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Home , Encephalomyelitis, Toxic encephalopathy

Postgrad Med J: first published as 10.1136/pgmj.45.524.392 on 1 June 1969. Downloaded from

Postgrad. med. J. (June 1969) 45, 392-400.

Para-infectious and post-vaccinal

P. B. CROFT The Tottenham Group ofHospitals, London, N.15

Summary of neurological disorders following vaccinations of The incidence of encephalomyelitis in association all kinds (de Vries, 1960). with acute specific fevers and prophylactic inocula- The incidence of para-infectious and post-vaccinal tions is discussed. Available statistics are inaccurate, encephalomyelitis in Great Britain is difficult to but these conditions are of considerable importance estimate. It is certain that many cases are not -it is likely that there are about 400 cases ofmeasles notified to the Registrar General, whose published in England and Wales in an epidemic figures must be an underestimate. In addition there year. is a lack of precise diagnostic criteria and this aspect The pathology of these neurological complications will be considered later. In the years 1964-66 the is discussed and emphasis placed on the distinction mean number of deaths registered annually in between typical perivenous demyelinating encepha- England and Wales as due to acute infectious litis, and the toxic type of which encephalitis was ninety-seven (Registrar General, occurs mainly in young children. 1967). During the same period the mean annual The clinical syndromes occurring in association number of deaths registered as due to the late effects with measles, chickenpox and German measles are of acute infectious encephalitis was seventy-four- considered. Although encephalitis is the most fre- this presumably includes patients with post-encepha-copyright. quent complication, and polyradiculitis also litic . During this 3-year period there occur. There is evidence that 'uncomplicated were five deaths from post-vaccinial encephalitis, measles' is associated with involvement in the while the mean number of deaths registered annually prodromal phase. Similar para-infectious disorders as due to 'encephalitis, myelitis and encephalomye- occur in association with other infections including litis, excluding acute infectious encephalitis' was 110. smallpox and influenza. To put these figures into perspective, in 1966 The post-vaccinal types of encephalomyelitis are 612 deaths were registered as due to motor neurone also considered with particular reference to post- disease, 836 to disseminated sclerosis, 7363 to motor http://pmj.bmj.com/ vaccinial encephalitis and rabies post-vaccinal vehicle traffic accidents and 18,554 to primary encephalitis. carcinoma of the lung. The pathogenesis of these disorders is discussed During 1966 the number of deaths from encepha- and it is concluded that there is direct viral invasion litis certified as secondary to infectious diseases was of the , followed by an antigen- fifteen for measles encephalitis (out of a total of antibody reaction. At times virus may remain latent eighty deaths attributed to measles) and two for

within the nerve cell without destroying it. chickenpox encephalitis (from a total of seventeen on September 29, 2021 by guest. Protected deaths due to chickenpox). Introduction Notifications of infectious diseases in 1966 in- Although the majority of cases of encephalitis and cluded 343,642 cases ofmeasles, eighty-three cases of other neurological disorders which occur in associ- acute infectious encephalitis and 114 cases of post- ation with acute viral infections such as measles, infectious encephalitis. Miller (1964) estimated the develop some days after the onset of the exanthem, incidence of measles encephalitis as 1 per 1000 and in a few patients the neurological disorder is either this agrees with other figures (Miller, Stanton & simultaneous with or precedes the development Gibbons, 1956). On this basis one would have of the rash. It is, thus, more logical to describe these expected over 340 cases of measles encephalitis in conditions as para-infectious rather than post- 1966, and of course not all cases of measles are infectious. Similarly, although the encephalitis notified. The figure of 114 cases of post-infectious following vaccination against smallpox (post- encephalitis of all kinds in 1966 is certainly much vaccinial encephalitis) is the typical example of below the true incidence. encephalitis as a sequel to prophylactic inoculations, The death rate in measles encephalitis has varied the tern post-vaccinal should be used for the range but has often been estimated at about 20 % (McNair Postgrad Med J: first published as 10.1136/pgmj.45.524.392 on 1 June 1969. Downloaded from

