Encephalitis lethargica: 100 years after the epidemic

Encephalitis lethargica is a neurological syndrome that spread across Europe and then the world beginning in the winter of 1916–17, and continuing into the 1930s. Although the exact number of people afflicted with encephalitis lethargica during the epidemic period is unknown, it is estimated to be more than one million worldwide (Ravenholt and Foege, 1982). Those who survived were sometimes left with lingering and permanent neurological sequelae that rendered them nearly akinetic. Although 100 years have elapsed since the beginning of the epidemic period, many questions remain about this mysterious illness: What causes it? How is it transmitted? Could an epidemic happen again? In late 1916, while treating patients in the Psychiatric-Neurological Clinic of the University of Vienna, Dr Constantin von Economo examined several patients who presented with unusual neurological symptoms. The patients had been admitted with varying diagnoses such as meningitis, multiple sclerosis, and delirium; however, none of them matched well into any known diagnostic scheme. In particular, many of the patients presented with marked lethargy. Von Economo considered the uniqueness of this set of symptoms as a distinct disease entity, which he described in a 1917 manuscript entitled Encephalitis Lethargica. Contemporaneous to von Economo, a French physician, René Cruchet was treating similar patients in a military hospital for neuropsychiatric disorders. Cruchet, too, believed that these cases differed from previous cases of encephalomyelitis, and his own description of the disease was published within a few days of von Economo’s. Cruchet and von Economo’s papers were followed by many more articles as the disease spread across Europe and then around the world. During the epidemic period, approximately 9000 papers were published about this perplexing illness (Peng, 1993). Although encephalitis lethargica was first officially recognized as a separate disease entity in 1917, Crookshank (1918) identified several historical epidemics that resembled encephalitis lethargica, including the English sweats (England, 1529), mal mazzuco (Italy, 1597), Kriebelkrankheit (Germany, 1672–75), Rafania (Sweden, 1754–57), and nona (Italy, 1890–91). Further, in 1921 Urechia proposed that the initial appearance of encephalitis lethargica during the epidemic period was in early 1915 rather than 1916, and most likely in Romania. The movement of troops across Europe during World War I likely facilitated the spread of encephalitis lethargica, which reached epidemic status in Vienna in 1917, followed by France and England in 1918. By 1919, the epidemic had overrun most of Europe, the USA, Canada, Central America, and India. During the epidemic period, peaks of encephalitis lethargica occurred in 1920 and 1924. Subsequently, acute cases became less common, although many patients suffered chronic neurological sequelae that persisted long after the epidemic period. There has been no epidemic recurrence of encephalitis lethargica since the early 20th century, but putative sporadic cases continue to occur. Encephalitis lethargica was classically characterized by acute and chronic phases, although the two often blended together. During the acute phase, patients typically experienced excessive sleepiness, disorders of ocular motility, fever, and movement disorders, although virtually any neurological sign or symptom could be exhibited, with day-to-day, and even hour-by-hour shifts in symptomatology. The chronic phase could occur months to years later and was most commonly characterized by parkinsonian-like signs. Acute encephalitis lethargica often presented as a gradual onset of non-descript flu-like symptoms, including malaise, low-grade fever, pharyngitis, shivering, headache, vertigo, and vomiting. Neurological symptoms followed and could present very quickly, as in the case of a girl who experienced a sudden hemiplegia while walking home from a concert. Within half an hour she was asleep, and died 12 days later. To facilitate diagnosis among the vast array of symptoms, von Economo classified acute encephalitis lethargica into three forms: somnolent-ophthalmoplegic, hyperkinetic, and amyostatic-akinetic; although many other types were described during the epidemic period. The somnolent-ophthalmoplegic form was the most common and typically developed soon after onset of prodromal symptoms. Patients became dazed, confused, and delirious, and often exhibited features of mild meningeal irritation. Cranial nerve palsies were also a common feature, particularly affecting nerves III, IV and VI, resulting in ophthalmoplegia and pupillary abnormalities. Most notably, patients experienced an overwhelming desire to sleep and would sleep for abnormally long periods of time, but were easily awakened and often aware of everything that had transpired around them while in this state of pseudosomnolence. The mortality rate for the somnolent-ophthalmoplegic form was higher than that of other forms of encephalitis lethargica, exceeding 50%; however, a greater number of survivors experienced few or no long-term sequelae than in the other forms. The hyperkinetic form presented with an initial manic phase during which the patient experienced chorea, vocalizations, myoclonic twitches, and myorhythmia of the ocular and masticatory muscles. (Oculomasticatory myorhythmia is also indicative of Whipple’s disease, but it is not known whether the movement disorder seen in the hyperkinetic form of encephalitis lethargica is the same or different from that seen in Whipple’s disease). The manic phase was followed by generalized restlessness, weakness, and fatigue that persisted for days. During