A role for pathogen risk factors and autoimmunity in encephalitis lethargica?

The encephalitis lethargica (EL) epidemic swept the world from 1916 to 1926 and is estimated to have afflicted between 80,000 to one million people. EL is an unusual neurological illness that causes profound sleep disorders, devastating neurological sequalae and, in many cases, death. Though uncommon, EL is still occasionally diagnosed today when a patient presents with an acute or subacute encephalitic illness, where all other known causes of encephalitis have been excluded and criteria for EL are met. However, it is impossible to know whether recent cases of EL-like syndromes result from the same disease that caused the epidemic. After more than 100 years of research into potential pathogen triggers and the role of autoimmune processes, the aetiology of EL remains unknown. The epidemic approximately coincided with the 1918 H1N1 influenza pandemic but the evidence of a causal link is inconclusive. This article reviews the literature on the causes of EL with a focus on autoimmune mechanisms. In light of the current pandemic, we also consider the parallels between the EL epidemic and neurological manifestations of COVID-19. Understanding how pathogens and autoimmune processes can affect the brain may well help us understand the conundrum of EL and, more importantly, will guide the treatment of patients with suspected COVID-19-related neurological disease, as well as prepare us for any future epidemic of a neurological illness.

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.

Encefalitis letárgica. La epidemia en los albores de la neurología / Encephalitis lethargica. The epidemic at the dawn of neurology

La encefalitis letárgica es un cuadro neurológico con una variada gama de manifestaciones clínicas en el ámbito neurológico y también en el psiquiátrico. El cuadro se ha presentado de manera epidémica en brotes que han seguido a los de la gripe. El último brote acaecido a comienzos del siglo XX lo describió en profundidad Constantin von Economo. La epidemia notificada inicialmente en Europa y luego en Norteamérica se presentó también en otras latitudes, incluyendo Chile. Así, las descripciones de Lea-Plaza, Tello, Iturra, Cienfuegos y otros médicos chilenos dieron cuenta del cuadro en Chile con toda la complejidad que también tuvo en Europa. El origen sigue siendo un misterio, aunque la evidencia creciente de que fuera autoinmune gana fuerza con los hallazgos de la tecnología médica actual. En este trabajo presentamos el cuadro, privilegiando la riqueza clínica y la belleza de las descripciones realizada por los médicos de la época en que esta enfermedad se presentó

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

Adele Bloch-Bauer (1881-1925): Possible diagnoses for Gustav Klimt's Lady in Gold.

One of the most famous works by the Austrian symbolist painter Gustav Klimt and one of the most widely reproduced works of art worldwide, Adele Bloch-Bauer I which portrays the beautiful wife of Austrian magnate Ferdinand Bloch-Bauer. Adele was the only woman painted by Klimt on more than one occasion. Apart from the beauty and value of the painting, the daring sea of gold that surrounds Adele and the gentle intimacy with which her fragile figure is portrayed have shrouded the history of this painting in mystery. Beyond speculation as to a special bond between artist and model, observation of the painting with a keener, clinical gaze yields evidence of potential illness in the model: facial erythema which, if not produced artificially by makeup, could represent a malar rash; pallor or cyanosis of the hands; and her draped fingers, which seemingly attempt to hide a deformity. This paper seeks to provide a biographical review both of the painter, Gustav Klimt, and of the subject, Adele Bloch-Bauer; to analyse Klimt's two portrayals of her in a search for evidence of a potential intimate relationship between artist and muse and, finally, to compile clinical evidence of possible diagnoses for the Lady in Gold.

Binswanger: mais que um epônimo / Binswanger: more than an eponym

Otto Ludwig Binswanger (1852-1929) foi um médico suíço, psiquiatra e neurologista, oriundo de uma linhagem de psiquiatras. Além de ser talentoso, recebeu educação privilegiada de mestres excepcionais, lembrados até hoje. Como psiquiatra, foi muito dinâmico e inovador na reorganização e modernização da Clínica Psiquiátrica e Neurológica que dirigiu, em Jena, durante 37 anos. Escreveu livros importantes e numerosos artigos científicos, entre os quais A delimitação da paralisia geral progressiva, no qual descreveu a "Encefalite subcortical progressiva crônica". Alzheimer denominou a condição, em 1902, de "Encefalite subcortical progressiva crônica de Binswanger", mais tarde conhecida por "doença de Binswanger". Apesar de críticas, chegando mesmo a se argumentar que o epônimo poderia ser impróprio, concluiu-se por sua manutenção, conservada até os dias de hoje.

Otto Ludwig Binswanger (1852-1929) was a Swiss physician, psychiatrist and neurologist, who stemmed from an extraction of psychiatrists. Besides being talented, he received a privileged education by exceptional masters, remembered up to the present days. As a psychiatrist he was very dynamic and innovative in the reorganization and modernization of the Psychiatric and Neurologic Clinic he directed, in Jena, for 37 years. He wrote several important books and numerous scientific papers, among them The delimitation of the progressive general paralysis, where he described the "Chronic progressive subcortical encephalitis". Alzheimer was the one that designated the condition, in 1902, as "Chronic progressive subcortical encephalitis of Binswanger", later acknowledged as "Binswanger's disease". Despite the critics, even reaching to arguments that the eponym was a misnomer, it was concluded for its maintenance, retained up to the present days.

