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Standing on the shoulders of giants: 100 years of neurology and epidemic infections | Journal of Neurology, Neurosurgery & Psychiatry

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
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Neural Antibody Testing in Patients with Suspected Autoimmune Encephalitis | Clinical Chemistry | Oxford Academic

Neural Antibody Testing in Patients with Suspected Autoimmune Encephalitis | Clinical Chemistry | Oxford Academic | AntiNMDA | Scoop.it
AbstractBackground. Autoimmunity is an increasingly recognized cause of encephalitis with a similar prevalence to that of infectious etiologies. Over the past d
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Ten Point Guide to Mental State Examination (MSE) in Psychiatry

Ten Point Guide to Mental State Examination (MSE) in Psychiatry | AntiNMDA | Scoop.it
This 10 point guide to mental state exam (MSE) enhaces your psychiatric evaluation skills. An accurate MSE assists in the diagnosis of mental illness.
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Hallucinations Lead to Ovarian Cancer Diagnosis for Young Woman

Hallucinations Lead to Ovarian Cancer Diagnosis for Young Woman | AntiNMDA | Scoop.it
Lauren went from a psychiatric ward in a local hospital to the ICU....
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Pathophysiology of paraneoplastic and autoimmune encephalitis: genes, infections, and checkpoint inhibitors - Alberto Vogrig, Sergio Muñiz-Castrillo, Virginie Desestret, Bastien Joubert, Jérôme Hon...

Pathophysiology of paraneoplastic and autoimmune encephalitis: genes, infections, and checkpoint inhibitors - Alberto Vogrig, Sergio Muñiz-Castrillo, Virginie Desestret, Bastien Joubert, Jérôme Hon... | AntiNMDA | Scoop.it
Paraneoplastic neurological syndromes (PNSs) are rare complications of systemic cancers that can affect all parts of the central and/or peripheral nervous system. A body of experimental and clinica...
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Relationship between serum NMDA receptor antibodies and response to antipsychotic treatment in first episode psychosis

Relationship between serum NMDA receptor antibodies and response to antipsychotic treatment in first episode psychosis | AntiNMDA | Scoop.it
When psychosis develops in NMDAR antibody encephalitis it usually has an acute or
subacute onset, and antipsychotic treatment may be ineffective and associated with
adverse effects. Serum NMDAR antibodies have been reported in a minority of patients with first episode psychosis (FEP), but their...
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https://www.researchgate.net/publication/343817904_Anti-N-methyl-D-Aspartate_NMDA_Receptor_Encephalitis_A_Case_Report

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Defying the odds, U of T's Carisse Samuel to graduate after spending five months in a coma

Defying the odds, U of T's Carisse Samuel to graduate after spending five months in a coma | AntiNMDA | Scoop.it
When Carisse Samuel joins her fellow graduates at the University of Toronto’s virtual convocation this Saturday, the celebration will be both an academic and personal victory.
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Clinical features which predict neuronal surface autoantibodies in new-onset focal epilepsy: implications for immunotherapies | Journal of Neurology, Neurosurgery & Psychiatry

