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Home , Encephalitis lethargica

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, ) 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 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, 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, somnolentium of 1780, Gerlier's vertige paralysante of 1887 and the dreaded Italian nona of 1889-1890, in which sleepiness, cranial nerve palsies and 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 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. , 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 . The commonest variety, the somnolent- ophthalmoplegic form, started with an -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 . 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 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 fluorescencet o the swine strain of influenza A within the hypothalamus and midbrain of patients with postencephalitic Parkinson's disease. They did, however, show fluorescencet o two other influenza A strains, NWS and WSN, in 6 patients with 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 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 firstbein g 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 firstoccasio n 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 , with twitching of the face and eye deviation; on two occasions the 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 3 years.

Case 2 A 63-year-old woman developed lumbar back pain, nausea and general malaise. Suddenly, two weeks later, she complained of double vision in all directions of gaze and blurring of vision. At this stage it was noted that she could not move her eyes easily or focus; megaphagia and a tendency to fall asleep during the day also occurred. She was admitted to hospital and was noted to have a visual acuity of 6/9 bilaterally, impaired colour vision, normal fundi and mild symmetric bilateral ptosis. She had absent pursuit and saccadic eye movements in the vertical plane and absent convergence. Horizontal eye movements and doll's head movements in the horizontal and vertical plane were normal. Optokinetic nystagmus was deranged to both right and left in the horizontal plane and absent in the vertical plane. She had on left lateral gaze. Over the next few weeks she became increasingly drowsy and confused, and she suffered two episodes of nocturnal incontinence. She was disorientated and had marked , an immobile fades and a right palmomental reflex. Her breathing became progressively more irregular 22 R. S. HOWARD AND A. J. LEES

over the following two weeks; at times she was tachypnoeic with a respiratory rate of up to 60/min and on other occasions she experienced apnoea lasting up to 10 s. She was intubated, ventilated and a tracheostomy was performed. She then developed spontaneous intermittent hypertension and fluctuation of her body temperature between 37° C and 39.5° C. Over the next two months she remained in an akinetic state and experienced at least twelve episodes during which her eyes became fixed in upgaze for about 30 min. She also had very frequent attacks of twitching of the mouth and facial muscles associated with blepharospasm and blepharoclonus. Second degree vertical nystagmus was noted and at times the eyes tonically deviated to the left. Reflex eye movements were full in all directions and the pupils were constricted to 2 mm bilaterally. Chvostek's sign was positive and she had brisk pout and bilateral grasp reflexes. There were no voluntary Downloaded from https://academic.oup.com/brain/article/110/1/19/273787 by guest on 01 October 2021 movements of the limbs. Cogwheel rigidity was present at both elbows and the reflexes were pathologically brisk in the arms with bilateral finger clonus. Abdominal reflexes were absent. The knee jerks were just present but the ankle jerks were absent and the right plantar response was extensor. The EEG showed bilateral diffuse slow wave activity. Visual evoked responses were bilaterally abnormal, half-fields showing bilateral delay, worse on the right; cortical somatosensory evoked potentials were also delayed. Repeated lumbar punctures showed CSF protein levels between 0.3 and 0.58 g/1 and white cell counts varying between 2 and 11 lymphocytes/mm3. However, a lumbar puncture performed during the terminal stages of the illness showed 61 white cells/mm3, predominantly histio- cytes and ependymal cells. Electrophoresis showed an oligoclonal IgG pattern consistent with local synthesis within the CSF on all five lumbar punctures. Serological and CSF viral titres and cultures were negative. During the last month of her life she remained in a vegetative state apart from occasional short interludes when she was more responsive and able to obey simple commands. Her breathing was erratic with episodes of rapid and shallow respiration. She finally died from a pseudomonal chest seven months after presentation. A post-mortem examination was performed. This showed inflammatory changes throughout the whole of the cerebral hemispheres, subcortical regions and brainstem. Perivascular lymphocytic infiltration involved the parahippocampal gyri, the caudate nucleus, putamen, globus pallidus, substantia innominata, hypothalamus, midbrain, pons and medulla. In the substantia nigra there was mild diffuse neuronal loss with degenerate neurons and extraneuronal pigment. Neurofibrillary tangles were not seen.

