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Clinical characterisation of patients in the post-acute stage of anti-NMDA receptor encephalitis: a prospective cohort study and comparison with patients with schizophrenia spectrum disorders

Clinical characterisation of patients in the post-acute stage of anti-NMDA receptor encephalitis: a prospective cohort study and comparison with patients with schizophrenia spectrum disorders | AntiNMDA | Scoop.it
Instituto Salud Carlos III, NEURON Network of European Funding for Neuroscience Research, National Alliance for Research in Schizophrenia and Affective Disorders, and la Caixa Health-Research Foundation.
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Autoimmune encephalitis: Epidemiology, pathophysiology and clinical spectrum (part 2) | South African Medical Journal

Autoimmune encephalitis: Epidemiology, pathophysiology and clinical spectrum (part 2)	| South African Medical Journal | AntiNMDA | Scoop.it
Authors J Hiesgen Department of Neurology, Faculty of Health Sciences, University of Pretoria, South Africa C M Schutte Department of Neurology, Faculty of Health Sciences, University of Pretoria, South Africa DOI: https://doi.org/10.7196/SAMJ.2023.v113i4.875 Keywords: autoimmune, encephalitis Abstract Autoimmune encephalitis (AE) represents a growing number of severe autoimmune-inflammatory diseases affecting both the white and grey matter of the brain. In part 1 of this series we focused on the epidemiology, pathophysiology and clinical presentation of this condition, with two illustrative cases. In this part, we will introduce the clinical criteria for AE, particularly for the diagnosis of anti-N-methyl-D-aspartate (NMDA) receptor encephalitis, which were developed to facilitate immune treatment in suspected cases before antibody results are available. We subsequently discuss the work up, differential diagnosis and treatment options for patients with this disease. Metrics Metrics Loading ... References Venkatesan A, Tunkel AR, Bloch KC, et al. International Encephalitis Consortium. Case definitions, diagnostic algorithms, and priorities in encephalitis: Consensus statement of the International Encephalitis Consortium. Clin Infect Dis 2013;57(8):1114-1128. https://doi/10.1093/cid/cit458 Graus F, Titulaer MJ, Balu R, et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol 2016;15(4):391-404. https://doi.org/10.1016/S1474-4422(15)00401-9. 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(2):157-165. https://doi.org/10.1016/S1474-4422(12)70310-1. Dalmau J, Graus F. Antibody-mediated encephalitis. N Engl J Med 2018;378:840-851. https://doi.org/10.1056/NEJMra1708712 Dalmau J, Lancaster E, Martinez-Hernandez E, et al. Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis. Lancet Neurol 2011;10(1):63-74. https://doi.org/10.1016/S1474-4422(10)70253-2 Kelley BP, Patel SC, Marin HL, et al. Autoimmune encephalitis: Pathophysiology and imaging review of an overlooked diagnosis. Am J Neuroradiol 2017;38(6):1070-1078. https://doi.org/10.3174/ajnr.A5086 Son DK, Cho SM, Ryu HU, et al. Anti-NMDAR encephalitis with bilateral basal ganglia MRI lesions at a distance of time: A case report. BMC Neurol 2022;22:121. https://doi.org/10.1186/s12883-022-02652-y Heine J, Prüss H, Bartsch T, et al. Imaging of autoimmune encephalitis – relevance for clinical practice and hippocampal function. Neuroscience 2015;19(309):68-83. https://doi.org/10.1016/j.neuroscience.2015.05.037 Kovac S, Alferink J, Ahmetspahic D, et al. Update Anti-N-Methyl-D-Aspartat-Rezeptor-Enzephalitis [Update on anti-N-methyl-D-aspartate receptor encephalitis]. Nervenarzt 2018;89(1):99-112. https://doi.org/10.1007/s00115-017-0405-0 Veciana M, Becerra JL, Fossas P, et al. EEG extreme delta brush: An ictal pattern in patients with anti-NMDA receptor encephalitis. Epilepsy Behav 2015;49:280-285. https://doi.org/ 10.1016/j.yebeh.2015.04.032. Schmitt SE, Pargeon K, Frechette ES, et al. Extreme delta brush: A unique EEG pattern in adults with anti-NMDA receptor encephalitis. Neurology 2012;11;79(11):1094-1100. https://doi.org/10.1212/WNL.0b013e3182698cd8 Parwani J, Ortiz JF, Alli A, et al. Understanding seizures and prognosis of the extreme delta brush pattern in anti-N-methyl-D-aspartate (NMDA) receptor encephalitis: A systematic review. Cureus 2021;21;13(9):e18154. https://doi.org/10.7759/cureus.18154 Gaspard N, Foreman BP, Alvarez V, et al. New-onset refractory status epilepticus: Etiology, clinical features, and outcome. Neurology 2015;85(18):1604-1613. https://doi.org/ 10.1212/WNL.0000000000001940 Granerod J, Ambrose HE, Davies NW, et al. Causes of encephalitis and differences in their clinical presentations in England: A multicentre, population-based prospective study. Lancet Infect Dis 2010;10(12):835-844. https://doi.org/10.1016/s1473-3099(10)70222-x Wang R, Guan HZ, Ren HT, et al. CSF findings in patients with anti-N-methyl-D-aspartate receptor-encephalitis. Seizure 2015;29:137-142. https://doi.org/10.1016/j.seizure.2015.04.005 Irani SR, Bera K, Waters P, et al. N-methyl-D-aspartate antibody encephalitis: Temporal progression of clinical and paraclinical observations in a predominantly non-paraneoplastic disorder of both sexes. Brain 2010;133(6):1655-1667. https://doi.org/ 10.1093/brain/awq113 Gresa-Arribas N, Titulaer MJ, Torrents A, et al. Antibody titres at diagnosis and during follow-up of anti-NMDA receptor encephalitis: A retrospective study. Lancet Neurol 2014;13(2):167-177. https://doi.org/10.1016/S1474-4422(13)70282-5 Prüss H, Finke C, Höltje M, et al. N-methyl-D-aspartate receptor antibodies in herpes simplex encephalitis. Ann Neurol 2012;72(6):902-911. https://doi.org/10.1002/ana.23689 Leypoldt F, Titulaer MJ, Aguilar E, et al. Herpes simplex virus-1 encephalitis can trigger anti-NMDA receptor encephalitis: Case report. Neurology 2013;81(18):1637-1639. https://doi.org/10.1212/WNL.0b013e3182a9f531 Lejuste F, Thomas L, Picard G, et al. Neuroleptic intolerance in patients with anti-NMDAR encephalitis. Neurol Neuroimmunol Neuroinflamm 2016;3(5):e280. https://doi.org/10.1212/NXI.0000000000000280 Abboud H, Probasco JC, Irani S, et al. Autoimmune encephalitis: Proposed best practice recommendations for diagnosis and acute management. J Neurol Neurosurg Psychiatr 2021;92:757-768. https://doi.org/10.1136/jnnp- 2021- 326096 Nepal G, Shing YK, Yadav JK, et al. Efficacy and safety of rituximab in autoimmune encephalitis: A meta-analysis. Acta Neurol Scand 2020;142(5):449-459. https://doi.org/10.1111/ane.13291 Uy CE, Binks S, Irani SR. Autoimmune encephalitis: Clinical spectrum and management. Pract Neurol 2021;21(5):412-423. https://doi.org/10.1136/practneurol-2020-002567 Dinoto A, Ferrari S, Mariotto S. Treatment Options in Refractory Autoimmune Encephalitis. CNS Drugs. 2022;2. https://doi.org/10.1007/s40263-022-00943-z Broadley J, Seneviratne U, Beech P, et al. Prognosticating autoimmune encephalitis: A systematic review. J Autoimmun 2019;96:24-34. https://doi.org/10.1016/j.jaut.2018.10.014. Zhong R, Chen Q, Zhang X. Relapses of anti-NMDAR, anti-GABABR and anti-LGI1 encephalitis: A retrospective cohort study. Front Immunol 2022;9(13):918396. https://doi.org/10.3389/fimmu.2022.918396 Liu X, Guo K, Lin J, et al. Long-term seizure outcomes in patients with autoimmune encephalitis: A prospective observational registry study update. Epilepsia 202;63(7):1812-1821. https://doi.org/10.1111/epi.17245 Hébert J, Day GS, Steriade C, et al. Long-term cognitive outcomes in patients with autoimmune encephalitis. Can J Neurol Sci 2018;45(5):540-544. https://doi.org/10.1017/cjn.2018.33 Balu R, McCracken L, Lancaster E. A score that predicts 1-year functional status in patients with anti-NMDA receptor encephalitis. Neurology 2019;92(3):e244-e252. https://doi.org/10.1212/WNL.0000000000006783 Thompson J, Bi M, Murchison AG, et al. Faciobrachial Dystonic Seizures Study Group. The importance of early immunotherapy in patients with faciobrachial dystonic seizures. Brain 2018;141(2):348-356. https://doi.org/10.1093/brain/awx323 Schubert J, Brämer D, Huttner HB, GENERATE and IGNITE network. Management and prognostic markers in patients with autoimmune encephalitis requiring ICU treatment. Neurol Neuroimmunol Neuroinflamm 2018;6(1):e514. https://doi.org/ 10.1212/NXI.0000000000000514
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Rare Conditions, Diagnostic Challenges, and Controversies in Clinical

Rare Conditions, Diagnostic Challenges, and Controversies in Clinical | AntiNMDA | Scoop.it
This book highlights those rare, difficult to diagnose or controversial cases in contemporary clinical neuropsychology.The evidence base relevant to this type...
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Announcing the New Neurology® Assistant Editors | American Academy of Neurology Journals

Announcing the New Neurology® Assistant Editors | American Academy of Neurology Journals | AntiNMDA | Scoop.it
Neurology announces the selection of two new Assistant Editors, Dr. Amy Kunchock and Dr. Andrea Schneider, who begin their positions on April 1, 2022.
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Autoimmune psychosis: an international consensus on an approach to the diagnosis and management of psychosis of suspected autoimmune origin

Autoimmune psychosis: an international consensus on an approach to the diagnosis and management of psychosis of suspected autoimmune origin | AntiNMDA | Scoop.it
There is increasing recognition in the neurological and psychiatric literature of patients with so-called isolated psychotic presentations (ie, with no, or minimal, neurological features) who have tested positive for neuronal autoantibodies (principally N-methyl-D-aspartate receptor antibodies) and...
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Viral, bacterial, metabolic, and autoimmune causes of severe acute encephalopathy in sub-Saharan Africa: a multicenter cohort study

To assess whether viral, bacterial, metabolic, and autoimmune diseases are missed
by conventional diagnostics among children with severe acute encephalopathy in sub-Saharan
Africa.
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Phylogenetic Analysis to Explore the Association Between Anti-NMDA Receptor Encephalitis and Tumors Based on microRNA Biomarkers

Phylogenetic Analysis to Explore the Association Between Anti-NMDA Receptor Encephalitis and Tumors Based on microRNA Biomarkers | AntiNMDA | Scoop.it
MicroRNA (miRNA) is a small non-coding RNA that functions in the epigenetics control of gene expression, which can be used as a useful biomarker for diseases. Anti-NMDA receptor (anti-NMDAR) encephalitis is an acute autoimmune disorder.
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How autoimmune disease can attack the brain, cause psychiatric symptoms - The

How autoimmune disease can attack the brain, cause psychiatric symptoms - The | AntiNMDA | Scoop.it
New research suggests that a subset of patients with psychiatric conditions like schizophrenia may actually have autoimmune disease that attacks the brain.
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Development and validation of a risk score to differentiate viral and autoimmune encephalitis in adults

This risk score allows clinicians to estimate the probability of AE in patients presenting with encephalitis and may assist with earlier diagnosis and treatment.
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Clinical characteristics of autoimmune encephalitis with co-existence of multiple anti-neuronal antibodies | Research Square

Background Autoimmune encephalitis (AE) usually referred to a single anti-neuronal antibody-mediated encephalopathy syndrome. AE with co-existence of multiple anti-neuronal antibodies was reported in a few case reports or single-center retrospective studies.
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Biomedicines | Free Full-Text | Spatial and Ecological Factors Modulate the Incidence of Anti-NMDAR Encephalitis—A Systematic Review

Anti-NMDAR encephalitis has been associated with multiple antigenic triggers (i.e., ovarian teratomas, prodromal viral infections) but whether geographic, climatic, and environmental factors might influence disease risk has not been explored yet.
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Josep Dalmau receives the “Scientific Breakthrough 2023” Award from the American Brain Foundation

The accolade recognises the commitment of this Clínic Barcelona-IDIBAPS researcher to deepening our understanding of autoimmune neurological diseases such...
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Granulocyte activation markers in cerebrospinal fluid differentiate acute neuromyelitis spectrum disorder from multiple sclerosis | Journal of Neurology, Neurosurgery & Psychiatry