this hypomanic phase, patients experienced neuralgic pain in the face and limbs, visual and tactile hallucinations, and day-night sleep cycle reversal. The amyostatic-akinetic form was the least common form of acute encephalitis lethargica proposed by von Economo. With this form, patients experienced rigidity and lack of movement with no noticeable weakness. Patients were very slow to alter their posture, and any such movements were minimal. Patients often exhibited flexibilitas cerea, or waxy flexibility. In this state, patients remained rigid and immobile for long periods of time, but the rigidity could be overcome with slight external force. Patients with the amyostatic-akinetic form remained mentally intact, but emotions were hardly noticeable on masked faces. Recovery could be slow or rapid, with the condition sometimes lasting several months. The chronic phase of encephalitis lethargica typically developed 1 to 5 years after the acute phase, but it could also follow immediately, or more than a decade later. One patient developed a postencephalitic syndrome 45 years after initial infection (Sacks, 1990). The chronic phase was characterized by parkinsonism, but sleep disturbances, oculomotor abnormalities, involuntary movements, speech and respiratory abnormalities, and psychiatric disorders were also common features. In the decades following the epidemic, it was estimated that as many as 50% of parkinsonism cases were postencephalitic (Krusz et al., 1987). Postencephalitic parkinsonism typically presented with stiffness and bradykinesia that affected the upper limbs more than the lower limbs. Unlike idiopathic Parkinson’s disease, patients who suffered from postencephalitic parkinsonism frequently displayed kinesia paradoxical—a condition in which the patient was akinetic one moment, and perfectly mobile the next. Movement was typically triggered by some external stimulus, such as a ball being thrown. Chronic encephalitis lethargica was also associated with other movement disorders including chorea, torsion spasms, myoclonus, and tics affecting the jaw, lips, tongue, and palate. Oculogyric crisis was a common feature of chronic encephalitis lethargica, occurring in 15–20% of patients at the height of the epidemic, and ∼30% of postencephalitic patients in the following decades (Sacks, 1990). Oculogyric crisis is an involuntary upward deviation of the eyes that persists seconds to hours. Consciousness remained intact during the crisis, but the patient was unable to voluntarily move his eyes, except with great effort and only momentarily. The frequency of oculogyric crises varied from patient to patient, and could sometimes be precipitated by emotions. Chronic encephalitis lethargica was also associated with psychiatric manifestations, which included changes in mood, feelings of euphoria, increased sexual drive, hallucinations, and excessive puns, joviality, and silliness. Psychosis was present in 30% of patients, but milder psychiatric disorders were very common. Mental changes appeared to be more pronounced in children than in adults, with reports of self-mutilation, including one extreme case involving an 8-year-old girl who extracted all of her teeth and self-enucleated both of her eyes. One of the authors (J.A.V.) has questioned the direct relationship between the acute and chronic phases of encephalitis lethargica owing partly to the long delay—decades, in some cases—between the acute infection and the development of postencephalitic parkinsonism. There are also reports of regional epidemics that were not followed by postencephalitic parkinsonism. Furthermore, many postencephalitic patients could not recall having had an acute case of encephalitis lethargica in the past. In fact, more patients recalled having had influenza than encephalitis lethargica. Therefore perhaps acute encephalitis lethargica is not a necessary prerequisite to developing postencephalitic parkinsonism, but merely a contributing factor. Gross examination of brains from patients who died of acute encephalitis lethargica showed hyperaemic meninges, a soft, oedematous brain, and reddish discolouration of the brainstem. Von Economo noted that the upper midbrain and substantia nigra showed the most evident changes, followed by the basal ganglia, pons, medulla, and thalamus, which he believed conformed well with the clinical features of the illness. He also noted lymphocytic infiltration of the adventitia of the blood vessels (especially small and medium-sized veins), and widespread, diffuse haemorrhagic and inflammatory lesions, suggestive of an acute infectious process. At the time of the encephalitis lethargica epidemic, narcolepsy was a recognized illness, and von Economo described a narcolepsy-like disorder associated with encephalitis lethargica. In the brains of patients who succumbed to the somnolent-ophthalmoplegic type of encephalitis lethargica, von Economo observed pathological involvement of the posterior hypothalamus. Given the similarities in symptoms, recent research on narcolepsy could shed light on the hypersomnolence observed in many encephalitis lethargica patients. The most common form of narcolepsy involves a deficiency in hypocretin (orexin), a neuropeptide that promotes wakefulness. The deficiency has been found to result from autoimmune destruction of hypocretin-secreting cells in the hypothalamus. In the chronic phase of encephalitis lethargica, the brain showed modest degrees of focused or generalized atrophy. Microscopic examination showed evidence of both old and new inflammation, suggestive of persistent infection. Neuropathology of postencephalitic parkinsonism shows marked neuronal loss and gliosis throughout the brainstem, but particularly in the substantia