Para-infectious andpost-vaccinal encephalomyelitis 393

Scott, 1967). If, making allowance for non-notifica- pathy oftoxic type characterized by cerebral oedema, tion, there were up to 400 cases of measles encepha- vacuolization of neurones and neuronal degenera- litis in 1966, deaths from this disorder should have tion, especially in the cortex. This syndrome occurs been about eighty. This contrasts with the fifteen mainly in children under 2 years, but may occur in patients actually registered as having died from older children. Acute encephalopathy is also found measles encephalitis. in fatal cases of para-infectious neurological illness However inaccurate the statistics may be, it is in young children. Lyon, Dodge & Adams (1961) clear that post-infectious encephalitis and encephalo- described similar cases in infants and children, myelitis is a significant problem in the United without obvious precipitating cause, though in most Kingdom, as it is in the United States, where about cases there was a febrile illness of variable and 30 % of the total cases of encephalitis are in the post- unidentified type. The lesions in post-vaccinal and infectious group (McNair Scott, 1967). para-infectious encephalopathy resemble those fol- lowing , anoxic episodes or severe Pathology hypoglycaemia. For many years a distinction has been drawn between primary polioclastic encephalitis, involving Clinical aspects predominantly neurones of the grey matter, and due There are many reviews of the neurological to direct invasion by virus (e.g. rabies and arbovirus), syndromes occurring after vaccination and in and secondary myelinoclastic leuco-encephalitis. association with acute viral infections. Miller et al. Here the myelin sheaths of the white matter are the (1956) made a detailed study of the literature at that main site of damage with axis cylinders less affected, time, and discussed their own experience, while the and neurones largely spared (Miller, 1961). The review of McNair Scott (1967) included more recent second group is often, but not always, a sequel to a work. viral infection. Miller et al. (1956) emphasized that although the The early work of Tumbull & McIntosh (1926) majority of patients under consideration had showed that in post-vaccinial encephalitis the usual encephalitis, in some the was the main underlying process is one of perivenous demyelina- site of the disease. Polyradiculitis was less common copyright. tion, mainly in relation to small veins in the white than these forms of central nervous system involve- matter. Similar changes were found in encephalitis ment. associated with measles, chickenpox and rubella In the para-infectious groups of disorders, the (Miller et al., 1956). distribution of the various syndromes was as follows Further studies led de Vries (1960) to consider (Table 1): that the classical change in post-vaccinial encepha- TABLE 1. Distribution of the various syndromes litis is one of perivenous demyelination, witlh an associated microglial reaction-'microglia encepha- German http://pmj.bmj.com/ litis'. In this type of encephalitis, which commonly Measles Chickenpox measles occurs 5-15 days after vaccination, the illness runs Encephalitis (%) 96 90 92 an acute course, and if recovery occurs there are Myelitis (Y.) 3 3 4 often few sequelae, though permanent neurological Polyradiculitis (%) 1 7 4 deficit is more common when the disorder is pri- latent marily a myelitis. Similar changes are found in the The average period between the acute infection and the neurological illness was shortest for para-infectious group of neurological disorders, and on September 29, 2021 by guest. Protected also in sporadically occurring acute disseminated rubella and longest for varicella, while measles held encephalomyelitis. an intermediate position. With each infectious In some patients acute haemorrhagic leuco- disease the latent period was shortest for cases of encephalitis occurs and Russell (1955) argued that encephalitis and longest for those of polyradiculitis this, and acute disseminated encephalomyelitis, are (Table 2). variants of a single pathological process. She referred TABLE 2. Latent period (days) to the literature on experimental allergic encephalitis German and discussed the possibility that the naturally Measles Chickenpox measles occurring acute disseminated encephalomyelitis and Encephalitis 4-7 6-3 3-8 acute haemorrhagic leuco-encephalitis are due to a Myelitis 5.5 8-3 6-7 process based on an allergic response to an antigenic Polyradiculitis 9 0 11-3 8-7 stimulus. de Vries (1960) emphasized that some children with There was a wide range of latent periods, and post-vaccinial encephalitis do not show the typical mention has already been made of the occasional demyelinating changes, but instead an encephalo- patient in whom the encephalitis precedes, or occurs Postgrad Med J: first published as 10.1136/pgmj.45.524.392 on 1 June 1969. Downloaded from