Granulocyte activation markers in cerebrospinal fluid differentiate acute neuromyelitis spectrum disorder from multiple sclerosis | Journal of Neurology, Neurosurgery & Psychiatry | AntiNMDA | Scoop.it
WHAT IS ALREADY KNOWN ABOUT THIS TOPICNeuromyelitis optica spectrum disorder (NMOSD) is difficult to differentiate from multiple sclerosis (MS) based on clinical and MRI features, and 20%–40% of patients score negative for the gold-standard diagnostic biomarker, anti-aquaporin-4 protein-antibodies (aAQP4).Furthermore, this biomarker does not associate with specific clinical disease features.Granulocyte invasion into brain lesions is a key feature of NMOSD, however the potential of granulocyte activation markers (GAM) to differentiate NMOSD from MS has not been explored.WHAT THIS STUDY ADDSIncreased cerebrospinal fluid levels of GAM differentiate NMOSD from MS as reliably as aAQP4 in acute stages of disease, including also patients with aAQP4− NMOSD.Furthermore, levels of GAM, but not of other biomarkers upregulated in NMOSD, correlate with the actual degree of neurological impairment in acute NMOSD.HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICYGAM are novel biomarkers for NMOSD that may close a diagnostic gap at the time of first clinical exacerbation, when timely initiation of effective therapy is crucial for therapeutic success.In addition, levels of GAM also associate with clinical disability scores at first presentation.Together with existing preclinical evidence, the current observations suggest a pathogenic role of GAM in NMOSD and may facilitate the development of novel therapeutic approaches for the treatment of acute-stage NMOSD.IntroductionNeuromyelitis optica spectrum disorder (NMOSD) and relapsing-remitting multiple sclerosis (RRMS) share clinical and imaging characteristics, which can make it difficult to differentiate them, and hence may delay the initiation and the choice of adequate therapy.1 The detection of auto-antibodies targeting the astrocyte water channel anti-aquaporin-4 protein (aAQP4) has become a pivotal biomarker tool to diagnose NMOSD. However, 20%–40% of patients eventually fulfilling NMOSD criteria remain aAQP4− which makes it even more difficult to establish the accurate diagnosis.2–5 Furthermore, the presence or the titre of aAQP4 is not related to clinical disease characteristics.4 Several biomarkers tend to be more highly elevated in NMOSD than in MS, for example, glial fibrillary acidic protein (GFAP), and S100B (both markers of astrocyte damage),6 7 neurofilament light chain (NfL, a marker of neuroaxonal injury),6 8 chemokine (C-X-C motif) ligand 13 (CXCL13, a B-cell attractant),9–11 intercellular adhesion molecule-1 (ICAM-1) and vascular cellular adhesion molecule-1 (VCAM-1) (both leucocyte adhesion molecules)12 and matrix metalloproteinase-9 (MMP-9, a matrix remodelling gelatinase).13 Yet, all lack the necessary diagnostic specificity due to overlapping concentration ranges in the two diseases, and the relation between levels in cerebrospinal fluid (CSF) or blood with clinical severity remains uncertain.6In NMOSD, activation of neutrophil granulocytes occurs in blood circulation, and their invasion into inflamed neural tissue is observed in 95% of NMOSD brain tissue specimens, a feature that differentiates it categorically from typical MS lesions; the involvement of granulocyte invasion in lesion formation has recently been demonstrated also in myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD).14–20 In the course of acute inflammation, granulocytes release a wide range of proteases and other proteins from their granular compartments, granulocyte activation markers (GAM), some of which are cell-specific such as neutrophil elastase (nEla), myeloperoxidase (MPO), matrix metalloproteinase-8 (MMP-8) and neutrophil gelatinase-associated lipocalin (NGAL), or are partially cell-specific, like tissue inhibitor of metalloproteinase-1 (TIMP-1) and MMP-9. We hypothesised that in NMOSD, including in aAQP4− cases, GAM produce a humoral footprint in CSF that allows to differentiate NMOSD from RRMS, and that their levels correlate with clinical severity at the time of CSF sampling to give support for their pathogenetic role in NMOSD, as suggested in preclinical models and neuropathological findings.16 In this case-control study, we quantified levels of GAM in acute and subacute/chronic (s/c) NMOSD and RRMS, along with MMP-9, NfL, GFAP, S100B, ICAM-1, VCAM-1, CXCL13 to define a precision medicine tool for the diagnosis of acute-stage NMOSD.MethodsParticipants and samplesThe diagnosis of NMOSD with/without aAQP4, and of RRMS was based on respective standard diagnostic criteria.21 22 Acute disease exacerbation/relapse was defined according to 2017 McDonald criteria.22 Disability was assessed using the Expanded Disability Status Scale (EDSS).23 The discovery cohort from Kyushu University Hospital (Fukuoka, Japan) consisted of 34 patients with NMOSD with 42 CSF samples (2 patients contributed 3 CSF samples, 4 patients contributed 2 CSF samples), and 36 patients with RRMS with 40 CSF samples (4 patients contributed 2 CSF samples); these repeated lumbar punctures were performed following independent disease exacerbations. The validation cohort consisted of 25 patients with NMOSD from Kyushu University Hospital (n=11), Ospedale San Raffaele and Mondino Foundation (Milan and Pavia, Italy) (n=8) and Karolinska University Hospital (Stockholm, Sweden) (n=6) and 46 patients with MS (Kyushu n=18, Karolinska n=28). Two control groups (University Hospital Basel, Switzerland) were used to determine values under physiological and highly inflammatory conditions, respectively: ‘symptomatic controls’ (SC)24 consisted of 25 patients in whom a structural neurological disease was excluded, based on normal findings in clinical and MRI evaluations, normal CSF cell composition and protein content and absence of signs of intrathecal immunoglobulin synthesis. The second control group comprised 15 patients with various types of acute inflammatory neurological disease controls24 (inflammatory neurological disease controls: meningoencephalitis/polyradiculitis due to (a) varicella zoster virus (n=5) and (b) tuberculosis (n=1), (c) viral meningitis (n=3), (d) neuroborreliosis (n=3), (e) eosinophilic encephalitis (n=1), (f) autoimmune encephalitis/myelomeningoradiculitis of unknown cause (n=2)).Measurement of biomarkersStandard CSF analyses were performed at each centre independently, while here investigated biomarkers were analysed centrally. Expression levels of 12 markers were determined by ELISA and single molecule array assay in the discovery cohort (table 1). CSF samples with >1 erythrocyte/µL were excluded from the analysis. Sample identities in both cohorts were blinded until all analyses had been completed. All samples and calibrators were assayed in duplicate. An explorative analysis of biomarker levels categorised for sites of origin of samples showed comparable values of GAM (not shown).View inline View popup Table 1 Analytical panel of biomarkersStatistical analysisCSF levels of biomarkers are presented as median and IQRs by diagnostic groups and were compared using the Wilcoxon rank-sum test. To determine the capacity of distinguishing between NMOSD and RRMS without the potential confounding effect of corticosteroid pretreatment, we repeated the same analyses in treatment-naïve patients. To investigate the temporal dynamics of biomarker concentrations, we used for each biomarker an individual linear model to describe the levels in NMOSD and RRMS within a 60-day period after acute disease exacerbation; this period was defined in days between the onset of acute disease exacerbation and lumbar puncture. Biomarker levels were log-transformed and served as dependent variable. Diagnosis (RRMS vs NMOSD) and time since disease exacerbation, as well as the interaction between these two variables, were used as independent variables. The interaction indicates whether the temporal dynamics differ between patients with NMOSD and RRMS. Again, sensitivity analyses were run after exclusion of pretreated patients. In accordance with the exploratory nature of these analyses, no correction for multiple testing was performed. Accordingly, p values should not be interpreted as confirmatory but rather as a continuous measure of evidence against the corresponding null-hypothesis.The correlation between biomarker levels and EDSS score was quantified using Spearman’s rank correlation coefficient. The diagnostic capacity of GAM to differentiate NMOSD from RRMS in acute stages (≤21 days after onset of exacerbations) was determined by a logistic model where the disease type (NMOSD vs RRMS) served as dependent variable, and biomarkers, or composites of biomarkers, as independent variables. The predictions from these models were assessed with receiver operating characteristic (ROC) curves, based on pooled data of discovery and validation cohorts. We performed this analysis with and without time of sampling since disease exacerbation as a covariate, in acute patients and in those without corticosteroid pretreatment. For each model, the area under the curve (AUC), as well as sensitivity, specificity, positive and negative predictive value, based on the optimal cut-off according to the Youden Index, are presented. To test the robustness of the model in terms of replicability and to address the risk of overfitting in function of the numbers of markers and time as a covariate in composite models, we validated them by calculating optimism-corrected AUCs based on 500 bootstrap replicates. All analyses were carried out using the statistical software R (V.4.1.2, The R Foundation for Statistical Computing). The significance level was set at p=0.05.ResultsDemographics of discovery and validation cohort of patientsTable 2 shows the baseline characteristics of patients with NMOSD and RRMS in the discovery and validation cohort; they were stratified into ‘acute’ (≤21 days) and s/c (>21 days) stages, depending on the time between onset of acute clinical symptoms and lumbar puncture. All patients with NMOSD were aAQP4+, except three in the discovery and four in the validation cohort (of those, one became positive during a later attack); of these seven patients, six scored negative for anti-MOG antibodies (one patient was not tested). Patients with NMOSD in both cohorts were older and had higher EDSS scores than patients with RRMS. The majority of CSF samples (76.2% in the discovery and 48.0% in the validation cohort) were from patients with NMOSD on continuous oral, or who had received intravenous corticosteroid therapy before the time of CSF sampling, while for patients with RRMS the corresponding proportions were much smaller (37.5% and 8.7%, respectively).View inline View popup Table 2 Demographic and clinical characteristics of patient groups and control personsBiomarker expression profiles in NMOSD and RRMS in discovery and validation cohortsIn the discovery cohort, GAM levels were higher in (a) NMOSD versus RRMS overall, (b) acute versus s/c NMOSD and (c) acute NMOSD versus acute RRMS. The astrocyte markers GFAP and S100B and adhesion molecules VCAM-1 and ICAM-1 were increased in NMOSD versus RRMS (overall and acute), while in acute versus s/c NMOSD this was only the case for S100B. In contrast, levels of NfL, MMP-9 and CXCL13 were not different for these three comparisons (table 3, online supplemental figure 1A).Supplemental material[jnnp-2022-330796supp001.pdf]View inline View popup Table 3 Levels of biomarkers, all patientsIn acute NMOSD, the median expression levels of granulocyte-specific GAM (nEla, MPO, NGAL) and of TIMP-1 were similar compared with INCDs; only MMP-8 was slightly higher in NMOSD versus INDC, while for MMP-9 levels were higher in INCD. All analysed markers were higher in acute NMOSD versus SC except for S100B (online supplemental table 1). In s/c NMOSD, all GAM markers, TIMP-1, ICAM-1 and VCAM-1 were lower compared with INCD (online supplemental figure 1A).Because many markers analysed in the discovery cohort have not been evaluated in NMOSD, we decided to confirm these results in an independent validation cohort. The findings for GAM were fully confirmed in the validation cohort for the comparison of NMOSD versus RRMS (both ‘all’ and ‘acute’), and in part for the comparison of acute versus s/c NMOSD (only four s/c NMOSD samples available) (table 3). Subsequent analyses were therefore performed in the merged discovery/validation set.Other than in NMOSD, there were no significant differences between acute and s/c levels of GAM and the other markers in RRMS, apart from NGAL and TIMP-1 being higher in s/c RRMS (p=0.013 and p=0.006, respectively), while all other markers were not different between these disease stages in the merged discovery/validation set.Impact on biomarker levels by immunomodulatory and corticosteroid therapy prior lumbar punctureGAM levels of patients under