Introduction Neuronal surface-directed antibodies (NSAbs) are considered pathogenic in patients with autoimmune encephalitis (AE). AE commonly presents with prominent seizures and neuropsychiatric features and shows a preferential response to immunotherapies versus anti-seizure medications (ASMs).1–4 This has prompted the introduction of ‘epilepsy of immune aetiology’ within the International League Against Epilepsy (ILAE) 2017 classification.5 The same NSAbs, as well as high levels of antibodies to intraneuronal glutamic acid decarboxylase-65 (GAD65), are also described in the serum of people with more isolated forms of epilepsy, without core features of encephalitis.6–8 In this context, their clinical, aetiological and therapeutic relevance is unclear, but of major potential importance to all neurologists who manage new-onset epilepsy. In our large, prospective, real-world study of new-onset focal epilepsy, we predicted that formes frustes of AE would help identify clinical features suggesting the presence of NSAbs and asked whether detection of these NSAbs should alter patient management. Materials and methods Between 9 December 2011 and 4 November 2015, consecutive adult patients (≥18 years) with a diagnosis of new-onset focal epilepsy and their first seizure within the previous 12 months were prospectively recruited from the routine practice of two epileptologists at the Oxford University Hospitals NHS Foundation Trust. Written informed consent and sera were obtained (Ethical approvals: Oxfordshire RECA 07/Q160X/28 and REC16/YH/0013). Clinical data gathered at onset (online supplemental table 1) included detailed phenotype and investigation results, Quality of Life in Epilepsy-31, Hospital Anxiety and Depression Score, Addenbrooke’s Cognitive Examination (ACE) and modified Rankin Score (mRS); as well as information to inform the Antibody Prevalence in Epilepsy and Encephalopathy (APE2) score (online supplemental table 2)9 10 and diagnostic criteria for possible or definite AE.11 Subsequently, 1-year and 3-year mRS were ascertained from patients with NSAbs. Supplemental material For NSAbs, sera were tested against autoantigen-expressing live HEK293 cells (live cell-based assay; online supplemental table 3), and for reactivity with the surface of live cultured hippocampal neurons, using sensitive protocols.12 13 Autoantibodies to GAD65 were determined using a commercial radioimmunoprecipitation assay. Statistical analysis was conducted in R (V.3.6.1). Dimensionality reduction was performed using Multiple Factor Analysis in ‘FactoMineR’ with up to 10% missing data imputed using missForest. Stepwise Bayesian general linear modelling analysis was undertaken using ‘arm’. Wilson 95% CIs with continuity correction were calculated using ‘DescTools’. Results NSAb findings Of 241 recruited patients, 22 were excluded (online supplemental table 4). Of the remaining 219, median age was 49 years (range 16–91) and 109 (49.8%) were female. In 23/219 (10.5%) patients, serum NSAbs were detected across candidate and novel autoantigens (table 1) including roughly equal frequencies against leucine-rich glioma inactivated-1 (LGI1), contactin-associated protein-like 2 (CASPR2), plus the N-methyl-d-aspartate receptor (NMDAR) and γ-aminobutyric acid A/B receptors (GABAAR and GABABR). An additional five patients had antibodies to the surface of live neurons, without an established autoantigen. Autoantibodies to contactin-2, the glycine receptor and the α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) were each found in one patient. No dipeptidyl-peptidase-like protein 6 (DPPX) or high-titre GAD65 antibodies were detected. Overall, from the 23 people with NSAbs, 9 had a clinical diagnosis of AE (7/9 fulfilling published criteria).11 By contrast, none of the 196 without NSAbs had a clinical diagnosis of AE (p<0.0001; Fisher’s exact test). VIEW INLINE VIEW POPUP Table 1 Clinical and laboratory features of patients with epilepsy and positive neuronal surface autoantibodies Factors associated with the presence of NSAbs and AE Dimensionality reduction with multiple factor analysis showed that patients were highly heterogeneous and the modest clustering of those with NSAbs was largely driven by a clinical diagnosis of AE (figure 1A,B). Univariate analysis identified 11 clinical parameters that differed significantly between patients with and without NSAbs: age (p=0.04), ictal piloerection (p=0.02), lesional MRI (p=0.04), self-reported mood disturbance (p=0.007), ACE attention domain (p=0.01), ACE total score (p=0.04), QOLIE-31 score (p=0.02), self-reported neuropsychiatric features (p=0.03), epilepsy risk factors (p=0.05), inflammatory cerebrospinal fluid (CSF; p=0.004) and limbic system lesions on MRI (p=0.0002). A multivariate stepwise regression model allocated weighted scores to six of these: age ≥54 years=+1, self-reported mood disturbance=+1, limbic system lesions on MRI=+2, ictal piloerection=+2.5, ACE attention score ≥16=−1.5 and epilepsy risk factors=−1.5 (figure 1C). The probability of NSAb positivity increased with higher scores (Spearman’s ρ=0.99, p<0.0001; figure 1C) and receiver operating characteristic (ROC) analysis confirmed these features strongly predicted NSAb status (area under the curve (AUC)=0.83; total score ≥0; sensitivity=66.7%, specificity=84.9%; figure 1D). By contrast, the APE2 score performed less well in predicting NSAb status (sensitivity 43.5%, specificity 79.1%, AUC=0.68) and more accurately predicted criteria-defined AE, particularly if associated with NSAbs (sensitivity 85.7%, specificity 78.8%, AUC=0.94; figure 1E). Figure 1 Clinical phenotypes associated with NSAb status in new-onset focal epilepsy. The first two dimensions are shown, highlighting: (A) NSAb-positive (red) or NSAb-negative (grey) status and (B) NSAb-positive (pale red) or NSAb-negative (grey) without encephalitis (dots), or NSAb-positive (dark red) with clinically diagnosed autoimmune encephalitis (triangles). (C) The proportion of patients by total model score. Error bars show 95% CIs. The inset shows the weighting and SE of each factor within the regression model. (D) Receiver operator characteristic (ROC) curve of the total model score for predicting NSAb status across all patients. (E) ROC curve of the APE2 score for predicting NSAb status across all patients (black), patients not meeting the criteria for autoimmune encephalitis (blue), patients meeting the criteria for autoimmune encephalitis (red) and predicting NSAb-positive criteria-confirmed autoimmune encephalitis across all patients. (F) Scatter plot of modified Rankin score in NSAb-positive patients by immunotherapy status over time (Mann-Whitney U test p values<0.05). AE, autoimmune encephalitis; APE2, Antibody Prevalence in Epilepsy and Encephalopathy; epilepsy RF, epilepsy risk factors; MRI limbic Δ, changes within the limbic system on MRI. Comparisons of those with and without AE From 23 patients with NSAbs (table 1), a comparison of those with (n=9) and without (n=14) a clinical diagnosis of AE revealed several differences in the AE cohort: more ASMs (median of 3 vs 1; p=0.0073), more frequent immunotherapies (7/9 vs 0/14, p=0.0001), higher APE2 scores (median of 6 vs 2; p<0.0001), more frequent MRI limbic inflammation (6/9 vs 0/14; p=0.0008) and a trend towards greater positivity of serum IgGs targeting the surface of live neurons (7/9 vs 5/14, p=0.09). Compared with the seven patients administered immunotherapy, those with NSAbs who were not administered immunotherapy showed lower disability after 1 and 3 years (both p<0.05), and 11/16 (68.8%) were asymptomatic at 3-year follow-up (mRS=0 ; figure 1F). Hence, despite no immunotherapy, patients with NSAbs, but without AE, generally showed good outcomes. Discussion In this prospective study of 219 consecutive adults with new-onset focal epilepsy, NSAb status was best predicted by a combination of clinical parameters which closely resemble features observed in AE. Almost half of our patients with NSAbs were diagnosed with AE, and ~30% fulfilled stringent criteria for AE.11 Of those with NSAbs and more isolated forms of epilepsy, without individual features of AE, almost all were treated with ASMs alone and typically remained asymptomatic at long-term follow-up. Overall, these findings suggest that detection of NSAbs in patients with new-onset seizures, but without features of AE, should not alter current clinical management. Our observations should help guide the frequent clinical dilemma of which patients with new-onset seizures to test for autoantibodies and subsequently treat with immunotherapy. Taken together, our data suggest the clinical phenotype is paramount in guiding the relevance of autoantibody results, and provide data to address an outstanding question from a recent ILAE consensus statement.7 This ILAE statement also highlighted controversy over the term ‘autoimmune epilepsy’.7 In routine clinical practice, this nomenclature acts as a valuable signpost and aide memoire when seeing patients with seizures.2 14 However, ‘epilepsy’ carries several social stigmata and is defined by an enduring tendency to seizures. In AE, this lifelong risk is refuted by a recent study,4 despite several forms of AE commonly leading to hippocampal atrophy.2–4 7 10 The alternative concept of acute symptomatic seizures may more accurately capture the nature of seizures in patients with AE. Data-driven modifications to nomenclature will benefit from longer-term follow-up studies. Ictal piloerection, low mood and attention and MRI limbic system changes are recognised features of late-onset AE, particularly in association with LGI1 antibodies.2 4 14 15 The absence of movement disorders or more diffuse cognitive impairment as predictive factors in our model suggests the overall syndrome may reflect a formes frustes of AE. This contrasts with APE2 score parameters,9 which appear to largely reflect more florid features seen in classical AE. Our observational study has several limitations. These include limited CSF autoantibody measurements, which reflected UK practice particularly at the start of the study period. Yet,w ithout this valuable parameter, a diagnosis of NMDAR-antibody encephalitis is still possible.11 Yet, two of our four patients with serum NMDAR antibodies did not have features consistent with encephalitis, likely suggesting detection of clinically unrelated serum antibodies in these cases. In addition, our series in total only identified nine AE cases, although this may be considered substantial given the largely outpatient-based recruitment. This, and the high (~10%) seroprevalence rate, may reflect a referral bias given Oxford’s interest in AE, but is well aligned with other available estimates.6 9 10 Our serological data identified some samples with NSAbs proven by live cell-based assays, but without concomitant cell surface neuronal reactivities. This was especially evident in the cohort without a clinical diagnosis of AE, and perhaps these antibodies reflect low-affinity or low-titre autoantibodies which are not disease relevant. Their specificity, however, remains reassuring given their typical selectivity for just one of eight surface-expressed autoantigens. In the future, our prediction model will benefit from validation in independent, larger studies which may compare the risk of enduring seizures in the NSAb-positive versus NSAb-negative populations, with and without AE, something which we did not survey at follow-up. Hence, we cannot comment on long-term seizure status in the 5/16 patients (31%) who had NSAbs, no diagnosis of AE and 3-year mRS >0. In these patients, it remains possible that immunotherapy would have led to a greater benefit. However, in our view, this finding is more likely to be consistent with the predicted ~30% of all people with epilepsy who are known to become ASM resistant: this provides a testable hypothesis for a future randomised controlled trial. Overall, our observations support the concept that, in patients who present with new-onset focal seizures, clinical features which are consistent with a ‘mild encephalitis’ helps identify those with NSAbs which should alter patient management. This clinico-serological syndrome appeared characteristic and its recognition will improve detection and treatment of these patients. These findings should discourage widespread screening strategies to identify patients with autoantibodies among unselected seizure cohorts. References ↵Irani SR, Michell AW, Lang B, et al. Faciobrachial dystonic seizures precede Lgi1 antibody limbic encephalitis. Ann Neurol 2011;69:892–900.doi:10.1002/ana.22307 ↵Thompson J, Bi M, Murchison AG, et al. The importance of early immunotherapy in patients with faciobrachial dystonic seizures. Brain 2018;141:348–56.doi:10.1093/brain/awx323OpenUrlCrossRef ↵Geis C, Planagumà J, Carreño M, et al. Autoimmune seizures and epilepsy. J Clin Invest 2019;129:926–40.doi:10.1172/JCI125178OpenUrlPubMed ↵de Bruijn MAAM, van Sonderen A, van Coevorden-Hameete MH, et al. Evaluation of seizure treatment in anti-LGI1, anti-NMDAR, and anti-GABABR encephalitis. Neurology 2019;92:e2185–96.doi:10.1212/WNL.0000000000007475pmid:30979857OpenUrlPubMed ↵Scheffer IE, Berkovic S, Capovilla G, et al. ILAE classification of the epilepsies: position paper of the ILAE Commission for Classification and Terminology. Epilepsia 2017;58:512–21.doi:10.1111/epi.13709pmid:http://www.ncbi.nlm.nih.gov/pubmed/28276062OpenUrlPubMed ↵Brenner T, Sills GJ, Hart Y, et al. Prevalence of neurologic autoantibodies in cohorts of patients with new and established epilepsy. Epilepsia 2013;54:1028–35.doi:10.1111/epi.12127pmid:http://www.ncbi.nlm.nih.gov/pubmed/23464826OpenUrlCrossRefPubMed ↵Steriade C, Britton J, Dale RC, et al. Acute symptomatic seizures secondary to autoimmune encephalitis and autoimmune-associated epilepsy: conceptual definitions. Epilepsia 2020;61:1341–51.doi:10.1111/epi.16571pmid:http://www.ncbi.nlm.nih.gov/pubmed/32544279OpenUrlPubMed ↵von Podewils F, Suesse M, Geithner J, et al. Prevalence and outcome of late-onset seizures due to autoimmune etiology: a prospective observational population-based cohort study. Epilepsia 2017;58:1542–50.doi:10.1111/epi.13834pmid:http://www.ncbi.nlm.nih.gov/pubmed/28681401OpenUrlPubMed ↵Dubey D, Alqallaf A, Hays R, et al. Neurological autoantibody prevalence in epilepsy of unknown etiology. JAMA Neurol 2017;74:397–402.doi:10.1001/jamaneurol.2016.5429pmid:http://www.ncbi.nlm.nih.gov/pubmed/28166327OpenUrlPubMed ↵Dubey D, Kothapalli N, McKeon A, et al. Predictors of neural-specific autoantibodies and immunotherapy response in patients with cognitive dysfunction. J Neuroimmunol 2018;323:62–72.doi:10.1016/j.jneuroim.2018.07.009pmid:http://www.ncbi.nlm.nih.gov/pubmed/30196836OpenUrlPubMed ↵Graus F, Titulaer MJ, Balu R, et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol 2016;15:391–404.doi:10.1016/S1474-4422(15)00401-9pmid:http://www.ncbi.nlm.nih.gov/pubmed/26906964OpenUrlCrossRefPubMed ↵Makuch M, Wilson R, Al-Diwani A, et al. N-Methyl-D-aspartate receptor antibody production from germinal center reactions: therapeutic implications. Ann Neurol 2018;83:553–61.doi:10.1002/ana.25173pmid:http://www.ncbi.nlm.nih.gov/pubmed/29406578OpenUrlPubMed ↵Ramberger M, Berretta A, Tan JMM, et al. Distinctive binding properties of human monoclonal LGI1 autoantibodies determine pathogenic mechanisms. Brain 2020;143:1731–45.doi:10.1093/brain/awaa104pmid:http://www.ncbi.nlm.nih.gov/pubmed/32437528OpenUrlPubMed ↵Quek AML, Britton JW, McKeon A, et al. Autoimmune epilepsy: clinical characteristics and response to immunotherapy. Arch Neurol 2012;69:582–93.doi:10.1001/archneurol.2011.2985pmid:http://www.ncbi.nlm.nih.gov/pubmed/22451162OpenUrlCrossRefPubMed ↵Rocamora R, Becerra JL, Fossas P, et al. Pilomotor seizures: an autonomic semiology of limbic encephalitis? Seizure 2014;23:670–3.doi:10.1016/j.seizure.2014.04.013pmid:http://www.ncbi.nlm.nih.gov/pubmed/24890932OpenUrlCrossRefPubMed
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Sleep disorders in autoimmune encephalitis