394 P. B. Croft at the same time as the exanthem. These pre- Pampiglione (1964) studied EEGs during the incu- exanthematous cases were excluded from their bation of and during measles, and found a moderate calculations of average latent periods, and the to severe excess of slow activity developing 1-4 numbers of cases of myelitis and polyradiculitis are days before the rash, unrelated to the height of small, especially after chickenpox and German the fever and often declining as the rash developed. measles. This would suggest that the brain is 'normally' involved during the prodromal phase. Para-infectious encephalomyelitis A precise definition of measles encephalitis is, Measles. The most common type of para-infec- therefore, impossible. From a practical standpoint tious encephalomyelitis is that associated with such a diagnosis will require the development of measles. The earliest account is that of Lucas (1790) significant neurological and/or psychiatric abnor- who described a young woman in whom myelitis malities, but excluding simple febrile convulsions. developed 6 days after the measles rash, and who EEG records will support the diagnosis, but cerebro- 9 years previously had had a similar illness after spinal fluid results are unhelpful. Although abnor- smallpox, although no details are given of the earlier malities in the fluid, mainly pleocytosis, have been neurological episode. found in 'uncomplicated measles' (Ojala, 1947), other The incidence of measles encephalitis varies in workers have found normal fluids frequently in different epidemics and is also affected by the process definite encephalitis, and invariably in those who are of selection of clinical cases. However, Miller et a!. considered not to have had brain involvement (1956) gave an estimate of 1 per 1000. Most cases (McKendrick, personal communication 1969). show a typical picture of perivenous demyelinating The latent period between the rash and encepha- 'microglia encephalitis'. Perivenous demyelinating litis varies from - 2 to + 13 days but is usually 4-5 encephalitis does not occur in children under 2 years days with 93 % developing between 2 and 7 days who may develop a , usually of (Boughton, 1964). Miller et al. (1956) had similar grave prognosis. It is important to note that not all findings. Holliday (1950) reviewed the pre-eruptive iieurological symptoms occurring in association neurological complications of measles and other with measles are due to measles encephalitis. Some exanthemata and concluded that pre-eruptive en- copyright. children may have febrile convulsions without any cephalitis and encephalomyelitis must be considered other manifestations of encephalitis. Boughton in the differential diagnosis of children's diseases (1964) pointed to the importance of distinguishing characterized by acute neurological symptoms of febrile convulsions from true measles encephalitis, unknown aetiology. and commented that a persisting postictal stupor, The clinical picture is very varied. Some patients especially if accompanied by meningism, was indica- have a sudden onset with convulsions, while in others tive of encephalitis. Tyler (1957) felt that cases of the onset is slower with the development ofheadache, sudden hemiplegia in association with photophobia, anorexia and vomiting just as the http://pmj.bmj.com/ complicating measles were due to a local vascular initial symptoms ofmeasles are improving. Retention occlusion and not encephalomyelitis. However, only of urine is a common presenting symptom of measles a minority of patients with permanent hemiplegia encephalitis. The physical signs vary greatly depend- after encephalopathy show evidence of old infarc- ing on the areas of central nervous system affected. tion. Most cases show cerebral hemiatrophy of the Neurological sequelae are found in 23 % (Bough- Schob type due to predominantly unilateral cortical ton, 1964) or more. Intellectual and behaviour dis-