immunomodulatory plus corticosteroid therapy showed a strong overlap compared with those of patients being treated only with corticosteroids, in both acute and s/c phases, suggesting that these compounds used for prevention of further NMOSD relapses have no significant impact on granulocyte activation; in contrast, patients under corticosteroid therapy had lower GAM levels in s/c, and to a lesser extent in acute NMOSD, compared with patients without treatment (online supplemental figure 1B). However, GAM and adhesion molecule levels were only numerically higher without as compared with the combined groups with corticosteroid (overall and intravenous); only for nEla this was significant (online supplemental table 2).After exclusion of corticosteroid treated patients, the higher levels of GAM and adhesion molecules in NMOSD versus RRMS (‘all’ and ‘acute’) as seen in overall patients (table 3) were confirmed, while those of MMP-9, NfL and CXCL13 were again not different; this was also the case for GFAP (not shown).Association between biomarker levels disease severity/disability status, aAQP4 status and CSF granulocyte countFigure 1 shows that CSF levels of GAM in all (with or without therapy) patients with NMOSD were correlated with EDSS scores (rho=0.31–0.46, all p≤0.01). In acute NMOSD, this was also the case for NGAL, MMP-8 and TIMP-1 (rho=0.39–0.50, p<0.001–0.011, but not for nEla and MPO, while in s/c NMOSD only nEla was correlated with the EDSS score (rho=0.41, p=0.036) (online supplemental table 3). GFAP levels, only analysed in the discovery set, did not correlate with the EDSS score in acute NMOSD and RRMS, while this was the case in s/c phase for NMOSD (rho=0.58 (0.21, 0.81), p=0.004), and a referring trend was found for RRMS (rho=0.40 (−0.01, 0.81), p=0.004). In the seven patients with aAQP4− NMOSD, GAM levels were similar to those of patients with aAQP4+ NMOSD (figure 1). Interestingly, there was not a general downregulation of GAM levels across all corticosteroid-treated patients, but instead a random distribution with many patients scoring 1–2 logs above average GAM levels (figure 1). In contrast, S100B, NfL, MMP-9 and CXCL13 were not associated with EDSS scores or had rho values ≤0.29 in NMOSD, with or without corticosteroid pretreatment; furthermore, in RRMS all these biomarkers showed only weak correlation (rho≤0.3) with EDSS scores (not shown).<img width="440" height="236" src="https://jnnp.bmj.com/content/jnnp/early/2023/04/23/jnnp-2022-330796/F1.medium.gif"; class="highwire-fragment fragment-image" alt="Figure 1">Download figure Open in new tab Download powerpoint Figure 1 Association between clinical disease severity and granulocyte activation markers levels in patients with NMOSD. Biomarker values are in pg/mL. Values on x-axis show the EDSS score at the time point of lumbar puncture. Regression lines show correlations in NMOSD patients without (acute <img class="highwire-embed" src="https://jnnp.bmj.com/sites/default/files/highwire/jnnp/early/2023/04/23/jnnp-2022-330796/F1/embed/inline-graphic-1.gif"; alt="Embedded Image">; s/c:<img class="highwire-embed" alt="Embedded Image" src="https://jnnp.bmj.com/sites/default/files/highwire/jnnp/early/2023/04/23/jnnp-2022-330796/F1/embed/inline-graphic-2.gif">;) corticosteroid pre-treatment; patients with (acute: <img class="highwire-embed" alt="Embedded Image" src="https://jnnp.bmj.com/sites/default/files/highwire/jnnp/early/2023/04/23/jnnp-2022-330796/F1/embed/inline-graphic-3.gif">; s/c:<img src="https://jnnp.bmj.com/sites/default/files/highwire/jnnp/early/2023/04/23/jnnp-2022-330796/F1/embed/inline-graphic-4.gif"; alt="Embedded Image" class="highwire-embed">) corticosteroid pre-treatment. Open symbols designate aAQP4− patients. The Spearman’s correlation analysis of all, acute and s/c cohorts of patients showed significant correlations with the EDSS score; note that intercellular adhesion molecule-1 and vascular cellular adhesion molecule-1 levels correlated as well with EDSS scores (see online supplemental table 3). EDSS, Expanded Disability Status Scale; MMP-8, matrix metalloproteinase 8; MPO, myeloperoxidase; nEla, neutrophil elastase; NGAL, neutrophil gelatinase-associated lipocalin; NMOSD, neuromyelitis optica spectrum disorder; TIMP-1, tissue inhibitor of metalloproteinase-1.The adhesion molecules ICAM-1 and VCAM-1 were similarly associated with EDSS scores as GAM in all, and partly in acute, NMOSD (online supplemental table 3). Being substrates for proteolytic cleavage from the cell surface by nEla and other granulocyte proteases,25 26 levels of nEla showed a strong correlation with those of ICAM-1 and VCAM-1, while this was not the case for RRMS (online supplemental figure 2); results remained essentially the same when corticosteroid-treated patients were excluded (not shown).Granulocytes were present in nine (21%) CSF samples of patients with NMOSD of the discovery cohort. The granulocyte CSF cell count showed strong correlation with levels of granulocyte-specific activation markers, while there was only a trend for TIMP-1 and MMP-9, and no correlation with NfL and CXCL13 (online supplemental figure 3). None of these markers correlated with the CSF granulocyte cell count in INDCs or in RRMS.Temporal dynamics of biomarker levels in relation to time between disease exacerbation and lumbar punctureTo further explore the temporal dynamics of biomarker levels observed by categorical analysis (table 3), we ran a time-dependent model applying a time window of up to 60 days after disease exacerbation (figure 2A,B). Thus, we identified three different kinetic patterns of biomarkers in NMOSD versus RRMS. Pattern 1, characterised by peak levels at NMOSD disease exacerbation with stably low or only slightly increased levels (NGAL, TIMP-1) in RRMS, comprised GAM, GFAP, S100B and adhesion molecules. All these markers discriminated NMOSD from RRMS based on the non-overlapping pointwise 95% CIs within the acute disease stage, that is, ≤21 days after disease exacerbations. In contrast, MMP-9, CXCL13 and NfL did not differ between acute stages of NMOSD and RRMS; the former two decreasing from onset in both conditions (pattern 2) and the latter increasing over time in NMOSD and RRMS (pattern 3).<img height="440" class="highwire-fragment fragment-image" alt="Figure 2" src="https://jnnp.bmj.com/content/jnnp/early/2023/04/23/jnnp-2022-330796/F2.medium.gif"; width="416">Download figure Open in new tab Download powerpoint Figure 2 Modelled kinetics of biomarker levels in NMOSD and RRMS in function of days after disease exacerbation. Biomarker values are in pg/mL. Values on x-axis show days after disease exacerbations. Dotted lines determine 95% CI, based on all patients. (A) Pattern 1: increased in NMOSD, stably low (nEla, MPO. MMP-8, GFAP, S100B, ICAM-1, VCAM-1), or slightly increasing over time (NGAL, TIMP-1) in RRMS. (B) Pattern 2: increased in both NMOSD and RRMS at disease exacerbation: MMP-9 and CXCL13; pattern 3: stably high in NMOSD and RRMS: NfL. NMOSD: yellow (pooled cohorts), red (discovery cohort only); RRMS: brown (pooled cohorts), green (discovery cohort only). CXCL13, C-X-C motif chemokine 13; GFAP, glial fibrillar acidic protein; ICAM-1, intercellular adhesion molecule-1; MMP, matrix metalloproteinase; MPO, myeloperoxidase; nEla, neutrophil elastase; NGAL, neutrophil gelatinase-associated lipocalin; NfL, neurofilament light chain; NMOSD, neuromyelitis optica spectrum disorder; RRMS, relapsing-remitting multiple sclerosis; TIMP-1, tissue inhibitor of metalloproteinase-1; S100B, S100 calcium-binding protein; VCAM-1, vascular cell adhesion molecule-1.Efficacy of single and combined biomarkers to differentiate between acute stages of NMOSD and RRMSWe next explored the diagnostic value of single GAM concentrations and of their composites to differentiate NMOSD from RRMS. To simulate a situation of unclear differential diagnosis at first disease exacerbation, we restricted the analyses to patients in acute disease stage who had not been exposed to corticosteroids before CSF sampling. Results were expressed as ROC curves with analyses being performed with and without time since exacerbation as covariate. Introducing the time elapsed from symptom onset to CSF sampling as cofactor did not improve AUC values of single GAM (0.74–0.91 with, and 0.69–0.85 without time as covariate), and had an inconsistent effect on measures of prediction of diagnosis (table 4). The combination of granulocyte-specific GAM (composite 1) alone, or in addition with TIMP-1 (composite 2), as an integrated marker raised AUC values to levels 0.90 and 0.94, respectively, leading to sensitivity and specificity values of 0.87 and 0.81 (composite 1) and 0.87 and 1.0 (composite 2), respectively (figure 3, table 4). Here, the inclusion of time as covariate further improved specificity and sensitivity values of composite 2 to 1.00 and 0.92. Neither the additional inclusion of S100B nor that of adhesion molecules into a larger composite improved the capacity to discriminate between NMOSD and RRMS further (not shown). When the risk of overfitting was addressed by calculating the AUC on 500 bootstrap replicates, these results were confirmed. Accordingly, the optimism-corrected AUCs showed a minimal reduction of both composite 1 and 2 to discriminate between NMOSD and RRMS (table 4). In essence, in untreated patients with NMOSD, with inclusion of time since disease exacerbation, specificity and sensitivity scores of these composites were within the same range as gold-standard live cell-based detection platforms for aAQP4, and better than referring ELISA-based assays27 (table 5). In patients with aAQP4− NMOSD, 71% overall (5/7 with and without corticosteroid or immunomodulatory pretreatment) and 100% (4/4) without corticosteroid pretreatment have been diagnosed based on GAM composite models as NMOSD; the two patients with NMOSD who scored negative in both algorithms had received intravenous corticosteroids or intravenous immunoglobulins 4 and 8 days prior lumbar puncture, respectively (table 6).View inline View popup Table 4 ROC analyses of pattern 1 biomarkers (granulocyte-activation markers, S100B, adhesion molecules) to differentiate NMOSD from RRMS of pooled cohorts in acute stages in patients without corticosteroid pretreatmentView inline View popup Table 5 Comparison of validity measures of biomarker composites and aAQP4 testing to differentiate between acute NMOSD and acute RRMSView inline View popup Table 6 Identification of patients with aAQP4− NMOSD by GAM composite algorithms<img width="405" alt="Figure 3" height="440" class="highwire-fragment fragment-image" src="https://jnnp.bmj.com/content/jnnp/early/2023/04/23/jnnp-2022-330796/F3.medium.gif">Download figure Open in new tab Download powerpoint Figure 3 ROC curves for the differentiation between NMOSD and RRMS in patients without corticosteroid pretreatment without (A, B) and with (C, D) time as covariate A B C D ROC curves of individual (A, C) GAM and their composites (B, D) (composite 1=nEla+ MPO+NGAL+MMP-8; composite 2=nEla+MPO+NGAL+MMP-8+TIMP-1). For numerical values of AUC (95% CIs), specificity and sensitivity, see table 4. AUC, area under the curve; MMP-8, matrix metalloproteinase 8; MPO, myeloperoxidase; nEla, neutrophil elastase; NGAL, neutrophil gelatinase-associated lipocalin; NMOSD, neuromyelitis optica spectrum disorder; ROC, receiver operating characteristics; RRMS, relapsing-remitting multiple sclerosis; TIMP-1, tissue inhibitor of metalloproteinase-1.DiscussionCurrent results demonstrate that GAM produce a humoral footprint in CSF that can be used clinically to differentiate these two diseases with equal sensitivity and specificity as aAQP4 in a setting of first disease exacerbation. Our findings also establish GAM as disease activity marker by the correlation of their levels with clinical severity at NMOSD exacerbation, a feature that distinguishes them from the purely diagnostic capacity of aAQP4.4 Moreover, as GAM are also upregulated in aAQP4− NMOSD, they can close a diagnostic gap for these patients.5 Accordingly, metabolomic approaches have allowed to differentiate with high accuracy aAQP4− NMOSD versus MS based on increased plasma levels of myoinositol and formate in the latter disease; different from our study cohort these results were derived from an out of relapse population and it is not known whether the differentiation between the two disease would apply as well in acute disease.28The correlations of GAM levels with CSF granulocytosis and acute disability scores strengthen the concept of a pathogenetic link between recruitment and activation of granulocytes, neural tissue damage and development of disability in NMOSD. In this context, it is notable that a significant number of patients with acute and s/c NMOSD had markedly increased GAM concentrations, despite corticosteroid or immunomodulating therapy prior to sampling. On the group level, current results suggest that such