Case 3 A 23-year-old woman presented with a two-week history of increasing drowsiness. Shortly afterwards her eyes were noted to be moving strangely and she complained of blurring of vision and diplopia in all directions of gaze. She had mild frontal and pain behind the eyes, particularly on movement, and developed clumsiness of her arms with a tendency to drop things. On examination she was obese with an expressionless face, drowsy and slow, but able to give a coherent account when awake. She was able to stand but her gait was unsteady and she tended to fall backwards. A rest tremor of her left hand was exacerbated when walking and she tended to stoop forwards with arms held in a dystonic flexed position. Her optic discs were pale and the pupils were medium sized with no reaction to light and only sluggish reaction to accommodation. There was bilateral ptosis, almost complete paralysis of eye movements to the left and right and severe limitation of vertical gaze. Doll's head eye movements were normal. There was marked neck rigidity and dystonic posturing of both hands; tone in all four limbs was increased with cogwheeling and marked rigidity on . Power was normal but the reflexes were exaggerated with tonic spread and bilateral extensor plantar responses. Her breathing was regular but she was unable to hold her breath voluntarily. Lumbar puncture yielded CSF with a protein of 0.36 g/l and 2 white cells/mm3. CSF and serological viral titres and cultures were negative. The EEG showed moderate bilateral excessive theta activity. Visual evoked responses were of normal amplitude but the latencies were increased and half-field ENCEPHALITIS LETHARGICA 23

responses in the nasal field on the right were almost abolished. Caloric testing revealed the presence of bilateral internuclear ophthalmoplegia; simultaneous cold irrigation in both ears caused some downward movement but there was no upward deviation with bilateral, hot irrigation. The patient became drowsy and the extrapyramidal features and ophthalmoplegia worsened; after six weeks, however, she became more alert, markedly aggressive arid frankly deluded. At the time of discharge at three months, her behaviour was inappropriate, she was clinically depressed and extrapyramidal features were still present although less striking. One year later the patient complained of , was severely depressed and had episodes of hyperventilation. On examination she had an expressionless fades, a wide-based gait and was slightly dysarthric and slow in response to commands although fully orientated. There was bilateral optic Downloaded from https://academic.oup.com/brain/article/110/1/19/273787 by guest on 01 October 2021 atrophy, impairment of pupillary reactions and continued impairment of upgaze. There was mild facial weakness, axial and limb rigidity and a mild tremor. The reflexes were symmetrical and brisk with bilateral Babinski signs and positive grasp reflexes. The visual evoked responses continued to show borderline delay and neuropsychological assessment suggested residual intellectual impairment. Five years after the acute illness she remains in residential care, socially isolated because of aggression and functioning at an intellectually retarded level.

Case 4 A 31-year-old woman, who emigrated from Tanzania in 1970, presented with a three-day history of sore throat, malaise, severe neck pain and an inability to look downwards. On the day of admission she was found to be mumbling incoherently and behaving in a bizarre and disinhibited manner, rushing unsteadily and aimlessly around the ward. She then had two episodes of unconsciousness with pin- point pupils, stertorous breathing, diminished gag reflex and no response to painful stimuli. On admission to The National Hospital three days later, she was pyrexial (38.5° C) and there was marked neck stiffness. She did not respond to commands or external stimuli but localized to painful stimuli, muttered incomprehensibly and covered herself when exposed. The eyes were divergent but moved in a conjugate manner. Her respiratory rate was 12/min with marked pauses during inspiration and expiration and she was therefore intubated and ventilated artificially. On the following day she had a tonic-clonic . Over the next four days she was intermittently agitated and her level of con- sciousness fluctuated; at times she responded to her relatives but at others only to deep pain by flexion. She suffered occasional episodes of cataleptic posturing with her legs flexed and abducted, her arms flexed above her head and her eyes deviated upwards; these were thought to be oculogyric crises. Serial lumbar punctures showed CSF protein levels varying from 0.48 g/1 to 2.1 g/1 and white cell counts varying from 7 to 44 lymphocytes/mm3. Oligoclonal IgG banding was present in the CSF but not in the serum. CSF and serological viral titres and cultures were negative. The EEG showed diffuse unresponsive slow background activity. Three months after presentation she continued to be restless with intermittent episodes of cataleptic posturing, responding inappropriately to external stimuli and muttering meaningless phrases.