neuronal damage (Norman, 1963). orders are common after encephalitis, and about on September 29, 2021 by guest. Protected In assessing the incidence of measles encephalitis, 50 % of patients with are left with it is important to realize that milder cases are residual signs. probably not recognized. and Boughton (1964) The fatality rate in different series varies greatly thought that such cases might have exclusively and la Bocetta & Tornay (1964) emphasized that the psychological symptoms which might be confused mortality rate has declined of recent years (32% with the usual miserable state of a child with before 1947 and 1 l5 % after this date). Other figures measles. This distinction, however, becomes almost for mortality rates are 20% (Miller et al., 1956) and theoretical when considering the findings of investi- 8-8 % (Boughton, 1964). In assessing prognosis, gation of cases of 'uncomplicated measles'. Gibbs continued convulsions, deep coma, hyperpyrexia et al. (1959) in investigating EEG changes found 51 % and toniic spasms in the arms are grave signs. of patients with uncomplicated measles had EEG Treatment includes control of convulsions and of abnormalities, while 100 % of patients with measles hyperpyrexia, and otlher methods of intensive care encephalitis had abnormal EEGs. Similar findings including intermittent positive pressure respiration. of EEG abnormalities were made in , chicken- There is no doubt that the recent decline in mortality pox, scarlet fever and German measles. is due largely to such intensive care. y-Globulin has Postgrad Med J: first published as 10.1136/pgmj.45.524.392 on 1 June 1969. Downloaded from

Para-infectious andpost-vaccinal encephalomyelitis 395 not proved effective (Greenberg et al., 1955). The demyelination but there were lesions mainly in the use of ACIH and steroids was recommended by grey matter of the cerebral cortex and . Miller, Stanton & Gibbons (1957) but considered They concluded that the essential abnormality was to be without demonstrable benefit by Ziegra (1961) damage to blood vessels possibly on an allergic basis. and Karelitz & Eisenberg (1961). B0e, Solberg & Severe fatal generalized varicella presents another Saeter (1965) found that both the mortality and the problem. If chickenpox encephalitis were due to incidence of sequelae were higher in post-infectious direct invasion of the central nervous system the meningo-encephalitis which had been treated with offatal disseminated cases should show ample corticosteroids. The difficulties in obtaining enough evidence of this. However, only a few reported cases cases for an adequately controlled trial in a relatively show cerebral involvement (Cheatham et al., 1956; rare disorder are self-evident. Rotter & Collins, 1961). One of the former authors' There is no relation between the severity of the cases showed inclusion bodies in posterior root measles and the incidence of encephalitis. Encepha- ganglia but not in the cord or brain. Chickenpox litis has occurred rarely after modification of measles encephalitis may follow relatively mild varicella. by y-globulin (Riley, 1958; Bauer & Howard, 1964) Abruzzi (1961) described a case dying within and extremely rarely after measles vaccination 36 hr. He found large areas of focal demyelination (Schneck, 1968). and small focal areas of subarachnoid haemorrhage and agreed with Heppleston et al. (1959) that the Chickenpox. Neurological disorders associated cerebral blood vessels might be sensitized to a with varicella are less common than with measles. circulating antibody related to the exanthematous Miller et al. (1956) found the frequency difficult to disease. assess but were able to review only 134 cases from Evidence of benefit from steroid therapy is con- the literature in contrast with 911 cases associated flicting and Boughton (1966) refers to the risk of withmeasles. As with measles, encephalitis accounted precipitating severe haemorrhagic varicella by the for the majority (90%) of the cases. Boughton (1966) use of steroids.

reviewed 1517 patients admitted to hospital with copyright. chickenpox of whom thirty-nine had neurological Rubella. This may affect the central nervous system complications-thirty-eight acute meningo-enceph- in two ways; (i) the congenital rubella syndrome, alomyelitis and one polyneuritis. The mortality rate and (ii) para-infectious encephalomyelitis. was 10% in the cases reviewed by Miller et al. (1956) The congenital rubella syndrome is a manifesta- and 18 % in the smaller series of Boughton (1966). tion ofa persistent infection and virus can be isolated The time from the rash to onset of encephalitis from the brain and other organs. The condition is was usually 3-7 days, but as with measles the reviewed by Horstman (1967). Desmond et al. (1967)