therapy has only limited capacity to reduce GAM expression in the course of NMOSD exacerbation.Most other markers tested here displayed overlapping concentration ranges in acute stages of NMOSD versus RRMS, making them unsuitable for differentiating the two diseases in case of individual exacerbations. Furthermore, their levels did not correlate with disability scores, likely because their modulation reflects downstream effects in the course of the inflammatory response in NMOSD. Nevertheless, generic tissue injury-markers, such as NfL and GFAP, may still be clinically useful, as they allow to monitor disease activity and therapeutic response in NMOSD and may predict its long-term disability course, not the least since blood-based samples allow for longitudinal assessments.6 29 30 Despite not being granulocyte products, the leucocyte adhesion molecules VCAM-1 and ICAM-1 were increased in NMOSD compared with RRMS in present results and as found by others.12 Their increase may be an indirect result of the release of enzymes in the course of granulocyte activation, since both molecules are substrates for proteolysis by elastase and other neutrophil secretory enzymes.25 26The half-life time and kinetics of GAM under physiological conditions and in disease are unknown and may show incongruent kinetics among them. Accordingly, as the time between start of their release in the course of disease exacerbation and lumbar puncture may vary, the individual levels of GAM did not show a consistent pattern of correlation. These findings have their correlate in a recent study in patients with type 2 diabetes mellitus where increased serum levels of nEla and MPO showed only a moderate (rho=0.56) correlation.31 Hence, the rational for the use of GAM composites, rather than a single marker, for the differentiation between NMOSD and MS is to compensate the variability of their levels at respective times of lumbar puncture. An advantage of the proposed GAM composites is that they rest on an analytical platform, ELISA, that is simple to execute and technically robust and allows to differentiate patients with aAQP4− NMOSD from MS, this within a day of sampling as compared with a 1–2 weeks laboratory turnaround time of gold-standard cell-based assays for aAQP4.32 33 Both aspects are clinically important, as the diagnosis of acute NMOSD necessitates a seamless start of plasma exchange (PEX), to optimise its effectiveness.34–36 PEX may not remain the only therapeutic option as novel immunomodulatory therapies specifically interfering with effector molecules of NMOSD pathogenesis, such as protease and complement inhibitors, may emerge as acute phase therapies. For example, eculizumab is currently registered only as interval therapy for secondary prophylaxis against acute exacerbations of NMOSD. However, this compound is in off-label use in acute phases of haemolytic-uraemic syndrome37 among other diseases that go along with acute complement factor 5 (C5) activation and may also be a therapeutic option in patients with NMOSD with acute exacerbations when PEX provides only limited or no benefit.38 Here, GAM composites may be a valuable biomarker for therapeutic decision making, on the background of the enormous costs of anti-C5-antibody therapies.The clinical finding of a correlation of GAM with neurological impairment corroborate a large body of evidence for the pathogenic role of granulocytes and their secretory products in preclinical models of NMOSD. Thus, granulocyte depletion preserves blood-brain barrier integrity and reduces lesional damage in in vivo rodent models of NMOSD, while induction of a neutrophilic state by granulocyte colony-stimulating factor led to increased neural damage.16 39 An ex vivo model of NMOSD showed extensive potentiation of complement-mediated spinal cord damage by the addition of elastase,40 which could partly be suppressed by the elastase-inhibitor sivelestat and other inhibitors of neutrophil enzymes.16 39 40 Sivelestat also demonstrated therapeutic effects in a rodent in vivo model of NMOSD, but not in MS-like experimental autoimmune encephalomyelitis.41 This study also observed increased serum levels of nEla in patients with NMOSD and provided a possible explanation why interferon-β seems to induce NMOSD exacerbations in humans, since this cytokine induces the release of nEla in cultured granulocytes.41LimitationsThe diagnostic capacity of GAM was only evaluated in NMOSD versus RRMS, while increasing evidence suggests that granulocytes are also involved in the pathogenesis of MOGAD, that is as well difficult to distinguish in acute stage from RRMS and NMOSD.18 19 In a preliminary report, we have found that patients with MOGAD, similarly to NMOSD, displayed a GAM pattern that differentiated it from RRMS.42 We are currently extending these preliminary data based on a larger cohort of patients with MOGAD, in an attempt to explore possible qualitative and quantitative differences of biomarker profiles between this condition, RRMS and NMOSD. Second, there is a need to expand the database of the capacity of GAM to identify aAQP4− NMOSD, as the number of patients is currently small.ConclusionsCurrent findings establish GAM as first biofluid markers of NMOSD reflective of the clinical degree of neurological impairment. Second, they establish GAM as an alternative biomarker to aAQP4 for the differential diagnosis of NMOSD versus RRMS, also comprising aAQP4− disease that shares with typical NMOSD granulocyte activation as a common pathomechanism. Third, together with previous preclinical evidence that inhibition of proteolytic activity of granulocyte-derived enzymes inhibits tissue damage in NMOSD models, this study identifies GAM as potential novel drug targets for acute-stage NMOSD.Data availability statementData are available on reasonable request.Ethics statementsPatient consent for publicationNot applicable.Ethics approvalThis study was approved by StockholmRegionala Etikprövningsnämnden i Stockholm 2010-02-16, amended several times, last amendment (including waiver for reconsenting those sampled previously), Etikprövningsmyndigheten (Stockholm avdelning 2 medicin), Dnr 2022-03650-022. San RafaeleIRCCS San Raffaele Hospital Ethical Committee, study acronym BANCA-INSPE, number DSAN 1178/53. BaselEthikkommission beider Basel Ref. Nr. EK: 332/064. Pavia Local Ethics Committee IRCCS San Matteo, Pavia, Italy, project code p-202000395415, Kyushu Ethical Committee of Kyushu University (reference number: 730-04). 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Brain 2021;144:2401–15. doi:10.1093/brain/awab102OpenUrlCrossRef↵Hochmeister S, Gattringer T, Asslaber M, et al. A fulminant case of demyelinating encephalitis with extensive cortical involvement associated with anti-MOG antibodies. Front Neurol 2020;11(February):31. doi:10.3389/fneur.2020.00031OpenUrl↵Höftberger R, Guo Y, Flanagan EP, et al. The pathology of central nervous system inflammatory demyelinating disease accompanying myelin oligodendrocyte glycoprotein autoantibody. Acta Neuropathol 2020;139:875–92. doi:10.1007/s00401-020-02132-yOpenUrlCrossRefPubMed↵Murata H, Kinoshita M, Yasumizu Y, et al. Cell-Free DNA derived from neutrophils triggers type 1 interferon signature in neuromyelitis optica spectrum disorder. Neurol Neuroimmunol Neuroinflamm 2022;9:1–11.:e1149. doi:10.1212/NXI.0000000000001149OpenUrl↵Wingerchuk DM, Banwell B, Bennett JL, et al. International consensus diagnostic criteria for neuromyelitis optica spectrum disorders. Neurology 2015;85:177–89. doi:10.1212/WNL.0000000000001729OpenUrlCrossRefPubMed↵Thompson AJ, Banwell BL, Barkhof F, et al. Diagnosis of multiple sclerosis: 2017 revisions of the mcdonald criteria. Lancet Neurol 2018;17:162–73. doi:10.1016/S1474-4422(17)30470-2OpenUrlCrossRefPubMed↵Neurostatus-UHB ltd c/o university hospital basel switzerland. 2016. Available: www.neurostatus.net↵Teunissen C, Menge T, Altintas A, et al. Consensus definitions and application guidelines for control groups in cerebrospinal fluid biomarker studies in multiple sclerosis. Mult Scler 2013;19:1802–9. doi:10.1177/1352458513488232OpenUrlCrossRefPubMed↵Champagne B, Tremblay P, Cantin A, et al. Proteolytic cleavage of ICAM-1 by human neutrophil elastase. J Immunol 1998;161:6398–405. doi:10.4049/jimmunol.161.11.6398OpenUrlAbstract/FREE Full Text↵Lévesque JP, Takamatsu Y, Nilsson SK, et al. Vascular cell adhesion molecule-1 (CD106) is cleaved by neutrophil proteases in the bone marrow following hematopoietic progenitor cell mobilization by granulocyte colony-stimulating factor. Blood 2001;98:1289–97. doi:10.1182/blood.v98.5.1289OpenUrlAbstract/FREE Full Text↵Prain K, Woodhall M, Vincent A, et al. AQP4 antibody assay sensitivity comparison in the era of the 2015 diagnostic criteria for NMOSD. Front Neurol 2019;10(October):1028. doi:10.3389/fneur.2019.01028OpenUrl↵Yeo T, Probert F, Jurynczyk M, et al. Classifying the antibody-negative NMO syndromes: clinical, imaging, and metabolomic modeling. Neurol Neuroimmunol Neuroinflamm 2019;6:e626. doi:10.1212/NXI.0000000000000626↵Schindler P, Grittner U, Oechtering J, et al. Serum GFAP and NFL as disease severity and prognostic biomarkers in patients with aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder. J Neuroinflammation 2021;18:105. doi:10.1186/s12974-021-02138-7OpenUrl↵Schindler P, Aktas O, Ringelstein M, et al. Glial fibrillary acidic protein as a biomarker in neuromyelitis optica spectrum disorder: a current review. Expert Rev Clin Immunol 2023;19:71–91. doi:10.1080/1744666X.2023.2148657 Available: from: http://www.ncbi.nlm.nih.gov/pubmed/36378751OpenUrl↵Alexandrovski M, Suciu S, Alexandrovski J. Joint measurements of leukocyte elastase and myeloperoxidase promote identification of the state of neutrophils in diabetic patients. Biores Open Access 2020;9:190–7. doi:10.1089/biores.2020.0012OpenUrl↵Mayo Clinical Laboratories. Neuromyelitis optica (NMO)/aquaporin-4-igG fluorescence-activated cell sorting (FACS) assay serum [internet]. 2021. Available: https://www.mayocliniclabs.com/test-catalog/Overview/38324↵Oxford University Hospitals. Neuromyelitis Optica Antibodies [Internet] 2021. Available: https://www.ouh.nhs.uk/immunology/diagnostic-tests/tests-catalogue/neuromyelitis-optica-antibodies.aspx↵Stiebel-Kalish H, Hellmann MA, Mimouni M, et al. Does time equal vision in the acute treatment of a cohort of AQP4 and MOG optic neuritis? Neurol Neuroimmunol Neuroinflamm 2019;6:e572. doi:10.1212/NXI.0000000000000572↵Kleiter I, Gahlen A, Borisow N, et al. Apheresis therapies for NMOSD attacks: a retrospective study of 207 therapeutic interventions. Neurol Neuroimmunol Neuroinflamm 2018;5:e504. doi:10.1212/NXI.0000000000000504↵Bonnan M, Valentino R, Debeugny S, et al. Short delay to initiate plasma exchange is the strongest predictor of outcome in severe attacks of NMO spectrum disorders. J Neurol Neurosurg Psychiatry 2018;89:346–51. doi:10.1136/jnnp-2017-316286OpenUrlAbstract/FREE Full Text↵Benoit SW, Fukuda T, VandenHeuvel K, et al. Case report: atypical HUS presenting with acute rhabdomyolysis highlights the need for individualized eculizumab dosing. Front Pediatr 2022;10(February):841051.:841051. doi:10.3389/fped.2022.841051OpenUrl↵Chatterton S, Parratt JDE, Ng K. Eculizumab for acute relapse of neuromyelitis optica spectrum disorder: case report [Internet]. Front Neurol 2022;13:951423. doi:10.3389/fneur.2022.951423 Available: https://www.frontiersin.org/articles/10.3389/fneur.2022.951423/full↵Saadoun S, Waters P, MacDonald C, et al. Neutrophil protease inhibition reduces neuromyelitis optica-immunoglobulin G-induced damage in mouse brain. Ann Neurol 2012;71:323–33. doi:10.1002/ana.22686OpenUrlCrossRefPubMed↵Zhang H, Bennett JL, Verkman AS. Ex vivo spinal cord slice model of neuromyelitis optica reveals novel immunopathogenic mechanisms. Ann Neurol 2011;70:943–54. doi:10.1002/ana.22551OpenUrlCrossRefPubMed↵Herges K, de Jong BA, Kolkowitz I, et al. Protective effect of an elastase inhibitor in a neuromyelitis optica-like disease driven by a peptide of myelin oligodendroglial glycoprotein. Mult Scler 2012;18:398–408. doi:10.1177/1352458512440060OpenUrlCrossRefPubMed↵Leppert D. Potential of neutrophil granulocyte markers in CSF to differentiate NMOSD and MOGAD from MS [internet]. in: MS virtual 2020. 2020. Available: https://touchneurology.com/multiple-sclerosis/conference-hub/david-leppert-msvirtual2020-potential-of-neutrophil-granulocyte-markers-in-csf-to-differentiate-nmosd-and-mogad-from-ms/Wang X, Rojas-Quintero J, Wilder J, et al. Tissue inhibitor of metalloproteinase-1 promotes polymorphonuclear neutrophil (PMN) pericellular proteolysis by anchoring matrix metalloproteinase-8 and -9 to PMN surfaces. J Immunol 2019;202:3267–81. doi:10.4049/jimmunol.1801466OpenUrlAbstract/FREE Full Text
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Dr. Dustin Anderson, Neurointensivist, talks Anti NMDA receptor encephalitis and ICU EEG. by The Critical Care Commute Podcast

