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Year : 2020  |  Volume : 8  |  Issue : 2  |  Page : 255-262

Encephalitis lethargica: The challenge of structure and function in neuropsychiatry

Department of Neurology, John Hunter Hospital and University of Newcastle, Newcastle NSW, Australia

Date of Submission02-Dec-2020
Date of Decision03-Dec-2020
Date of Acceptance04-Dec-2020
Date of Web Publication23-Dec-2020

Correspondence Address:
Dr. David Bruce Williams
Faculty of Medicine and Health Sciences, University of Newcastle, Department of Neurology, John Hunter Hospital, Newcastle, NSW
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/amhs.amhs_308_20

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From its initial description, encephalitis lethargica (EL) challenged the existing understanding of neurology, psychiatry, neurophysiology, and neuropathology in multiple areas, including disease classification, states of alertness, the phenomenology of sleep and consciousness, the voluntary and involuntary control of thought and movement, and the neural underpinnings of emotional and behavioral phenomena (which in turn had important legal ramifications in assessing criminal culpability), not to mention the interrelationship of neural and endocrine systems. This paper reviews the phenomenology of EL, highlighting some of the puzzles it generated by demonstrating that abstract notions of consciousness, sleep, thought, volition, and will were in fact intimately connected to brain function in regions not formerly suspected of subserving such roles.

Keywords: Encephalitis lethargica, neuropsychiatry, von Economo

How to cite this article:
Williams DB. Encephalitis lethargica: The challenge of structure and function in neuropsychiatry. Arch Med Health Sci 2020;8:255-62

How to cite this URL:
Williams DB. Encephalitis lethargica: The challenge of structure and function in neuropsychiatry. Arch Med Health Sci [serial online] 2020 [cited 2022 May 18];8:255-62. Available from: https://www.amhsjournal.org/text.asp?2020/8/2/255/304725

  Introduction and Overview Top

Encephalitis lethargica (EL) was first described in 1917 as an acute illness with high mortality. Neuropathological examination revealed maximal injury in the region of the mesencephalon, corresponding with the most common focal neurological signs, being abnormalities of oculomotility. Initially appearing sporadically, EL recurred on a seasonal basis in most European countries over the next 7 years, the incidence peaking with the UK epidemic of 1924. Thereafter, the seasonal epidemic pattern gradually dissipated, and acute infections declined. Whether the disease completely disappeared or persisted in sporadic form in East Asia into the 1990s remains uncertain.[1]

A persisting confounder in acute EL (aEL) diagnosis was the absence of a confirmed etiological agent. Diagnosis could be difficult because of highly variable clinical manifestations, many of which defied precise anatomical localization. The boundaries of the clinical syndrome could be defined only by comparing overlapping clinical pictures occurring in different patients in the context of an epidemic or recognizing unfamiliar clinical manifestations in an otherwise typical aEL patient.

Diagnostic difficulties were compounded by temporal changes in the typical aEL presentation, as well as oligosymptomatic and (eventually recognized) asymptomatic cases. A major change in presentation was from the lethargic-somnolent form to the insomniac-hyperkinetic form, beginning in 1920 and progressing thereafter.

Reports of aEL neuropathology typically centered on the mesencephalon, though in individual cases, it could extend rostrally to the hypothalamus or caudally to the lower medulla (or both simultaneously). Cortical and spinal cord involvement was reportedly rare, and if present, usually modest in severity. Microscopic pathology was exquisitely focal (sometimes affecting only a fraction of the neurons in a given nucleus), with foci scattered in gray matter, but scrupulously avoiding myelinated tracts.

Although some of the initial aEL survivors had persisting neurological deficits, a gradual recognition developed that some symptoms assumed to be “normal” for patients recovering from a severe illness were actually indicators of persistent disability, albeit of a somewhat nebulous or ill-defined type. This period of the illness became known as the “pseudoneurasthenic” (PN) phase of EL.

Compared with adults, children and adolescents were at greater risk of significant and persisting antisocial behavioral changes that challenged both carers and in more extreme cases, existing definitions of criminality.