Infectious causes of encephalitis and meningoencephalitis in Thailand, 2003-2005.

Acute encephalitis is a severe neurologic syndrome. Determining etiology from among ≈100 possible agents is difficult. To identify infectious etiologies of encephalitis in Thailand, we conducted surveillance in 7 hospitals during July 2003-August 2005 and selected patients with acute onset of brain dysfunction with fever or hypothermia and with abnormalities seen on neuroimages or electroencephalograms or with cerebrospinal fluid pleocytosis. Blood and cerebrospinal fluid were tested for >30 pathogens. Among 149 case-patients, median age was 12 (range 0-83) years, 84 (56%) were male, and 15 (10%) died. Etiology was confirmed or probable for 54 (36%) and possible or unknown for 95 (64%). Among confirmed or probable etiologies, the leading pathogens were Japanese encephalitis virus, enteroviruses, and Orientia tsutsugamushi. No samples were positive for chikungunya, Nipah, or West Nile viruses; Bartonella henselae; or malaria parasites. Although a broad range of infectious agents was identified, the etiology of most cases remains unknown.

Encephalitis hospitalization rates and inpatient mortality in the United States, 2000-2010.

BACKGROUND: Encephalitis rates by etiology and acute-phase outcomes for encephalitis in the 21st century are largely unknown. We sought to evaluate cause-specific rates of encephalitis hospitalizations and predictors of inpatient mortality in the United States. METHODS: Using the Nationwide Inpatient Sample (NIS) from 2000 to 2010, a retrospective observational study of 238,567 patients (mean [SD] age, 44.8 [24.0] years) hospitalized within non-federal, acute care hospitals in the U.S. with a diagnosis of encephalitis was conducted. Hospitalization rates were calculated using population-level estimates of disease from the NIS and population estimates from the United States Census Bureau. Adjusted odds of mortality were calculated for patients included in the study. RESULTS: In the U.S. from 2000-2010, there were 7.3±0.2 encephalitis hospitalizations per 100,000 population (95% CI: 7.1-7.6). Encephalitis hospitalization rates were highest among females (7.6±0.2 per 100,000) and those <1 year and >65 years of age with rates of 13.5±0.9 and 14.1±0.4 per 100,000, respectively. Etiology was unknown for approximately 50% of cases. Among patients with identified etiology, viral causes were most common (48.2%), followed by Other Specified causes (32.5%), which included predominantly autoimmune conditions. The most common infectious agents were herpes simplex virus, toxoplasma, and West Nile virus. Comorbid HIV infection was present in 7.7% of hospitalizations. Average length of stay was 11.2 days with mortality of 5.6%. In regression analysis, patients with comorbid HIV/AIDS or cancer had increased odds of mortality (odds ratio [OR]  = 1.70; 95% CI: 1.30-2.22 and OR = 2.26; 95% CI: 1.88-2.71, respectively). Enteroviral, postinfectious, toxic, and Other Specified causes were associated with lower odds vs. herpes simplex encephalitis. CONCLUSIONS: While encephalitis and encephalitis-related mortality impose a considerable burden in the U.S. in the 21st Century, the reported demographics of hospitalized encephalitis patients may be changing.

Encephalitis caused by pathogens transmitted through organ transplants, United States, 2002-2013.

The cause of encephalitis among solid organ transplant recipients may be multifactorial; the disease can result from infectious or noninfectious etiologies. During 2002-2013, the US Centers for Disease Control and Prevention investigated several encephalitis clusters among transplant recipients. Cases were caused by infections from transplant-transmitted pathogens: West Nile virus, rabies virus, lymphocytic choriomeningitis virus, and Balamuthia mandrillaris amebae. In many of the clusters, identification of the cause was complicated by delayed diagnosis due to the rarity of the disease, geographic distance separating transplant recipients, and lack of prompt recognition and reporting systems. Establishment of surveillance systems to detect illness among organ recipients, including communication among transplant center physicians, organ procurement organizations, and public health authorities, may enable the rapid discovery and investigation of infectious encephalitis clusters. These transplant-transmitted pathogen clusters highlight the need for greater awareness among clinicians, pathologists, and public health workers, of emerging infectious agents causing encephalitis among organ recipients.

Insights into antibody-associated encephalitis--Bickerstaff's 1950's papers revisited.

Edwin Bickerstaff and Philip Cloake reported in the 1950's three cases of reversible encephalitis. The concept of antibody associated encephalitis had not been proposed at the time they astutely recognized the importance of disease pattern recognition and postulated a potential immune based mechanism. The syndrome defined by Bickerstaff of progressive, external ophthalmoplegia and ataxia, with disturbance of consciousness or hyperreflexia, has subsequently been associated with anti-GQ1b antibodies. Interestingly one of the three original cases, a young woman who developed seizures, an eye movement disorder and acute psychosis while awaiting ovarian cystectomy, has features that may be more consistent with anti-NMDA receptor encephalitis.

