127

VIRAL INFECTIONS OFTHE HUMAN NERVOUS SYSTEM*

Classification and General ConsiderationsBy ALBERT B. SABIN, M.D.

Professor ofResearch Pediatrics, University of Cincinnati College of Medicine. The Children's Hospital Research Foundation,Cincinnati, Ohio

The diseases of the human nervous system forwhich a virus etiology has been definitely estab-lished may be classified into those which have theirbasic reservoir in human beings and, therefore,are world-wide in distribution, and those whosebasic reservoir is extra-human, with consequentvariations in distribution in different parts of theworld (Table i). The most important disease inthe first category is unquestionably poliomyelitis.The other viruses, which affect the nervous

system and whose reservoir is in human beings,are those of mumps (parotitis), herpes simplexand lymphogranuloma venereum.Although the occurrence of mumps meningitis

has been suspected for many years on clinicalgrounds, the very recent development by Endersand his associates1'2 of satisfactory serologicmethods for diagnosis not only established thetruth of this suspicion, but provided unequivocalproof that the nervous system is not infrequently

TABLE I

VIRAL INFECTIONS OF THE HUMAN NERVOUS SYSTEM(Classification based on information available in January '949t)

A. DISEASES AND VIRUSES KNOWNi. Basic reservoir in human beings; world-wide in

distribution.(a) Sporadic and epidemic:

Poliomyelitis.(b) Sporadic:

Mumps (parotitis).Herpes simplex.Lymphogranuloma venereum.

2. Basic reservoir extra-human; few widespread, mostlimited in distribution.(a) Arthropod-borne encephalitides:

St. Louis.Western equine.Eastern equine.Venezuelan equine.Japanese B.Russian tick-borne.Louping Ill.

(b) Transmitted by animal secretions or excreta:Rabies.Lymphocytic choriomeningitis.(Pseudolymphocytic choriomeningitis?).B virus (monkey).

B. VIRUS ETIOLOGY POSSIBLE, BUT VIRUSES LITTLEKNOWN OR UNKNOWNVon Economo's encephalitis lethargica.

Herpes zoster.Australian ' X ' (may have been Japanese B).

C. NEUROTROPIC VIRuSEs KNOWN, BUT DIsEASES OFHUMAN NERVOUS SYSTEM UNKNOWNViruses discovered in:

Africa: West Nile, Bwamba fever, Semliki Forest,Bunyamwera.

South America: Ilheus, Columbia 'mosquito'viruses.

Virus discovered in:North America: Califomia 'mosquito' virus(Hammon and Reeves).

North America+Africa: Apparently same virusrediscovered several times and described undernames of 'Columbia SK,' MM poliomyelitis,EMC (encephalomyocarditis), Mengo encepha-lomyelitis.

D. DISEASES SOMETIMES GROUPED WITH VIRUS IN-FECTIONS WITHOUT ADEQUATE EVIDENCEInfectious polyneuritis (Guillain-Barre syndrome).Post-infection and post-vaccination (demyelinating)

encephalitis: Measles, varicella, rubella, vaccinia,variola, mumps, 'influenza,' etc.

Acute hemorrhagic encephalitis.

t Since this paper was prepared for presentation at the FourthInternational Neurological Congress, it has become necessary toconsider the inclusion of a new virus in this classification. Thisvirus has been recovered from the stools and nasopharyngeal secre-tions of patients with the clinical diagnosis of poliomyelitis. Thevirus is characterized by its pathogenicity for suckling, but not older,mice in which it produces a myositis resulting in paralysis; althoughit multiplies in the brain as well as in most other tissues of thesuckling mice, there is no histological evidence of neuronal involve-ment. The virus is not pathogenic for monkeys and is distinct fromthe viruses of poliomyelitis. There are multiple immunologicaltypes of the new virus, and it has also been recovered from urbansewage and non-biting, 'filth' flies separately and in conjunctionwith poliomyelitis virus. Whether or not the basic reservoir of thisnew virus is limited to human beings is not as yet known. It has