Finally, after a variable period of relative stability, the majority of survivors began to develop additional deficits, the most common and most widely recognized being the syndrome of post-encephalitic  Parkinsonism More Details (PEP), which was eventually distinguished, both clinically and pathologically, from idiopathic parkinsonism. The signature pathology in PEP was the near-complete destruction of the substantia nigra (SN) pars compacta.

The epidemiological study of EL was complicated by difficulties in case definition, inability to define the base population of case series, the unexpectedly prolonged disease course, and the relative lack of pathognomonic features, as well as the long-term failure to confirm the strongly suspected infectious etiology.

Estimates of total (symptomatic) cases range from 100,000 to 1,000,000 worldwide. While the very young and the very elderly were not definitely spared, the highest risk was among adolescents and young adults. Men were somewhat more likely to be affected, but women were a little more likely to die in the acute phase. Estimates of mortality in the acute phase varied between 15% and 40%, depending on geographic region and epidemic wave. With increasing familiarity, clinicians became wary of asserting that any patient had truly “recovered,” because chronic EL (cEL) syndromes, such as PEP, could take decades to develop.[1],[2],[3] (For an extensive historical review and discussion, see: Encephalitis lethargica. The mind and brain virus[4]).

  Initial Recognition Top

In 1917, von Economo, a Macedonian polymath, neurologist, and pioneer aviator working in Vienna,[5],[6] reported a new neurological condition he had seen in six patients. His report included autopsy findings concerning two patients and noted “similarities” between polio, Wernicke's encephalitis, and EL.[7] French neurologist, Cruchet, disputed von Economo's priority, but most contemporary, and all subsequent authors, favored von Economo's more clearly defined syndrome to the perception that Cruchet's report grouped a number of heterogenous conditions together.

  Clinical Manifestations of Acute Encephalitis Lethargica Top

In the 3 years subsequent to Economo's report, increasing numbers of patients were identified in seasonal wintertime waves in Italy, Austria, France, Germany, the USSR, and the UK, as well as elsewhere. The notable aEL symptom at that time was described using a variety of terms, including hypersomnia, lethargy, stupor, torpor, and coma. Few of these terms were well defined and were unlikely to have been used consistently by different clinicians, even when reporting the same phenomenon, so the nature of this emblematic symptom remains uncertain. In retrospect, perhaps the clearest distinction that can be made is between wakeful inactivity contrasting with impaired wakefulness, vigilance, or attention.[8] However, a significant confounder is the possibility of two or more coincident dysfunctions.

The term hypersomnolence seemed appropriate for patients who could be roused and respond lucidly, albeit with greater than expected effort, but would suddenly become unresponsive if unstimulated. Waking only to eat, or go to the toilet, they would beg to be allowed to sleep, while denying feeling “weary.” Some patients described dreaming or dreamless sleep. Others described experiences which might now be interpreted as sleep paralysis or lucid dreaming. Later in the acute illness, observers noted sleep-walking and sleep-talking.

By contrast, some clinicians described patients whose immediate and appropriate response to whispered questions seemed inconsistent with somnolence and who reported an “inability” to move suggesting to the clinician that their problem was one of “akinesia.”

The range of different oculomotility disturbances in EL attests to the focal, but nonetheless scattered, lesions. Diplopia was even more commonly experienced than lethargy. CN III muscles were more often affected than the superior oblique muscle innervated by CN IV, and impaired accommodation due to medial rectus weakness or paralysis could be bilateral or unilateral. Aside from nuclear lesions, rarely seen conjugate gaze palsies, including vertical gaze palsies, were common. Nystagmus, including previously undescribed “tremor-like” and rotatory nystagmus, was common, but usually transitory. Partial ptosis, with a tendency for the eyes to drift vertically, normally considered an indicator of sleep onset, was not correlated with sleepiness in aEL.

