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.