not as yet been recovered from the human nervous system, butpatients harbouring this virus have exhibited pleocytosis. Thechief importance of this virus, thus far, is as a frequent cause of the' aseptic meningitis syndrome' occurring during the very monthsof the year when it could most readily pass for non-paralytic polio-myelitis. However, simple virological and serological proceduresare now available for the laboratory diagnosis of infection with thisvirus. There is as yet no unequivocal evidence that the new viruscan produce paralysis in human beings (either due to muscle lesionssimilar to those in suckling mice or by some other mechanism). Itis possible that a patient may be infected simultaneously with bothpoliomyelitis virus and the new virus, and the ultimate pathogenicpotentialities of the new virus can be elucidated only by additionalobservations in human beings (58, 59, 6o, 6I and personal com-munications from Dr. J. L. Melnick).

* Opening paper delivered to the Fourth International Congress of Neurology in Paris, September 1949. It isreproduced here by kind permission of the Editors of the Proceedings of the Congress.

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attacked by the mumps virus in the absence of anyclinical signs of involvement of the salivary glandsor of a history of exposure to a known case ofmumps3. It has been shown very recently thatapproximately 40 per cent. of the population mayexhibit no clinically recognizable signs of infectionwith the mumps virus4. It thus becomes clearhow it is possible to have mumps infection of thenervous system which cannot be traced to aknown case of parotitis. Characteristically, in-fection of the human nervous system by mumpsvirus is associated with only mild clinical mani-festations of aseptic meningitis (nuchal-spinalrigidity with predominantly mononuclear pleo-cytosis) and only rarely, if ever, are there signs ofcerebral involvement to justify the diagnosis ofencephalitis-a term which unfortunately is com-monly and loosely used. Thus far, there is not asingle fatal case in which death can be attributed tothe primary effect of mumps virus on the nervoussystem, and the precise pathological changes pro-duced by this virus in the nervous system are,therefore, unknown. In a patient with the clinicalsigns of aseptic meningitis, the diagnosis ofmumps virus infection is most readily establishedby complement fixation tests on acute and con-valescent serum specimens. The demonstrationof the mumps virus in the cerebrospinal fluid of asuspected case is a more laborious procedure, buthas been accomplished by several investigators inthe last few years-on one occasion by inoculationof the fluid through Stensen's duct into the parotidgland of a monkey5 and, more recently with greaterregularity, in at least seven cases by inoculationinto the amniotic sac of the chick embryo6,7. Itshould be pointed out here that the only way oneknows that mumps virus has beenpropagated in thechick embryo is by demonstrating the presence ofspecific hemagglutinating or, better still, comple-ment-fixing antigen in the amniotic fluid ormembrane.The status of the relation of the virus of herpes

febrilis or simplex to infection of the humannervous system has passed through at least threephases during the past 30 years. In the decadefollowing I920, the occasional, admittedly rare,isolation of herpes virus from the brain of ex-ceptional cases of encephalitis led to the seriousconsideration of this virus as the cause of vonEconomo's encephalitis lethargica by such re-nowned investigators as Levaditi', Doerr9, Per-drau10, Gay"' and their associates. The in-adequacy of the evidence for this hypothesis wasso strong, howeverl2, that in the next decade itcame to be regarded as highly improbable that thevirus of herpes simplex was ever the primarycause of severe, apparent disease of the humannervous system. The question was reopened in

I94I, when Smith, Lennette and Reames"5demonstrated unequivocally, both by isolation ofthe virus and the presence of acidophilic intra-nuclear inclusions in the patient's brain, that thevirus of herpes simplex was indeed the cause of afatal, acute encephalitis in a four-week-old child.Similar conclusive proof was provided in reportspublished in I94414 and I94615 on three additionalfatal cases, all of which occurred in adults aged25 to 28 years. A nonfatal case of mild meningo-encephalitis in a 15-year-old boy with recovery ofthe virus from the cerebrospinal fluid and de-velopment of antibodies during convasescence wasreported by Armstrong"' in 1943.