DISCUSSION Despite recent sporadic case reports of encephalitis lethargica in the literature, many physicians remain sceptical about its continued occurrence. In many of these the diagnosis has been based on the subsequent development of parkinsonian features following an acute, poorly documented encephalitis (Wohlfart et al., 1961; Onuaguluchi, 1961; Duvoisin and Yahr, 1965; Williams et al., 1979; Sacks, 1982; Clough et al., 1983), or an encephalitic illness which differed in a number of ways from von Economo's classical descriptions (Leigh, 1946; Bickerstaff and Cloake, 1951; Barrett et al, 1952; Espir and Spalding, 1956; Hunter and Jones, 1966; Poser 24 R. S. HOWARD AND A. J. LEES et al., 1969; Bojinov, 1971; Misra and Hay, 1971; Herishanu and Noah, 1973; Miyasaki and Fujita, 1977). Only Rail etal. (1981) can be said to have described the clinical features of an acute encephalitic illness resembling those described by von Economo and even in this series the accounts of the acute illness are often absent or incomplete. Extrapyramidal syndromes may follow a number of different viral encephalitides but a causal relationship has not conclusively been established, nor can these conditions be considered identical to encephalitis lethargica (Burnell, 1922; Marinesco and Draganesco, 1928; Meyer, 1943; Dimsdale, 1946; Mulder et al., Downloaded from https://academic.oup.com/brain/article/110/1/19/273787 by guest on 01 October 2021 1951; Barrett etal., 1952;Brewis, 1954; Walters, 1960; Richter and Shimojyo, 1961; Warembourg et al., 1962; Thieffrey et al., 1963; Eadie et al., 1965; Bojinov, 1971; Marttila and Rinne, 1976; Fahn, 1977; Miyasaki and Fujita, 1977). Acute transient parkinsonian states have been seen during western equine encephalitis (Mulder et al., 1951), coxsackie B (Walters, 1960; Poser et al., 1969), measles (Meyer, 1943), Murray Valley (Burnell, 1922) and chicken pox encephalitis (Marinesco and Draganesco, 1928; Warembourg et al., 1962; Thieffrey et al., 1963). Japanese B encephalitis (Richter and Shimojyo, 1961; Goto, 1962) has been reported to be followed by parkinsonian sequelae but the postencephalitic syndrome differs from that following encephalitis lethargica in being more benign, without oculogyric crises and not showing a latent period. Molder et al. (1951) described two episodes of presumed oculogyric crises in a patient with parkinsonism following Western equine encephalitis. The 4 patients described fulfil many of the criteria for the diagnosis of acute encephalitis lethargica. Cases 1 and 4 manifest features of the hyperkinetic form and Cases 2 and 3 the somnolent ophthalmoplegic form. Three patients presented with a nonspecific illness, headache and mild meningism. Cases 2 and 3 had hypersom- nolence at presentation with day-night reversal. Cases 1 and 4 manifested an acute onset of general unrest and disturbed behaviour, to such an extent that an initial diagnosis of catatonic schizophrenia was made and the progression over the next week suggested the diagnosis of the neuroleptic malignant syndrome. Three of the patients were pyrexial within a few days of admission and Case 1 suffered a severe toxic disturbance with disseminated intravascular coagulation and hepatocellular abnormalities. Despite extensive investigations no underlying cause for this could be found. These systemic disturbances, commonly reported in von Economo's original cases, were ascribed to the toxic effects of the virus. During the acute illness some patients develop catatonic psychotic states, hallu- cinations, , hyperexcitability, obsessional behaviour, Korsakoff psychoses and klazomania (compulsive coprolalia) (Benedek, 1925; Wohlfart et al., 1961). The importance of the mental sequelae of encephalitis lethargica was emphasized by Hunter and Jones (1966) who described 6 cases with a variety of psychiatric syndromes, hypomania, depression or anxiety. Disorders of mood with apathy, emotional dullness and loss of affective responsiveness have also been noted in survivors, as have permanent impairment of intellect and persistent psychotic ENCEPHALITIS LETHARGICA 25 behaviour. Psychiatric disturbances occurred in all the patients. Case 2 was con- fused and disorientated on admission but the hypersomnolence and akinetic mutism which were features of the remaining course of her illness made later assessment impossible. The other 3 patients showed severe prolonged psychiatric disturbances. The first patient presented a remarkable picture throughout her illness. Following an initial period of restlessness, uncooperativeness, emotional lability and mutism, she developed a bizarre form of compulsive behaviour, pseudomasturbation and

