Back to the future: encephalitis lethargica as an autoimmune disorder?

More than 100 years after its emergence, the exact pathophysiological mechanisms underlying encephalitis lethargica (EL) are still elusive and awaiting convincing and complete elucidation. This article summarizes arguments proposed over time to support or refute the hypothesis of EL as an autoimmune neuropsychiatric disorder triggered by an infectious process. It also provides a critical evaluation of modern cases labeled as EL and a comprehensive differential diagnosis of autoimmune neurological conditions that could mimic EL. The evidence supporting the autoimmune nature of historical EL is sparse and not entirely convincing. It is possible that autoimmune mechanisms were involved in the pathogenesis of this disease as an idiosyncratic response to a yet unidentified infectious agent in genetically predisposed individuals. Although there has been an increase in the incidence of presumed autoimmune encephalomyelitis since the peak of EL pandemics, most evidence does not support an underlying autoimmune mechanism. There are significant differences between historical and recent EL cases in terms of clinical symptomatology, epidemiology, and neuropathological features, suggesting that they are different entities with only superficial similarity. The term "encephalitis lethargica," still frequently used in the medical literature, should not be used for cases occurring at present in the sporadic form. Historical EL should be kept apart from recent EL, as they differ in important aspects.

Encephalitis lethargica. What is still wrong?

Encephalitis lethargica developed in epidemic from 1919 to 1926 in Europe and throughout the world. From the clinical point of view, the disturbances of consciousness and alertness and the possible outcomes of a postencephalitic Parkinsonism has attracted much attention. For a long time, it was thought that such a disease may still occur sporadically. In this review, the authors examined historical and current pictures of epidemics that may be related to Encephalitis lethargica. The previous Nona and Russian Influenza exhibited frequent neurological symptoms. The Spanish flu, formerly related to Encephalitis lethargica, would appear an epidemic that had its development in a partially overlapping period. The current pandemic linked to COVID-19 sometimes has aspects that can resemble Encephalitis lethargica. Based on historical analysis and the more recent immunological data, it could be suggested that Encephalitis lethargica was an autoimmune encephalitis that arose in a secondary form to the action of a viral agent. It cannot be ruled out that this agent was a coronavirus. From the nosological point of view, the term Encephalitis lethargica should be abolished in designating autoimmune encephalitis pictures that run sporadically.

Arnold Netter Netter (1855-1936) and infectious pathology of the nervous system.

Arnold Netter (1855-1936) was a paediatrician who clinically applied the progress that his Pasteurian contemporaries had made possible through their bacteriological discoveries. From a neurological point of view, he brought looking for Kernig's sign into mainstream use to confirm the clinical diagnosis of meningitis and made diagnostic lumbar puncture systematic. He was one of the first to cure meningococcal and pneumococcal meningitis, long before the era of antibiotics, using subtractive lumbar puncture and intraspinal serotherapy. Netter's attentive vigilance enabled him to recognise, from its onset, the first poliomyelitis epidemic of the 20th century which took place in the summer of 1909. He described the clinical and epidemiological characteristics, identifying the viral rather than microbial origin. Netter detected the first cases of encephalitis lethargica in Paris in 1918. The disease had been described by Constantin von Economo (1876-1931) in Vienna the previous year. Netter spent fifteen years studying this new disease, which caused a pandemic a century ago. He filled in the clinical picture and used his understanding of cerebrospinal fluid and pathological anatomy to enhance knowledge and improve treatment of this neurological pathology.

A history of oculogyric crises during the encephalitis lethargica pandemic.

A pandemic of what came to be known as encephalitis lethargica spread starting in the winter of 1916-1917 and continued into the 1930s. Neurological after-effects, namely permanent parkinsonian syndromes and various abnormal movements, permanently disabled the survivors of the one or two million victims, often children or young adults. Among them, a small proportion developed a symptom that was little known up to that point and that is currently exceptional: oculogyric crises; that is, a lateralised, dystonic upward movement of the eyes known as a tonic eye fit. This paper proposes a history of the recognition of this symptom, its inclusion in the neurological nosography, and the pathophysiological hypotheses postulated a century ago.

The first psychiatric pandemic: Encephalitis lethargica, 1917-27.