Clinically, the proved infections of the humannervous system by this virus were characterizedby acute illnesses of 5 to 13 days' duration,with severe manifestations including coma, con-vulsions and focal muscular twitching pointing tocerebral involvement. Since the strains of virusrecovered from all these cases were highly patho-genic for mice, and since mouse inoculation hasbeen common practice during the past 15 years inmany laboratories searching for etiological agentsin infections of the human nervous system, thesefew reports may perhaps indicate that, while thevirus of herpes simplex can unquestionably be oneof the causes of sporadic, acute encephalitis inman, it is perhaps not too frequent an occurrence.Nevertheless, the frequency of its detection isundoubtedly dependent on one's alertness, forDr. Margaret Smith of St. Louis recently in-formed me that she has recovered this virus fromtwo additional fatal cases of acute encephalitis inadolescents. It is noteworthy that in not a singleone of the proved cases of herpes simplex en-cephalitis reported thus far was there any evidenceof herpetic eruption on the skin or mucousmembranes.

Satisfactory evidence that the virus of lympho-granuloma venereum can give rise to severemeningoencephalitis in man was first brought forthin I942 7, with the complete identification of virusrecovered on two occasions (four days and again36 days after onset) from the cerebrospinal fluidof the same patient. It is noteworthy that,despite the severity and long duration of theneurological manifestations in this patient, theother clinical manifestations of lymphogranulomavenereum were negligible, although the same viruswas recovered from insignificant vesicular lesionson the penis and from a slightly enlarged inguinallymph node. Infection due to this virus should beparticularly suspected when the disease is drawnout over a period of weeks or months, and isassociated with persisting pleocytosis and ex-ceptionally high content of protein in the cerebro-spinal fluid. In the patient just mentioned, con-

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centrations of protein up to I,400 mg. per cent.were found more than two months after onset, andin another patient reported in I944, who developedan adhesive arachnoiditis, as much as 3,570 mg.per cent. was present in the spinal fluid severalmonths after onset18. The Frei test was negativein the first few months after involvement of thenervous system"7"8, and, for diagnosis, reliancemust be placed on complement fixation tests andisolation of the virus from the cerebrospinal fluid.Although there are some who would excludelymphogranuloma venereum from the class ofviruses, it is noteworthy that it is one of the veryfew agents in this group which have been foundto be favourably affected by sulphonamides andmore recently by the antibiotic, aureomycin"l.An interesting instance of many recurrences ofmeningoencephalitis most likely due to lympho-granuloma venereum in a man, who was probablytreated inadequately with sulphonamides was re-ported20 in 1945.Among the diseases caused by viruses, whose

basic reservoir is extra-human, is the large groupof arthropod-borne encephalitides, recognized thusfar only in certain parts of the world, and thegroup of diseases, including rabies, lymphocyticchoriomeningitis, pseudolymphocytic chorio-meningitis and B virus, transmitted to man by thesecretions or excreta of the animals which harbourthem in nature. With regard to B virus infectionI would merely like to say that thus farit has been recognized only as a fatal infectionin two physicians who were either bittenby, or had a minor wound contaminated withthe saliva of, apparently normal rhesus monkeys,which were being used as experimentalanimals. Early this year, for the second time sinceI932, I recovered this virus from the axillarylymph node and nervous system of a young doctorwho died of an encephalomyelitis following con-tamination of a cut on his finger by the oralsecretions of rhesus monkeys with which he wasworking. Our present data suggest that the B virusis carried by monkeys much as the virus of herpessimplex, to which, it is related antigenically, iscarried by human beings 21,22,23