nigra and, to a lesser extent, locus coeruleus. It is not known whether there are pathological differences in the brains of postencephalitic patients with and without a preceding history of acute encephalitis lethargica. Neurofibrillary tangles (NFTs), which were first identified in 1907 by Alois Alzheimer in the brain of a demented patient, were discovered in 1932 in the brainstem of a postencephalitic patient who showed no signs of dementia. Subsequent studies of postencephalitic parkinsonism found NFTs in various other regions of the brain including the substantia nigra, locus ceruleus, pons, hypothalamus, subthalamic nucleus, red nucleus, globus pallidus, corpus striatum, and hippocampus. Neurofibrillary tangles are found in a variety of neurodegenerative disorders, and the use of NFTs as a means to distinguish between various degenerative neurological diseases has been a recurrent topic of interest. For example, postencephalitic parkinsonism and progressive supranuclear palsy are nearly identical histopathologically; however, the NFTs present in postencephalitic parkinsonism are composed of both 3R and 4R tau isoforms, similar to those seen in Alzheimer’s disease, whereas the NFTs present in progressive supranuclear palsy are almost exclusively 4R tau isoforms. The significance of the NFTs and the differences in their compositions remain to be determined. The number of people worldwide who contracted encephalitis lethargica during the epidemic period is unknown, although the highest estimate puts the figure at more than one million (Ravenholt and Foege, 1982). Early in the epidemic, encephalitis lethargica was not a notifiable illness in all countries, therefore many cases went unreported. The most ambitious survey of encephalitis lethargica was conducted by the Matheson Commission for the Study of Epidemic Encephalitis (in New York). William Matheson was a wealthy businessman who was diagnosed with encephalitis lethargica during the epidemic period, and in 1927 established the Matheson Commission to study the disease. He believed the commission would find a cure for encephalitis lethargica within 2 years. Instead, the commission was defunded in 1940 with no cure in sight. The Matheson Commission’s first survey, published in 1929, reported 52 781 cases of encephalitis lethargica between 1919 and 1928. However, the survey only included data from 14 countries where encephalitis lethargica was a reportable illness. And even then, it only included cases that had been formally diagnosed. It has been estimated that 50–75% of cases went unreported, putting the true figure far above that suggested in the Matheson report. Whereas many cases of encephalitis lethargica likely went unreported, it is equally probable that encephalitis lethargica was over-diagnosed during the epidemic period based on the wide array of non-specific signs and lack of established diagnostic criteria. Because there was no pathognomonic sign or symptom, or diagnostic test, encephalitis lethargica was diagnosed based on the exclusion of other conditions. It seems reasonable that encephalitis lethargica was a heterogeneous group of conditions, rather than a unitary entity, that presented with unexplained neurological symptoms. Post-mortem examinations of alleged encephalitis lethargica cases during the epidemic period sometimes revealed an alternate diagnosis such as tubercular meningitis, cerebral tumours, meningismus, or other neurological pathology. However, due to the variability in neuropathology, even a post-mortem diagnosis of encephalitis lethargica could not be verified. Although encephalitis lethargica affected all ages, individuals between ages 10 and 45 were most susceptible with 50% of cases occurring between the ages of 10 and 30. There was no overall sex predilection, although specific outbreaks had higher incidences in one sex or the other. Some reports also suggested a higher prevalence of encephalitis lethargica among Jews and among ‘natives’ in South Africa, India, and the Philippines. There were higher incidences of encephalitis lethargica in large cities and industrial centres than in rural areas; however, this may have been due to these areas having larger populations and better diagnostic facilities than the rural areas. After 100 years of research, the aetiology of encephalitis lethargica is still unknown. Although a number of theories have been proposed, there are two main categories of plausible aetiologies: environmental (toxicological) and infectious (viral, bacterial, etc.). More recently, however, there is evidence to support a third theory: auto-immunity. It is also that encephalitis lethargica has multiple which could the wide array of that have been the years. with his first cases of encephalitis lethargica in 1917, von Economo on the of the disease. He any such as patients exhibited no Furthermore, there was often only a case within a and some were exclusively He also and as causes of the disease. that all of the patients had presented with an and the influenza epidemic, von Economo considered the that encephalitis lethargica was an influenza there have been of or encephalitis associated with influenza Although there were differences in the brains of patients who died of encephalitis lethargica with those who died of influenza von Economo could not that there to be an between influenza and encephalitis lethargica. on studies brain from patients, von Economo that encephalitis lethargica was by an infectious and other at the time, proposed that influenza a to infection with encephalitis lethargica, by the of the the to more In the years since the epidemic, studies have both and the influenza studies have examined the between influenza and encephalitis lethargica