Finding a link between COVID-19 and subsequent psychiatric symptoms has resulted in renewed interest in the psychiatric sequelae of pandemics. The first such instance was apparently the encephalitis lethargica pandemic which arose around the time of the First World War, moving in the shadow of a repiratory virus pandemic. The epidemic of encephalitis lethargica (EL), or Von Economo's Disease, in the years 1917-27 was the first pandemic involving the central nervous system. It moved in some places in parallel with the Great Flu Pandemic but does not seem to have been caused by it. Unlike the coronavirus, pandemic EL affected children heavily, leading often to bizarre changes in character and personality. It often left sequelae lasting for decades in the form of postencephalitic Parkinsonism (PEP). Unlike the coronavirus, it had a high mortality of around 20 percent. Although encephalitis lethargica involved a number of systems, psychiatric morbidity was most prominent and entailed severe depression, mania, catatonia and psychosis. It ended without therapeutic or public-health measures; today, sporadic cases of EL continue to be reported. The hypothesis is that we can derive from the EL psychiatric pandemic certain lessons that might be useful in studying tardive COVID symptoms today.

La Von Economo's encephalitis lethargica and the Spanish flu pandemic in Bogotá and Medellín (Colombia): An historic review one hundred years after / La encefalitis letárgica de von Economo y la pandemia de la gripe española en Bogotá y Medellín: reseña histórica cien años después.

Von Economo's encephalitis is a neuropsychiatric disorder of possible autoimmune origin, which affects basal ganglia. This reaction may occur secondary to infection by different viral or bacterial agents. Given that it appears after the acute episode has disappeared, molecular mimetism has been proposed to explain the autoimmune lesion. Several cases have been reported through time, but it was with the 1918 flu pandemic, known as the Spanish flu, that lethargic encephalitis reached epidemic levels with cases reported until 1923 in various countries. The Spanish flu pandemic appeared in Colombia at the end of 1918 in several cities but it affected especially Bogotá where the highest number of patients and deaths was reported. Our purpose with the present work was to commemorate the arrival of the Spanish flu to our country after one hundred years, as well as to reflect on its main complications, which included some lethargic encepahilitis cases.

La encefalitis letárgica de von Economo es un trastorno neuropsiquiátrico de posible origen autoinmunitario, en el cual se afectan los ganglios basales. Esta reacción puede ocurrir luego de una infección aguda por diversos agentes virales o bacterianos. Dado que aparece cuando ya se ha resuelto el cuadro agudo, se ha propuesto el mecanismo del mimetismo molecular para explicar la lesión autoinmunitaria. Se han reportado diversos casos a lo largo del tiempo, pero fue con la pandemia de influenza de 1918, conocida como la gripe española, que la encefalitis letárgica alcanzó niveles de epidemia, con casos reportados hasta 1923 en diversos países. La pandemia de la gripe española se extendió a Colombia durante los últimos meses de 1918 y afectó varias ciudades, principalmente Bogotá, donde se reportó el mayor número de enfermos y muertos. Con este trabajo se busca rememorar, cien años después, el ingreso de la gripe española a nuestro país y sus principales complicaciones, entre las que se describieron algunos casos de encefalitis letárgica.

[Encephalitis lethargica. The epidemic at the dawn of neurology]. / Encefalitis letargica. La epidemia en los albores de la neurologia.

Lethargic encephalitis is a neurological illness that shows a wide range of symptoms and signs, including neurological and psychiatric spectrum. It presented in an epidemic way, following influaenza relapses. The last relapse started at the beginning of 20th century and it was deeply described by Constantin von Economo. The illness described first in Europe and North America, was described in many others countries including Chile. There were beautiful descriptions by Chilean physicians like Lea-Plaza, Tello, Iturra and Cienfuegos. Their works showed the complexity of the illness like European physicians did too. The etiology is still unknown; however growing evidence about autoinmune aetiology is gaining force with the use of actual medical technology. In this work, we show encephalitis lethargica, focusing in clinical picture, the beauty of medical descriptions that physicians did at this date.

TITLE: Encefalitis letargica. La epidemia en los albores de la neurologia.La encefalitis letargica es un cuadro neurologico con una variada gama de manifestaciones clinicas en el ambito neurologico y tambien en el psiquiatrico. El cuadro se ha presentado de manera epidemica en brotes que han seguido a los de la gripe. El ultimo brote acaecido a comienzos del siglo XX lo describio en profundidad Constantin von Economo. La epidemia notificada inicialmente en Europa y luego en Norteamerica se presento tambien en otras latitudes, incluyendo Chile. Asi, las descripciones de Lea-Plaza, Tello, Iturra, Cienfuegos y otros medicos chilenos dieron cuenta del cuadro en Chile con toda la complejidad que tambien tuvo en Europa. El origen sigue siendo un misterio, aunque la evidencia creciente de que fuera autoinmune gana fuerza con los hallazgos de la tecnologia medica actual. En este trabajo presentamos el cuadro, privilegiando la riqueza clinica y la belleza de las descripciones realizada por los medicos de la epoca en que esta enfermedad se presento.