Dr. Dustin Anderson, Neurointensivist, talks Anti NMDA receptor encephalitis and ICU EEG. by The Critical Care Commute Podcast | AntiNMDA | Scoop.it
Join us as we talk to the ridiculously talented Dr. Dustin Anderson, Neurointensivist from the University Hospital in Edmonton, Canada, as he unpacks anti-NMDA encephalitis and the EEG in the ICU.
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How to diagnose autoimmune encephalitis | Tuesday lunch with RITA | Speaker: Prof. Jerome Honorat

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MyJournals.org - Science - 'Catatonia in adult anti-NMDAR encephalitis: an observational cohort study' (BMC Psychiatry)

MyJournals.org - Science - 'Catatonia in adult anti-NMDAR encephalitis: an observational cohort study' (BMC Psychiatry)...
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JCM | Free Full-Text | Autoimmune Encephalitis and Related Syndromes

JCM | Free Full-Text | Autoimmune Encephalitis and Related Syndromes | AntiNMDA | Scoop.it
The field of autoimmune neurology has greatly expanded in the last decade [...]...
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MRI Features and Their Association With Outcomes in Children With Anti-NMDA Receptor Encephalitis | Neurology Neuroimmunology & Neuroinflammation

MRI Features and Their Association With Outcomes in Children With Anti-NMDA Receptor Encephalitis | Neurology Neuroimmunology & Neuroinflammation | AntiNMDA | Scoop.it
AbstractObjectives How brain MRI lesions associate with outcomes in pediatric anti-NMDA receptor encephalitis (pNMDARE) is unknown. In this study, we correlate T2-hyperintense MRI brain lesions with clinical outcomes in pNMDARE.Methods This was a multicenter retrospective cohort study from 11 institutions. Children younger than 18 years with pNMDARE were included. One-year outcomes were assessed by the modified Rankin Score (mRS) with good (mRS ≤2) and poor (mRS ≥3) outcomes.Results A total of 175 pNMDARE subjects were included, with 1-year mRS available in 142/175 (81%) and 60/175 (34%) had abnormal brain MRIs. The most common T2-hyperintense lesion locations were frontal, temporal, and parietal. MRI features that predicted poor 1-year outcomes included abnormal MRI, particularly T2 lesions in the frontal and occipital lobes. After adjusting for treatment within 4 weeks of onset, improvement within 4 weeks, and intensive care unit admission, MRI features were no longer associated with poor outcomes, but after multiple imputation for missing data, T2 frontal and occipital lesions associated with poor outcomes.Discussion Abnormal frontal and occipital lesions on MRI may associate with 1-year mRS in pNMDARE. MRI of the brain may be a helpful prognostication tool that should be examined in future studies.Anti-NMDA receptor encephalitis (NMDARE) causes neuropsychiatric symptoms1,2 resulting in morbidity in 20%3 and mortality in 10%.4 NMDARE can be paraneoplastic, occurring in 3% of children with ovarian teratomas.5 Management includes immunotherapy and supportive care.6 Predicting outcomes in NMDARE are challenging, but risk factors for poor outcomes include delayed immunotherapy, younger than 2 or older than 65 years, and extreme delta brush on electroencephalography.2 The anti-NMDA 1-Year Functional Status (NEOS) score, which includes abnormal MRI, can predict 1-year NMDARE outcomes.7 However, in a pediatric NMDARE (pNMDARE) validation study, NEOS was applicable to the entire group, but not in an individual subject.8MRI abnormalities, usually T2-hyperintense lesions, occur in one-third of children and adults with NMDARE.1,2 Little is known about MRI features and their associated outcomes in NMDARE, especially in children. In 53 NMDARE subjects (17 of which were children), T2-hippocampal lesions associated with worse outcomes in adults, but not in children.9 Here, we assess the association of T2-hyperintense brain MRI lesions and clinical outcomes in a multicenter pNMDARE cohort.MethodsStandard Protocol Approvals, Registrations, and Patient ConsentsA multicenter retrospective study with 11 institutions included children younger than 18 years with pNMDARE between January 1, 2008, and September 1, 2022. Diagnosis of pNMDARE was confirmed with positive CSF NMDA receptor (NMDAr) antibodies and at least 1 of 6 neuropsychiatric symptoms.10 Institutional Review Board approval was obtained at each study site, which waived patient consent. Clinical data were collected, including outcomes using the modified Rankin Scale (mRS). NEOS scores were calculated, as a 5-point scale with 1 point for each variable: ICU admission, abnormal MRI, CSF WCC >20, treatment >4 weeks, and lack of improvement <4 weeks7 An MRI lesion was defined as any T2-brain hyperintensity. MRI data were collected from the initial pretreatment brain MRI after neuroradiologist review for clinical purposes; then, lesion location was extracted by a neurologist at each site. Subjects with prior herpes simplex virus encephalitis were excluded. A subset of 36 subjects has been previously published.5,8,11,12Statistical analysis, including descriptive statistics and comparisons, was performed as appropriate for continuous and discrete data, including for data with normal vs skewed distributions. Significance was set at p < 0.05 with 2-sided hypothesis testing. Multivariable regression modeling with odds ratios with 95% confidence intervals were used to calculate odds of persistent disability based on neuroimaging abnormalities. Initially, complete case analyses were performed. For sensitivity analysis, multiple imputation was performed for missing data. The variables used in the 1-year mRS outcomes to impute values included age of onset, ICU admission, treatment <4 weeks, improvement <4 weeks, and 1-year mRS scores. We also performed mediation and interaction analyses between MRI lesions and ICU admission (SAS 16.0, Cary, NC).Data AvailabilityData are available to qualified researchers based on reasonable request.ResultsData were collected from 192 pNMDARE subjects at 11 institutions. Seventeen subjects were excluded: 5 subjects had unavailable MRI data, 7 subjects did not have confirmed CSF NMDAr antibodies, and 5 subjects had prior HSV encephalitis (Figure). A total of 175 subjects were included, with an average age of 11.6 years (SD: 5.0 years) and 70% were female (Table 1).<img class="highwire-fragment fragment-image" alt="Figure" height="197" src="https://nn.neurology.org/content/nnn/10/4/e200130/F1.medium.gif"; width="440">Download figure Open in new tab Download powerpoint Figure Flow Diagram of Pediatric Anti-NMDA Receptor Encephalitis Subjects Included and Excluded From This StudyView inline View popup Table 1 Demographic Information for the Entire Cohort of Pediatric Anti-NMDA Receptor Encephalitis Subjects With MRI Data Available (N = 175)Thirty-four percent (60/175) had abnormal brain MRIs with the most common abnormalities including T2-hyperintense frontal (31/60 = 52%), temporal (28/60 = 47%), and parietal (21/60 = 35%) lesions (Table 1). Abnormal brain MRI was associated with ICU admission, intubation, higher NEOS score, and poor 1-year mRS (mRS ≥3) scores.For 1-year outcomes, 142 participants had available data, with poor (mRS ≥3) outcomes in 29 and 113 had good (mRS ≤2) outcomes (Table 2). Abnormal brain MRI correlated with poor 1-year outcomes (OR 2.9; 95% CI 1.2–7.0), as did frontal (OR 4.2; 95% CI 1.5–11.6) and occipital lobe T2-hyperintense lesions (OR 6.8; 95% CI 1.1–43.3). Other variables associated with poor 1-year outcomes included prolonged hospital length of stay, intubation, ICU admission, gastrostomy placement, plasma exchange and/or second-line treatments (including rituximab and cyclophosphamide), and no improvement <4 weeks from symptom onset (Table 2). Data from 12 patients were not included because 1 year had not passed from symptom onset. We also assessed those lost to 1-year follow-up by assessing faster recovery or milder disease by comparing mRS at 3 and 6 months or improvement <4 weeks. No differences were observed in these characteristics between those included vs excluded at the 1-year follow-up.View inline View popup Table 2 Demographic Information for the Cohort of Pediatric Anti-NMDA Receptor Encephalitis Subjects With Available 1-Year Outcomes Assessed by Modified Rankin Score (mRS) (N = 143)Using multivariable logistic regression, adjusting for ICU admission, improvement <4 weeks, and treatment <4 weeks, abnormal MRI, T2 frontal, and T2 occipital lesions no longer associated with poor outcomes; ICU admission was the only predictor for poor outcomes (eTable 1, links.lww.com/NXI/A860). Interaction and mediation analyses of ICU admission did not affect the relationship between MRI lesions and outcomes. Sensitivity analyses were performed using multiple imputation to fill in missing data for 1-year mRS outcomes in 33 patients, with missing mRS scores (23), missing treatment <4 weeks (8), missing ICU admission (1), and missing ICU admission/treatment <4 weeks (1). After multiple imputation, T2 frontal (OR 2.81, 95% CI 1.10–6.66) and occipital lobe lesions (OR 8.58, 95% CI 1.15–64.3) were associated with poor 1-year outcomes, even when adjusting for ICU admission, treatment <4 weeks, and improvement <4 weeks (eTable 2).DiscussionIn this pNMDARE cohort, abnormal brain MRI was associated with poor 1-year outcomes, particularly T2-hyperintense frontal and occipital lesions. Abnormal brain MRIs were also associated with intubation and ICU admission. This is one of the largest studies to date that examines T2-hyperintense lesion locations and their association with outcomes in pNMDARE.Despite multiple neurologic symptoms, only 34% of pNMDARE had brain MRI abnormalities. As executive dysfunction and impulsivity are common residual symptoms in NMDARE,1 T2-hyperintense frontal lobe lesions may help to identify those at higher risk for long-term neuropsychological dysfunction. Residual memory problems are also common, but T2-hippocampal/temporal lesions did not associate with outcomes in this study. Surprisingly, T2-hyperintense occipital lobe lesions associated with poor outcomes but may be due to other brain involvement. Although ICU admission altered the associations of MRI lesions with 1-year outcomes and ICU admission did not have a mediation or interaction effect, multiple imputation did demonstrate an association between T2 frontal and occipital lesions with outcomes. This suggests that missing data are affecting the results, which were mitigated by multiple imputation. Moreover, T2 lesions may overlap with demyelinating diseases13 and/or reflect cytotoxic injury, suggestive of more severe disease and affect outcomes.Limitations include that we performed a descriptive and retrospective study of MRI lesion location without including lesion volume or networks. Multiple observers inputted MRI data, which could introduce bias. Another limitation includes that we cannot confirm that all T2-hyperintense lesions present on acute imaging are related to NMDARE as prior MRIs are unavailable. The timing of MRI from symptom onset or its relationship to the number of abnormalities was not included, which may confound this study. In those without 1-year mRS scores, many of these subjects had not reached 1-year follow-up time and our subjects lost to follow-up appeared random. Compounding this, data were collected from tertiary and quaternary pediatric medical centers, and thus, severity bias and convenience sampling are present in this data set. This could affect the rates of neuroimaging abnormalities and 1-year disability. Finally, mRS was used as a standardized and efficient outcome measure that is consistent across institutions; however, the mRS may not adequately capture residual cognitive/neuropsychiatric symptoms in NMDARE.1,14,15T2-hyperintense frontal and occipital lobe lesions may associate with poor outcomes in pNMDARE. Future studies should also explore the association of MRI lesions, their locations, and networks with residual neuropsychological outcomes.Study FundingThis work was supported by the National Center for Advancing Translational Sciences (NCATS) of the NIH under Award Nos. UL1TR002378 and KL2TR002381 and the 2021-2022, 2022-2025 Pediatric Epilepsy Research Foundation Grants, Emory School of Medicine Doris Duke Charitable Foundation COVID-19 Fund to Retain Clinical Scientists, and the Georgia CTSA NIH (Award No. UL1-TR002378).DisclosureG.Y. Gombolay, J.N. Brenton, J.H. Yang, C.M. Stredny, R. Kammeyer, C. Otten, N. Vu, J.D. Santoro, K. Robles-Lopez, A. Christiana, C. Steriade, M, Morris, M. Gorman, M. Moodley, D. Hardy, A. Kornbluh, I. Kahn, and L. Sepeta have no relevant disclosures. A. Yeshokumar is an employee of Bristol Myers Squibb but does not affect this study. Go to Neurology.org/NN for full disclosures.Appendix Authors<img height="3019" alt="Table" class="highwire-fragment fragment-image" width="599" src="https://nn.neurology.org/content/nnn/10/4/e200130/T3.medium.gif">FootnotesGo to Neurology.org/NN for full disclosures. Funding information is provided at the end of the article.The Article Processing Charge was funded by NIH.Submitted and externally peer reviewed. The handling editor was Editor Josep O. Dalmau, MD, PhD, FAAN.Received January 18, 2023.Accepted in final form April 12, 2023.Copyright © 2023 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.References1.↵Dalmau J, Armangue T, Planaguma J, et al. An update on anti-NMDA receptor encephalitis for neurologists and psychiatrists: mechanisms and models. Lancet Neurol. 2019;18(11):1045-1057.OpenUrlCrossRefPubMed2.↵Nosadini M, Eyre M, Molteni E, et al. Use and safety of immunotherapeutic management of N-Methyl-d-aspartate receptor antibody encephalitis: a meta-analysis. JAMA Neurol. 2021;78(11):1333-1344.OpenUrl3.↵Zekeridou A, Karantoni E, Viaccoz A, et al. Treatment and outcome of children and adolescents with N-methyl-D-aspartate receptor encephalitis. J Neurol. 2015;262(8):1859-1866.OpenUrlPubMed4.↵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(2):157-165.OpenUrlCrossRefPubMed5.↵Li JH, Milla SS, Gombolay GY. Rate of anti-NMDA receptor encephalitis in ovarian teratomas. Neuropediatrics. 2021;53(2):133-135.OpenUrl6.↵Nosadini M, Thomas T, Eyre M, et al. International consensus recommendations for the treatment of pediatric NMDAR antibody encephalitis. Neurol Neuroimmunol Neuroinflamm. 2021;8(5):e1052.OpenUrlAbstract/FREE Full Text7.↵Balu R, McCracken L, Lancaster E, Graus F, Dalmau J, Titulaer MJ. A score that predicts 1-year functional status in patients with anti-NMDA receptor encephalitis. Neurology. 2019;92(3):e244–e252.OpenUrlCrossRefPubMed8.↵Loerinc LB, Blackwell L, Howarth R, Gombolay G. Evaluation of the anti-N-methyl-D-aspartate receptor encephalitis one-year functional status score in predicting functional outcomes in pediatric patients with anti-N-methyl-D-aspartate receptor encephalitis. Pediatr Neurol. 2021;124:21-23.OpenUrl9.↵Zhang T, Duan Y, Ye J, et al. Brain MRI characteristics of patients with anti-N-methyl-D-aspartate receptor encephalitis and their associations with 2-year clinical outcome. AJNR Am J Neuroradiol. 2018;39(5):824-829.OpenUrlAbstract/FREE Full Text10.↵Graus F, Titulaer MJ, Balu R, et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol. 2016;15(4):391-404.OpenUrlCrossRefPubMed11.↵Kashyap N, Morris M, Loerinc LB, et al. The neutrophil-to-lymphocyte ratio is associated with intubation in pediatric anti-NMDA receptor encephalitis: a retrospective study. J Neuroimmunol. 2022;370:577931.OpenUrl12.↵Lin J, Elkins K, Bhalla S, et al. Electroencephalography characteristics to predict one-year outcomes in pediatric anti-NMDA receptor encephalitis. Epilepsy Res. 2021;178:106787.OpenUrl13.↵Titulaer MJ, Hoftberger R, Iizuka T, et al. Overlapping demyelinating syndromes and anti-N-methyl-D-aspartate receptor encephalitis. Ann Neurol. 2014;75(3):411-428.OpenUrlCrossRefPubMed14.↵de Bruijn M, Aarsen FK, van Oosterhout MP, et al. Long-term neuropsychological outcome following pediatric anti-NMDAR encephalitis. Neurology. 2018;90(22):e1997–e2005.OpenUrl15.↵Heine J, Kopp UA, Klag J, Ploner CJ, Pruss H, Finke C. Long-term cognitive outcome in anti-N-Methyl-D-Aspartate receptor encephalitis. Ann Neurol. 2021;90(6):949-961.OpenUrlCrossRef
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Autoimmune Encephalitis Criteria in Clinical Practice | Neurology Clinical Practice