Lower cranial nerves were less frequently affected than CN III, and while CN V was rarely affected, almost half of all patients experienced lower motor neuron (CN VII) facial weakness or immobility. Once again, asymmetrical, unilateral, or partial lesions (affecting only the upper or lower face on one side) reflected highly focal pathology. These symptoms and signs usually resolved. Hearing deficits were exceedingly rare, but nystagmus without vertigo, or vertigo without nystagmus suggested that the vestibular division of CN VIII, or its connections, was more vulnerable than the cochlear division. Vagal affliction could cause (sometimes fatal) dysphagia, respiratory dysfunction, and/or impaired vasomotor control. [3,9-11]

Laboratory investigations in aEL were unremarkable. Some patients, but not all, showed a degree of lymphopenia. CSF examination could be normal or show minor lymphocytosis. There were no pathognomonic abnormalities.[11]

Somnolence gives way to insomnia: The hyperkinetic variant

From the winter of 1919/1920, as pandemic influenza disappeared, a remarkable aEL variant disseminated northwards from Italy to Sweden. This variant featured insomnia and hyperkinesis rather than somnolence and lethargy and gradually became the dominant presentation – at the same time as the distinctive EL epidemic seasonality subsided, and overall case numbers declined.

The hyperkinetic–insomniac variant featured a prodrome of fever, as well as neuralgic pains unrelieved by morphine. Those symptoms tended to settle after the 1st week, as insomnia and hyperkinesis developed. The majority of patients failed to develop lethargy or cranial nerve palsies, but some did, and the “overlap” syndromes in individual patients, in the context of an epidemic, with comparable neuropathological features, were sufficient to confirm the underlying unity of the EL disease entity. [3,9-11]

In the same way that many different terms were used to characterize “lethargy,” hyperkinetic manifestations were variously characterized as “rapid spasms,” including myoclonus, and stimulus-dependent myoclonus, or as other involuntary movements described as chorea, athetosis, dystonia, myokymia, or tremor.[12] Rapid spasms, or myoclonus, more commonly affected the diaphragm or abdomen before affecting the face or limbs, and often manifested asymmetrically, affecting only one quadrant of the abdomen, one limb, or even a single extraocular muscle.

The amyostatic-akinetic variant

While PEP is considered emblematic of cEL, parkinsonian symptoms could also manifest in the acute phase of the disease. Lethargic unresponsiveness had to be distinguished from the so-called “amyostatic” state, in which the expressionless patient lay motionless in bed, staring fixedly, apparently unable to initiate movement. The limbs, described as manifesting “waxy rigidity,” would persist indefinitely in any posture shaped by the examiner. This state was distinguished from catatonia by the lack of cognitive impairment in aEL. [3,9-11] As with most aEL symptoms and signs, parkinsonian features usually resolved, though with a strong tendency to recur as PEP after an indeterminate period of up to a decade or more.[13]

Epidemic hiccup – clue or distraction

Von Economo's enumeration of EL symptoms included hiccup, which was later more frequently linked with the hyperkinetic–insomniac variety of EL.[13] Despite historical accounts of epidemic hiccup (EH) preceding the EL period, none have been reported subsequent to those occurring between 1920 and 1930. While the geographical extent of EH was broadly consistent with that of EL, no temporal correlation was evident. Consequently, opinions differed as to whether EH was a forme fruste or EL or not. Household clusters of EH and EL, the development of EL following EH, and autopsy findings that were microscopically consistent, though anatomically much more limited than EL, suggested that it was a milder forme fruste.

Vegetative and endocrine symptoms

Vegetative symptoms, while occurring in both acute and chronic periods, were more frequent in aEL than cEL and included cardiovascular dysregulation, excessive sweating, and seborrhea. Pain was typically unresponsive to sedatives or standard analgesia.

Endocrine symptoms were a feature of cEL, but only in patients who were infected in 1922/23 or subsequently. Diabetes insipidus, either temporary or chronic, was the most common endocrine syndrome, but was not associated with structural changes in the pituitary.