encephalitis may occur with the rash or even up to concluded that encephalitis or encephalomyelitis http://pmj.bmj.com/ 3 days before its onset (Rotens, 1961). might be a major manifestation of the congenital The clinical features are in general very like those rubella syndrome, even in the absence of ocular or ofmeasles encephalitis, but cerebellar signs are much cardiac lesions. Rorke & Spiro (1967) reviewed the more common with chickenpox encephalitis (34%o) cerebral lesions in the congenital rubella syndrome than with measles encephalitis (10 %), while in and found extensive degenerative change in vessels contrast hemiplegia, coma and convulsions, and (arteries and veins) and vascular damage with foci abnormal plantar responses are all less common in of necrosis in both grey and white matter. In infants chickenpox than in measles encephalitis. In non- surviving for several months there was evidence of on September 29, 2021 by guest. Protected fatal cases sequelae are less frequent after chickenpox retardation of myelination in the neuraxis. encephalitis. Acute encephalomyelitis complicating acquired may be a complication of chickenpox rubella was considered by Miller et al. (1956) to be and the prognosis for functional recovery seems to be much less common even than varicella encephalo- better than with cord lesions due to measles (White, myelitis. Margolis, Wilson & Top (1943) had 1962). Polyneuropathy may also occur (Miller et al., estimated the incidence at 1 per 6000 and Sherman, 1956; Welch, 1962). Michaels & Kenny (1965) at 1 per 5000. From a The pathological changes are usually said to be limited number of cases in the literature both groups similar to the perivenous demyelination of measles of authors concluded the mortality to be about 20 %. encephalitis, but not all cases fall into this pattern. Cantwell (1957) considered sequelae to be rare, Blair, Jamieson & Smith (1965) reported a case with and Kenny, Michaels & Davis (1965) commented changes of '' without demyelina- that this was probably because demyelination was tion, but with gross fatty changes in the liver. not so constant a finding as in measles encephalitis. Heppleston, Pearce & Yates (1959) described a fatal Pathologically there are fewer cases with typical case in a girl of 4 years in which there was little perivenous demyelination and more with non- Postgrad Med J: first published as 10.1136/pgmj.45.524.392 on 1 June 1969. Downloaded from