This completes the list of viral infections of thehuman nervous system in which the diseases areknown and the viruses have been isolated andstudied. In the next category we deal with knownclinical entities, for which the viruses are eitherunknown or ill-defined, although a virus etiologyis most likely on the basis of the pathologicalmanifestations. In the case of von Economo'sencephalitis lethargica, no etiological agent wasestablished during the years when the disease wasprevalent, and its relative rarity during the past20 years has precluded any further work. The

virus of herpes zoster has as yet not been trans-mitted to any experimental animal, and the prob-lems concerning its relationship to the virus ofvaricella and the natural history and pathogenesisof the disease have received no significant elucida-tion in recent years. The virus recovered fromAustralian 'X' disease, an epidemic encephalitisfirst recognized in Australia in 19I7-I9I8 and notseen or recognized since 192624, was unfortunatelylost, but its known properties correspondmost closely to the virus of Japanese B en-cephalitis.The next category, in which are listed at least

eight viruses which have been reported since I940,poses a special problem because while the virusesare all neurotropic in experimental animals, theyhave not as yet been definitely identified with anynaturally occurring disease of the nervous systemin human beings. Two of these viruses (WestNile25 and Bwamba Fever26) were recovered inAfrica from the blood of natives suffering from amild febrile illness, and serological surveys havesuggested that infection with these viruses may notbe uncommon in certain parts of Africa. The' Semliki Forest '27 and ' Bunyamwera '28 viruseswere isolated from wild-caught mosquitoes inAfrica, the ' Ilheus '29 and ' Colombia Mosquito'viruses30 from mosquitoes in South America, andthe ' California Mosquito' virus from mosquitoesin North America$'. Serological surveys haveyielded suggestive evidence that most of theseviruses recovered from mosquitoes have beenresponsible for inapparent or unrecognized in-fections in human beings. The latest virus to havebeen discovered in mosquitoes caught in theMengo district of Uganda, Africa, and reported asthe ' Mengo encephalomyelitis ' virus32'33 has aparticularly intriguing history, because (a) it hasrecently been proved to be immunologicallyidentical with an agent, known as encephalo-myocarditis or EMC virus, which was recoveredin I945 from chimpanzees in Florida and alsowith the so-called ' MM ' and Columbia ' SK 'viruses which have been erroneously called polio-myelitis viruses34; (b) recent serological surveysby Warren36 have shown that this virus is in-digenous to rats in certain parts of the UnitedStates; (c) the Mengo virus was the cause of anillness which may have been encephalitis in oneof the laboratory workers engaged in its investiga-tion32, and (d) although preliminary serologicalsurveys in the United States and Africa indicatedthat this virus is not ordinarily disseminatedamong humar) beings, suggestive serologicalevidence was nevertheless obtained that it mighthave been the cause of an acute, short, febrile,non-fatal illness associated with signs of asepticmeningitis and occasionally coma in a small group

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of American soldiers in the Philippine Islands inI94636. It seems to me that it is important for usto keep in mind two possibilities with regard tothis new group of viruses. One is that theirmarked neurotropic property in experimentalanimals does not necessarily mean that they arepredominantly neurotropic in man; in support ofthis possibility might be mentioned the fact thatyellow fever virus is almost strictly neurotropic inthe mouse and that recent work has shown that thevirus of dengue fever is strictly neuronotropic inthe mouse37 and predominantly so in the rhesusmonkey38. Furthermore, 139 have recently foundthat the yellow fever and dengue viruses, which areso predominantly viscerotropic in man, are anti-genically related not only to the West Nile viruswhich is a member of this new group, but also toJapanese B encephalitis virus which has been thecause of so many epidemics of encephalitis inhuman beings in Japan. The other possibility tokeep in mind is that at least some of this new groupof viruses may one day prove to be the cause of anextensive epidemic of encephalitis in humanbeings. It may be worth remembering that if bychance the virus of Western equine encephalo-myelitis had been discovered in mosquitoes 20 to30 years ago, we would have been in a similarquandary then; for, as it happened, although thisvirus was first recovered from horses in Californiain I930, it was not until I94I that it caused thefirst recognized epidemic affecting over 3,000people in West North-Central United States andthe adjacent regions of Canada40,4".