While death was ascribed to cachexia in some cases of PEP with dysphagia, pathological obesity, either general or regional, could also occur. The syndrome of adipose–genital dystrophy typically featured genital dysfunction in the form of amenorrhea, or loss of libido, with or without impotence. Paradoxically, prepubescent children might fail to develop mature sexual characteristics, or less frequently, manifest precocious puberty.[9],[10],[11],[13]

The pseudoneuroasthenic phase of encephalitis lethargica

Following resolution of the acute phase of EL, which often left residual neurological signs, many patients entered what became known as the PN period before developing cEL. The symptoms of PN were difficult to quantify, often subjective, and easily misinterpreted as hysteria, particularly in the aftermath of civilian and military trauma during World War I. Mental and motor fatigue, apathy, and sleep disturbance formed a prominent, interrelated symptom cluster. In addition, nonspecific headache, vertigo, and intermittent pains were difficult to categorize. Emotional lability, cycling unpredictably from irritability to “inane cheerfulness,” caused intimates to complain that the patient was “no longer the same person.” Mental hyperactivity, and motor restlessness with torticollis, athetosis and dystonia affected many patients, but was more common, and more disruptive, in the lives of children.[14]

In the Mayo clinic series of 752 cEL patients, 39% had some features of PEP immediately following the acute phase, but after 5.5 years, there were almost twice as many with signs of PEP. Importantly, as this was a retrospective study of patients who had already developed cEL, it could not estimate the likelihood of aEL evolving into cEL, and necessarily underestimated the time it might take to happen, because there were cases that had not manifested at the time of the study.[15] Accordingly, after accumulating several decades of experience, clinicians accepted that there was no upper limit to the duration before cEL might develop, but some features characterized patients who were more likely to experience a longer duration of PN. Those who contracted aEL before 1920 tended to be younger, to be more likely to have experienced the ophthalmoplegic–lethargic form of aEL, and to have suffered milder symptoms for a shorter duration. These were the patients most likely to experience the longest intervals before developing cEL. Consistent with the features of their prodrome, these patients' PEP symptoms tended to be milder and more frequently hemilateral, perhaps indicating a greater resilience or reserve in the younger brain.[16]

The chronic phase of encephalitis lethargica

The chronic phase of EL, often characterized by progressive, crippling disability, could last for decades, and created the lasting impression of EL described by Oliver Sacks in “Awakenings,”[17] and portrayed in the movie of the same name. (Also see video compilations.[18],[19]) The features of cEL included motor dysfunction, vegetative and endocrine disorders, along with psychiatric and behavioral abnormalities.[12],[13]

The development of parkinsonian symptoms in apparently “recovered” aEL patients in the 1920s was controversial until PEP was differentiated on both clinical and pathological grounds from idiopathic Parkinson's Disease (iPD), although a simple cause–effect relationship between aEL and PEP has been questioned.[20],[21]

The prominent PEP motor symptoms were hypertonia and bradykinesia–akinesia, which could occur independently, but tended to evolve toward an amalgam of the two. Hypertonia typically affected the face, producing a fixed, “mask-like” expression, and then gradually progressed caudally to involve the arms and then the legs. As bradykinesia and akinesia could occur independently of hypertonia, they were not solely the consequence of rigidity.

Bradykinesia–akinesia, with consequent poverty of movement, was attributed to a lack of volition. Voluntary actions appeared to be, and were experienced by the patient as, conscious and effortful. They tended to slow and diminish in amplitude as the movement progressed. Physical exhaustion did not appear to explain the failure to complete motor acts, as the patient would simply “freeze” in a given posture, regardless of how uncomfortable or precarious that might be. Conscious “willing” of action could be distinguished from more “natural” movements by the absence of automatic movements that unconsciously adjust balance or posture. Consciously motivated action ceased completely if the patient became in any way distracted.[12],[14],[22]

Both rhythmic and arrhythmic involuntary movements occurred in cEL, either in isolation or associated with parkinsonism.[12],[13] When present, tremor most commonly affected one or both arms, but could also affect the head, jaw, tongue, eyelids, or eyes. It sometimes alternated with myoclonus and chorea and had a more marked postural component than the tremor of iPD.