Autoimmune Encephalitis Criteria in Clinical Practice | Neurology Clinical Practice | AntiNMDA | Scoop.it
AbstractBackground and Objectives To assess the clinical practice applicability of autoimmune encephalitis (AE) criteria (2016).Methods Medical records of 538 adults diagnosed with AE or related autoimmune encephalopathy at Mayo Clinic (not including pure movement disorders) were reviewed and AE guideline criteria applied.Results Of 538 patients, 288 were male (52%). The median symptom onset age was 55 years (range, 11–97 years; 16 had onset as children). All had other non-AE diagnoses reasonably excluded. Of 538 patients, 361 (67%) met at least possible criteria, having all 3 of subacute onset; memory deficits, altered mental status or psychiatric symptoms, and ≥1 supportive feature (new focal objective CNS finding, N = 285; new-onset seizures, N = 283; supportive MRI findings, N = 251; or CSF pleocytosis, N = 160). Of 361 patients, AE subgroups were as follows: definite AE (N = 221, 61%, [87% AE-specific IgG positive]), probable seronegative AE (N = 18, 5%), Hashimoto encephalopathy (N = 20, 6%), or possible AE not otherwise categorizable (N = 102, 28%). The 221 patients with definite AE had limbic encephalitis (N = 127, 57%), anti–NMDA-R encephalitis (N = 32, 15%), ADEM (N = 8, 4%), or other AE-specific IgG defined (N = 54, 24%). The 3 most common definite AE-IgGs detected were as follows: LGI1 (76, 34%), NMDA-R (32, 16%), and high-titer GAD65 (23, 12%). The remaining 177 patients (33%) not meeting possible AE criteria had the following: seizures only (65, 12% of all 538 patients), brainstem encephalitis without supratentorial findings (55, 10%; none had Bickerstaff encephalitis), or other (57, 11%). Those 57 “others” lacked sufficient supportive clinical, radiologic, or CSF findings (N = 26), had insidious or initially episodic onset of otherwise typical disorders (N = 21), or had atypical syndromes without clearcut memory deficits, altered mental status, or psychiatric symptoms (N = 10). Fifteen of 57 were AE-specific IgG positive (26%). Among the remaining 42, evidence of other organ-specific autoimmunity (mostly thyroid) was encountered in 31 (74%, ≥1 coexisting autoimmune disease [21, 50%] or ≥1 non–AE-specific antibodies detected [23, 53%]), and all but 1 had an objective immunotherapy response (97%).Discussion The 2016 AE guidelines permit autoimmune causation assessment in subacute encephalopathy and are highly specific. Inclusion could be improved by incorporating AE-IgG–positive patients with isolated seizures or brainstem disorders. Some patients with atypical presentations but with findings supportive of autoimmunity may be immune therapy responsive.Certain neural autoantibodies have a very high specificity for autoimmune encephalitis (AE) and have led to an improved recognition of AE and related disorders in general.1 However, many patients are seronegative (possibly as high as 50%), lending further emphasis to the importance of accurate clinical history, examination, and supportive paraclinical diagnostic tests (such as MRI, inflammatory CSF parameters, and EEG).2,3 Guidelines to aid the prompt diagnosis of AE were published in 2016.4 These provide a framework for the assessment of patients presenting with subacute onset altered mental status and short-term memory loss principally using clinical assessment, MRI, and CSF white cell count.4 In that algorithmic assessment, to meet at least possible AE criteria, patients require subacute onset (rapid progression of less than 3 months) of working memory deficits (short-term memory loss), altered mental status (altered level of consciousness, lethargy, or personality change) or psychiatric symptoms with at least 1 of new focal CNS findings, new-onset seizures, CSF pleocytosis, and supportive MRI. These tests are complemented by AE-specific IgG antibody testing, CSF IgG index and oligoclonal bands, EEG, and brain biopsy to further refine diagnostic certainty. Specificity is assured by the requirement for reasonable exclusion of other diagnoses and differing levels of diagnostic certainty (possible, probable, and definite). Discerning the characteristics and relative frequencies in the clinical practice of different AE disorder subcategories (possible, probable, definite, and seropositive or seronegative) and related encephalopathies not meeting at least possible AE criteria (e.g., those with primarily seizure disorders without encephalopathy, brainstem disorders without altered awareness, and atypical presentations) would be informative for clinical treatment decisions, epidemiologic studies, and clinical trial design.In this study, we applied the AE guidelines to 538 adult patients diagnosed with diverse autoimmune encephalopathies within our practice (Autoimmune Neurology Clinic, Mayo Clinic, Rochester, MN).4 The scope of this assessment did not include pure ataxias, stiff-person syndrome, or other pure movement disorders.5MethodsStandard Protocol Approvals, Registrations, and Patient ConsentsThis retrospective study was approved by the Mayo Clinic Institutional Review Board (IRB, 21-001297). Medical records of patients who consented to research review were included.Initially surveyed medical records were from 2,733 adult patients evaluated clinically by one of the authors (January 1, 2006 until December 31, 2020) who had at least one of the following diagnoses recorded: encephalitis, encephalopathy, epilepsy, seizures, dementia, encephalomyelitis, limbic encephalitis, meningoencephalitis, brainstem encephalitis, rhombencephalitis, Bickerstaff encephalitis, Hashimoto encephalopathy, and its alternative moniker steroid-responsive encephalopathy associated with autoimmune thyroiditis (SREAT), Figure 1. Patients evaluated in the Autoimmune Neurology Clinic were either referred directly as outpatient or had been initially evaluated at the Mayo Clinic Hospital. Of those 2,733 patients, 212 lacking documented research authorization were excluded from further review. Of 2,521 charts reviewed, 1,983 patients were excluded from the study because they had one of the following: other nonautoimmune final diagnosis, uncertain diagnosis, isolated autoimmune movement disorder (myoclonic disorder, cerebellar ataxia, chorea, or stiff-person syndrome), or autoimmune myelopathy or autoimmune neuropathy occurring in isolation.<img src="https://cp.neurology.org/content/neurclinpract/13/3/e200151/F1.medium.gif"; width="440" class="highwire-fragment fragment-image" height="255" alt="Figure 1">Download figure Open in new tab Download powerpoint Figure 1 Study Inclusion AlgorithmThe remaining 538 patients all had AE or related disorder diagnosis made by a Mayo Clinic neuroimmunologist (≥1 of the coauthors) and had a reasonable exclusion of other nonimmune-mediated diagnoses.4 The medical records for those 538 patients were further reviewed. Clinical and testing data were abstracted from the medical records and documented in a password-protected database. Data were evaluated for each patient to determine whether at least “possible AE” criteria were met (Table 1). For those meeting at least possible AE criteria, clinical, MRI, CSF, brain biopsy, and autoantibody data were reviewed to determine whether criteria were met for other AE subgroups (definite, seronegative but probable, Hashimoto encephalopathy/SREAT, acute disseminated encephalomyelitis [ADEM], and Bickerstaff brainstem encephalitis). The same data points were also recorded for the remaining patients not meeting possible criteria. In addition, for those cases, antibody status, coexisting autoimmune diseases, immune therapies used, and physician-observed responses were recorded.View inline View popup Table 1 Autoimmune Encephalitis Diagnostic GuidelinesAll 538 patients had undergone evaluation in the Mayo Clinic Neuroimmunology Laboratory for neural antibodies pertinent to AE in both the serum and CSF (486), the CSF only (1), or the serum only (51). AE-specific neural IgG antibodies included in our analyses included those antibodies already described during publication of the 2016 AE Guidelines (e.g., n-methyl-d-aspartate [NMDA] receptor [R]-IgG [in the CSF]; high-titer [≥ 20 nmol/L, equivalent to >10,000 IU/mL] glutamic acid decarboxylase 65 kDa isoform [GAD65] antibody [in the serum or any titer detected in the CSF]; and leucine-rich glioma-inactivated [LGI11] antibody, contactin-associated protein 2 [CASPR2], or antineuronal nuclear antibody type 1 [ANNA-1, anti-Hu] detected in any specimen type).4 We excluded those antibodies with a limited specificity for AE (e.g., non-LGI-1/CASPR2 voltage-gated potassium channel antibodies, calcium channel antibodies, low-positive GAD65 antibody, and NMDA-R-IgG detected in the serum only).4,6,-,8 In addition, we included antibodies with high disease specificity reported since 2016 (glial fibrillary acidic protein [GFAP] and neuronal intermediate filament [NIF] IgGs detected in the CSF) and adenylate kinase 5 antibody.9,-,11 Because we included cases with brainstem encephalitis in our analyses, we also included ANNA-2 (anti-Ri), immune globulin–like family member 5 (IgLON5), and kelch-like protein 11 (KLHL11) IgGs as AE-specific biomarkers.12,-,14 Positivity in either the serum or CSF was acceptable except for NMDA-R, GFAP, and NIF IgGs, where CSF positivity was required. Paraneoplastic associations where pertinent were as previously reported (e.g., ANNA-1 and small cell carcinoma).15 Intergroup nonparametric categorical data were compared using the Fisher exact test (p < 0.05 was considered significant).Data AvailabilityAnonymized data used for this study are available on request.ResultsOf 538 included patients who were evaluated in our Autoimmune Neurology Clinic, 288 were male (52%). The median symptom onset age was 55 years (range, 11–97 years). Sixteen patients had symptom onset as children but were assessed in our clinic for AE diagnosis after turning 18 years. Two hundred ninety-one patients had ≥1 AE-specific IgG detected (54%), and 247 were seronegative (Figure 2). Of the 247 seronegative cases, 12 had an unclassified neural-restricted IgG antibody detected by tissue IFA (5%). These were detected in the CSF only where the serum showed negative results (9), in both the serum and CSF (2), and in the serum only where the CSF was not submitted for testing (1). The distribution of diagnoses of the 538 patients based on the 2016 AE criteria is summarized in Figure 3.<img alt="Figure 2" height="333" width="440" src="https://cp.neurology.org/content/neurclinpract/13/3/e200151/F2.medium.gif"; class="highwire-fragment fragment-image">Download figure Open in new tab Download powerpoint Figure 2 Autoantibody Findings Among All 538 Patients and 221 Cases With Definite AEAb = antibody; AGNA = antiglial/neuronal nuclear antibody; AK5 = adenylate kinase 5; AMPA = α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid; Amphi = amphiphysin; ANNA = antineuronal nuclear antibody; AQP4 = aquaporin-4; CASPR = contactin-associated protein; CRMP = collapsin-response mediator protein; DPPX = dipeptidyl peptidase; GABA = gamma amino butyric acid; GAD65 = glutamic acid decarboxylase 65 kDa isoform; GFAP = glial fibrillary acidic protein; IgLON = immunoglobulin-like cell adhesion molecule; KLHL = kelch-like protein; LGI1 = leucine-rich glioma-inactivated 1; mGluR5 = metabotropic glutamate receptor-5; MOG = myelin oligodendrocyte glycoprotein; NIF = neuronal intermediate filaments; NMDA = n-methyl-d-aspartate; R = receptor.