In the final category of the classification pre-sented here, I believed it necessary to list thosediseases which are so frequently grouped with thevirus infections but without any adequate evi-dence; among these may be mentioned infectiouspolyneuritis or the Guillain-Barre syndrome withall its numerous synonyms, the post-infection andpost-vaccination demyelinating encephalitides andthe so-called acute haemorrhagic encephalitis.The specific diagnosis of the known viral in-

fections of the nervous system still has manylimitations. For example, there is still no simplelaboratory test that can be used routinely for thespecific diagnosis of infection with the virus whichmost commonly and universally affects the humannervous system, namely the virus of poliomyelitis.This perhaps is the reason for our failure, up tothe present time, to account for the etiology of themajor portion of cases diagnosed as aseptic orlymphocytic meningitis. However, great progresshas been made in the past eight years in thedevelopment, purification and standardization ofviral antigens for complement fixation. Theaccumulated experience of the last few years hasindicated that the complement fixation test on

acute and convalescent serum specimens now pro-.vides the simplest laboratory procedure for theroutine, specific diagnosis not only of all thearthropod-borne virus encephalitides, but also ofthe infections caused by the viruses of mumps,lymphogranuloma venereum and lymphocyticchoriomeningitis. Infection of the nervous systemby the virus of herpes simplex can be establishedin the surviving patient only when recovery of thevirus from the cerebrospinal fluid can be associatedwith the demonstrations that neutralizing anti-bodies for the virus either appeared or markedlyincreased in concentration during convalescence.The only known viruses which one may expect torecover with regularity from the cerebrospinal fluidof infected persons are those of mumps, herpessimplex, lymphogranuloma venereum and lympho-cytic choriomeningitis.The pathways by which viruses invade the

central nervous system and spread within it havereceived extensive experimental investigation inthe attempt to elucidate the pathogenesis of thediseases resulting from such invasion. The resultsavailable thus far, which are much too extensivefor detailed review in this communication, indicatethat the cellular affinities of a given virus and thelevel of multiplication it may attain in certainsusceptible cells can determine not only the path-ways of invasion, but also the extent of its spread-and accordingly can vary not only in differentspecies of animals, but also in the same speciesdepending on age, nutrition or genetic constitutionof the host42. The property which differentiatesthe spread of the true neuronotropic viruses, i.e.those actually multiplying within the neurones,from that of all other infectious agents, is con-cerned with the capacity of these viruses to spreadalong insulated tracts not only in the axonal pro-cesses of the neurone, but also across the synapsesfrom one special group of neurones to another'3.The capacity of a virus to move centripetallyalong an axon to the cell body of the neurone hasbeen shown to depend on certain influencesemanating from the cell body rather than on simplediffusion, since it was found that such a viruscould move neither in the axons nor in otherportions of nerve fibres which had been severedfrom the cell bodies of the neurones, but retainedtheir blood and lymph supplies. It has also beenfound that the incubation period in such in-stances is determined not by the length of thenerve fibre, that is to say not by the distance whichit has to travel, but rather by (i) a latent periodbefore it begins to spread, and (2) the time be-tween invasion of the cell bodies of the neuroneand the appearance of sufficient damage to giverise to clinical signs-and both of these latterfactors can vary considerably even for closely

