the true neuronotropic viruses, i.e. sented here, I believed it necessary to list those those actually multiplying within the neurones, diseases which are so frequently grouped with the from that of all other infectious agents, is con- virus infections but without any adequate evi- cerned with the capacity of these viruses to spread http://pmj.bmj.com/ dence; among these may be mentioned infectious along insulated tracts not only in the axonal pro- polyneuritis or the Guillain-Barre syndrome with cesses of the neurone, but also across the synapses all its numerous synonyms, the post-infection and from one special group of neurones to another'3. post-vaccination demyelinating encephalitides and The capacity of a virus to move centripetally the so-called acute haemorrhagic encephalitis. along an axon to the cell body of the neurone has The specific diagnosis of the known viral in- been shown to depend on certain influences fections of the nervous system still has many emanating from the cell body rather than on simple limitations. For example, there is still no simple diffusion, since it was found that such a virus on September 25, 2021 by guest. laboratory test that can be used routinely for the could move neither in the axons nor in other specific diagnosis of infection with the virus which portions of nerve fibres which had been severed most commonly and universally affects the human from the cell bodies of the neurones, but retained nervous system, namely the virus of poliomyelitis. their blood and lymph supplies. It has also been This perhaps is the reason for our failure, up to found that the incubation period in such in- the present time, to account for the etiology of the stances is determined not by the length of the major portion of cases diagnosed as aseptic or nerve fibre, that is to say not by the distance which lymphocytic meningitis. However, great progress it has to travel, but rather by (i) a latent period has been made in the past eight years in the before it begins to spread, and (2) the time be- development, purification and standardization of tween invasion of the cell bodies of the neurone viral antigens for complement fixation. The and the appearance of sufficient damage to give accumulated experience of the last few years has rise to clinical signs-and both of these latter indicated that the complement fixation test on factors can vary considerably even for closely March 1950 SABIN: Viral Infections of the Human Nervous System 131 Postgrad Med J: first published as 10.1136/pgmj.26.293.127 on 1 March 1950. Downloaded from related viruses44. A remarkable example of a case of poliomyelitis and rabies, there is as yet* no closed pathway pursued by some viruses across confirmed evidence that these viruses can multiply synaptic junctions within the central nervous in any cells other than the neuro-nes, and the avail- system is to be found in the behaviour of vesicular able data is all in favour of the hypothesis that in stomatitis or eastern equine encephalomyelitis human beings these viruses invade and spread by virus after injection into the vitreous of the eye of a neuronal pathways49'50. The severe generalized mouse45. These viruses produce necrosis of the encephalitis and widespread cerebral lesions in the nerve cells they attack and their earliest pro- proved fatal human infections due to herpes gression can be followed by tracing these lesions simplex virus, thus far have given no clue to the in serial sections. As mav be seen in the accom- mode of invasion and spread of this virus. On panying illustration (Fig. i), the virus destroys the the other hand, in the fatal human infections due to nerve cells in the retina of the inoculated eye and the related monkey ' B ' virus, the evidence progressing along the insulated, decussating fibres strongly suggested invasion and spread along in the optic chiasm produces necrosis only in the neuronal pathways. All the arthropod-borne contralateral superior colliculus. Necrosis can be encephalitis viruses are to varying degrees both produced either in the right or the left superior viscerotropic and neuronotropic, and the diffuse colliculus depending on which eye is inoculated cortical lesions which have been observed in fatal with the virus; it should, furthermore, be noted human cases5l652'53 strongly suggest that the that the neurones through which the fibres of the nervous system may be invaded from the blood by optic tract pass on the way to the superior colli- a ' growth' of these viruses directly across the culi remain intact and that no necrosis of the blood vessels. superior colliculi is found in animals which de- One of the most striking phenomena in relation velop encephalitis after inoculation of the virus by to most of the viruses which affect the human any other route. It is also noteworthy that not all nervous system is that only a small and varyingProtected by copyright. neuronotropic viruses invade along the same path- proportion of individuals who become infected way from the same site in the same host. Thus, ever exhibit clinical signs of involvement of the pseudorabies virus introduced into the mouse's nervous system. In the case of poliomyelitis eye invades the brain along the sympathetic, throughout the world and in the case of Japanese parasympathetic and ophthalmic sensory fibres B encephalitis in certain endemic regions, it has rather than along the decussating optic pathway. been possible to show by means of serological tests Similarly while some viruses (e.g. vesicular that beyond a certain age almost every person had stomatitis, equine encephalitis, St. Louis en- at one time or another been infected with these cephalitis, rabies, etc.) after nasal instillation in- viruses. In some parts of the world where this vade the central nervous system only along the obtains there are occasional large-scale epidemics olfactory pathway, other viruses like those of of clinically manifest poliomyelitis or encephalitis, herpes simplex and pseudorabies can invade along while in others clinically recognized cases are ex- the trigeminal