  Clinical and Neuropathological Features Differentiating Postencephalitic Parkinsonism from Idiopathic Parkinson's Disease Top

Unlike the gradual onset with slowly progressive, asymmetrical symptoms typical of iPD, PEP often commenced abruptly and progressed rapidly, as well as spreading inferiorly from the face and neck. Tremor was more likely to have an intentional component than to be a resting tremor. Rigidity was more often proximal, and variable, with a tendency to manifest after bradykinesia developed. Patients with PEP often had a prior history of PN symptoms and were more likely than iPD patients to experience psychiatric symptoms. Patients with more advanced PEP were also more likely to have oculomotility and vestibular symptoms and to display more vegetative symptoms. Oculogyric crises were never seen in iPD.[22]

Initially, the only neuropathological feature distinguishing PEP from iPD was the almost complete absence of SN neurons in the former compared with the small number of surviving neurons found in the latter. Not until later years were ultrastructural features such as neurofibrillary tangles and the absence of Lewy bodies identified as additional indicators of PEP rather than iPD.[3],[23]

  Episodic Symptoms – Agrypnia and Oculogyric Crises Top

Especially notable among the many symptoms of EL were those which appeared episodically, including the syndromes of “agrypnia” and oculogyric crisis, typically seen in children and adults, respectively.[12]

Agrypnia, or nocturnal excitation crises, affected most young children with aEL, manifesting as a somewhat manic motor restlessness that developed at dusk, and persisted until the exhausted child fell lightly asleep in the morning. Accompanying the compulsive sucking, chewing, plucking, and re-arrangement of bedclothes were suggestions of disorientation, and significant character change. Placid children became angry, disobedient, and aggressive. Disruption of the sleep–wake cycle led to an overall reduction in total sleep, but paradoxically, sedatives perversely exacerbated the problem.[12],[24]

Oculogyric crises (OC) had never been reported prior to 1922, and while relatively few children were affected, an estimated 50% of adults with cEL experienced “attacks.”[3] Appearing irregularly some years after the aEL illness, OC tended to become predictably recurrent, usually with a periodicity which was both circadian and peculiar to each individual. The complex phenomenology involved psychomotor, vestibular, and vegetative features. The attack was preceded by anxious anticipation, compulsive thoughts, and inwardly focused attention. Tonic gaze, usually, but not always, up and to the side, was associated with synchronous twisting of the head, neck, and torso in the same direction. Parkinsonian symptoms were exacerbated during an attack. Salivation, sweating, facial flushing, and changes in (cardio) respiratory rate, amplitude, or character were also common features. Triggers included both emotional experience and suggestion, and while conscious effort or countermanding suggestion could modulate the timing or magnitude of the psychomotor response to a degree, it was difficult to abort an episode. Patients reported the sense of a growing force or energy that needed to be discharged in order to provide relief. Intriguingly, amphetamines provided more relief than anticholinergics, but iproniazid and physostigmine exacerbated the problem.[3],[25]

  Psychiatric Manifestations of Encephalitis Lethargica Top

All phases of EL posed enormous challenges in understanding the myriad psychiatric and behavioral features of the disease. EL challenged the conceptual separation of mind and brain, as well as the nature of consciousness, attention, and volition. Attempts to interpret the psychopathology in Freudian and even Marxist frameworks failed. Kinnier Wilson preferred to interpret symptoms such as bradyphrenia purely in terms of slowing of motor responses. Among UK neurologists, he was not alone in concentrating on the physical manifestations of EL and minimizing emotional dysfunction as a secondary phenomenon.[26]

Efforts to link psychopathology to underlying brain dysfunction unhelpfully split into those who saw the cortex as preeminent,[12],[27] and those who perceived an important role for the subcortical structures in supporting consciousness, or in expressing the “vegetative” personality.[13] Intermediate positions emphasized the importance of “relations” between different regions of the central nervous system (CNS) over strict localization.[12],[28]

In the acute phase of EL, delirium or confusion could manifest, just as might be expected in many febrile and inflammatory conditions. The most common symptom specific to EL was profound apathy. Despite the patient being easily roused, orientated, and able to communicate, apathy hindered or prevented all goal-orientated activity, including sustained verbal intercourse (See above).