klazomania. Over the ensuing weeks she remained in a state of akinetic mutism, Downloaded from https://academic.oup.com/brain/article/110/1/19/273787 by guest on 01 October 2021 occasionally appearing to recognize her mother but otherwise not responding to external stimuli. However, on a number of occasions she seemed to undergo episodes of profound agitation in which she would violently thrash around in the bed and seem to be more alert. Slowly, after four weeks, she became more responsive but behaved in an infantile and inappropriate manner, with violent outbursts. She had previously been an intelligent woman but by the time of her return to the referring hospital, psychological testing showed her to be functioning at a mental age of approximately 3 years. Case 3 became violent and attempted to bite members of the staff in the firstsi x weeks of her admission. Although she had probably always functioned below the average range, there was residual intellectual impairment one year after admission. She was also noted to be clinically depressed, emotionally labile with tearful outbursts, and hypochondriacal. In Case 4 the illness presented with disinhibited behaviour and her intellect and behaviour remained seriously disturbed several months after resolution of the acute phase of the illness. All the patients showed alterations in the state of consciousness. This varied from lethargy to coma. In Case 1 the sleep pattern was noted to be reversed during the initial stages of the disease. She then lapsed into stupor (Plum and Posner, 1983) for two months. Although her level of consciousness improved she has continued to show inversion of sleep pattern. In the initial stages Case 2 showed a tendency to fall asleep inappropriately during the day. She became increasingly somnolent, lapsing into coma and ultimately a persistent vegetative state before death. All the patients showed signs compatible with basal ganglia damage: cogwheel rigidity, an expressionless mask-like facies and slowness and paucity of movement were present to varying degrees. There was a coarse rest tremor in 3 of the patients and chorea and dystonia were present in 2. Monosyllabic, hesitant speech was also a feature in 2 patients. The development of oculogyric crises and blepharospasm during the acute phase of the illness is characteristic (von Economo, 1931; Onuaguluchi, 1961; Clough et al., 1983). Oculogyric crises may occur as an idiosyncratic reaction to certain drugs, especially metoclopramide and pheno- thiazines. However, if a drug cause can be excluded, and when associated with parkinsonism, oculogyric crises are considered to be pathognomonic of encephalitis lethargica, both during the acute encephalitic phase and as a feature of postencepha- litic Parkinson's syndrome. Oculogyric crises occur in 30 to 60% of patients with postencephalitic parkinsonism but their frequency during the acute encephalitic ill- ness is not known (Onuaguluchi, 1961; Clough et al., 1983). This phenomenon was 26 R. S. HOWARD AND A. J. LEES observed in 3 of the patients in whom it persisted throughout the course of the illness, although becoming somewhat less frequent with time. The bulbar nuclei are also involved in the acute encephalitic illness. One patient showed facial weakness and another frequent cardiac arrhythmias. In Case 2 episodic hypertension was noted. The most striking brainstem feature, however, was the presence of respiratory abnormalities. Respiratory disorders of several kinds were described, including increased respiratory rate, apnoeic episodes,

myoclonic jerking of the diaphragm, and staccato, ratchet and cluster breathing. Downloaded from https://academic.oup.com/brain/article/110/1/19/273787 by guest on 01 October 2021 Respiratory disturbances and cardiac arrhythmias are particularly serious and the most life-threatening feature of the acute illness. Respiratory abnormalities occurred in all the patients; sleep recordings of respiratory movements in Case 1 showed episodes of apnoea, ratchet and cluster breathing which resulted in hypoxic episodes without obvious upper airway obstruction. Case 2 suffered episodes of tachypnoea, respiratory irregularities and apnoea necessitating artificial ventilation. In Case 3 the respiratory pattern was regular but she was unable to hold her breath voluntarily, and in Case 4 inspiration and expiration were interrupted by irregular pauses. Megaphagia suggested hypothalamic involvement in Case 2 during the initial phase of the illness. We propose that a number of clinical features may be considered as major criteria supporting the diagnosis of encephalitis lethargica. It should comprise an acute or subacute encephalitic illness which has as part of its clinical picture at least three of the following major criteria: (1) signs of basal ganglia involvement, (2) oculogyric. crises, (3) ophthalmoplegia, (4) obsessive-compulsive behaviour, (5) akinetic mutism, (6) central respiratory irregularities, and (7) and/or sleep inversion. The CSF is also frequently abnormal, particularly in those forms which manifest meningeal irritation. Some patients show a modest increase in pressure and protein content. In the early stages a mild/moderate pleocytosis may be