Encephalitis Lethargica
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flra/n (1987), 110, 19-33 ENCEPHALITIS LETHARGICA A REPORT OF FOUR RECENT CASES Downloaded from https://academic.oup.com/brain/article/110/1/19/273787 by guest on 01 October 2021 by R. s. HOWARD and A. J. LEES (From The National Hospital for Nervous Diseases, Queen Square, London) SUMMARY Four patients are described with an encephalitic illness identical to that described by von Economo. Electroencephalographic, evoked potential and autopsy data suggest that involvement of the cerebral cortex is more extensive than has been generally recognized. Serological tests and viral cultures failed to reveal the infectious agent but the presence of oligoclonal IgG banding in the cerebrospinal fluid in 3 of the patients during the acute phase of the illness would be in keeping with a viral aetiology. INTRODUCTION Accounts of febrile somnolent illnesses with residual apathy, ophthalmoplegia, chorea and weakness abound in the early literature. The Schlafkrankheit of 1580, Sydenham's febris comatosa of 1672-1675 in which hiccough was a prominent symptom, febre lethargica of 1695, coma somnolentium of 1780, Gerlier's vertige paralysante of 1887 and the dreaded Italian nona of 1889-1890, in which sleepiness, cranial nerve palsies and tremor occurred, are some examples of what may be a recur- ring plague caused by the same aetiological agent (Wilson, 1940; Sacks, 1982). Despite these historical forerunners, the sleeping sickness pandemic of 1916-1927 burst forth spontaneously in several different European cities unrecognized and then relentlessly spread around the world leaving an estimated half a million people dead or disabled. Constantin von Economo, however, relying in part on recollec- tions of his parents' descriptions of nona, was able to show that what appeared as a series of unrelated polymorphous outbreaks was in fact a disease caused by a single transmissible factor. He delineated three main clinical presentations which seemed to breed true to form in local epidemics. The commonest variety, the somnolent- ophthalmoplegic form, started with an influenza-like illness which was followed by increasing drowsiness and confusion, then progression to continuous sleep, stupor and finally coma. External ophthalmoplegia, often with pupillary involve- ment, oculogyric crises and nystagmus were early features and some patients developed basal ganglia, cerebellar or upper motor neuron signs. A smaller number of people presented with bradykinesia, catalepsy and mutism (amyostatic-akinetic Correspondence to: Dr A. J. Lees, The National Hospital for Nervous Diseases, Queen Square, London WC1 3BG, UK. © Oxford University Press 1987 20 R. S. HOWARD AND A. J. LEES form), whereas a third hyperkinetic group mimicked acute catatonic schizophrenia with extreme motor restlessness, impulsions, visual hallucinations and dyskinesias. Rapid debility with marked weight loss occurred in most patients and in the survivors convalescence was protracted, often with recrudescences. One-third of patients died in the acute phase, another third survived with chronic disability and the rest seemingly recovered (Yahr, 1978). By far the most destructive residual sequel was Parkinson's syndrome and some of those who had apparently recovered from the acute illness developed extrapyramidal symptoms after latent intervals of as long as twenty years. Others were left with sleep disorders, depression, obsessional Downloaded from https://academic.oup.com/brain/article/110/1/19/273787 by guest on 01 October 2021 ideation and repetitive motor behaviour. The aetiology of epidemic encephalitis lethargica is unknown. At first exogenous toxins were thought to be important but subsequently an infectious cause was sought on the basis of epidemiological, clinical and pathological features. The agent was shown to pass through filters and the disease was transmissible to monkeys by injec- tion of brain tissue from affected patients (von Economo, 1931). During the 1918 pandemic a number of authors also noted an illness, indistinguishable from that produced by inoculation with encephalitis lethargica tissue, could be produced in rabbits by subdural injection of herpes virus. Because the swine influenza pandemic occurred at the same time as encephalitis lethargica, some physicians have assumed a causal relationship (Ravenholt and Foege, 1982). The appearance of encephalitis lethargica, however, often showed no temporal relationship to the influenza and von Economo pointed out that half his cases occurred before the influenza epidemic. Although there are occasional reports of transmission of encephalitis lethargica (Wilson, 1940), the condition lacks the highly contagious characteristics of influenza and its spread throughout the world followed