The vague symptoms characterizing the PN phase of EL seemed to merge seamlessly into the chronic phase of EL. Following the acute syndrome, the PN phase was characterized by irritability, anhedonia, and asocial tendencies, which blighted family relationships. Loss of initiative combined with slowed responses and impaired memory made it difficult to reestablish any prior career requiring significant degrees of skill or expertise. Adding to their misery, patients could experience insomnia, narcoleptic attacks, or episodic anxiety. For some, akathisia, or the feeling of a need to move despite having no motive or purpose, further complicated the situation.[29]

Psychiatric symptoms in children

In children, the profound behavioral disturbances immediately following aEL are reported to be unknown in any other condition.[30] The changes were most severe in boys between the ages of 5 and 18 years, and the younger they were when first affected, the more severe the manifestations tended to be. The most common afflictions consisted of a change in personality (always for the worse and often pugnacious) and emotional instability manifesting as irritability, crying spells, and temper tantrums. The children were described as restless in both wakefulness and sleep, with irregular sleep habits.[31] More extreme hyperkinetic states associated with asocial aggression and shameless sexual activity were less common, but more difficult to manage.

Assessment of intelligence is difficult unless the subject willingly engages in the process. Nonetheless, children who contracted aEL under the age of 5 years suffered severe mental retardation. Between 5 and 14 years of age, intelligence apparently slowed, and acquisition of new skills and knowledge was impeded, but the significance of these observations was controversial. Attentional deficits and misbehavior that impeded educational endeavors could account for some of the observed testing deficits.[32]

In older children, the combination of relatively intact cognitive capacity with impaired, impulsive, and unpredictable behavior challenged family and institutional carers, as well as the legal establishment. They failed to make the normal transition from the child's external locus of control to the mature adult's internal locus, demonstrating remarkable switches between their pre-EL personality and displays of what von Economo described as “moral insanity.” The unpredictable aggression, hypersexuality, thieving, and dishonesty were variously interpreted. Some ascribed the symptoms to increased suggestibility, mental apathy, and impaired attention, while others postulated “blockage” of pathways that normally suppressed more instinctual responses. Still others saw the behavior as a psychological response to the illness and its consequences.[33] Some children admitted to shame concerning their actions, and complained that their abnormal behavior felt alien to their psyche, posing a dilemma when criminal culpability was being assessed. Unfortunately, regardless of every effort to discipline, restrain, and train these children, the pathological behavior of the majority remained unchanged or deteriorated.[34]

Psychiatric symptoms in adults

Psychiatric symptoms in adults with cEL were estimated to affect between 25% and 90% of cEL patients, reflecting both differences in study populations and controversies concerning diagnosis. Individual cEL patients posed significant diagnostic dilemmas. In any psychosocial context thought to imply increased risk for hysteria, abnormal behavior and movement, especially if they appeared to be externally motivated, or modifiable, could be interpreted as hysterical.[12],[35] Movement dysfunction in cEL patients that might otherwise be interpreted as catatonia due to psychosis was distinguished from the latter by the retention of unimpaired cognition in the former.[12],[36],[37] Thus, EL forced a reconsideration of the diagnostic boundaries of both hysteria and psychosis and a recognition that EL was not typically associated with either.

A large minority of cEL patients experienced bradyphrenia (slowing of thought). Patients reported difficulty in concentrating that their thoughts and speech no longer “flowed,” and that they could go for long periods without thought, or any sense of their own existence. Bradyphrenia might seem an unsurprising accompaniment of bradykinesia and akinesia. However, this lockstep relationship was not universal. In some patients, bradyphrenia preceded the development of bradykinesia, and in other cases hyperphrenia (accelerated thought) accompanied the development of progressive immobility.[38]

Mood in cEL varied from patient to patient and showed individual fluctuations. While most patients were observed to be detached, or apathetic, depression was uncommon.[8] Some reported that their affect was unchanged, but that their capacity to express it was impaired. Patients experiencing frequent mood shifts later reported insight into the inappropriateness of their moods. Some patients complained that their emotional expression was inauthentic and failed to reflect their true feelings.