present, the number of cells, predominantly lymphocytes, varying generally between 5 to 20/mm3 but rarely as high as 500/mm3. Lumbar puncture showed the CSF protein level to be elevated in 3 of the patients and 2 showed a mild to moderate increase in the lymphocyte count. The CSF glucose was normal in all cases. Williams and colleagues (1979) described 2 cases of progressive parkinsonism after an encephalitic illness in whom oligoclonal IgG bands were present in the CSF. There was no oligoclonal banding in 6 controls with idiopathic Parkinson's disease. Oligoclonal IgG bands may be observed in the CSF during acute viral such as herpes simplex encephalitis (Felgenhauer et al., 1980; Vaheri et al., 1982), (Vandvike et al., 1978), and chronic mumps encephalitis (Julkunen et al., 1985). Oligoclonal IgG proteins may be detected in the CSF during the second week after the onset of mumps meningitis and as early as the sixth day after the onset of herpes simplex encephalitis and may persist for many months. It is unclear whether a con- tinued presence of oligoclonal IgG in the CSF reflects an antibody response to an active infection or an activation of selective antibody-producing cells due to other factors. In this series, 3 patients had serial lumbar punctures performed during the ENCEPHALITIS LETHARGICA 27 course of the illness and in all of them CSF electrophoresis was performed with simultaneous serum electrophoresis. All the specimens of CSF showed oligoclonal IgG banding throughout the course of the illness. This includes the initial lumbar punctures which were performed between fivean d thirteen days after the firstsymp - toms. These findings are the first report indicating local IgG synthesis within the CSF in the acute phase of clinically definite encephalitis lethargica and add support to the view that the condition is caused by a viral infection. The EEG findings during the acute phase of the illness have only rarely been reported; they seem to reflect a diffuse encephalitic illness. There may be diffuse Downloaded from https://academic.oup.com/brain/article/110/1/19/273787 by guest on 01 October 2021 unilateral or bilateral slowing in the delta or theta frequencies but more focal sharp wave activity is seen in some cases. In the present study all 4 patients had diffuse slow wave activity with no definite lateralizing features. However, in Case 1 an EEG performed during an epileptic seizure showed occasional long runs of sharp theta activity in the right hemisphere before the tracing became obscured by movement artefact. Abnormalities of evoked potentials have not previously been reported in encepha- litis lethargica. The abnormal visual evoked potentials in Cases 2 and 3, despite reasonable fixation on the target, and delayed cortical component somatosensory evoked potentials in Case 3 suggested the presence of cortical involvement, as did the development of focal epilepsy in the same patient. These findingsad d support to von Economo's suggestion that diffuse cortical involvement is a feature of encepha- litis lethargica. The pathological findings of von Economo suggest there are nonpurulent, non- haemorrhagic alterations limited to the grey matter, with preferential localization to the midbrain. Perivascular infiltration with engorged blood vessels and nerve cell necrosis are evident. Although the changes are most severe in the brainstem and basal ganglia, there was also involvement of the cerebral cortex and . These findings, characterizing the acute cases, are replaced by more extensive tissue damage in the postencephalitic state. The neurofibrillary tangle was first described by Hallervorden in 1935 and the presence of this cytoplasmic inclusion in the sub- stantia nigra has come to be regarded as one of the hallmarks of postencephalitic Parkinson's disease. Typically the tangles are found in connection with severe diffuse nerve cell loss. The histological findings in Case 2 are compatible with the early descriptions of the pathological findings in acute encephalitis lethargica. In 1971 Bojinov stated that no author in the preceding forty years had observed the typical clinical features of encephalitis lethargica. This view was reinforced by Herishanu and Noah (1973) who commented that the majority of neurologists thought that von Economo's disease was a condition of the past. Poser et al. (1969) have suggested that paraencephalitic parkinsonism may not be a distinct syndrome but merely follow a number of different, nonspecific viral encephalitides. They have suggested that all parkinsonism, including the idiopathic and arteriosclerotic types, are essentially viral in origin and that the damage to the cells of the basal ganglia is the result of a viral , the parkinsonism becoming manifest later 28 R. S. HOWARD AND A. J. LEES as a result of a secondary noxious insult. However, the clinical picture described by von Economo and manifested by a number of patients in the literature is