The Anti-NMDA Receptor Encephalitis Foundation Newsletter

On Tuesday October 6, we launch an exciting new Advocacy program: AE on the Hill  Our long-term goal for the ‘AE on the Hill’ program is bold, empowering the AE community to advocate for themselves and their families at the local, state, and federal levels to improve the lives of all those affected…

medRxiv – The Preprint Server for Health Sciences…

In search of lost time from “Demonic Possession” to anti-N-methyl-D-aspartate receptor encephalitis…

A 20-year-old female presented with fine motor deficits and visual field defect was
admitted to our hospital. CSF tests for autoimmune encephalitis antibodies and onconeuronal
antibodies were unremarkable.

Articles appearing in the March 2020 issue Clinical approach to the diagnosis of autoimmune encephalitis in the pediatric patient Objective Autoimmune encephalitis (AE) is an important and treatable cause of acute encephalitis. Diagnosis of AE in a developing child is challenging because of overlap in clinical presentations with other diseases and complexity of normal behavior changes. Existing diagnostic criteria for adult AE require modification to be applied to children, who differ from adults in their clinical presentations, paraclinical findings, autoantibody profiles, treatment response, and long-term outcomes. Methods A subcommittee of the Autoimmune Encephalitis International Working Group collaborated through conference calls and email correspondence to consider the pediatric-specific approach to AE. The subcommittee reviewed the literature of relevant AE studies and sought additional input from other expert clinicians and researchers. Results Existing consensus criteria for adult AE were refined for use in children. Provisional pediatric AE classification criteria and an algorithm to facilitate early diagnosis are proposed. There is also discussion about how to distinguish pediatric AE from conditions within the differential diagnosis. Conclusions Diagnosing AE is based on the combination of a clinical history consistent with pediatric AE and supportive diagnostic testing, which includes but is not dependent on antibody testing. The proposed criteria and algorithm require validation in prospective pediatric cohorts. NPub.org/N2/9512a Intrathecal B-cell activation in LGI1 antibody encephalitis Objective To study intrathecal B-cell activity in leucine-rich, glioma-inactivated 1 (LGI1) antibody encephalitis. In patients with LGI1 antibodies, the lack of CSF lymphocytosis or oligoclonal bands and serum-predominant LGI1 antibodies suggests a peripherally initiated immune response. However, it is unknown whether B cells within the CNS contribute to the ongoing pathogenesis of LGI1 antibody encephalitis. Methods Paired CSF and peripheral blood (PB) mononuclear cells were collected from 6 patients with LGI1 antibody encephalitis and 2 patients with other neurologic diseases. Deep B-cell immune repertoire sequencing was performed on immunoglobulin heavy chain transcripts from CSF B cells and sorted PB B-cell subsets. In addition, LGI1 antibody levels were determined in CSF and PB. Results Serum LGI1 antibody titers were on average 127-fold higher than CSF LGI1 antibody titers. Yet, deep B-cell repertoire analysis demonstrated a restricted CSF repertoire with frequent extensive clusters of clonally related B cells connected to mature PB B cells. These clusters showed intensive mutational activity of CSF B cells, providing strong evidence for an independent CNS-based antigen-driven response in patients with LGI1 antibody encephalitis but not in controls. Conclusions Our results demonstrate that intrathecal immunoglobulin repertoire expansion is a feature of LGI1 antibody encephalitis and suggests a need for CNS-penetrant therapies. NPub.org/N2/9512b Most-Read Articles As of July 21, 2020 Aquaporin-4 autoimmunity Zekeridou and V.A. Lennon. 2015;2:e110. doi.org/10.1212/NXI.0000000000000110 MOG cell-based assay detects non-MS patients with inflammatory neurologic disease Patrick Waters, Mark Woodhall, Kevin C. O’Connor, et al. 2015;2:e89. doi.org/10.1212/NXI.0000000000000089 Increased frequency of anti-Ma2 encephalitis associated with immune checkpoint inhibitors Alberto Vogrig, Marine Fouret, Bastien Joubert, et al. 2019;6:e604. doi.org/10.1212/NXI.0000000000000604 Next-generation sequencing in neuropathologic diagnosis of infections of the nervous system Steven L. Salzberg, Florian P. Breitwieser, Anupama Kumar, et al. 2016;3:e251. doi.org/10.1212/NXI.0000000000000251 Does time equal vision in the acute treatment of a cohort of AQP4 and MOG optic neuritis? Hadas Stiebel-Kalish, Mark Andrew Hellmann, Michael Mimouni, et al. 2019;6:e572. doi.org/10.1212/NXI.0000000000000572 © 2020 American Academy of Neurology