Sleep disorders in autoimmune encephalitis | AntiNMDA | Scoop.it
Sleep disorders in people with autoimmune encephalitis have received little attention,
probably overshadowed by the presence of other neurological and psychiatric symptoms
in this group of conditions.
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Cerebrospinal fluid CD20 positive B-cell expansion in a case of anti-NMDAR encephalitis - ScienceDirect

Cerebrospinal fluid CD20 positive B-cell expansion in a case of anti-NMDAR encephalitis - ScienceDirect | AntiNMDA | Scoop.it
Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis is a potentially fatal autoimmune encephalitis with a strong B-cell response. We measured the …
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Clinical, cognitive and neuroanatomical associations of serum NMDAR autoantibodies in people at clinical high risk for psychosis

Clinical, cognitive and neuroanatomical associations of serum NMDAR autoantibodies in people at clinical high risk for psychosis | AntiNMDA | Scoop.it
Serum neuronal autoantibodies, such as those to the NMDA receptor (NMDAR), are detectable in a subgroup of patients with psychotic disorders. It is not known if they are present before the onset of psychosis or whether they are associated with particular clinical features or outcomes. In a case–control study, sera from 254 subjects at clinical high risk (CHR) for psychosis and 116 healthy volunteers were tested for antibodies against multiple neuronal antigens implicated in CNS autoimmune disorders, using fixed and live cell-based assays (CBAs). Within the CHR group, the relationship between NMDAR antibodies and symptoms, cognitive function and clinical outcomes over 24 month follow-up was examined. CHR subjects were not more frequently seropositive for neuronal autoantibodies than controls (8.3% vs. 5.2%; OR = 1.50; 95% CI: 0.58–3.90). The NMDAR was the most common target antigen and NMDAR IgGs were more sensitively detected with live versus fixed CBAs (p < 0.001). Preliminary phenotypic analyses revealed that within the CHR sample, the NMDAR antibody seropositive subjects had higher levels of current depression, performed worse on the Rey Auditory Verbal Learning Task (p < 0.05), and had a markedly lower IQ (p < 0.01). NMDAR IgGs were not more frequent in subjects who later became psychotic than those who did not. NMDAR antibody serostatus and titre was associated with poorer levels of functioning at follow-up (p < 0.05) and the presence of a neuronal autoantibody was associated with larger amygdala volumes (p < 0.05). Altogether, these findings demonstrate that NMDAR autoantibodies are detectable in a subgroup of CHR subjects at equal rates to controls. In the CHR group, they are associated with affective psychopathology, impairments in verbal memory, and overall cognitive function: these findings are qualitatively and individually similar to core features of autoimmune encephalitis and/or animal models of NMDAR antibody-mediated CNS disease. Overall the current work supports further evaluation of NMDAR autoantibodies as a possible prognostic biomarker and aetiological factor in a subset of people already meeting CHR criteria.
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What the acute physician needs to know about Anti-NMDA receptor encephalitis: two case presentations. - The University of Liverpool Repository

What the acute physician needs to know about Anti-NMDA receptor encephalitis: two case presentations. - The University of Liverpool Repository | AntiNMDA | Scoop.it
These case reports look at two patients with anti-N-methyl-D-aspartate receptor (NMDAr) encephalitis presenting to the same acute medical unit within a month of each other. The following covers the characteristic signs, symptoms and timeline associated with this condition and discusses whether we...
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Clinical features which predict neuronal surface autoantibodies in new-onset focal epilepsy: implications for immunotherapies | Journal of Neurology, Neurosurgery & Psychiatry