Review: neuropathology of acute phase encephalitis lethargica: a review of cases from the epidemic period.

INTRODUCTION: Encephalitis lethargica (EL), an epidemic disease of the early 20th century, has continued to be diagnosed sporadically since that time, including a report of 20 new cases in 2004. Many of the recent case reports state that the primary neuropathology of acute EL consists of inflammatory changes and lesions within the midbrain, basal ganglia and substantia nigra. However, the neuropathology of acute EL cases from the epidemic period was actually much more widespread. METHODS: In order to characterize the neuropathology of acute phase EL, we developed a database of EL pathology based on 112 cases from the years 1915 to 1940, of which most died within 2 weeks of EL onset. RESULTS: Our analysis revealed that cortical damage was prevalent in 75% of the 112 cases; damage to the meninges and brainstem occurred in approximately half of the cases; and the substantia nigra was damaged in only 13% of these acute cases. We also found that after 1921, damage to cranial nerve nuclei was not reported. An analysis of the neuropathology and clinical symptoms revealed little correlation. CONCLUSIONS: Based on these findings, putative modern cases of acute EL with MRI/CT indicated lesions confined solely to the midbrain, brainstem, and/or basal ganglia should not be considered, consistent with that reported during epidemic period.

Encephalitis lethargica and influenza. I. The role of the influenza virus in the influenza pandemic of 1918/1919.

An investigation of the characteristics of influenza epidemics in the nineteenth and early twentieth centuries was undertaken, principally in order to analyze the role of the 1918/1919 influenza pandemic in the etiology of encephalitis lethargica. Expectations regarding a future influenza pandemic derive principally from experiences in the 1918 epidemic. It is proposed that this pandemic was atypical with respect to many of its features, and that these have not been appropriately regarded in mapping expectations and responses of a future pandemic. Both a longer historical viewpoint (incorporating knowledge from all major nineteenth and twentieth century epidemics) and closer examination of individual epidemics at the town level is essential for producing an accurate picture of the challenge.

Encephalitis lethargica in the Soviet Union.

Although encephalitis lethargica (EL) appeared in epidemic form in the Soviet Union during the 1920s as it did in most of the world, the Western literature, particularly English, contains little information about the manifestations of the disease there. Here we summarize articles by prominent Russian neurologists who wrote about the disease as they viewed it during the epidemic period. As in the West, Russian clinicians found EL to be remarkably polymorphic, although some signs and symptoms, especially those pertaining to the psychological aspects of the disease, seemed to be more prevalent or were described better and perhaps more frequently by these clinicians. Some Russian clinicians emphasized an increased prevalence of EL among Jews and a relationship with illness and trauma, whereas others found strong evidence for contagion, especially in rural areas.

The relationship between encephalitis lethargica and influenza: a critical analysis.

Since encephalitis lethargica's (EL) prevalence in the 1920s, epidemiologic and clinical debate has persisted over whether EL was caused by, potentiated by, or merely coincident with the Spanish influenza pandemic. Epidemiologic analyses generally suggest that the disorders were coincidental. Beginning in the 1970s, modern experiments on archival brain samples mainly failed to confirm a direct relationship between influenza and EL. These experimental studies have technical limitations, e.g., the appropriateness of antibodies, polymerase chain reaction (PCR) primers and controls, and the extreme paucity and age of available material. These factors render the case against influenza less decisive than currently perceived. Nevertheless, there is little direct evidence supporting influenza in the etiology of EL. Almost 100 years after the EL epidemic, its etiology remains enigmatic, raising the possibility of a recurrence of EL in a future influenza pandemic.