a different course (Weinstein, 1976). The isolation of influenza virus in 1931 and the further characterization of its properties militated against its being the cause of encephalitis lethargica. Gamboa et al. (1974) were unable to demonstrate antibody fluorescence to the swine strain of influenza A within the hypothalamus and midbrain of patients with postencephalitic Parkinson's disease. They did, however, show fluorescence to two other influenza A strains, NWS and WSN, in 6 patients with parkinsonism following encephalitis lethargica. Four cases of encephalitis lethargica seen the The National Hospital for Nervous Diseases, London, between 1980 and 1985 are described. PATIENTS Case 1 Following a visit to the United States a 17-year-old West Indian girl became withdrawn, mute and childish and, over the next week, agitated, uncooperative and emotionally labile. Her mother commented that she had become 'fidgety' and drowsy by day and screamed uncontrollably throughout the night. A diagnosis of catatonic schizophrenia was made and she received electroshock treatment twice and was treated with haloperidol for two days before it was noted that she was pyrexial and had developed abnormal physical signs. On arrival at The National Hospital she was agitated and febrile ENCEPHALITIS LETHARGICA 21 (38° C) and was having frequent oculogyric crises. There was marked sialorrhoea and between crises she uttered a repetitive obscenity and carried out stereotyped masturbatory movements. She exhibited occasional dystonic posturing but was able to follow and grasp to order. There was marked neck rigidity and bilateral optic disc swelling, the pupils were medium sized and responded to light and accommodation, external ocular movements were unrestricted with no nystagmus. All four limbs were rigid and she had bilateral grasp reflexes. She continued to show dystonia even when not in oculogyric crises and the breathing pattern was irregular. She was severely dehydrated with prerenal uraemia which resolved with appropriate rehydration. However, she also developed disseminated intravascular coagulation which persisted for three weeks; this eventually resolved with continued infusion of fresh frozen plasma. Liver function tests indicated Downloaded from https://academic.oup.com/brain/article/110/1/19/273787 by guest on 01 October 2021 marked hepatocellular damage during the first three weeks of the illness. These abnormalities settled as the patient's metabolic state came under satisfactory control. CSF examination was performed on three occasions, the first being on the day of admission. The protein content varied between 0.25 g/1 and 0.69 g/1, with white cell counts of 18/mm3 lymphocytes on the first occasion reducing to 1 lymphocyte/ mm3. CSF and serological viral cultures and antibody titres were all negative. CSF with simultaneous serum electrophoresis showed an oligoclonal IgG banding pattern which was present on each examination, suggesting local synthesis. Serial EEGs remained dominated by diffuse slow wave activity unresponsive to spontaneous eye opening or hyperventilation. During the next four weeks she suffered episodes of profound agitation during which she would moan and cry; on occasions she seemed to be more alert although never responsive. She continued to have frequent oculogyric crises and dystonic posturing. It was noted that in the neutral position her eyes were divergent and there was impaired convergence. Her breathing pattern was deranged, consisting of hyperventilation followed by prolonged apnoeic periods of up to 12 s; inspiratory and expiratory movements were broken in a characteristic 'ratchet' fashion. There was a persistent inappropriate tachycardia with frequent short bursts of supraventricular tachycardia and occasional premature ventricular ectopic beats. She remained unresponsive and rigid with some cogwheeling on passive movement, the reflexes became asymmetrical and pathologically brisk with a right Babinski sign. Over the course of the following month she developed focal epilepsy, with twitching of the face and eye deviation; on two occasions the seizures became generalized. An EEG taken during one of the attacks showed, at the beginning of the twitching, prominent sharp wave activity and on one occasion long runs of sharp theta activity in the right hemisphere. An interictal EEG showed generalized high amplitude delta activity with some intermixed fast activity. She returned to the hospital of referral after three months, still with day-night sleep reversal and occasional oculogyric crises. Her speech was monosyllabic, and she was poorly compliant and disruptive. The neurological signs were unchanged apart from the development of right-sided facial weakness. Formal psychometry showed her to be functioning at a mental age of approximately