To examine EEG features in a retrospective 13-year cohort of children with encephalitis.354 EEGs from 119 patients during their admission were rated b……

Possible autoimmune encephalitis with claustrum sign in case of acute SARS-CoV-2 infection…

Abstract Objective Our aim was to identify patients with probable anti-NMDA receptor encephalitis among historical medical cases. Method A case report published in leading Hungarian-, German- and Italian-language medical journals in the early 1840s was revisited. Results In 1830, an 18-year-old, healthy woman suffered epileptic seizures, followed by a 6-day-long state characterized by catalepsy, unresponsiveness, motionless, and light breathing. Her symptoms regularly returned in the following 1.5 years. Meanwhile, a progressively growing huge abdominal tumor appeared. One day, she suddenly started vomiting a large amount of foul-smelling pus mixed with blood, accompanied by bone fragments. Pus mixed blood with some membranous substance was also evacuated through the anus and vagina. After this event, she completely recovered; 1.5 years later, she married and later gave birth to 3 healthy children. The patient remained healthy during the 11-year follow-up. Conclusions We suggest that in the description of a paraneoplastic case, an anti-NMDA receptor encephalitis can be dated back as far as to the 19th century, with an especially rare type of resolution: the disappearance of the symptoms after the spontaneous elimination of an ovarian teratoma. Anti-NMDA receptor encephalitis was discovered by Dalmau et al.1,2 in 2005/2007, although cases were probably described already in 1997.3,4 Moreover, because of revisiting published cases dating back as far as the 19th century, more and more cases are suggested to be of anti-NMDA receptor encephalitis etiology. Merwick et al.5 pointed out that from the case series published by Bickerstaff—in which Bickerstaff encephalitis was described—in one patient, the symptoms were indicative of anti-NMDA receptor encephalitis. In the late 1800s, ovariotomy (Battey’s operation) was introduced as a treatment of—among others—“histeroepilepsy.”6 In the course of the recent revisitation of these published cases, symptoms can also be attributed to anti-NMDA receptor encephalitis in more than one patient; this suggestion is also supported by the observation of Battey, namely that “cystic degeneration” was common in the resected ovaries.6 This is the most common autoimmune encephalitis, where 80% of patients are women with a median age of 21.7 Epileptic seizures occur in 76%,8 catatonia-like episodes in 70%,9 whereas hypoventilation in 66% of patients.8 In adult women patients, anti-NMDA receptor encephalitis is associated with ovarian teratoma in 58% of cases.7 Other tumors are rare: in paraneoplastic cases, 94% of the underlying tumor is ovarian teratoma.7 We found an interesting case report published in leading Hungarian-, German- and Italian-language medical journals referring to a presentation at the 3rd Meeting of the Italian Scientists in Florence held in 1841.10,–,12 We suggest that the description of an anti-NMDA receptor encephalitis can be dated back as far as to the 19th century. Case On September 17, 1841, the case was presented by Dr. Odoardo Linoli (figure).10,–,12 In 1830, an 18-year-old, hitherto healthy female patient suffered epileptic seizures, followed by a strange 6-day-long state characterized by a “catalepsy” pose and an unresponsive motionless state. The only sign of life was a very light breathing. Epileptic seizures and the catalepsy regularly returned in the following 1.5 years. Meanwhile, a progressively growing huge abdominal tumor appeared, which reached the level of the chest on the left side. One day, she suddenly started vomiting a large amount of coffee-colored liquid. Two weeks later, she vomited a foul-smelling pus mixed with blood. This was accompanied by more than 100 bone fragments. Some of these fragments were flat, others were long- or ball-shaped. Pus-mixed blood with some membranous substance was also evacuated through the anus and vagina. After this event, both epileptic seizures and “catalepsy” states disappeared, and she apparently became healthy again; 1.5 years later, she married and later gave birth to 3 healthy children. At the time of Dr. Linoli’s presentation (11 years after the disease onset), she was in excellent health. During the discussion, Dr. Linoli