Introduction Neuronal surface-directed antibodies (NSAbs) are considered pathogenic in patients with autoimmune encephalitis (AE). AE commonly presents with prominent seizures and neuropsychiatric features and shows a preferential response to immunotherapies versus anti-seizure medications (ASMs).1–4 This has prompted the introduction of ‘epilepsy of immune aetiology’ within the International League Against Epilepsy (ILAE) 2017 classification.5 The same NSAbs, as well as high levels of antibodies to intraneuronal glutamic acid decarboxylase-65 (GAD65), are also described in the serum of people with more isolated forms of epilepsy, without core features of encephalitis.6–8 In this context, their clinical, aetiological and therapeutic relevance is unclear, but of major potential importance to all neurologists who manage new-onset epilepsy. In our large, prospective, real-world study of new-onset focal epilepsy, we predicted that formes frustes of AE would help identify clinical features suggesting the presence of NSAbs and asked whether detection of these NSAbs should alter patient management. Materials and methods Between 9 December 2011 and 4 November 2015, consecutive adult patients (≥18 years) with a diagnosis of new-onset focal epilepsy and their first seizure within the previous 12 months were prospectively recruited from the routine practice of two epileptologists at the Oxford University Hospitals NHS Foundation Trust. Written informed consent and sera were obtained (Ethical approvals: Oxfordshire RECA 07/Q160X/28 and REC16/YH/0013). Clinical data gathered at onset (online supplemental table 1) included detailed phenotype and investigation results, Quality of Life in Epilepsy-31, Hospital Anxiety and Depression Score, Addenbrooke’s Cognitive Examination (ACE) and modified Rankin Score (mRS); as well as information to inform the Antibody Prevalence in Epilepsy and Encephalopathy (APE2) score (online supplemental table 2)9 10 and diagnostic criteria for possible or definite AE.11 Subsequently, 1-year and 3-year mRS were ascertained from patients with NSAbs. Supplemental material For NSAbs, sera were tested against autoantigen-expressing live HEK293 cells (live cell-based assay; online supplemental table 3), and for reactivity with the surface of live cultured hippocampal neurons, using sensitive protocols.12 13 Autoantibodies to GAD65 were determined using a commercial radioimmunoprecipitation assay. Statistical analysis was conducted in R (V.3.6.1). Dimensionality reduction was performed using Multiple Factor Analysis in ‘FactoMineR’ with up to 10% missing data imputed using missForest. Stepwise Bayesian general linear modelling analysis was undertaken using ‘arm’. Wilson 95% CIs with continuity correction were calculated using ‘DescTools’. Results NSAb findings Of 241 recruited patients, 22 were excluded (online supplemental table 4). Of the remaining 219, median age was 49 years (range 16–91) and 109 (49.8%) were female. In 23/219 (10.5%) patients, serum NSAbs were detected across candidate and novel autoantigens (table 1) including roughly equal frequencies against leucine-rich glioma inactivated-1 (LGI1), contactin-associated protein-like 2 (CASPR2), plus the N-methyl-d-aspartate receptor (NMDAR) and γ-aminobutyric acid A/B receptors (GABAAR and GABABR). An additional five patients had antibodies to the surface of live neurons, without an established autoantigen. Autoantibodies to contactin-2, the glycine receptor and the α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) were each found in one patient. No dipeptidyl-peptidase-like protein 6 (DPPX) or high-titre GAD65 antibodies were detected. Overall, from the 23 people with NSAbs, 9 had a clinical diagnosis of AE (7/9 fulfilling published criteria).11 By contrast, none of the 196 without NSAbs had a clinical diagnosis of AE (p<0.0001; Fisher’s exact test). VIEW INLINE VIEW POPUP Table 1 Clinical and laboratory features of patients with epilepsy and positive neuronal surface autoantibodies Factors associated with the presence of NSAbs and AE Dimensionality reduction with multiple factor analysis showed that patients were highly heterogeneous and the modest clustering of those with NSAbs was largely driven by a clinical diagnosis of AE (figure 1A,B). Univariate analysis identified 11 clinical parameters that differed significantly between patients with and without NSAbs: age (p=0.04), ictal piloerection (p=0.02), lesional MRI (p=0.04), self-reported mood disturbance (p=0.007), ACE attention domain (p=0.01), ACE total score (p=0.04), QOLIE-31 score (p=0.02), self-reported neuropsychiatric features (p=0.03), epilepsy risk factors (p=0.05), inflammatory cerebrospinal fluid (CSF; p=0.004) and limbic system lesions on MRI (p=0.0002). A multivariate stepwise regression model allocated weighted scores to six of these: age ≥54 years=+1, self-reported mood disturbance=+1, limbic system lesions on MRI=+2, ictal piloerection=+2.5, ACE attention score ≥16=−1.5 and epilepsy risk factors=−1.5 (figure 1C). The probability of NSAb positivity increased with higher scores (Spearman’s ρ=0.99, p<0.0001; figure 1C) and receiver operating characteristic (ROC) analysis confirmed these features strongly predicted NSAb status (area under the curve (AUC)=0.83; total score ≥0; sensitivity=66.7%, specificity=84.9%; figure 1D). By contrast, the APE2 score performed less well in predicting NSAb status (sensitivity 43.5%, specificity 79.1%, AUC=0.68) and more accurately predicted criteria-defined AE, particularly if associated with NSAbs (sensitivity 85.7%, specificity 78.8%, AUC=0.94; figure 1E). Figure 1 Clinical phenotypes associated with NSAb status in new-onset focal epilepsy. The first two dimensions are shown, highlighting: (A) NSAb-positive (red) or NSAb-negative (grey) status and (B) NSAb-positive (pale red) or NSAb-negative (grey) without encephalitis (dots), or NSAb-positive (dark red) with clinically diagnosed autoimmune encephalitis (triangles). (C) The proportion of patients by total model score. Error bars show 95% CIs. The inset shows the weighting and SE of each factor within the regression model. (D) Receiver operator characteristic (ROC) curve of the total model score for predicting NSAb status across all patients. (E) ROC curve of the APE2 score for predicting NSAb status across all patients (black), patients not meeting the criteria for autoimmune encephalitis (blue), patients meeting the criteria for autoimmune encephalitis (red) and predicting NSAb-positive criteria-confirmed autoimmune encephalitis across all patients. (F) Scatter plot of modified Rankin score in NSAb-positive patients by immunotherapy status over time (Mann-Whitney U test p values<0.05). AE, autoimmune encephalitis; APE2, Antibody Prevalence in Epilepsy and Encephalopathy; epilepsy RF, epilepsy risk factors; MRI limbic Δ, changes within the limbic system on MRI. Comparisons of those with and without AE From 23 patients with NSAbs (table 1), a comparison of those with (n=9) and without (n=14) a clinical diagnosis of AE revealed several differences in the AE cohort: more ASMs (median of 3 vs 1; p=0.0073), more frequent immunotherapies (7/9 vs 0/14, p=0.0001), higher APE2 scores (median of 6 vs 2; p<0.0001), more frequent MRI limbic inflammation (6/9 vs 0/14; p=0.0008) and a trend towards greater positivity of serum IgGs targeting the surface of live neurons (7/9 vs 5/14, p=0.09). Compared with the seven patients administered immunotherapy, those with NSAbs who were not administered immunotherapy showed lower disability after 1 and 3 years (both p<0.05), and 11/16 (68.8%) were asymptomatic at 3-year follow-up (mRS=0 ; figure 1F). Hence, despite no immunotherapy, patients with NSAbs, but without AE, generally showed good outcomes. Discussion In this prospective study of 219 consecutive adults with new-onset focal epilepsy, NSAb status was best predicted by a combination of clinical parameters which closely resemble features observed in AE. Almost half of our patients with NSAbs were diagnosed with AE, and ~30% fulfilled stringent criteria for AE.11 Of those with NSAbs and more isolated forms of epilepsy, without individual features of AE, almost all were treated with ASMs alone and typically remained asymptomatic at long-term follow-up. Overall, these findings suggest that detection of NSAbs in patients with new-onset seizures, but without features of AE, should not alter current clinical management. Our observations should help guide the frequent clinical dilemma of which patients with new-onset seizures to test for autoantibodies and subsequently treat with immunotherapy. Taken together, our data suggest the clinical phenotype is paramount in guiding the relevance of autoantibody results, and provide data to address an outstanding question from a recent ILAE consensus statement.7 This ILAE statement also highlighted controversy over the term ‘autoimmune epilepsy’.7 In routine clinical practice, this nomenclature acts as a valuable signpost and aide memoire when seeing patients with seizures.2 14 However, ‘epilepsy’ carries several social stigmata and is defined by an enduring tendency to seizures. In AE, this lifelong risk is refuted by a recent study,4 despite several forms of AE commonly leading to hippocampal atrophy.2–4 7 10 The alternative concept of acute symptomatic seizures may more accurately capture the nature of seizures in patients with AE. Data-driven modifications to nomenclature will benefit from longer-term follow-up studies. Ictal piloerection, low mood and attention and MRI limbic system changes are recognised features of late-onset AE, particularly in association with LGI1 antibodies.2 4 14 15 The absence of movement disorders or more diffuse cognitive impairment as predictive factors in our model suggests the overall syndrome may reflect a formes frustes of AE. This contrasts with APE2 score parameters,9 which appear to largely reflect more florid features seen in classical AE. Our observational study has several limitations. These include limited CSF autoantibody measurements, which reflected UK practice particularly at the start of the study period. Yet,w ithout this valuable parameter, a diagnosis of NMDAR-antibody encephalitis is still possible.11 Yet, two of our four patients with serum NMDAR antibodies did not have features consistent with encephalitis, likely suggesting detection of clinically unrelated serum antibodies in these cases. In addition, our series in total only identified nine AE cases, although this may be considered substantial given the largely outpatient-based recruitment. This, and the high (~10%) seroprevalence rate, may reflect a referral bias given Oxford’s interest in AE, but is well aligned with other available estimates.6 9 10 Our serological data identified some samples with NSAbs proven by live cell-based assays, but without concomitant cell surface neuronal reactivities. This was especially evident in the cohort without a clinical diagnosis of AE, and perhaps these antibodies reflect low-affinity or low-titre autoantibodies which are not disease relevant. Their specificity, however, remains reassuring given their typical selectivity for just one of eight surface-expressed autoantigens. In the future, our prediction model will benefit from validation in independent, larger studies which may compare the risk of enduring seizures in the NSAb-positive versus NSAb-negative populations, with and without AE, something which we did not survey at follow-up. Hence, we cannot comment on long-term seizure status in the 5/16 patients (31%) who had NSAbs, no diagnosis of AE and 3-year mRS >0. In these patients, it remains possible that immunotherapy would have led to a greater benefit. However, in our view, this finding is more likely to be consistent with the predicted ~30% of all people with epilepsy who are known to become ASM resistant: this provides a testable hypothesis for a future randomised controlled trial. Overall, our observations support the concept that, in patients who present with new-onset focal seizures, clinical features which are consistent with a ‘mild encephalitis’ helps identify those with NSAbs which should alter patient management. This clinico-serological syndrome appeared characteristic and its recognition will improve detection and treatment of these patients. These findings should discourage widespread screening strategies to identify patients with autoantibodies among unselected seizure cohorts. References ↵Irani SR, Michell AW, Lang B, et al. Faciobrachial dystonic seizures precede Lgi1 antibody limbic encephalitis. Ann Neurol 2011;69:892–900.doi:10.1002/ana.22307 ↵Thompson J, Bi M, Murchison AG, et al. The importance of early immunotherapy in patients with faciobrachial dystonic seizures. Brain 2018;141:348–56.doi:10.1093/brain/awx323OpenUrlCrossRef ↵Geis C, Planagumà J, Carreño M, et al. Autoimmune seizures and epilepsy. J Clin Invest 2019;129:926–40.doi:10.1172/JCI125178OpenUrlPubMed ↵de Bruijn MAAM, van Sonderen A, van Coevorden-Hameete MH, et al. Evaluation of seizure treatment in anti-LGI1, anti-NMDAR, and anti-GABABR encephalitis. Neurology 2019;92:e2185–96.doi:10.1212/WNL.0000000000007475pmid:30979857OpenUrlPubMed ↵Scheffer IE, Berkovic S, Capovilla G, et al. ILAE classification of the epilepsies: position paper of the ILAE Commission for Classification and Terminology. Epilepsia 2017;58:512–21.doi:10.1111/epi.13709pmid:http://www.ncbi.nlm.nih.gov/pubmed/28276062OpenUrlPubMed ↵Brenner T, Sills GJ, Hart Y, et al. Prevalence of neurologic autoantibodies in cohorts of patients with new and established epilepsy. Epilepsia 2013;54:1028–35.doi:10.1111/epi.12127pmid:http://www.ncbi.nlm.nih.gov/pubmed/23464826OpenUrlCrossRefPubMed ↵Steriade C, Britton J, Dale RC, et al. Acute symptomatic seizures secondary to autoimmune encephalitis and autoimmune-associated epilepsy: conceptual definitions. Epilepsia 2020;61:1341–51.doi:10.1111/epi.16571pmid:http://www.ncbi.nlm.nih.gov/pubmed/32544279OpenUrlPubMed ↵von Podewils F, Suesse M, Geithner J, et al. Prevalence and outcome of late-onset seizures due to autoimmune etiology: a prospective observational population-based cohort study. Epilepsia 2017;58:1542–50.doi:10.1111/epi.13834pmid:http://www.ncbi.nlm.nih.gov/pubmed/28681401OpenUrlPubMed ↵Dubey D, Alqallaf A, Hays R, et al. Neurological autoantibody prevalence in epilepsy of unknown etiology. JAMA Neurol 2017;74:397–402.doi:10.1001/jamaneurol.2016.5429pmid:http://www.ncbi.nlm.nih.gov/pubmed/28166327OpenUrlPubMed ↵Dubey D, Kothapalli N, McKeon A, et al. Predictors of neural-specific autoantibodies and immunotherapy response in patients with cognitive dysfunction. J Neuroimmunol 2018;323:62–72.doi:10.1016/j.jneuroim.2018.07.009pmid:http://www.ncbi.nlm.nih.gov/pubmed/30196836OpenUrlPubMed ↵Graus F, Titulaer MJ, Balu R, et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol 2016;15:391–404.doi:10.1016/S1474-4422(15)00401-9pmid:http://www.ncbi.nlm.nih.gov/pubmed/26906964OpenUrlCrossRefPubMed ↵Makuch M, Wilson R, Al-Diwani A, et al. N-Methyl-D-aspartate receptor antibody production from germinal center reactions: therapeutic implications. Ann Neurol 2018;83:553–61.doi:10.1002/ana.25173pmid:http://www.ncbi.nlm.nih.gov/pubmed/29406578OpenUrlPubMed ↵Ramberger M, Berretta A, Tan JMM, et al. Distinctive binding properties of human monoclonal LGI1 autoantibodies determine pathogenic mechanisms. Brain 2020;143:1731–45.doi:10.1093/brain/awaa104pmid:http://www.ncbi.nlm.nih.gov/pubmed/32437528OpenUrlPubMed ↵Quek AML, Britton JW, McKeon A, et al. Autoimmune epilepsy: clinical characteristics and response to immunotherapy. Arch Neurol 2012;69:582–93.doi:10.1001/archneurol.2011.2985pmid:http://www.ncbi.nlm.nih.gov/pubmed/22451162OpenUrlCrossRefPubMed ↵Rocamora R, Becerra JL, Fossas P, et al. Pilomotor seizures: an autonomic semiology of limbic encephalitis? Seizure 2014;23:670–3.doi:10.1016/j.seizure.2014.04.013pmid:http://www.ncbi.nlm.nih.gov/pubmed/24890932OpenUrlCrossRefPubMed
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Specialists and Care Centers for Autoimmune Encephalitis