As the cEL phase of the illness could last decades, and the intellect was relatively spared, there were numerous credible reports from patients describing their interior life. A study by Alfred Hauptmann recognized two dysfunctions. Among those whose normal feelings were insufficient to initiate action, concentrated attention, heightened emotion, or the urgings of respected others could temporarily overcome the blockage. Among the remainder, the absence of all affective responses removed any urge to decide or to act. Despite this, patients with loss of drive and poverty of thought reported an active inner life with a vital interest in all things, and surprising equanimity, despite their unenviable situation (see discussion in Foley[38]).

  Neuropathology of Acute Encephalitis Lethargica Top

In the search for the causal underpinnings of clinical observations, potentially precise neuropathological localization afforded great significance to EL autopsy findings. However, microscopic clinical–neuropathological correlations in aEL were poor, and interpretations of the findings could be fraught, depending on the experience and a priori hypotheses of the examiner. Most aEL autopsy reports concerned patients who died of the disease, rather than with the disease, and younger patients, or those with formes frustes were less frequently studied, leaving significant opportunity for contradictory interpretations. A recent, extensive review of historical reports noted much more frequent cortical pathology than previously acknowledged, while conceding that some cortical features might be ascribable to agonal hypoxia or ischemia.[39]

Contemporary observers were less impressed by changes in the meninges and cortex than they were by the marked edema and hyperemia affecting gray matter from the basal ganglia to the upper spinal cord.[3],[40] The gray matter, especially of the mesencephalic tegmentum, featured focal perivascular inflammation affecting small–medium veins more than capillaries. However, localized infiltration by small lymphocytes and plasma cells was not obviously correlated with specific symptoms or signs. After the first few days of infection, only scattered lymphocytes remained, concentrated in the SN, locus coeruleus (LC), and periaqueductal gray matter.[13],[41]

Microglial and astrocytic responses in EL were initially interpreted as a phagocytic response to damaged or necrotic cells. Acutely, glial “nodules” were prominent, and widely scattered, most commonly in the brainstem and cranial nerve nuclei. Later, the nodules either regressed as inflammation settled or persisted as “glial scars” in more severely affected regions. Neuropathologist Hugo Spatz suspected that glial tissue, mobilized early, and sometimes found surrounding apparently healthy neurons, might be part of the primary inflammatory response, rather than representing a secondary, reparative role.

That suspicion was not confirmed for some decades. Intriguingly, the sites most likely to be permanently injured in EL (and particularly the SN) normally host high numbers of resident microglia.

Neuronal degeneration was relatively mild compared with the cell loss seen in poliomyelitis.[40] Thus, even in the areas suffering the most marked cell loss (SN, LC, and dorsal pneumogastric center), scattered degenerating cells were usually accompanied by many apparently normal neurons. Cellular damage was even less marked in the oculomotor and facial nuclei.

  Neuropathology of Chronic Encephalitis Lethargica Top

From early stages in the era of EL, some authors identified the pathology in the SN as having special significance,[1],[42],[43] while others demurred.[44],[45] As data accumulated, it became clear that SN degeneration was present in the majority of cEL cases, regardless of whether the patient exhibited parkinsonian symptoms or not.[46]

Autopsy examination of patients assessed as having previously recovered from aEL confirmed the clinical suspicion that no one could be confident of having a “complete” recovery. In most cases, the brain appeared macroscopically normal, or perhaps showed minor atrophy, but microscopic abnormalities were almost universal. Degenerative, but not inflammatory, features dominated, and affected neurons were shrunken, distorted, or replaced by astroglia, with or without oligodendrocytes. These changes were scattered extensively, but were “devastating” in the SN pars compacta. The LC and dorsal vagal nucleus of the rhombencephalon, as well as the raphe nuclei of the pons and mesencephalon, were commonly affected, sometimes severely. By contrast, the rest of the mesencephalon, along with the diencephalon pallidum and striatum, were less severely injured.