Bickerstaff brainstem encephalitis and Fisher syndrome: anti-GQ1b antibody syndrome.

In the 1950s, Bickerstaff and Fisher independently described cases with a unique presentation of ophthalmoplegia and ataxia. The neurological features were typically preceded by an antecedent infection and the majority of patients made a spontaneous recovery. In the cases with Bickerstaff brainstem encephalitis, there was associated altered consciousness and in some, hyperreflexia, in support of a central pathology whereas in Fisher syndrome, patients were areflexic in keeping with a peripheral aetiology. However, both authors recognised certain similarities to Guillain-Barré syndrome such as the presence of peripheral neuropathy and cerebrospinal fluid albuminocytological dissociation. The discovery of immunoglobulin G anti-GQ1b antibodies in patients with Fisher syndrome and later in Bickerstaff brainstem encephalitis was crucial in providing the necessary evidence to conclude that both conditions were in fact part of the same spectrum of disease by virtue of their common clinical and immunological profiles. Following this, other neurological presentations that share anti-GQ1b antibodies emerged in the literature. These include acute ophthalmoparesis and acute ataxic neuropathy, which represent the less extensive spectrum of the disease whereas pharyngeal-cervical-brachial weakness and Fisher syndrome overlap with Guillain-Barré syndrome represent the more extensive end of the spectrum. The conditions can be referred to as the 'anti-GQ1b antibody syndrome'. In this review, we look back at the historical descriptions and describe how our understanding of Fisher syndrome and Bickerstaff brainstem encephalitis has evolved from their initial descriptions more than half a century ago.

Encefalitis de Bickerstaff, síndrome oespectro de Fisher Bickerstaff, reporte de dos casos / Bickerstaff encephalitis/Fisher Bickerstaff syndrome, report of two cases

La encefalitis de Bickerstaff es una entidad infrecuente de origen posinfeccioso, de presentación grave y con un curso clínico generalmente benigno, cuya diferenciacióncon el síndrome de Fisher aún no es clara y su asociación con el síndrome de Guillain - Barré está ya establecida. Presentamos dos casos atendidos en el Hospital Universitario San Ignacio...

Bickerstaff encephalitis is a rare post-infectious origin disease, with an acute severe presentation form, but generally with a benign course, its differentiation from Fisher syndrome is unclear, and its association with Guillain - Barre syndrome is alreadyestablished. We report two cases treated at the Hospital Universitario San Ignacio...

On doing nothing: descriptions of sleep, fatigue, and motivation in encephalitis lethargica.

Epidemics of encephalitis lethargica (EL), from 1917 to the 1930s, are an important milestone in the history of movement disorders. Today, the two best-known features of EL are somnolence and parkinsonism but the full clinical picture was variable and complex. States of wakeful inactivity--as opposed to drowsiness--were often described both in the acute and postacute stages and were referred to in the EL literature as "lethargy" or "torpor." The study described here is based on a survey of clinical descriptions published in English, French, and German from 1917 to 1942. Its focus is on the history of clinical ideas, rather than applying modern pathophysiological concepts retrospectively. Descriptions of lethargy are explored as a way of elucidating concepts of sleep, fatigue, and motivation during the study period. The literature described many patients who had (1) lethargy without interruption in consciousness; (2) slowness of movement and catalepsy without other prominent parkinsonian features; and (3) apathy and lack of initiative without severe disorders of mood or thought content. Hence observers distinguished a state of wakeful inactivity from primary disorders of sleep, movement and behavior. Contemporaneous accounts suggest that writers had difficulty in reconciling their observations with preexisting concepts; there still may be limitations in our ability to describe and classify the clinical states connected during the epidemic era with the term "lethargy."

Linguistic history of posterior reversible encephalopathy syndrome: mirror of developing knowledge.

BACKGROUND: the term posterior reversible encephalopathy syndrome (PRES) was first proposed in 2000. Since then, the acronym PRES has become very popular in imaging and clinical literature as it is short, easy to say and remember, and neatly couples the frequent localization of neuroimaging findings along with the typical outcome of this syndrome. Another possible reason for the popularity of this acronym in clinical circles is the connotation of PRES with (elevated blood) PRESsure, as a majority of cases are believed to be associated with hypertension. However, problems exist with the interpretation and common understanding of PRES, questioning the appropriateness of "P" and "R" in the acronym. The linguistic issues related to the acronym of PRES are interesting. OBJECTIVES: the aim of this work is to analyze the controversies related to the acronym of PRES. RESULTS: in 2006, modifying the meaning of the acronym was suggested, renaming it Potentially Reversible Encephalopathy Syndrome in order to adjust to the cases when posterior involvement is not prominent and emphasize that the reversibility is not spontaneous. This meant the creation of a backronym, where the new phrase is constructed by starting with an existing acronym. CONCLUSION: this new backronym indicates that the original acronym of PRES has become a misnomer.