argued that the abdominal tumor was probably a “fetal cyst” or “fetus in fetu.” Prof. Carlo Burci—the chairman of the section—suggested that the tumor could have been a “skin cyst,” whereas others speculated that it could have been an extrauterine pregnancy. Figure Case presentation The title page of the Österreichische Medizinische Wochenschrift from 1843 (A) and the case presentation in German (B). Available at the Bayerische Staatsbibliothek München, H.misc. 33 t-16, S. 244, urn:nbn:de:bvb:12-bsb10737557-2. Discussion The medical language in the first half of the 19th century was certainly different from today. The reliability of the description is enhanced by the fact that the case has been described in 3 different languages in the 1840s.10,–,12 The case was presented by Odoardo Linoli (1801–1886), a well-known surgeon from Pietrasanta,13 and discussed by Carlo Burci,14 who was the professor of surgery at the University of Pisa, indicating that the case was observed and discussed by the most prestigious professionals of that time. We tried to interpret this case report according to today’s medical concepts. Although catatonia was not described as such until 1874, the described motionless and unresponsive state accompanied by catalepsy meet the criteria of a catatonia.15 Another issue is the type of the described huge abdominal tumor that contained bone fragments. According to Dr. Linoli’s interpretation, it was a “fetus in fetu.” Fetus in fetu is extremely rare in adulthood16 and should contain vertebral axis or limbs, otherwise it should classify as teratoma.17 Dr. Burci suggested that the tumor was a “skin cyst.” According to today’s nomenclature, dermoid cyst (i.e., skin-like cyst) is a synonym for teratoma. The presence of bone is not unusual in teratoma.18 Based on the presence of bone, a teratoma was diagnosed during a paleopathological examination of a female skeleton from the late Roman age.19 Ovarian teratomas without treatment can reach a huge size, some of them can be up to 30 cm in diameter.18 Not only the size, localization, and the presence of bone but also the strange elimination of the tumor through the gastrointestinal system and vagina may also support the concept of teratoma. Teratomas (dermoid cysts) can perforate into the adjacent organs including bowel and vagina.20,–,23 For example, Flood et al.22 reported a 23-year-old woman who discovered teeth-like structures in her underwear, which were the contents of an ovarian teratoma excreted in the vagina through a fistula. Mitui et al.23 reported a 72-year-old woman whose diarrhea, in which she found hair, was caused by an ovarian teratoma perforating into the bowels. Summarizing our interpretation, a young woman had newly onset seizures, followed by catatonia-like symptoms and hypoventilation. This was associated with an abdominal tumor, which was probably a teratoma. The symptoms disappeared after the spontaneous elimination of the tumor, and the patient remained healthy during the 11-year follow-up. According to a recent position study, new-onset seizures and altered mental status (unresponsive state) with subacute onset meet the criteria for “possible autoimmune encephalitis.”24 Epileptic seizures, altered mental status, abnormal posturing, and hypoventilation meet the symptoms criteria for “possible anti-NMDA receptor encephalitis.”24 The young age and female sex as well as the presence of ovarian teratoma also strengthen our assumption that Dr. Linoli’s case study might be the first description of anti-NMDA receptor encephalitis. In paraneoplastic anti-NMDA receptor encephalitis, the symptoms usually resolve after tumor removal, may that be either ovarian or extraovarian.7,25 Regarding Dr. Linoli’s patient, the symptoms were present when the tumor was present and disappeared after the tumor also disappeared. Thus, we state that the description of a paraneoplastic story can be dated back as far as to 1830, ahead of the description of Trousseau’s syndrome in 1865.26 Study funding Study funded by the Hungarian Brain Research Program (2017-1.2.1-NKP-2017-00002), NKFIH EFOP-3.6.2-16-2017-00008 government-based funds. Our research was partly financed by the Higher Education Institutional Excellence Program of the Ministry of Human Capacities in Hungary, within the framework of the 5th thematic program of the University of Pécs, Hungary (20765/3/2018/FEKUSTRAT). The study was furthermore supported by the University of Pécs Medical School. Disclosure None of the authors report anything to disclose. Go to Neurology.org/NN for full disclosures. Appendix Authors Footnotes Go to Neurology.org/NN for full disclosures. Funding information is provided at the end of the article. The Article Processing Charge was funded by University of Pécs. Received July 30, 2020. Accepted in final form August 12, 2020. Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. References 1.↵Dalmau J, Tüzün E, Wu HY, et al. Paraneoplastic anti-N-methyl-D-aspartate receptor encephalitis associated with ovarian teratoma. Ann Neurol 2007;61:25–36.OpenUrlCrossRefPubMed 2.↵Vitaliani R, Mason W, Ances B, Zwerdling T, Jiang Z, Dalmau J. Paraneoplastic encephalitis, psychiatric symptoms, and hypoventilation in ovarian teratoma. Ann Neurol 2005;58:594–604.OpenUrlCrossRefPubMed 3.↵Nokura K, Yamamoto H, Okawara Y, Koga H, Osawa H, Sakai K. Reversible limbic encephalitis caused by ovarian teratoma. Acta Neurol Scand 1997;95:367–373.OpenUrlCrossRefPubMed 4.↵Okamura H, Oomori N, Uchitomi Y. An acutely confused 15-year-old girl. Lancet 1997;350:488.OpenUrlCrossRefPubMed 5.↵Merwick A, Dalmau J, Delanty N. Insights into antibody-associated encephalitis—Bickerstaff’s 1950’s papers revisited. J Neurol Sci 2013;334:167–168.OpenUrlPubMed 6.↵Komagamine T, Kokubun N, Hirata K. Battey’s operation as a treatment for hysteria: a review of a series of cases in the nineteenth century. Hist Psychiatry 2020;31:55–66.OpenUrl 7.↵Titulaer MJ, McCracken L, Gabilondo I, et al. Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. Lancet Neurol 2013;12:157–165.OpenUrlCrossRefPubMed 8.↵Dalmau J, Gleichman AJ, Hughes EG, et al. Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies. Lancet Neurol 2008;7:1091–1098.OpenUrlCrossRefPubMed 9.↵Espinola-Nadurille M, Flores-Rivera J, Rivas-Alonso V, et al. Catatonia in patients with anti-NMDA receptor encephalitis. Psychiatry Clin Neurosci 2019;73:574–580.OpenUrl 10.↵Linoli O. Fall von Epilepsie mint Katalepsie [A case of epilepsy with catalepsy, German]. Österreichische Medizinische Wochenschrift 1843;12:319. Available at (free access): opacplus.bsb-muenchen.de/Vta2/bsb10086743/bsb:5976959?page=325. Accessed June 23, 2020.OpenUrl 11.↵Third Meeting of Italian Scientists in Florence. Annali Universali di Medicina 1842;40:17–20. Available at (free access): archive.org/details/s12id13209690/page/17. Accessed June 23, 2020.OpenUrl 12.↵Bugát P, Flór F. Kivonatok idegen lapokbul és munkákbul. Kór- és gyógytudomány. Nehézkor dermengéssel. [Extracts from foreign works. Pathology and medicine. Epilepsy with catalepsy, Hungarian] Orvosi Tár 1843;17:295. Available at (free access): library.hungaricana.hu/hu/view/ORSZ_ORVO_OT_1843_04/. Accessed June 23, 2020.OpenUrl 13.↵Wikipedia article. Available at: treccani.it/enciclopedia/odoardo-linoli_(Dizionario-Biografico)/. Accessed June 12, 2020. 14.↵Wikipedia article. Available at: it.wikipedia.org/wiki/Carlo_Burci. Accessed June 12, 2020. 15.↵Tandon R, Heckers S, Bustillo J, et al. Catatonia in DSM-5. Schizophr Res 2013;150:26–30.OpenUrlCrossRefPubMed 16.↵Kumar A, Paswan SS, Kumar B, Kumar P. Fetus in fetu in an adult woman. BMJ Case Rep 2019;12:e230835.OpenUrl 17.↵Willis RA. The structure of teratoma. J Pathol Bacteriol 1935;40:1–36.OpenUrlCrossRef 18.↵Caruso PA, Marsh MR, Minkowitz S, Karten G. An intense clinicopathologic study of 305 teratomas of the ovary. Cancer 1971;27:343–348.OpenUrlCrossRefPubMed 19.↵Armentano N, Subirana M, Isidro A, Escala O, Malgosa A. An ovarian teratoma of late Roman age. Int J Paleopathol 2012;2:236–239.OpenUrl 20.↵von-Walter AR, Nelken RS. Benign cystic ovarian teratoma with a fistula into the small and large bowel. Obstet Gynecol 2012;119:434–436.OpenUrlPubMed 21.↵Zarain García F. Teratoma quístico del ovario con absceso y fístula a vagina (Cystic teratoma of the ovary with abscess and fistula in the vagina [in Spanish]). Ginecol Obstet Mex 1974;36:49–53.OpenUrlPubMed 22.↵Flood K, Breathnach F, Gleeson N. An unusual presentation of a dermoid cyst. J Obstet Gynaecol 2010;30:72–73.OpenUrlPubMed 23.↵Mitui AH, Fujita R, Sugata F, Kienebuchi M, Suzuki K, Sagawa F. A case of ovarian dermoid cyst with malignant transformation perforated into the rectosigmoid colon and small intestine. Endoscopy 1983;15:331–333.OpenUrlCrossRefPubMed 24.↵Graus F, Titulaer MJ, Balu R, et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol 2016;15:391–404.OpenUrlCrossRefPubMed 25.↵Kümpfel T, Gerdes LA, Heck C, Prüss H. Delayed diagnosis of extraovarian teratoma in relapsing anti-NMDA receptor encephalitis. Neurol Neuroimmunol Neuroinflamm 2016;3:e250. doi: 10.1212/NXI.0000000000000250. 26.↵Darnell RB, Posner JB. Paraneoplastic Syndromes. Oxford/New York: Oxford University Press; 2011.