which influenza present in the of postencephalitic which for influenza in brain and which to for influenza in brain Although the in the of studies the influenza this aetiology would a for the of encephalitis lethargica the influenza that the influenza epidemic During the epidemic period, a was to the of encephalitis lethargica. and from encephalitis lethargica were into various in to an of the disease. Most were and no recognized of could be in a with in of the that had been that encephalitis lethargica was most likely by an had been by the Matheson Commission to direct clinical on encephalitis lethargica. Most of the Matheson Commission’s research to a for encephalitis lethargica, and was by two main that encephalitis lethargica was a form of or that it was a infection resulting from a form of In could be considered the of the Matheson described some from the studies although the of evidence at the time was this early proposed by et is that encephalitis lethargica could be a autoimmune with an aetiology similar to that of The authors suggested that encephalitis lethargica may be to basal and may be a autoimmune neuropsychiatric disorder associated with infection disease. The is and for several a third of patients showed no evidence of previous and two of his patients were at symptom which the Furthermore, is not a recognized diagnosis in the of and or the and of Mental and encephalitis lethargica was considered to be a disease. and in a later et al., to the and proposed that encephalitis lethargica, the hyperkinetic form, was an autoimmune disorder by encephalitis is an autoimmune encephalitis that is commonly associated with in It has a to encephalitis lethargica in and often with an narcolepsy has been found to result from in Furthermore, several countries reported an in cases of narcolepsy following influenza or infection with influenza during the influenza which could the between influenza and encephalitis lethargica following World War of these to an as a of disorders, and to the autoimmune In the most recent study on the aetiology of encephalitis lethargica, et to an to as the of encephalitis lethargica, based on and from cases of epidemic encephalitis lethargica, two encephalitis lethargica and one case of postencephalitic parkinsonism. was a conducted study has not been of the on encephalitis lethargica research on the aetiology of encephalitis lethargica is by the and of from the epidemic period and the of new encephalitis lethargica epidemic, may the of this disease. However, research on similar disorders such as narcolepsy and encephalitis could to shed light on this a true of causes encephalitis lethargica, it is also to it is There are often theories the disease was Some cases from the epidemic period evidence that encephalitis lethargica was but these cases to be the rather than the One of the most was the of encephalitis lethargica at the and and in Within a period of 2 12 of and in the were affected and died within 10 days of of the was conducted by Dr a in who that the disease had been from to the cases at the and many that encephalitis lethargica is there are as many reports to such a as in the case of a with children in a small One was with encephalitis lethargica for while the of the remained Further, among cases in Vienna, cases in and cases in there was to no evidence of direct of encephalitis lethargica from to there may have been multiple of encephalitis lethargica, with some being and It is also that encephalitis lethargica was spread by who had some type of that The Matheson about for encephalitis lethargica that were during the epidemic however, none of these were particularly for treating acute encephalitis lethargica. of patients died during the acute phase of the illness, survived without and showed neurological there were few for parkinsonism during the epidemic period or in the decades to the of in the the most for parkinsonism were In the to the of his described the of his postencephalitic patients to the new as that into after had been and as the period of from was and within several months most of the patients to such as chorea, and More recently, however, a postencephalitic patient who had to was with brain of the subthalamic and 1940 there have been published reports of encephalitis lethargica however, the of these diagnoses is by the variability in diagnostic criteria. the epidemic period, most encephalitis lethargica diagnoses were based on von Economo’s criteria. In and proposed new diagnostic that have been to more recent and description included oculogyric which were not known to be associated with acute encephalitis lethargica during the it was more commonly associated with postencephalitic parkinsonism than with acute encephalitis lethargica. and also described and akinetic as occurring in acute encephalitis lethargica, but there is no evidence that was of encephalitis lethargica during the epidemic, and akinetic was only associated with the amyostatic-akinetic form described by von Economo. One of the authors (J.A.V.) proposed that any diagnosis of encephalitis lethargica be to patients signs and symptoms be to any known neurological disease, and who the following prodromal and psychiatric changes et al., reports of cases of encephalitis lethargica that were published between and that only 14 reports to these although it is to be that any patient diagnosed with encephalitis lethargica has the same syndrome that during the The of Dr was in The the that were postencephalitic patients in a home in New with and and all with some of the of encephalitis lethargica following the epidemic period. the disease, it is to to it or it Encephalitis lethargica was characterized in a as the of the 20th century, and that to this was this