sufficiently characteristic to allow a clinical diagnosis and to suggest a unifying aetiology. We agree that a number of case reports of supposed encephalitis lethargica remain open to considerable doubt. Bickerstaff and Cloake (1951) described 3 cases of mesencephalitis and rhombencephalitis. The authors thought the cases unlikely to be encephalitis lethargica because of the gradual onset, minimal systemic disturbance, absence of reversal of sleep or disturbances of respiratory rhythm, the presence of complete bulbar palsies and the transitory nature of the parkinsonism in one patient. Downloaded from https://academic.oup.com/brain/article/110/1/19/273787 by guest on 01 October 2021 They considered a possible relationship to . Hunter and Jones (1966) described 6 cases of possible encephalitis lethargica with psychiatric and ocular abnormalities. However, they make little mention of any extrapyramidal or pyra- midal features and as the cases are not discussed individually, it is difficult to be sure on what grounds the diagnosis of 'mild or attenuated' encephalitis lethargica was made. Poser et al. (1969) described a case of a severe transient parkinsonian syndrome following a meningoencephalitis associated with the coxsackie virus type B2 in a 16-year-old boy. Fifteen months later the patient returned completely to his premorbid state. Apart from the development of an extrapyramidal syndrome he showed few of the features previously described as 'major diagnostic criteria', namely somnolence, ophthalmoplegia and oculogyric crises. Bojinov (1971) described 11 patients with encephalitis and an acute parkinsonian syndrome. Although these cases showed extrapyramidal and pyramidal disorders, ophthalmoplegia and sleep disorders, the authors preferred to call the condition a polioencephalitis of viral origin. Pathological examination of the brains of the fatal cases revealed a severe inflammatory necrosis of the substantia nigra with proliferation of phagocytic cells and abundant plasma cells and lymphocytes. A number of gliomesenchymal nodules and areas of perivascular round cell infiltration were found in the inferior olive, the dentate nucleus, the cerebellar cortex, the basal nuclei and the thalamus. The cerebral cortex, striate body and spinal cord were spared. Misra and Hay (1971) described 3 patients who developed symptoms of acute schizophrenia. There were no abnormal neurological signs on presentation, but all the patients later showed clinical evidence of encephalitis. One developed a postencephalitic parkinsonian disorder and a second remained in a chronic schizophrenic state. However, the clinical details of the encephalitic illness are insufficient to sustain a diagnosis of acute encephalitis lethargica. Crow (1983) has cited the psychiatric abnormalities that occur in encephalitis lethargica as supportive evidence for the theory that schizophrenia could be due to a virus which is transmitted predominantly from schizophrenic patients to genetically predisposed individuals. Recently Carne et al. (1985) have reported 3 patients who suffered an acute associated with the appearance of antibodies to human T-lymphotropic virus (HTLV-HI, HIV). These patients suffered mood changes and epileptiform seizures during the course of the illness but the neurological symptoms and signs resolved in all of them, and no residual CNS sequelae were noted. ENCEPHALITIS LETHARGICA 29 Miyasaki and Fujita (1977) described a case of parkinsonism following a mild encephalitis of unknown aetiology, clinically distinct from von Economo's encepha- litis. A post-mortem examination was performed five years after the acute encephalitis and showed that the neurons in the substantia nigra were extensively degenerated and presented Alzheimer's neurofibrillary tangles. Perivascular cuffing was observed in the frontal, parietal and temporal lobes, hippocampus and thalamus, as well as the substantia nigra. Rail et al. (1981) presented 8 patients who were believed to conform to the clinical features of encephalitis lethargica as defined within the Downloaded from https://academic.oup.com/brain/article/110/1/19/273787 by guest on 01 October 2021 paper. The encephalitic illness was reviewed retrospectively and in a number of cases the acute encephalitic illness was either poorly documented or not clearly distinguished from the postencephalitic sequelae, indeed 2 of the cases did not have a clear encephalitic illness. Most showed extrapyramidal abnormalities during the acute phase and all developed such features ultimately. Two patients showed florid positive motor symptoms and 3 suffered psychiatric manifestations. Other important features seen in some of the patients included focal motor abnormalities, oculogyric crises (3 cases), pupillary changes or gaze palsies (2 cases) and respiratory abnor- malities (2 cases). The authors described the pathological appearances in 2 of their cases of postencephalitic Parkinson's