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related viruses44. A remarkable example of aclosed pathway pursued by some viruses acrosssynaptic junctions within the central nervoussystem is to be found in the behaviour of vesicularstomatitis or eastern equine encephalomyelitisvirus after injection into the vitreous of the eye of amouse45. These viruses produce necrosis of thenerve cells they attack and their earliest pro-gression can be followed by tracing these lesionsin serial sections. As mav be seen in the accom-panying illustration (Fig. i), the virus destroys thenerve cells in the retina of the inoculated eye andprogressing along the insulated, decussating fibresin the optic chiasm produces necrosis only in thecontralateral superior colliculus. Necrosis can beproduced either in the right or the left superiorcolliculus depending on which eye is inoculatedwith the virus; it should, furthermore, be notedthat the neurones through which the fibres of theoptic tract pass on the way to the superior colli-culi remain intact and that no necrosis of thesuperior colliculi is found in animals which de-velop encephalitis after inoculation of the virus byany other route. It is also noteworthy that not allneuronotropic viruses invade along the same path-way from the same site in the same host. Thus,pseudorabies virus introduced into the mouse'seye invades the brain along the sympathetic,parasympathetic and ophthalmic sensory fibresrather than along the decussating optic pathway.Similarly while some viruses (e.g. vesicularstomatitis, equine encephalitis, St. Louis en-cephalitis, rabies, etc.) after nasal instillation in-vade the central nervous system only along theolfactory pathway, other viruses like those ofherpes simplex and pseudorabies can invade alongthe trigeminal sympathetic and parasympatheticpathways without utilizing the olfactory pathway46.The importance of the host is strikingly ex-emplified by the different behaviour of easternequine encephalitis in mice, guinea-pigs47 andmonkeys48-in mice the centripetal spread is in-variably along some neuronal pathway while inmonkeys and guinea-pigs, With rare exceptions,the central nervous system appears to be invadedfrom the blood by a growth of the virus directlyacross the blood vessels.From what has just been said, it must be

apparent that the behaviour of some of theseviruses in human beings cannot be deduced fromobservations on experimental animals. With re-gard to at least three viruses which affect thehuman nervous system, namely, mumps, lympho-granuloma venereum and lymphocytic chorio-meningitis, there is no evidence that they multiplyin the neurones, and it is therefore most likely thatthey invade the choroid plexus and meningesacross the blood vessels. On the other hand, in the

case of poliomyelitis and rabies, there is as yet* noconfirmed evidence that these viruses can multiplyin any cells other than the neuro-nes, and the avail-able data is all in favour of the hypothesis that inhuman beings these viruses invade and spread byneuronal pathways49'50. The severe generalizedencephalitis and widespread cerebral lesions in theproved fatal human infections due to herpessimplex virus, thus far have given no clue to themode of invasion and spread of this virus. Onthe other hand, in the fatal human infections due tothe related monkey ' B ' virus, the evidencestrongly suggested invasion and spread alongneuronal pathways. All the arthropod-borneencephalitis viruses are to varying degrees bothviscerotropic and neuronotropic, and the diffusecortical lesions which have been observed in fatalhuman cases5l652'53 strongly suggest that thenervous system may be invaded from the blood bya ' growth' of these viruses directly across theblood vessels.One of the most striking phenomena in relation

to most of the viruses which affect the humannervous system is that only a small and varyingproportion of individuals who become infectedever exhibit clinical signs of involvement of thenervous system. In the case of poliomyelitisthroughout the world and in the case of JapaneseB encephalitis in certain endemic regions, it hasbeen possible to show by means of serological teststhat beyond a certain age almost every person hadat one time or another been infected with theseviruses. In some parts of the world where thisobtains there are occasional large-scale epidemicsof clinically manifest poliomyelitis or encephalitis,while in others clinically recognized cases are ex-tremely rare among the native populations andepidemics of these diseases are unknown. Koreais a striking illustration for both poliomyelitis andJapanese B encephalitis53. Serological surveyswhich we have carried out in Korea indicated thatiot per cent. of the population, five years of ageor older, had antibodies for the Lansing strain ofpoliomyelitis virus 64, and 8o to ioo per cent. ofthe population, over ten years of age, had anti-bodies for the Japanese B encephalitis virus55.And yet no epidemics of either poliomyelitis orencephalitist have occurred in the native population