Specialists and Care Centers for Autoimmune Encephalitis | AntiNMDA | Scoop.it
The Northwestern Medicine Autoimmune Encephalitis and Paraneoplastic Disorders clinic takes a multidiscplinary approach to the diagnosis and care of patients affected by these disorders.
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Neurologic Emergencies at the Extremes of Age

Neurologic Emergencies at the Extremes of Age | AntiNMDA | Scoop.it
The diagnosis and management of neurologic conditions are more complex at the extremes
of age than in the average adult. In the pediatric population, neurologic emergencies
are somewhat rare and some may require emergent consultation.
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(PDF) Anti-N-methyl-D-Aspartate (NMDA) Receptor Encephalitis: A Case Report

(PDF) Anti-N-methyl-D-Aspartate (NMDA) Receptor Encephalitis: A Case Report | AntiNMDA | Scoop.it
PDF | We report case of a 42 years old female who came with a constellation of behavioral symptoms, delirium, body stiffness, and fever for one week....| Find, read and cite all the research you need on ResearchGate...
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RACGP - Old doc, new disease: Anti-NMDA receptor encephalitis

RACGP - Old doc, new disease: Anti-NMDA receptor encephalitis | AntiNMDA | Scoop.it
Dr Casey Parker reflects on an intriguing presentation that made him ask: What else do I not know?
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Cost-Effectiveness of Routine Screening for Autoimmune Encephalitis in Patients With First-Episode Psychosis in the United States |J Clin Psychiatry

Autoimmune encephalitis (AE) is a highly treatable neurologic condition that can cause psychosis. This study estimated the cost-effectiveness of routine screening for AE compared with clinically targeted screening in first-episode psychosis patients.
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Unremitting diarrhoea in a girl diagnosed anti-N-methyl-D-aspartate-receptor encephalitis: A case report | Read by QxMD