Spatz hypothesized that a connected “system” involving the SN, dentate, red and subthalamic nuclei, the globus pallidus, and the striatum could potentially explain the marked variety of extrapyramidal symptoms seen in EL. He postulated connections among these specific regions because of similar staining reactions for iron, believing that functional chemical relationships had a greater potential explanatory power than the previously sought correspondences between specific CNS sites and clinical phenomena. It later transpired that high levels of iron in the CNS correspond with high levels of dopamine in the same locations.[47]

  Epidemiology Top

Epidemiology of acute encephalitis lethargica

While the epidemic pattern of aEL eventually left little doubt of its contagious nature, very few cases of aEL (<3%) were considered to be even suggestive of person-to-person transmission through cohabitation or close contact. The few reported case clusters were very much exceptions to the rule.[48] By analogy with poliomyelitis, and in the context of epidemic cases of EL, infection via asymptomatic or minimally symptomatic carriers seemed the most likely explanation. Early attempts at mathematical modeling of the UK epidemic implied that more than 99% of infections were asymptomatic.[49]

The syndrome of hyperkinetic–insomnia following the winter of 1919/1921 was seen more often in younger patients, with older patients more likely to manifest the oculolethargic presentation. The hyperkinetic form was initially associated with a higher mortality rate, but quickly reverted to a rate comparable with the lethargic form. Aside from (male) sex and (relatively young) age, and despite intensive investigation, no convincing environmental risk factors were identified.

Epidemiology of postencephalitic parkinsonism

PEP was eventually estimated to affect a majority of those who had experienced aEL, more often following the oculolethargic form than the hyperkinetic–insomniac form. However, cases were also diagnosed in patients from whom no history of the acute illness could be elicited, and consequently a direct causal link has been questioned.[21] The overall prognosis was poor, with most patients dying of cachexia or “sudden death” within 10 years of cEL onset.

  Etiology Top

Even before viruses had been discovered, EL was considered contagious, though not easily transmitted in symptomatic form, and its epidemiology and clinical and neuropathological features were compared with both human polio and equine “Borna disease.” While it remains debatable, influenza virus is unlikely to have been the causal agent for numerous reasons,[50],[51] the most compelling of which being the unique neuropsychiatric features of cEL, including PEP.[48],[52],[53] Alternative hypotheses utilizing modern investigative techniques depend on rare, long-preserved autopsy material,[51],[54] or the continued existence of sporadic EL cases, rather than EL phenocopies.[55],[56],[57] Thus, the mystery persists.

  Conclusion Top

Prior to EL, neuroscience had progressed to such a degree that weakness or paralysis of even a single ocular muscle could reliably be ascribed to a specific, localized lesion in the CNS. The difficulty that EL posed was that, unlike uncomplicated weakness and paralysis, most of the disturbed CNS functions in EL were difficult or impossible to describe objectively. Attempts to localize responsible lesion(s) were unsuccessful, except in the broadest sense,[1],[12] with the one exception of the SN in PEP.[43] Complicating matters further, many of the disturbed functions manifested in ways that appeared almost irreconcilably contradictory. Somnolence and insomnia, bradykinesia and hyperkinesia, or bradyphrenia and hyperphrenia could, remarkably, be seen in different patients during the same epidemic wave, or episodically in the same patient. Astute clinicians analyzing these features suspected that no single “center” or “pathway” could account for them.[27] Functional “interactions” were proposed, hypothesizing that the proposed connections might underlie the observed function and dysfunction.[28],[47]

Since that time, there have obviously been remarkable developments in the understanding of neuroepidemiology, neuropathology, neurophysiology, and neurochemistry, not the least of which has been the recognition of the regulatory role of dopamine in the CNS and its temporary efficacy in treating Sacks' late-surviving PEP patients. Perhaps an equally salient development has been the discovery of the reticular activating system,[58],[59] a neuronal network extending through the brainstem, with multiple feedback controls regulating vigilance and sleep. The concept of neuronal networks controlled by multiple neural, neurochemical, and endocrine feedback mechanisms can and is being broadened to address, and better understand the remarkable psychomotor, emotional and behavioral dysfunctions that characterized EL.

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Conflicts of interest

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  References Top

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