* See Enders, J. F., Weller, T. H., and Robbins,F. C., 'Cultivation of the Lansing strain of polio-myelitis virus in cultures of various human embryonictissues,' Science, I949, 1O9, 85-87; and Weller, T. H.,Robbins, F. C., and Enders, J. F., 'Cultivation ofpoliomyelitis virus in cultures of human foreskin andembryonic tissues,' Proc. Soc. Exp. Biol. Med., i949,72, I53-155.

t Information transmitted to the Commission. onVirus and Rickettsial Diseases, U.S. Army Epidenpio-

(Continued at foot of next column)

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and sporadic cases are rare or unknown amongthem, although small outbreaks of both diseaseshave by now occurred among American soldiersstationed in their midst. China is another countrywith a very high incidence of inapparent infection56while Japan across the sea has suffered manylarge epidemics of Japanese B encephalitis, thelast one in I948 with approximately 8,ooo re-ported cases. For years our inquiring spirit andcuriosity with respect to this problem has beendeadened by the explanation, which has no ex-perimental foundation, that repeated exposure tosmall subinfective doses of virus (i.e. amounts toosmall to undergo multiplication) can give rise to animmunity which permits the host to resist sub-sequent infection with larger doses. It has be-come increasingly evident, however, in recentyears that the situation may actually perhaps bethe other way around; namely, that the reasonmany individuals have immunity without knownhistory of disease is that upon first exposure toan infective dose their tissues were so constitutedas to keep viral multiplication down to a low levelor successfully to halt its dissemination.The most striking experimental evidence of the

logical Board, of which the author is a member, in-dicated that an epidemic of acute encephalitis affectingover 5,ooo natives, with a case fatality rate of 44 percent., occurred in Southern Korea during September1949. Work on the etiology of this epidemic is still inprogress.

dependence of clinical manifestations on the levelof viral multiplication, and of the dependence ofthe level of viral multiplication on the constitutionof the host cells was supplied by Webster57 in hisstudies on the behaviour of the virus of St. Louisencephalitis in two very slightly different geneticbreeds of mice. In the resistant variety, which re-mained well after intracerebral inoculation, thevirus also multiplied but reached only onethousandth of the concentration of that achievedin the susceptible mice which died of encephalitis.Various other types of resistance, in which age anddiet are contributing factors, have also beenbrought to light by experimental work in recentyears42.The possibility of controlling the epidemic viral

infections of the human nervous system by meansof vaccines, even where good ones could be pre-pared, seems to be most impractical except underspecial circumstances, first, because the immunityproduced by them takes too long to develop andis too short-lived, and secondly, because suchepidemics are of short duration and occur atvarying and unpredictable intervals. For thisreason it becomes most important to search forcompounds, which might so affect the meta-bolism of the susceptible nerve cells that virusmultiplication could be kept down to the sub-clinical level without jeopardizing the life of thecell. Our ultimate ability to control these diseasesmay well depend upon the success of this search.

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FELLOWSHIP OF POSTGRADUATE MEDICINEI Wimpole Street, London, W.1

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 PostgraduateMedicine, but not to those who subscribe only to the Postgraduate Medical Journal.

AGENDA1. 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.

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OXFORD MEDICAL PUBLICATIONS

MAJOR ENDOCRINE DISORDERSby S. LEONARD SIMPSON, M.D., F.R.C.P.

Physician to Willesden General Hospital, with Charge of Diabetic andEndocrine Clinics; Endocrinologist to Princess Louise Children's Unit ofSt. Mary's Hospital ; Consulting Physician and Endocrinologist to the Soho

and Samaritan Hospitals for Women.'The style of the book is throughout stimulating and thought-provoking.'

-British Medical Journal.'The best work of its kind we have seen in recent years.'-Clinical Journal.'An admirable introduction and guide to a difficult subject.'-Postgraduate

Medical Journal.

SECOND EDITION. 574 pages. 122 illustrations. 42s. net.

OXFORD UNIVERSITY PRESS

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