Unremitting diarrhoea in a girl diagnosed anti-N-methyl-D-aspartate-receptor encephalitis: A case report | Read by QxMD | AntiNMDA | Scoop.it
Create a free QxMD account to take advantage of the features offered by Read like saving your papers and creating collections. Get Started Unremitting diarrhoea in a girl diagnosed anti-N-methyl-D-aspartate-receptor encephalitis: A case report Norrapat Onpoaree, Montida Veeravigrom, Anapat Sanpavat, Narissara Suratannon, Palittiya Sintusek World Journal of Clinical Cases 2020 October 26, 8 (20): 4866-4875 BACKGROUND: Asymptomatic cytomegalovirus (CMV) infection is common in children; in contrast, in children with a weakened immune system, invasive CMV can occur. This is the first case report of a severe manifestation of CMV esophago-enterocolitis in a girl diagnosed with anti-N-methyl-D-aspartate-receptor (anti-NMDAR) encephalitis who received only a moderate dose of corticosteroid therapy. CASE SUMMARY: A 12-year-old-Thai girl presented with acute behavioural change and headache for 6 d. Electroencephalogram and positivity for NMDAR autoantibodies were compatible with anti-NMDAR encephalitis. Hence, she received pulse methylprednisolone 10 mg/kg per day for 4 d and continued with prednisolone 1.2 mg/kg per day. On day 42 of corticosteroid therapy, she developed unremitting vomiting and diarrhoea. Endoscopy showed multiple ulcers and erythaematous mucosa along the gastrointestinal tract. Tissue CMV viral load and viral-infected cells confirmed CMV esophago-enterocolitis. Therefore, the patient received ganciclovir 5 mg/kg per dose every 12 h for 3 wk and then 5 mg/kg per dose once daily for 3 wk. Unremitting diarrhoea slowly improved from stool output 1-4 L per day to 1-2 L per day after 3 wk of treatment. Pulse methylprednisolone 20 mg/kg for 5 d was initiated and continued with prednisolone 1 mg/kg per day. After this repeated pulse methylprednisolone treatment, surprisingly, diarrhoea subsided. Immunologic work-up was performed to rule out underlying immune deficiency with unremarkable results. CONCLUSION: Unremitting diarrhoea from CMV esophago-enterocolitis subsided with antiviral and methylprednisolone therapy, implying the immune and NMDAR dysregulation in anti-NMDAR encephalitis. Full Text Links We have located links that may give you full text access. Additional links Discussion You are not logged in. Sign Up or Log In to join the discussion. Trending Papers Colchicine in Patients with Chronic Coronary Disease. Stefan M Nidorf, Aernoud T L Fiolet, Arend Mosterd, John W Eikelboom, Astrid Schut, Tjerk S J Opstal, Salem H K The, Xiao-Fang Xu, Mark A Ireland, Timo Lenderink, Donald Latchem, Pieter Hoogslag, Anastazia Jerzewski, Peter Nierop, Alan Whelan, Randall Hendriks, Henk Swart, Jeroen Schaap, Aaf F M Kuijper, Maarten W J van Hessen, Pradyot Saklani, Isabel Tan, Angus G Thompson, Allison Morton, Chris Judkins, Willem A Bax, Maurits Dirksen, Marco M W Alings, Graeme J Hankey, Charley A Budgeon, Jan G P Tijssen, Jan H Cornel, Peter L Thompson New England Journal of Medicine 2020 August 31 Extracorporeal life support for adults with acute respiratory distress syndrome. Alain Combes, Matthieu Schmidt, Carol L Hodgson, Eddy Fan, Niall D Ferguson, John F Fraser, Samir Jaber, Antonio Pesenti, Marco Ranieri, Kathryn Rowan, Kiran Shekar, Arthur S Slutsky, Daniel Brodie Intensive Care Medicine 2020 November 2 Clinical strategies for implementing lung and diaphragm-protective ventilation: avoiding insufficient and excessive effort. Ewan C Goligher, Annemijn H Jonkman, Jose Dianti, Katerina Vaporidi, Jeremy R Beitler, Bhakti K Patel, Takeshi Yoshida, Samir Jaber, Martin Dres, Tommaso Mauri, Giacomo Bellani, Alexandre Demoule, Laurent Brochard, Leo Heunks Intensive Care Medicine 2020 November 2 Emergency Department Management of COVID-19: An Evidence-Based Approach. Nicholas M McManus, Ryan Offman, Jason D Oetman Western Journal of Emergency Medicine 2020 September 25 Glucocorticoids: surprising new findings on their mechanisms of actions. Frank Buttgereit Annals of the Rheumatic Diseases 2020 November 8 Prone position in ARDS patients: why, when, how and for whom. Claude Guérin, Richard K Albert, Jeremy Beitler, Luciano Gattinoni, Samir Jaber, John J Marini, Laveena Munshi, Laurent Papazian, Antonio Pesenti, Antoine Vieillard-Baron, Jordi Mancebo Intensive Care Medicine 2020 November 10 Severe organising pneumonia following COVID-19. István Vadász, Faeq Husain-Syed, Peter Dorfmüller, Fritz C Roller, Khodr Tello, Matthias Hecker, Rory E Morty, Stefan Gattenlöhner, Hans-Dieter Walmrath, Friedrich Grimminger, Susanne Herold, Werner Seeger Thorax 2020 November 11 Analgesia and sedation in patients with ARDS. Gerald Chanques, Jean-Michel Constantin, John W Devlin, E Wesley Ely, Gilles L Fraser, Céline Gélinas, Timothy D Girard, Claude Guérin, Matthieu Jabaudon, Samir Jaber, Sangeeta Mehta, Thomas Langer, Michael J Murray, Pratik Pandharipande, Bhakti Patel, Jean-François Payen, Kathleen Puntillo, Bram Rochwerg, Yahya Shehabi, Thomas Strøm, Hanne Tanghus Olsen, John P Kress Intensive Care Medicine 2020 November 10
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Possible coexistence of MOG-IgG-associated disease and anti-Caspr2 antibody-associated autoimmune encephalitis: a first case report

Possible coexistence of MOG-IgG-associated disease and anti-Caspr2 antibody-associated autoimmune encephalitis: a first case report | AntiNMDA | Scoop.it
Myelin oligodendrocyte glycoprotein antibody-associated disease has been proposed as a separate inflammatory demyelinating disease of the central nervous system (CNS) since the discovery of pathogenic antibodies against myelin oligodendrocyte glycoprotein ...
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The Anti-NMDA Receptor Encephalitis Foundation Newsletter

The Anti-NMDA Receptor Encephalitis Foundation Newsletter | AntiNMDA | Scoop.it
On your Marks, Get Set, Register for the WORLD ENCEPHALITIS DAY CONFERENCE 2021 From...
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Autoimmune encephalitis: When your body attacks your brain, and people think you’re going mad

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Four PhD candidates from Monash University, who are already Doctors of the medical kind, are conducting research on a rare and debilitating neurological illness affecting the Australian population. It’s described as feeling like your brain is on fire.
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Characteristics of internalization of NMDA-type GluRs with antibodies to GluN1 and GluN2B - ScienceDirect

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To characterize internalization of NMDA-type glutamate receptors (GluRs) by antibodies to NMDA-type GluRs, we produced rabbit antibodies to N-terminal…
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