sympathetic and parasympathetic tremely rare among the native populations and http://pmj.bmj.com/ pathways without utilizing the olfactory pathway46. epidemics of these diseases are unknown. Korea The importance of the host is strikingly ex- is a striking illustration for both poliomyelitis and emplified by the different behaviour of eastern Japanese B encephalitis53. Serological surveys equine encephalitis in mice, guinea-pigs47 and which we have carried out in Korea indicated that monkeys48-in mice the centripetal spread is in- iot per cent. of the population, five years of age variably along some neuronal pathway while in or older, had antibodies for the Lansing strain of monkeys and guinea-pigs, With rare exceptions, poliomyelitis virus 64, and 8o to ioo per cent. of the central nervous system appears to be invaded the population, over ten years of age, had anti- on September 25, 2021 by guest. from the blood by a growth of the virus directly bodies for the Japanese B encephalitis virus55. across the blood vessels. And yet no epidemics of either poliomyelitis or From what has just been said, it must be encephalitist have occurred in the native population apparent that the behaviour of some of these viruses in human beings cannot be deduced from * See Enders, J. F., Weller, T. H., and Robbins, F. C., 'Cultivation of the Lansing strain of polio- observations on experimental animals. With re- myelitis virus in cultures of various human embryonic gard to at least three viruses which affect the tissues,' Science, I949, 1O9, 85-87; and Weller, T. H., human nervous system, namely, mumps, lympho- Robbins, F. C., and Enders, J. F., 'Cultivation of granuloma venereum and lymphocytic chorio- poliomyelitis virus in cultures of human foreskin and meningitis, there is no evidence that they multiply embryonic tissues,' Proc. Soc. Exp. Biol. Med., i949, in the neurones, and it is therefore most likely that 72, I53-155. t Information transmitted to the Commission. on they invade the choroid plexus and meninges Virus and Rickettsial Diseases, U.S. Army Epidenpio- across the blood vessels. On the other hand, in the (Continued at foot of next column) 132 POSTGRADUATE MEDICAL JOURNAL March 1950 Postgrad Med J: first published as 10.1136/pgmj.26.293.127 on 1 March 1950. Downloaded from and sporadic cases are rare or unknown among dependence of clinical manifestations on the level them, although small outbreaks of both diseases of viral multiplication, and of the dependence of have by now occurred among American soldiers the level of viral multiplication on the constitution stationed in their midst. China is another country of the host cells was supplied by Webster57 in his with a very high incidence of inapparent infection56 studies on the behaviour of the virus of St. Louis while Japan across the sea has suffered many encephalitis in two very slightly different genetic large epidemics of Japanese B encephalitis, the breeds of mice. In the resistant variety, which re- last one in I948 with approximately 8,ooo re- mained well after intracerebral inoculation, the ported cases. For years our inquiring spirit and virus also multiplied but reached only one curiosity with respect to this problem has been thousandth of the concentration of that achieved deadened by the explanation, which has no ex- in the susceptible mice which died of encephalitis. perimental foundation, that repeated exposure to Various other types of resistance, in which age and small subinfective doses of virus (i.e. amounts too diet are contributing factors, have also been small to undergo multiplication) can give rise to an brought to light by experimental work in recent immunity which permits the host to resist sub- years42. sequent infection with larger doses. It has be- The possibility of controlling the epidemic viral come increasingly evident, however, in recent infections of the human nervous system by means years that the situation may actually perhaps be of vaccines, even where good ones could be pre- the other way around; namely, that the reason pared, seems to be most impractical except under many individuals have immunity without known special circumstances, first, because the immunity history of disease is that upon first exposure to produced by them takes too long to develop and an infective dose their tissues were so constituted is too short-lived, and secondly, because such as to keep viral multiplication down to a low level epidemics are of short duration and occur at or successfully to halt its dissemination. varying and unpredictable intervals. For thisProtected by copyright. The most striking experimental evidence of the reason it becomes most important to search for compounds, which might so affect the meta- logical Board, of which the author is a member, in- bolism of the susceptible nerve cells that virus dicated that an epidemic of acute encephalitis affecting multiplication could be kept down to the sub- over 5,ooo natives, with a case fatality rate of 44 per clinical level without jeopardizing the life of the cent., occurred in Southern Korea during September 1949. Work on the etiology of this epidemic is still in cell. Our ultimate ability to control these diseases progress. may well depend upon the success of this search.

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THE ANNUAL GENERAL MEETING Will be held at the above address at 5.0 p.m. on Wednesday, April 19, 1950. The Meeting is open to all Members of the Fellowship of Postgraduate Medicine, but not to those who subscribe only to the Postgraduate Medical Journal. AGENDA 1. To read the Minutes of the last Annual General Meeting. 2. To (a) receive the Reports of the Hon. Treasurer and Hon. Secretaries. (b) elect (i) The Honorary Officers*; (ii) Seven Members* to serve on the Executive Committee; (iii) The Auditors. Protected by copyright. 3. Any other business. * Nominations tor the Honorary Officers aznd for the elected Members of the Executive Committee must be sent to, the Honorary Secretaries by March 16, 1950.

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