Description An Indian woman in her 40s without any medical or psychiatric history presented with a seizure. She had become uncharacteristically quiet before suddenly cackling and banging her hands and feet repeatedly. She developed facial and upper limb dystonic posturing including the extension of one arm. The acute onset, short duration, loss of responsiveness and unilateral dystonic posturing were compatible with a frontal lobe seizure. Several episodes occurred during transfer to the hospital, each lasting 3–30 min. CT head imaging was unremarkable (figure 1). Figure 1 CT head reported as normal. She was discharged and seen in ambulatory care 3 days later. Her lymphocytosis, neutrophilia (described as ‘reactive’) and elevated creatine kinase (10 006 IU/L) were attributed to recent motor seizure activity, despite the broad differential. An electroencephalogram, brain MRI and neurology appointment were arranged, in accordance with the Trust’s ‘first fit’ pathway, which mandates follow-up within 2 weeks, similar to the established National Institute for Health and Care Excellence guidelines.1 Five days later, she was brought back to hospital: she had become increasingly withdrawn, expressing a delusion that ‘someone’ was controlling her. She had stopped recognising her children. On examination, she stared unblinkingly and demonstrated echolalia, echopraxia and stereotyped, repetitive, slow rotation of both wrists. However, she had intervals of apparent lucidity when she was able to answer simple questions. Physical examination was limited by behavioural disturbance, but no other abnormal neurological signs were noted. This syndrome of frontal lobe seizures, acute psychiatric disturbance, unusual mixed hyperkinetic movement disorder and encephalopathy with normal CT brain imaging was suggestive of N-methyl D-aspartate (NMDA) receptor encephalitis. In particular, her movements did not fit more common disorders such as tremor, chorea, myoclonus, dystonia or tics and had a bizarre appearance that experts have found difficult to classify.2 However, an MRI brain revealed a 18×16×17 mm ring-enhancing intra-axial lesion at the frontal pole with extensive surrounding vasogenic oedema and mass effect (figure 2). Given the neutrophilia and lymphocytosis, an infective lesion (particularly a tuberculoma due to her ethnicity) was then considered the foremost differential. Figure 2 MRI head showing a frontal lobe ring-enhancing lesion (left), with extensive surrounding oedema (right). She was transferred to a tertiary neuroscience centre, where investigations interrogating an infectious process were negative, including lumbar puncture, QuantiFERON, cysticercal, HIV and fungal serology. A chest–abdomen–pelvis CT was normal. A brain biopsy revealed a grade IV glioblastoma. She has been treated with levetiracetam, radiotherapy and temozolomide. Her psychiatric and motor symptoms have resolved since treatment and she has been seizure-free for 6 months. We attribute her previous symptoms to ictal activity. Glioblastoma multiforme accounts for >60% of all adult brain tumours.3 Although presentation can vary depending on the location of the lesion, this case is unusual in that the initial presentation was a phenocopy of NMDA encephalitis and fits clinical criteria for diagnosis.4 However, recognised differentials of NMDA receptor encephalitis are varied, including infective, psychiatric, metabolic, neoplastic, paraneoplastic, cerebrovascular and other inflammatory disorders.4 The orbitofrontal location of this lesion explained all the clinical features. The refutation of the top two clinical differentials (NMDA encephalitis and tuberculoma) highlights the importance of having a wide differential diagnosis with unusual neurological presentations. Learning points Simplified pathways for common presentations like ‘first fits’ can streamline services, but without careful history-taking, complex presentations such as this may be inappropriately funnelled into a standardised pathway. A psychiatric presentation with movement disorder and seizure activity may represent a frontal space-occupying lesion, not necessarily NMDA receptor encephalitis.

Introduction One hundred years ago, neurologists were faced with a surge of cases of uncertain cause manifesting a protean array of symptoms. Through careful semiological description, pattern recognition and histopathological analysis, von Economo and others unified these seemingly disparate cases, defining the epidemic of encephalitis lethargica. Several landmark papers in the Journal of Neurology and Psychopathology (now JNNP) helped to illuminate clinical and pathological aspects of this new disease. In the subsequent hundred years, there have been other infectious epidemics affecting the nervous system, with causative agents including flaviviruses, influenza, enteroviruses (eg, poliomyelitis) and coronaviruses (CoV). Neurologists seeing patients in the age of COVID-19 have much to gain from the historical lessons of the epidemics of the last 100 years in responding to these new challenges. A case of encephalitis lethargica involving chiefly the cerebral cortex Authors: Watson GA Year Published: 1920 Epidemic encephalitis: Clinical papers by various authors Authors: Horder T Year Published: 1920 Encephalitis lethargica The first systematic descriptions