<img height="200" alt="Figure 3" class="highwire-fragment fragment-image" src="https://cp.neurology.org/content/neurclinpract/13/3/e200151/F3.medium.gif"; width="440">Download figure Open in new tab Download powerpoint Figure 3 Diagnostic Categories for 538 Patients After Application of 2016 Autoimmune Encephalitis CriteriaAb = antibody; ADEM = acute disseminated encephalomyelitis; AE = autoimmune encephalitis; NMDA-R = n-methyl-d-aspartate receptor.Two-Thirds of Patients Fulfilled at Least Possible AE Criteria, Most of Whom Had Definite AEOf 538 patients, 361 (67%) met at least possible criteria, having all 3 of subacute onset, memory deficits, altered mental status or psychiatric symptoms, and had at least 1 supportive feature (new focal objective CNS finding, 285 [79%]; new-onset seizures, 283 [78%]; supportive MRI findings, 251 [70%], or CSF pleocytosis, 160 [44%]). Of the 361 patients, 221 (61%) had definite AE, 18 (5%) had probable AE, and 102 (28%) had possible AE not otherwise categorized. Twenty patients (6%) met Hashimoto encephalopathy criteria, Table 2.View inline View popup Table 2 Characteristics of All Patients With Possible, Probable, and Definite Autoimmune Encephalitis and Those Not Meeting at Least Possible CriteriaPatients With Definite AE Were Usually AE-Specific IgG Positive (87%)The 221 patients with definite AE had limbic encephalitis (N = 127, 57%), had anti–NMDA-R encephalitis (N = 32, 15%), had ADEM (N = 8, 4%), or were classified as “other” (N = 54, 24%), Figure 3. Of 221 cases with definite AE, 193 were neural antibody positive (87%). Among seropositive patients, 18 different neural antibodies were detected in the serum, the CSF, or both, the 3 most common being leucine-rich glioma-inactivated protein 1 (LGI1; 76, 34%), NMDA-R (32, 16%), and high-titer GAD65 (23, 12%), Figure 2, eTable 1, links.lww.com/CPJ/A412. Coexisting antibodies in 8 patients were in 3 with anti-NMDA-R encephalitis with either GFAP-IgG (2 patients) or myelin oligodendrocyte glycoprotein (MOG)–IgG (1 patient) coexisting, all with typical anti–NMDA-R encephalitis; 4 with limbic encephalitis (with 1 each of gamma amino butyric acid [GABA]AR and GAD65; LGI1 and contactin-associated protein-2 [CASPR2]; ANNA-1, amphiphysin and GABABR, or antiglial/neuronal nuclear antibody type 1 [AGNA-1, also known as SOX-1]; and GABABR); and 1 with typical GABAAR encephalitis and coexisting GAD65 antibody.Of 221 definite cases, 141 (60%) required antibody positivity to fulfill definite criteria (Figure 3, eTable 1, links.lww.com/CPJ/A412). Subgroups of patients requiring antibody positivity to meet the definite criteria were as follows: limbic encephalitis, 64/127 (50%, including 56 of 76 cases with LGI1, 74%); anti–NMDA-R encephalitis, 23/32 (72%), ADEM, 1/8 (13%, MOG-IgG positive), and all 54 “other” cases fulfilling criteria based on meeting possible criteria and being AE-specific antibody positive, eTable 1, links.lww.com/CPJ/A412. Among 127 cases that met definite limbic encephalitis criteria, 11 (9%) did not meet criteria in the absence of antibody positivity because T2 MRI changes were unilateral only (LGI1, 5; GAD65, 4; ANNA-1, and Ma2, 1 each), Figure 4. The 54 “other” patients not meeting definite limbic encephalitic criteria but still had antibody positivity to meet definite AE criteria had either: nonlimbic syndromes (16 patients [30%], with autoimmune GFAP astrocytopathy [9, with radiologic features of meningoencephalitis], dipeptidyl peptidase-6 [DPPX] autoimmunity [6, with multifocal encephalomyelitis, with gastrointestinal symptoms and weight loss], and GABAAR encephalitis [1, encephalopathy with extratemporal seizures]) or lack of sufficient supportive findings despite having a typical limbic syndrome (38, 70%). While those 38 patients without sufficient supportive findings had temporal lobe EEG changes in most cases (33, 89%), they all lacked supportive CSF and MRI findings (pleocytosis and bilateral limbic encephalitic changes). Of note, 6 of those patients did have unilateral T2 changes (5 cases with LGI1 and a single case with metabotropic glutamate receptor-5 [mGluR5]).<img alt="Figure 4" width="440" class="highwire-fragment fragment-image" src="https://cp.neurology.org/content/neurclinpract/13/3/e200151/F4.medium.gif"; height="201">Download figure Open in new tab Download powerpoint Figure 4 Illustrative MRI Brain FindingsImages are T2 axial FLAIR, except A (T2 coronal FLAIR) and G (T1 axial postgadolinium). (A) Normal appearing hippocampal formations in a patient with anti–NMDA-receptor encephalitis. (B) Bilateral hyperintensity of hippocampal formations in a patient with LGI1 encephalitis. (C) Subtle left hippocampal hyperintensity in a patient with LGI1 encephalitis. (D) Prominent right amygdalar hyperintensity in a patient with anti-Ma2 encephalitis. (E) Multifocal white matter lesions with ill-defined borders in a patient with MOG antibody–associated disease and an ADEM attack. (F) Peri-IVth ventricular hyperintensity in a patient with aquaporin-4-IgG–positive neuromyelitis optica spectrum disorder with brainstem encephalitis; (G) Periventricular leptomeningeal enhancement in a patient with autoimmune GFAP astrocytopathy. (H) Bifrontal lobar hyperintensities in a patient with GABAA receptor encephalitis. (I) Left frontal hyperintensity in a patient with possible autoimmune encephalitis. (J) Diffuse T2 signal abnormalities in a patient with probable autoimmune encephalitis. ADEM = acute disseminated encephalomyelitis; FLAIR = fluid-attenuated inversion recovery; GABA = gamma amino butyric acid; GFAP = glial fibrillary acidic protein; LGI1 = leucine-rich glioma-inactivated 1; MOG = myelin oligodendrocyte glycoprotein; NMDA-R = n-methyl-d-aspartate receptor.No cases of Bickerstaff brainstem encephalitis were encountered. A wider search of the Mayo medical records beyond the scope of our Autoimmune Neurology group (2006–2020) yielded 1 case with Bickerstaff encephalitis case evaluated in our department 2 years after hospitalization elsewhere (ganglioside GQ1B antibody positive). Twenty patients met 2016 criteria for Hashimoto encephalopathy (Table 2).Patients Meeting Probable Seronegative or Possible AE Criteria Had Diverse FindingsAll 18 patients with probable but seronegative AE had both MRI and CSF findings supportive of the diagnosis, 5 of whom also underwent brain biopsy (all 5 had supportive histologic evidence of inflammatory infiltrates, Table 2). The other 102 patients met possible criteria only (Table 2), one of whom did not meet definite limbic encephalitis criteria owing to unilateral rather than bilateral hippocampal T2 hyperintensity. Inflammatory-appearing MRI findings were diverse among the probable and possible group patients (examples shown in Figure 4).Two-Thirds of Patients Not Meeting at Least Possible AE Criteria Had Isolated Seizures or Brainstem EncephalitisOf the 177 patients (33% of 538) evaluated and diagnosed with autoimmune encephalopathy who did not meet at least 2016 possible AE criteria (Tables 2 and 3, Figure 3), 120 (68%) had either seizures only (65, 12% of all patients) or brainstem encephalitis without supratentorial findings (55, 10% of all patients), and 83 cases were neural antibody positive (69%, Table 3). Patients with brainstem encephalitis had diverse combinations of eye movement disorders (35), ataxic (28) or postural (32) difficulties, vestibulocochlear symptoms (18, including deafness in 5), upper motor neuron signs (13), dysarthria (13), dysphagia (9), other cranial neuropathies (7), and tremulousness (5). Seven of 11 patients with KLHL-11-IgG positivity had vestibulocochlear symptoms. One patient had AQP4-IgG positivity and isolated (radiologically inflammatory appearing) brainstem encephalitis, thus meeting NMO diagnostic criteria.16 Twenty-one patients without pleocytosis in the CSF had oligoclonal bands (20) or an elevated IgG index (8) detected, 4 of whom did not meet possible criteria for lack of supportive findings. Epileptiform EEG abnormalities in the “seizure-only” patients (captured in 36 of 65, 55%) were temporal (28), extratemporal (4), or both (4).View inline View popup Table 3 177 Patients Who Did Not Meet Possible Autoimmune Encephalitis Criteria: Reasons for Not Meeting Criteria and Characteristics Leading to Autoimmune DiagnosesThe Remaining 57 Patients Did Not Meet at Least Possible AE Criteria for Diverse ReasonsThe remaining 57 of 177 patients (32%) lacked supportive clinical, radiologic, or CSF findings (26), had insidious or initially episodic onset of otherwise typical disorders (21), or atypical multifocal syndromes with cognitive symptoms in the absence of memory deficits or altered mental status (10), Table 3. Characteristic features supporting an autoimmune diagnosis in the 57 patients were diverse. These were typical neurocognitive syndrome by AE criteria (47, 82%), subacute onset (36, 63%), new focal CNS findings (15, 26%), inflammatory CSF abnormalities (15, 26%; 1 or more of CSF-exclusive oligoclonal bands [11], pleocytosis [9], or an elevated IgG index [3]), AE-specific antibodies (15, 26%: CASPR2, 3; GAD65, 2; LGI1, 2; NIF, 2; GFAP, NMDA-R, collapsin-response mediator protein-5, Ma2, MOG, and IgLON5, 1 each), inflammatory MRI findings (13), seizures (5), and supportive brain biopsy findings (2). In addition, physician-reported immune therapy responses were recorded in 52 of 57 patients (91%). One of the 57 patients had 6 of these 8 abovementioned characteristics (2%), 6 had 5 (11%), 14 had 4 (26%), 32 had 3 (56%), and 3 had 2 (5%). When compared with the 102 patients meeting 2016 possible AE criteria only, the 57 patients were as likely to have coexisting seizures (39/102 v 14/57, p = 0.083), supportive MRI findings (36/102 v 13/57, p = 0.150), or CSF pleocytosis (31/102 v 9/57, p = 0.057) but were less likely to have new focal CNS findings (56/102 v 14/57, p = 0.004).Coexisting Autoimmunity and Treatment Responses Were Diagnostically Useful in 8% of the CohortAmong 42 (of the 57) patients who were neural IgG negative, other evidence of diverse organ-specific autoimmunity was encountered in 31 (74%), eTable 2, links.lww.com/CPJ/A412. Twenty-one had ≥1 coexisting autoimmune disease (50%, autoimmune thyroid disease, 14; B12 deficiency, 4; type 1 diabetes, 2; celiac disease, 2; and 1 each of autoimmune hemolytic anemia, immune thrombocytopenic purpura, sclerosing cholangitis, ulcerative colitis, systemic lupus erythematous, rheumatoid arthritis, leukocytoclastic vasculitis, and preexisting Lambert-Eaton syndrome) and 23 had ≥1 non-neurological disease–specific antibodies detected (55%, thyroid, 17 [thyroid peroxidase, 16; thyroglobulin, 1]; low-positive [≤ 20 nmol/L] GAD65, 5; p-ANCA, 1; phospholipid antibody, 1), and 1 had an unclassified neural antibody detected in the CSF. Twenty-five of 42 patients had clinical or serologic evidence of thyroid autoimmunity (60%). All but 1 of 42 patients had objective improvements in neurologic examination reported by the treating clinician (97%), supported by improvements on formal bedside cognitive or neuropsychometric testing (14), EEG (7), MRI (4), or PET-CT (1).Among the 3 most common seropositive subgroups in the entire cohort of 538 patients (LGI1, GAD65, and NMDA-R), 54 of 160 patients did not meet at least possible 2016 criteria (34%): LGI1 26/76 patients (34%, seizures only, 24; and lack of supportive features, 2); GAD65 27/51 patients (53%, seizures only 22, brainstem encephalitis, 3, lack of subacute onset, 2); NMDA-R 1/33 patients (3%, lack of supportive features), Table 3.Psychiatric Symptom–Predominant Phenotypes Were Uncommon and Not Typical of Primary Psychiatric DisordersThirteen of 538 patients presented with predominant or exclusive psychiatric symptoms (2.5%). They had subacute symptom onset of multimodal neuropsychiatric presentations consisting of altered mental status (all 13), behavior or personality change (10), paranoid delusions (5), auditory and/or visual hallucinations (4), agitation (3), catatonia (3), and suicidal ideation (2). Nine of 13 (69%) had focal objective CNS findings (abnormal cognitive examination [8], aphasia [1], hypomimia [1], and apraxia with hyperreflexia [1]), 4 had supportive MRI findings, and 3 had supportive CSF pleocytosis (an additional 2 had CSF-exclusive oligoclonal bands). All but 1 of 13 met at least possible AE criteria. Diagnoses were anti–NMDA-R encephalitis, 6 (all were NMDA-R antibody positive in the CSF); anti-DPPX encephalitis, 1, and Hashimoto encephalopathy/SREAT, 1. Of the 5 remaining patients (seronegative), 4 met only possible criteria, and 1 met definite limbic encephalitis criteria. Immune therapy responses were evident in all 13.DiscussionWe applied the 2016 AE guidelines to our patients diagnosed with diverse autoimmune encephalopathies encountered in our clinical practice to understand their utility in assisting diagnostic decision-making.4 We found two-thirds of our patients diagnosed with an autoimmune brain disease (excluding ataxias and other movement disorders) met at least possible criteria. The guidelines permit structured assessment of patients with subacute-onset brain disorders using clinical and paraclinical data points to determine differing levels of diagnostic certainty (probable, definite, or possible, not otherwise specified). These are helpful in delineating the key diagnostic features for clinical practice and have also been used in the design of clinical