Síndromes postencefalíticos en la literatura médica española / Post-encephalitic syndromes in the spanish medical literature

Objetivo. Un gran número de pacientes de encefalitis letárgica desarrollaba diferentes síndromes postencefalíticos (SPE), de importante impacto medicosocial. Hemos estudiado los aspectos clínicos e históricos de los SPE en España, mediante una revisión de la literatura médica publicada en este país en el período 1918-1936. Desarrollo. No existen datos estadísticos sobre los SPE en España, aunque médicos españoles llamaron la atención sobre su alta prevalencia y su repercusión sociosanitaria. La mayoría de los 140 pacientes revisados (74%) presentaron parkinsonismo predominante, pero en casi todos se apreciaba algún rasgo parkinsoniano. Se describieron otros trastornos del movimiento (distonías focales, corea, mioclonías, crisis oculógiras, anomalías del ritmo respiratorio), así como trastornos del sueño, endocrinos y vegetativos. A menudo se comunicaron alteraciones psiquiátricas: la más frecuente era la bradifrenia asociada a parkinsonismo, pero fue muy característico un cuadro hipomaníaco con conducta impulsiva en jóvenes. El diagnóstico del SPE se realizó una media de dos años después del episodio de encefalitis letárgica aguda, aunque con frecuencia apareció inmediatamente después. En muchos trabajos se discute sobre la contribución de los SPE al desarrollo del conocimiento de la fisiopatología de las enfermedades extrapiramidales y sobre la implicación de los ganglios basales en los trastornos psiquiátricos y de conducta. Conclusiones. En ausencia de datos estadísticos, los autores españoles reflejaron la importante repercusión sociosanitaria de los SPE, así como su papel en el conocimiento de la fisiopatología de los ganglios basales. Predominaron los parkinsonismos, aunque se describieron todo tipo de manifestaciones postencefalíticas

Aim. A large number of patients with encephalitis lethargica developed different post-encephalitic syndromes (PES), which have an important medical and social impact. We studied the clinical and historical aspects of PES in Spain by reviewing the medical literature published in this country between 1918 and 1936. Development. There are no statistical data concerning PES in Spain, although Spanish physicians drew attention to their high rate of prevalence and their repercussions on community health. Most of the 140 patients that were reviewed (74%) presented predominant Parkinsonism, but some features of Parkinsonism were observed in nearly all cases. Other movement disorders (focal dystonias, chorea, myoclonus, oculogyric crises, abnormalities affecting breathing rate) were described, as well as sleep, endocrine and vegetative disorders. Psychiatric disorders were often reported, the most frequent being bradyphrenia associated to Parkinsonism, but a hypomanic picture with impulsive behaviour was very characteristic among young people. PES was diagnosed on average two years after the episode of acute encephalitis lethargica, although it often appeared immediately afterwards. Many studies discuss the contribution made by PES to further our knowledge of the pathophysiology of extrapyramidal diseases and about the involvement of the basal ganglia in psychiatric and behavioural disorders. Conclusions. Despite the absence of statistical data, Spanish authors highlighted the important repercussions the PES had on community health, as well as the role they played in extending our knowledge of the pathophysiology of the basal ganglia. Cases of Parkinsonism were predominant, although all kinds of post-encephalitic manifestations were reported

Avian influenza and the brain--comments on the occasion of resurrection of the Spanish flu virus.

Recent incidences of direct passage of highly pathogenic avian influenza A virus strains of the H5N1 and H7N7 subtypes from birds to man have become a major public concern. Although presence of virus in the human brain has not yet been reported in deceased patients, these avian influenza subtypes have the propensity to invade the brain along cranial nerves to target brainstem and diencephalic nuclei following intranasal instillation in mice and ferrets. The associations between influenza and psychiatric disturbances in past epidemics are here commented upon, and the potentials of influenza to cause nervous system dysfunction in experimental infections with a mouse-neuroadapted WSN/33 strain of the virus are reviewed. This virus strain is closely related to the Spanish flu virus, which is characterized as a uniquely high-virulence strain of the H1N1 subtype. The Spanish flu virus has recently been reconstructed in the laboratory and it passed once, most likely, directly from birds to humans to cause the severe 1918-1919 pandemic.

Neuropsychiatric interpretations of postencephalitic movement disorders.

This study reviews the impact of encephalitis lethargica (EL) on concepts of behaviour and movement during the 1920s and 1930s. Clinicopathological correlations were imprecise but supported the role of subcortical structures in complex patterns of motor behaviour. This possibility challenged the widely assumed hegemony of the cerebral cortex. There was a perceived link between involuntary movements and reduced impulse control and also between parkinsonism and a defect in volition. Contemporary observers interpreted postencephalitic phenomena such as oculogyria in psychodynamic as well as in neurophysiological terms. EL also gave some support to the idea that neuroses such as obsessional neurosis and hysteria might have an organic basis. These speculations recently have acquired more credibility. The large amount of literature on EL and its sequelae could perhaps make further contributions to understanding the pathology of voluntary movement and action.