of encephalitis lethargica were those of von Economo in 1916–1917, who coined the term (figure 1),1 which is also known as ‘von Economo’s disease’.2 However, there were probable cases in 1915 predating the ‘influenza epidemic’, and von Economo and others suggested that earlier epidemics throughout modern history may also have been related.3 Figure 1 Constantin Freiherr Economo von San Serff (von Economo (1876–1931)) Austrian neurologist, psychiatrist, pilot and originator of the diagnosis encephalitis lethargica (https://commons.wikimedia.org/wiki/Category:Constantin_von_Economo). Encephalitis lethargica appears to have spread from Eastern Europe to Germany, France and Britain between 1916 and 1918 and and then to have affected much of the rest of the world in the following few years.1 4 It probably affected more than a million people during the first half of the twentieth century, before apparently disappearing, although some clinicians have continued to apply the diagnosis, particularly in children.4 Three forms were recognised by von Economo: ‘somnolent-ophthalmoplegic form’ characterised by mild prodrome and somnolence with ophthalmoplegia; ‘hyperkinetic form’ in which the patients had sudden onset neck and back pain followed by mental and motor unrest; a ‘myostatic-akinetic form’ that had a milder acute phase of weakness and rigidity and was more likely to have chronic sequelae which could occur immediately after the acute phase or after months or years.1 4 Most patients had change in conscious level, and von Economo discriminated carefully between somnolence as a result of brain dysfunction versus that caused by systemic disease2—a distinction which clearly remains important for COVID-19. Histopathology of most cases in the acute phase showed reddish-grey discolouration of the brainstem grey matter with lymphocytic infiltrates surrounding vessels and diffuse inflammation with haemorrhage.1 In the chronic phase, persistent inflammation was evident with generalised brain atrophy and degeneration of the substantia nigra.1 The aetiology remains unproven, and it is not clear whether all the cases in the literature truly represent a single disease.5 The prevailing contemporary hypothesis was that proposed by von Economo himself—that the disease was owing to an infectious agent, although he observed that cases appeared to predate the emergence of the 1918 influenza pandemic.2 5 von Economo’s view that the disease was the result of direct viral infection of the central nervous system (CNS) has now been largely superseded by the proposition that the disease reflected a para/post-infectious inflammatory process.5 Although evidence for this is lacking, it fits neatly with the modern view of other neurological syndromes such as Guillain-Barré syndrome (GBS), acute disseminated encephalomyelitis (ADEM) and N-methyl-D-aspartate receptor (NMDA-R) antibody encephalitis, the latter of which may be triggered by herpes simplex virus in some.6 7 Indeed, NMDA-R antibodies were present in serum (and cerebrospinal fluid (CSF) when available for study) in around 50% of 20 children with dyskinetic ‘encephalitis lethargica’ (collected over many years),8 and antibodies to the dopamine receptor in a proportion of the remaining more akinetic cases. Many of the clinical features overlap, although encephalitis lethargica is more heterogeneous in both its acute symptoms and its natural history.2 A para/postinfectious pathogenesis, rather than direct viral infection, is in keeping with the observations that single members of families were often affected, which puzzled epidemiologists at the time; and that an infectious agent was not readily detected in CSF or brain tissue.2 It is possible that encephalitis lethargica represented a final common pathway of brain inflammation potentially triggered by several different infectious agents, although were this the case the reasons for the disease’s decline remain obscure. Clinical material from patients with encephalitis lethargica is no longer available in sufficient quantity to support or refute the myriad aetiological hypotheses proposed over the last 100 years.5 Encephalitis lethargica in JNNP The British epidemic began in earnest in 1918, and was a major burden on neurological, psychiatric and public health services for much of the first half of the twentieth century.9 Cases published in the Journal of Neurology and Psychopathology provide a glimpse of the struggles of neurologists trying to understand the emergence of this new enigma.10 11 In 1920, the journal published a case described by Watson, of the Rainhill asylum near Liverpool, then one of the largest asylums in Europe.10 While the condition was often thought to affect the brainstem, this case mainly affected the cerebral cortex. A young patient had been admitted in April 1918 with self-inflicted laceration across the neck, preceded by headache and sleeplessness for 2 weeks.10 Six months after the initial presentation, they developed neck and back pain with reduced mobility, 2 months later developing expressive aphasia with retained comprehension, and death occurred less than a month later.10 The postmortem results describe a widespread meningoencephalomyelitis with vascular proliferation, perivascular inflammation, thrombosis, haemorrhage and destruction of nervous tissue.10 A subsequent case