396 P. B. Croft specific changes with perivascular infiltration with Wales in 1962. They emphasized the view of de Vries mononuclear cells, although Cijarelli & Freiriech that distinction must be made between post- (1966) described a fatal case with perivascular vaccinial encephalomyelitis and encephalopathy. demyelination. Miller et al. (1956) speculated that Encephalomyelitis, which is unknown in children as many fatal cases died within 72 hr of the onset of under 2 years, occurs after an incubation period of encephalitis, they might have developed typical 8-15 days, has an acute onset, and if the patient demyelination had they survived longer. However, recovers there are usually few sequelae. If death de Vries (1960) found typical demyelination in occurs, typical perivenous demyelination is found. patients with post-vaccinial encephalitis who died In children under 2 years, and occasionally in older within 24-48 hr, and there is no evidence that there children, there may be a more explosive onset of a is any progress from acute encephalopathy to micro- post-vaccinial encephalopathy, frequently fatal and glia encephalitis. characterized by cerebral oedema. The incidence of these sequelae of vaccination Encephalitis after other infections. Apart from the against smallpox varies greatly in different countries three infectious exanthemata already discussed, with figures per 100,000 vaccinations ranging from encephalitis follows other infections but more one to fourteen or more. Conybeare (1964) reviewed rarely. It occasionally follows smallpox (Freind, the neurological illnesses associated with smallpox 1730); and Marsden & Hurst (1932) emphasized vaccination in the decade 1951-60, and reported to that it is more often after a mild clinical attack than the Ministry of Health. Among a total of just over a severe one. It is well recognized that mumps may 5 x 106 vaccinations the incidence was 13 per 100,000 be associated with a mild lymphocytic meningeal There was a greater incidence after primary than reaction in as many as 51 % of cases (Bang & Bang, after re-vaccination, while a long interval between 1943). Less often encephalitis occurs and Donohue, primary and re-vaccination increased the incidence. Playfair & Whitaker (1955) reported two fatal cases The highest incidence was for primary vaccination with perivenous demyelination. Scheid (1961) in children of school age (3 per 100,000). emphasized that neurological symptoms are as much Death rates of about 300% have been recorded, copyright. a manifestation of mumps as are orchitis and pan- but in some series no distinction has been drawn creatitis. He felt that most cases ofmeningo-encepha- between encephalopathy and encephalomyelitis litis were due to direct invasion by the virus, which (Miller, 1953). Conybeare (1964) found an overall may sometimes be recovered from the cerebrospinal mortality rate of 34 % (or 4-3 per 106 vaccinations). In fluid. young children under 2 years the prognosis in acute The neurological complications of glandular fever encephalopathy is grave, but Hoefnagel (1962) were reviewed by Gautier-Smith (1965). He con- reported a group of such patients presumed to have sidered that they might be due either to direct virus had acute transient post-vaccinial encephalopathy. http://pmj.bmj.com/ invasion or to an allergic encephalomyelitis similar In three cases of encephalopathy in older children to that with the specific fevers. Lymphocytic reported by Spillane & Wells (1964) there were no was most common, followed by encepha- fatalities. They emphasized that prognosis in typical lomyelitis, polyneuritis and mononeuritis. post-vaccinial encephalomyelitis may be better than Influenza may be associated with encephalo- is usually accepted-only one of their eleven patients myelitis and there were several reports of cases of died. They found marked improvement after use of this type in the 1957 epidemic of Asian influenza. ACTH and steroids but were unable to draw any Flewett & Hoult (1958) and Hoult & Flewett (1960) firm statistical conclusions as to the effectiveness of on September 29, 2021 by guest. Protected concluded that there were two main types of dis- such treatment. Persisting sequelae were especially order-an acute encephalopathic variety occurring likely to result from cord lesions. early in an attack of influenza with minimal histo- logical lesions, and a perivascular demyelinating Encephalomyelitis after rabies vaccination. Neuro- leuco-encephalitis as with the specific exanthemata. logical complications after rabies vaccination include meningeal reactions, and mononeuritis and poly- Post-vaccinal encephalomyelitis neuritis as well as encephalomyelitis. The situation Smallpox vaccination. Post-vaccinial encephalo- differs from that of post-vaccinial reactions in that, myelitis is the classical form of post-vaccination until recently, rabies vaccination involved the use of neurological reaction, and reference has already been vaccines containing neural tissue so that there were made to the early studies of Turnbull & McIntosh some resemblances to the circumstances of produc- (1926), who described the typical perivenous de- tion of experimental allergic encephalomyelitis. In myelination. Spillane & Wells (1964) discussed the recent years vaccines prepared from duck embryos of Jennerian vaccination in the light of have been used, but although the incidence of neuro- their experience in the smallpox epidemic in South logical complications is lower with vaccines free Postgrad Med J: first published as 10.1136/pgmj.45.524.392 on 1 June 1969. Downloaded from