disease. There was severe neuronal loss in the substantia nigra and locus coeruleus. The remaining neurons showed prominent neurofibrillary tangles but no Lewy bodies or Alzheimer's plaques were found. Neurofibrillary tangles were also seen in the dentate nucleus, corpus striatum and cortical neurons in 1 patient. Rail and colleagues defined 9 clinical features of encephalitis lethargica and our experience concurs that these are amongst the most important criteria for establishing the diagnosis. Certainly in the presence of an acute encephalitic illness, the development of extrapyramidal signs, oculogyric crises (provided there is no relevant drug history), behavioural disturbances, ocular, respiratory and sleep abnormalities are the main characteristic features. Evidence of pyramidal or diffuse cortical involvement during the acute encephalitic illness is common but cannot be considered diagnostic. We do not accept that the previous administration of neuroleptics should exclude the diagnosis although it is important to recognize that acute dystonic reactions and the neuroleptic malignant syndrome may superficially mimic the disorder. Herpes simplex encephalitis may resemble encephalitis lethargica with focal motor signs, isolated cranial nerve palsies, behavioural disturbances, amnesia and confusional states preceding coma (Drachman and Adams, 1962). However, extra- pyramidal features, oculogyric crises, sleep inversion, ophthalmoplegia and respiratory disturbances are rarely, if ever, seen during the course of herpes simplex encephalitis and necrotic damage of the temporal and frontal lobes is not a feature of encephalitis lethargica. (MS) may also present with a leucoencephalitic picture of drowsiness, stupor and cranial nerve palsies which may be clinically indistinguish- able from focal brainstem encephalitis. Patients with acute 'leucoencephalitic' MS do not suffer oculogyric crises and extrapyramidal features, and mental 30 R. S. HOWARD AND A. J. LEES

disturbances are extremely unusual. Although psychiatric disturbances are common in MS, presentation with schizophrenic has only rarely been reported (Parker, 1956; Geocaris, 1957). Elizan and her colleagues (1980) found an increased frequency of HLA B14 (44%) in postencephalitic parkinsonism compared with matched controls. However, Lees et al. (1982) failed to show any difference in phenotypic frequencies of HLA types in 21 patients with parkinsonism secondary to von Economo's encephalitis compared with a large group of controls. These findings failed to support the hypothesis of genetic susceptibility to postencephalitic parkinsonism. A possible explanation for Downloaded from https://academic.oup.com/brain/article/110/1/19/273787 by guest on 01 October 2021 the findings of Elizan et al. was that all the patients they described shared a common East European Jewish origin. Marttila et al. (1977) failed to find increased serum titres to four strains of influenza A in 20 patients with postencephalitic parkinsonism and Elizan etal. (1978) found similar results in 27 patients. A later study of Elizan et al. (1979) failed to show increased CSF or serum titres for haemagglutination inhibition antibodies to arborvirus. They did, however, show lowering of titres of type 2 in postencephalitic patients compared with controls but it is unlikely that this virus could be causally associated with the disease. We have been unable to demonstrate any significantly elevated or rising viral titres in blood or CSF in our patients. It is possible that encephalitis lethargica may be a specific response to a variety of viral infections or a rare illness due to a specific neurotropic virus which stimulates a B cell immunoglobulin response within the CSF. These cases, however, re-emphasize that sporadic cases identical to those reported by von Economo in the 1917-1928 pandemic continue to occur and may be responsible for cases of Parkinson's syndrome in the community. The delayed appearance of Parkinson's syndrome following a seemingly full recovery from the acute encephalitic illness may be due to a continuing virally-mediated nigral damage or alternatively to decompensation as a result of ageing effects in an already compromised substantia nigra.

ACKNOWLEDGEMENTS We thank the following physicians of The National Hospitals for Nervous Diseases, London, for permission to publish the cases under their care: Professors W. I. MacDonald, J. Marshall and J. Newsom-Davies and Drs L. Loh, G. D. Schott and R. S. Kocen. Dr W. R. Gibb supplied the patho- logical data and Dr E. Thompson provided invaluable advice on the interpretation of the CSF findings. We also thank Miss V. Spencer for her secretarial assistance.

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Oxford: North-Holland, pp. 451^57. Downloaded from https://academic.oup.com/brain/article/110/1/19/273787 by guest on 01 October 2021 {Received October 21, 1985. Revised March 4, 1986. Accepted March 25,1986)