series collated by Sir Thomas Horder, also published in 1920, comprises 25 cases described by several neurologists from Bristol, and is notable for detailed and varied descriptions of cases of encephalitis lethargica in patients of all ages.11 Their dilemmas trying to unify these disparate clinical presentations are clearly evident. While lethargy and/or psychiatric features are almost universal, movement disorders were variably present, as were corticospinal tract and cerebellar signs.11 The outcomes were varied with death in 10/25 (40%) and residual neurological or psychiatric symptoms in most survivors.11 Speculation on aetiology in this study is limited, but there is an assumption that an infectious agent is responsible. Horder states that “it therefore becomes a matter of prime importance that clinicians should marshal their experiences, and set down their observations, with as much care and exactness as possible, and this whilst questions of exact pathology await the results of laboratory research”.11 In subsequent years, papers in the journal analysed the phenomenology of sleep disorders in encephalitis lethargica,12 behavioural abnormalities in children13 and a case series of postencephalitic Parkinsonism14 among many others. Subsequently, fascinating reports emerged of the efforts to treat patients suffering with postencephalitic Parkinsonism with levodopa.15 Other respiratory epidemics affecting the nervous system Influenza Although 1918 influenza has been suggested as the causative agent of encephalitis lethargica, similar clinical phenotypes have not been seen in association with other pandemic strains of influenza.5 However, a wide range of other neurological manifestations are described. The 2009 H1N1 pandemic was associated with complications of the nervous system in up to 4% of those diagnosed with H1N1 influenza infection and most commonly included altered mental status, seizures, narcolepsy and encephalopathy, particularly in children.16–18 Several seemingly pathognomic encephalopathy syndromes have emerged, including acute necrotising encephalopathy with bilateral thalamic involvement.16–18 The virus is rarely identified by molecular tests of the CSF in these patients, and it has been suggested that the mechanism for the complications may be a parainfectious cytokine storm.18 Coronaviruses The severe CoV, severe acute respiratory syndrome (SARS) and MERS, have been associated with limited reports of both central and peripheral nervous system disease, including ADEM.19 Sporadic, seasonal CoV have also occasionally been implicated in neurological disease.20 COVID-19, caused by SARS-CoV-2, represents the most devastating respiratory pandemic since the influenza pandemics of 1918 (‘Spanish flu’; H1N1), 1957 (‘Asian flu’; H2N2) and 1968 (‘Hong Kong flu’; H3N2).21 Reports of neurological syndromes associated with SARS-CoV2 are frequent, initially reported where the virus began in Wuhan,22 and continued in case reports and series from across the world.21 23 24 A UK-wide surveillance study identified 153 cases with CNS disorders reflecting cerebrovascular events, altered mental status including 7 patients with encephalitis, and a surprising number of psychiatric syndromes, such as psychosis and catatonia.21 It is currently unclear how many cases are causally related to SARS-CoV-2 and in what proportion this is a coincidental infection.23 It is becoming apparent that dysfunction of the clotting cascade, together with possible endotheliopathy, is in some cases associated with cerebrovascular disease in COVID-19.21 23 24 The number of patients with encephalopathy is also striking, and in a few cases the virus has been detected in CSF.21 25 Many cases of GBS and its variants are also emerging.26 Conclusion The historical papers of von Economo, Horder and others are refreshing in their straightforward and detailed accounts of the symptoms, signs and clinical course of their patients, which risk being diminished in current studies if there is over-reliance on investigations alone. The reporting of cases should be systematic and collaborative, which is far easier now, in the age of online platforms, than it was 100 years ago; such as is currently being employed through the UK-wide CoroNerve study (www.CoroNerve.com) and international collaborations, such as the COVID-19 NeuroNetwork (https://braininfectionsglobal.tghn.org/covid-neuro-network/). In addition to analysis of clinical samples, these historic cases emphases the importance of histopathological descriptions, which may be more difficult to conduct now that postmortem material may be less frequently obtained. We are indebted to those who donate and their families, so that we, like von Economo and those before us, might better understand the impact of pandemic respiratory viruses on the CNS. Perhaps the greatest lesson from our predecessors is to maintain clinical curiosity and a healthy degree of scepticism, to drive logical enquiry and experiment. Nevertheless, we are left with the original questions posed throughout this history: to what extent are these manifestations due to direct viral CNS infection, the host inflammatory response to non-CNS infection, or the broader psychosocial effects of pandemic infection, and who is at risk? Despite the human and economic suffering of COVID-19, this pandemic represents