Para-infectious andpost-vaccinal encephalomyelitis 397 from neural material, they do occur (Prussin & Following the extensive work on experimental Katabi, 1964). The incidence with non-neural allergic encephalitis, support grew for the concept vaccines is ofthe order of 1 per 50,000 compared with that the para-infectious and post-vaccinal syndromes 1 per 7000 or even higher with neural vaccine. The were due to an allergic response. The usual latent modern management of rabies immunization in the period between the specific infection and the United States is reviewed by Habel (1967). The encephalitis were regarded as support for this view, death-rate in post-rabies-vaccination encephalo- as were the histological similarities. However, it myelitis is about 25 %, and sequelae occur in about must be remembered that in some patients, the one-third of cases, being more severe in patients neurological illness occurs at the same time as, or who have dorsolumbar myelitis. ACTH and steroids even antedates the rash of the acute specific fever. have apparently been of value in isolated cases. Acute disseminated encephalomyelitis occurring naturally, but without known precipitating cause Other vaccinations. Encephalopathy may occasion- except possibly some banal upper respiratory infec- ally occur after pertussis vaccination (Berg, 1958), tion, has been accepted as forming a link between and after influenzal immunization (Woods & the para-infectious and post-vaccinal cases and Ellison, 1964). experimental allergic encephalitis. Although relapse is rare in para-infectious and post-vaccinal encepha- Pathogenesis litis, in some cases of acute disseminated encephalo- The mechanism of production of para-infectious myelitis such relapses do occur. Campbell (1961) and post-vaccinal encephalomyelitis is not yet described a boy who recovered from measles established. Three main theories have been con- encephalitis, and 18 months later became blind sidered: following a coryzal illness. Both episodes were (a) That the condition is due to direct viral treated with steroids with good results. It is of invasion of the nervous system, interest that the original case of Lucas (1790) (b) That there is activation of some other virus showed neurological complications after both previously present but quiescent within the smallpox and measles. Alcock & Hoffman (1962) patient, and discussed children with recurrent encephalomyelitis copyright. (c) That the disorders are due to some form of -they commented that in adults it is difficult to allergic reaction occurring within the nervous distinguish relapsing encephalomyelitis from chronic system. disseminated sclerosis. Miller (1954) described cases There are many facts which have been taken as of familial recurrent encephalomyelitis in three evidence against the first theory. The pathological members of a family, and in some episodes the use changes of perivenous demyelination are quite unlike of ACTH was followed by rapid improvement. those of an acute viral Selling & Meilman (1955) and Ziegler also encephalitis. Usually there is (1966) http://pmj.bmj.com/ a latent interval of 5-15 days between the develop- discussed the treatment of acute disseminated ment of the acute specific fever and the associated encephalomyelitis by steroids. encephalitis. Also there has been very little evidence Uchimura & Shiraki (1957) studied cases of rabies of virus material in the nervous system in cases of post-vaccination syndromes in Japan, and found parainfectious encephalitis. For many years the close similarities with disseminated sclerosis and report of Shaffer, Rake & Hodes (1942) stood alone acute disseminated encephalomyelitis. -they reported the recovery of measles virus from Ferraro & Roizin (1957) and Ferraro (1958) con- the brain of a fatal case of encephalitis, the patient sidered that there was little appreciable difference on September 29, 2021 by guest. Protected dying 9 days after developing the measles rash. between acute disseminated sclerosis, early dissem- Many other workers studied fatal cases of para- inated sclerosis and acute and subacute post- infectious and post-vaccinal encephalitis without infectious, post-vaccinal and post-exanthematic succeeding in isolating virus or finding evidence of encephalomyelitis. They commented that relapses inclusion bodies. and remissions could not be regarded as diagnostic The similarities between the various syndromes of disseminated sclerosis. They thought that the under consideration were taken by some as evidence toxic aetiological agent (measles, varicella, influenza, of a latent virus activated by the vaccination or by vaccinia virus, etc.) combined with a partial antigen the specific fever. In considering measles encephali- to create a complete encephalitogenic antigen which tis, Greenfield (1929) concluded that 'it is therefore triggers off an allergic reaction. probable that these diseases are caused by an Waksman (1959) reviewed the problem of unknown virus which spreads in epidemic waves, but experimental allergic encephalomyelitis and the produces no disease unless stimulated to activity 'autoallergic' diseases. As far as human disease is by the exanthem'. However, no evidence of such a concerned, he felt that the acute monocyclic para- virus of wide distribution has ever been found. or post-infectious diseases associated with viral Postgrad Med J: first published as 10.1136/pgmj.45.524.392 on 1 June 1969. 