the first time ever, for the neuroscience community to use the many tools at our disposal, including digital global collaboration and biobanking for next-generation and single-cell sequencing, ‘omics, immunophenotyping, and genome-wide association, to finally begin to answer these questions. Keep up to date with the latest developments in the neurological and psychiatric complications of COVID-19 via our JNNP blog: https://blogs.bmj.com/jnnp/2020/05/01/the-neurology-and-neuropsychiatry-of-covid-19/ References ↵Hoffman LA, Vilensky JA. Encephalitis lethargica: 100 years after the epidemic. Brain 2017;140:2246–51.doi:10.1093/brain/awx177OpenUrl ↵Turner MR, Kieran MCVincent A. Encephalitis Lethargica. In: Turner MR, Kieran MC, eds. Landmark papers in neurology. Oxford University Press, 2015: 478–83. ↵Crookshank FG. A note on the history of epidemic encephalomyelitis. Bost Med Surg J 1920;182:34–45.doi:10.1056/NEJM192001081820203OpenUrl ↵Reid AH, McCall S, Henry JM, et al. Experimenting on the past: the enigma of von Economo’s encephalitis lethargica. J Neuropathol Exp Neurol 2001;60:663–70.doi:10.1093/jnen/60.7.663OpenUrlPubMed ↵Tappe D, Alquezar-Planas DE. Medical and molecular perspectives into a forgotten epidemic: encephalitis lethargica, viruses, and high-throughput sequencing. J Clin Virol 2014;61:189–95.doi:10.1016/j.jcv.2014.07.013OpenUrl ↵Kaida K. Pathogenic roles of antiganglioside antibodies in immune-mediated neuropathies. Clin Exp Neuroimmunol 2013;4:60–9.doi:10.1111/cen3.12007OpenUrl ↵Salovin A, Glanzman J, Roslin K, et al. Anti-Nmda receptor encephalitis and nonencephalitic HSV-1 infection. Neurol Neuroimmunol Neuroinflamm 2018;5:e458.doi:10.1212/NXI.0000000000000458 ↵Dale RC, Irani SR, Brilot F, et al. N-Methyl-D-Aspartate receptor antibodies in pediatric dyskinetic encephalitis lethargica. Ann Neurol 2009;66:704–9.doi:10.1002/ana.21807 ↵Bramwell E, Miller J. Encephalitis lethargica (epidemic encephalitis). The Lancet 1920;195:1152–8.doi:10.1016/S0140-6736(00)92412-7OpenUrl ↵Watson GA. A case of encephalitis lethargica involving chiefly the cerebral cortex. J Neurol Psychopathol 1920;1:34–44.doi:10.1136/jnnp.s1-1.1.34pmid:http://www.ncbi.nlm.nih.gov/pubmed/21611435OpenUrlPubMed ↵Horder T. Epidemic encephalitis: Clinical papers by various authors. J Neurol Neurosurg Psychiatry 1920;s1-1:221–35.doi:10.1136/jnnp.s1-1.3.221OpenUrl ↵Coburn M. Short notes and clinical cases: report of a case of insomnia following encephalitis lethargica. J Neurol Psychopathol 1921;2:249–53.doi:10.1136/jnnp.s1-2.7.249pmid:http://www.ncbi.nlm.nih.gov/pubmed/21611473OpenUrlPubMed ↵Parkes Weber F, Shrubsall F, Cameron H, et al. Section for the study of disease in children: cases: hypertelorism. Proc R Soc Med 1928;21. ↵Young AW. A clinical analysis of an extrapyramidal syndrome; paralysis agitans and postencephalitic parkinsonism. J Neurol Neurosurg Psychiatry 1927;S1-8:9–18.doi:10.1136/jnnp.s1-8.29.9OpenUrl ↵Duvoisin RC, Lobo-Antunes J, Yahr MD. Response of patients with postencephalitic parkinsonism to levodopa. J Neurol Neurosurg Psychiatry 1972;35:487–95.doi:10.1136/jnnp.35.4.487 ↵Surana P, Tang S, McDougall M, et al. Neurological complications of pandemic influenza A H1N1 2009 infection: European case series and review. Eur J Pediatr 2011;170:1007–15.doi:10.1007/s00431-010-1392-3OpenUrlCrossRefPubMed ↵Reed C, Chaves SS, Perez A, et al. Complications among adults hospitalized with influenza: a comparison of seasonal influenza and the 2009 H1N1 pandemic. Clin Infect Dis 2014;59:166–74.doi:10.1093/cid/ciu285OpenUrlCrossRefPubMed ↵Goenka A, Michael BD, Ledger E, et al. Neurological manifestations of influenza infection in children and adults: results of a national British surveillance study. J Neurol Neurosurg Psychiatry 2014;58:775–84.doi:10.1093/cid/cit922OpenUrl ↵Ng Kee Kwong KC, Mehta PR, Shukla G, et al. COVID-19, SARS and MERS: a neurological perspective. J Clin Neurosci 2020;77:13–16.doi:10.1016/j.jocn.2020.04.124OpenUrl ↵Morfopoulou S, Brown JR, Davies EG, et al. Human coronavirus OC43 associated with fatal encephalitis. N Engl J Med 2016;375:497–8.doi:10.1056/NEJMc1509458OpenUrlCrossRefPubMed ↵Varatharaj A, Thomas N, Ma E, et al. UK-wide surveillance of neurological and neuropsychiatric complications of COVID-19 : The first 153 patients. Lancet Psychiatry 2020. ↵Mao L, Jin H, Wang M, et al. Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China. JAMA Neurol 2020;77:683–90.doi:10.1001/jamaneurol.2020.1127OpenUrl ↵Ellul M, Varatharaj A, Nicholson TR, et al. Defining causality in COVID-19 and neurological disorders. J Neurol Neurosurg Psychiatry 2020;6. doi:doi:10.1136/jnnp-2020-323667. [Epub ahead of print: 05 Jun 2020].pmid:http://www.ncbi.nlm.nih.gov/pubmed/32503883OpenUrlPubMed ↵Beyrouti R, Adams ME, Benjamin L, et al. Characteristics of ischaemic stroke associated with COVID-19. J Neurol Neurosurg Psychiatry 2020. doi:doi:10.1136/jnnp-2020-323586. [Epub ahead of print: 30 Apr 2020].pmid:http://www.ncbi.nlm.nih.gov/pubmed/32354768OpenUrlPubMed ↵Ellul M, Benjamin L, Singh B, et al. Neurological associations of COVID-19. SSRN Journal 2020.doi:10.2139/ssrn.3589350 ↵Toscano G, Palmerini F, Ravaglia S, et al. Guillain-Barré syndrome associated with SARS-CoV-2. N Engl J Med 2020;382:2574–6.doi:10.1056/NEJMc2009191pmid:http://www.ncbi.nlm.nih.gov/pubmed/32302082OpenUrlPubMed