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398 P. B. Croft infections were part of the viral disease and due to a reaction between antibodies and virus-protein anti- hypersensitivityreactionto the virus. He thought that gens at varied sites in the nervous system. They chronic diseases of remittent character with no postulated that when there is neurological involve- known precipitating cause were true autoallergies. ment, there is a biphasic illness as typified by para- A similar histological picture resulted although the lytic poliomyelitis. In the first phase, sometimes mild responsible antigens differed. and unnoticed, viraemia occurs, while in the second Koprowski (1962) discussed at length the concept phase recovery of virus is very rare. The disappear- of hyperergy in measles encephalitis. He felt that a ance of the viraemia is associated with antibody hypersensitive reaction of the host to multiplying production, which means that the virus cannot per- virus or to the products of damage inflicted by the sist in the blood, but passes into the cells where virus on the tissues is a better, although more com- replication may occur if the environment is suitable plicated explanation of the disease syndrome than is -that is if the virus has an affinity for that particular an inflammatory reaction of tissues associated with cell. They discussed instances of recovery of certain spread of the virus. Damage of brain by the virus viruses from nervous tissue in the face of established would release antigenic material which would pass immunity in the blood. The virus might persist for the blood-brain barrier to reach immunologically varying times-even indefinitely as with herpes active host cells passing through brain capillaries. simplex-and any change in cell-membrane per- These sensitized cells might then be removed in meability would permit an allergic reaction. organs of the reticulo-endothelial system, where Angulo & de Salles Gomes (1964) described a fatal some might divide to form a clone from which cells case of post-vaccinial meningo-encephalitis inwhich could attack the brain tissue of the host. Since little vaccinia virus was isolated from the brain, but felt is known of the changes in the antigenic make-up of that this did not prove that the encephalitis was virus-infected cells, he thought that it was im- caused directly by the virus, but rather that it was possible to speculate whether antigen, which possibly an allergic reaction. Adams, Baird & Filloy (1966) provoked immunological reaction of the host against reviewed the evidence in favour of direct involve- itself, was associated with the virus or not. If it were, ment of the central nervous system by virus in then sensitized lymphoid cells would attack only measles encephalitis, including cytoplasmic andcopyright. virus-infected cells of the central nervous system. nuclear inclusion bodies, and the onset of the neuro- Conversely if virus invasion had by logical illness before the rash. A leading article in caused only an initial release of antigen by the the same journal concluded that 'it is now generally central nervous system, and from then on the antigen agreed that several of the so-called post-infectious were essentially unrelated to the virus, the number of encephalitides are due directly to virus invasion of brain cells destroyed by the sensitized cells of the the nervous system'. Adams (1968) discusses this host would be large. Some as yet unknown mecha- further. nism would be necessary to halt the process of pro- The recent work on measles and subacute scleros- http://pmj.bmj.com/ duction of antibodies against brain tissue. ing panencephalitis (Sever & Zeman, 1968) is of There are several theoretical ways in which an especial interest in this connection, but is discussed allergic process might be established. The virus in detail elsewhere in this symposium (Dayan, 1969). might share antigenic determinants with some com- The reasons why the host only occasionally de- ponent of brain tissue-the brain would then be velops a neurological illness in association with a damaged incidentally by anti-virus antibodies. viral infection are not understood, but are discussed Alternatively the virus might damage other tissues by Webb (1968). They include interferon production, on September 29, 2021 by guest. Protected sharing antigenic determinants with brain, so that antibody production (which may take place within specific antibody to the tissue antigen would again the nervous system-Connolly, 1968; Webb et al., damage the brain incidentally. 1968), the development of latent viruses and trans- Other mechanisms would require the presence of formation of cells. Illavia & Webb (1969) have virus in the brain. After entering the brain the virus recently reported on the long-term continued pro- might damage brain cells, releasing brain antigens duction of two highly encephalitogenic viruses in into the circulation and causing the production of tissue-cultured mouse and glial tissues, anti-brain antibodies, as suggested by Koprowski. without apparent cytopathic effect. Alternatively the virus might enter the brain and The tendency for children under 2 years to remain latent in ceUs until an explosive antigen- develop an acute encephalopathy rather than a antibody reaction destroys both virus and host cell. perivenous demyelinating encephalomyelitis may Webb & Smith (1966) and Webb (1967) considered represent in part at least differences in immuno- the two mechanisms whereby viruses might damage logical capabilities of the young child. the nervous system-direct cellular destruction by Although many problems remain, it seems likely multiplying virus, and hypersensitivity due to that the para-infectious and post-vaccinal neuro- Postgrad Med J: first published as 10.1136/pgmj.45.524.392 on 1 June 1969. Downloaded from

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