trials and other research studies.3,17 Although our study was not designed to address the specificity of criteria among a control cohort, in our clinical experience, the definite AE criteria are highly specific, which is assured by the “reasonable exclusion of other diagnoses” requirement. In addition, we did not find alternative diagnoses among the cases where there was less certainty (possible, probable, or not meeting 2016 criteria). A longitudinal data collection to assess for any changes in diagnoses over time will be conducted in the future.These 2016 AE criteria focused on being as specific as possible and were moderately sensitive in our patients. We respect the work conducted by others to date and acknowledge the impossibility of capturing all patients with disparate autoimmune encephalopathies using a single set of criteria without losing specificity. Some modification of the criteria could improve inclusion of AE-specific IgG-positive patients with seizure-only presentations, brainstem encephalitides, and perhaps some atypical presentations. This would ensure broader inclusion of affected patients in relation to epidemiologic studies, clinical trials, treatment guidelines, healthcare policies, and insurance rules developed in the future.From our experience, the most common presentation beyond those specified in the AE guidelines was isolated seizures (12%), similar to the frequency previously reported for isolated seizures in general for LGI1 encephalitis (13%) and anti–NMDA-receptor encephalitis (12%).18,19 In our experience, LGI1 encephalitis presents with seizures in the absence of the full clinical picture of limbic encephalitis in one-third of cases (and thus would not be included in AE criteria). By contrast, the AE guidelines were sufficiently sensitive to detect anti–NMDA-R encephalitis except in 1 patient, who lacked subacute onset. The next most common category of patients not meeting criteria were those with brainstem encephalitis (10%), with neither altered awareness nor bilateral external ophthalmoplegia typical of Bickerstaff encephalitis, which was included in the 2016 guidelines.4,20 Despite being included in the diagnostic criteria, we never encountered a patient with Bickerstaff encephalitis in our practice, and only encountered 1 within our institution who met AE diagnostic guidelines during the study epoch. In our experience, brainstem encephalitis most commonly presents with subacute onset of cerebellar ataxic signs, postural instability, and symptomatic eye movement abnormalities. One or more of deafness, vertigo, speech and swallow difficulties, jaw dystonia, upper motor neuron signs, spasms, bowel or bladder dysfunction, myoclonus, or tremor were other accompaniments. Vestibulocochlear symptoms are frequent in KLHL11 autoimmunity.21Though highly specific, the 2016 guidelines were not designed to capture the heterogenous group of patients (10% of our entire cohort) who did not meet possible AE criteria yet had a constellation of features suspicious for an autoimmune cause and who responded to immune therapy in almost all cases. One of the defining features of the 2016 AE criteria (subacute onset, typical neurocognitive syndrome, and sufficient supportive features) was absent in those 57 patients, yet suspicion for an autoimmune cause persisted. For 15 (25%) of those patients, autoimmune diagnoses were straightforward to confirm because AE-specific IgG testing in the serum or CSF was positive. However, for the remaining 42 seronegative patients, the diagnoses were less certain and illustrative of the importance of continued biomarker discovery for seronegative autoimmune neurologic disorders. Additional features we have found helpful over the years include a preexisting personal history of autoimmune disease (most commonly thyroid disease), CSF markers beyond pleocytosis (elevated IgG index, IgG synthesis rate, and oligoclonal bands), research-based testing for novel unclassified neural IgGs, and occasionally brain biopsy.22 Furthermore, all but 1 of those 42 patients had a physician-observed response to immune therapy. Although ideal to ascertain an autoimmune diagnosis before treatment, our experience and these data portend a lack of feasibility in some cases.23 Where there is uncertainty, before an immune therapy trial, we emphasize the importance of reasonable exclusion of other reversible disorders, such as neoplastic, infectious, toxic, and metabolic disorders, so as to leave 2 main possibilities remaining: an immune-mediated disorder or a neurodegenerative diagnosis with limited treatment options. Patients should be followed up expeditiously to determine whether there is an objective response to immune therapy and treatment promptly tapered and discontinued where there is none.Some of our patients met criteria for Hashimoto encephalopathy (2016) while others (among our 42 seronegative cases not meeting possible criteria) met the less stringent SREAT criteria.24 Either way, the significance of thyroid autoantibodies (and other non-neural IgGs such as low-positive GAD65 antibody) should be interpreted with caution because they can be encountered in healthy people also. Three-quarters of patients referred to our practice for Hashimoto encephalopathy/SREAT received a final nonautoimmune diagnosis.25 In general, in this study, we diagnosed autoimmune encephalopathy in 1 in 5 of all patients assessed.From a practical perspective, it would be difficult to capture all diverse patients from our practice we have described in this study in diagnostic criteria without losing specificity. Nonetheless, the sensitivity for possible AE could be improved by including some well-recognized seropositive “seizure-only” presentations, as previously described.26 A recent review of conceptual definitions suggested the terms “acute symptomatic seizures secondary to AE” to refer to seizures occurring in the setting of the active phase of immune-mediated encephalitis and provided a detailed summary of typical features of new-onset seizures in that context.27 The 2016 AE guidelines could be modified to include isolated new-onset, frequent, focal seizures among the clinical presentations, while retaining the other supportive criteria and requirement to exclude competing diagnoses.27 Similarly, a category could be added to current AE guidelines to include brainstem encephalitides, especially if seropositive for relevant neural autoantibodies, though the presentations are sufficiently diverse, distinct, and nascent in their recognition, that development of a separate brainstem-specific set of criteria could also be considered.28,29Similar to our previous hospital-based experience, and the experience of others, psychiatric symptom–predominant autoimmune encephalopathies were distinct in presentation from primary psychiatric disorders. Our patients had multimodal psychiatric presentations, usually admixed with neurocognitive signs.30,31 In addition, those patients almost always had supportive findings and met AE diagnostic criteria. Therefore, a separate category of “autoimmune psychiatric” diagnoses seems unnecessary.32 Similarly, autoimmune dementia, rather than being a separate diagnostic category, serves as “aide memoire” to cases of AE where rapidly progressive cognitive decline, without delirium, might mimic CJD or rapidly progressive Alzheimer disease or diffuse Lewy body disease.23 The most challenging clinical presentations in our practice from a diagnostic standpoint include the 10% of patients with 1 of 3 central features atypical: nonsubacute onset (typically insidious with fluctuations), those with atypical symptomatology (such as admixed vague cognitive symptoms, language difficulties, and motor symptoms, where altered mental status and memory loss are not apparent), and those with a dearth of supportive clinical and paraclinical test findings. Nonetheless, those patients met 2 of the 3 central features, and if were AE-specific Ab negative, three-quarters had other clues supporting autoimmunity. Though not readily addressable in diagnostic criteria, in general within our practice, those patients would be diagnosed with possible autoimmune encephalopathy initially, and a likely diagnosis subsequently, if an objective immune therapy response occurred. We have found 1 or more of “before and after” MRI, EEG, and neuropsychometric testing to be of assistance in documenting treatment responses.Limitations of our study include the potential for referral bias, favoring patients with unusual presentations not meeting AE criteria, given our tertiary outpatient subspecialty practice. In addition, our institution's emphasis on US national ambulatory practice likely influenced LGI1 encephalitis being more common than anti–NMDA-R encephalitis. While we did encounter occasional patients without subacute symptom onset, it is also possible that some of those may have been artifacts of patient and family recall or documentation. In addition, antibody diagnostic evaluations were incremental in their sensitivity over time as new AE-specific IgGs were characterized. The largest AE subgroup was limbic encephalitis, 50% of whom required AE-specific IgG positivity to fulfill definite criteria, emphasizing the importance of antibody biomarkers in clinical practice.1 Although patients with occasional limbic encephalitis in our series had unilateral limbic MRI changes, only 1 seronegative patient with possible AE did not fulfill limbic encephalitis criteria based on not having bilateral findings, and glioma should also be considered in these cases.33In summary, for patients with a subacute onset cerebral syndrome, key details from the clinical history and examination, CSF, MRI findings and EEG, and utilization of the 2016 AE guidelines criteria assist in assessing the likelihood of an autoimmune cause. Antibody testing assists in confirming the diagnosis and may provide guidance for cancer evaluation in those with identification of a high-risk paraneoplastic antibody. In our view, it is also important to have a low threshold for EEG, MRI, CSF, and serum/CSF antibody testing in a patient with an “outlier” clinical presentation in whom an alternative diagnosis is not immediately apparent and to consider an immune therapy trial. Future iterations of AE guidelines could capture more patients, particularly seropositive patients with isolated seizures and brainstem encephalitides. This would ensure optimized estimation of the epidemiologic burden of autoimmune encephalopathies and inform clinical trial design.Study FundingNational Institute of Neurologic Disorders and Stroke RO1NS126227 U01NS120901.DisclosureE. Orozco and C. Valencia-Sanchez report no disclosures relevant to the manuscript; J.W. Britton has consulted for UCB pharmaceuticals; D. Dubey has research support from the Department of Defence (CA210208), Centers of Multiple Sclerosis and Autoimmune Neurology and Clinical and Translational Science, Mayo Clinic, and Grifols pharmaceuticals, has consulted for UCB, Immunovant, Argenx, and Astellas pharmaceuticals (compensation for consulting activities paid directly to Mayo Clinic), and has patents pending for KLHL11-IgG, LUZP4-IgG, and cavin-4-IgG as markers of neurologic autoimmunity; E.P. Flanagan has funding from NIH (R01NS113828), has served on advisory boards for Alexion, Genentech, Horizon Therapeutics, and UCB, has received honoraria from Pharmacy Times and UpToDate, and has a patent pending for DACH1-IgG as a biomarker of paraneoplastic autoimmunity; A.S. Lopez-Chiriboga has consulted for Horizon Therapeutics and Genentech; N. Zalewski reports no disclosures relevant to the manuscript. A. Zekeridou has patent applications pending on PDE10A-IgG and DACH1-IgG as biomarkers of paraneoplastic neurologic autoimmunity and has received research funding from Genentech; S.J. Pittock is a named inventor on filed patents that relate to functional AQP4/NMO-IgG assays and NMO-IgG as a cancer marker, has patents pending for KLHL11-IgG and Septin-5-IgG and issued for MAP1B-IgG as markers of neurologic autoimmunity and paraneoplastic disorders, has consulted for Alexion and Medimmune, and has received research support from Genentech, Grifols, Medimmune, and Alexion; A. McKeon reports research funding from the NIH (NIH: RO1NS126227, U01NS120901), patents issued for GFAP and MAP1B-IgGs and patents pending for PDE10A, Septins-5 and Septins-7, and KLCHL11-IgGs, and has consulted for Janssen and Roche pharmaceuticals, without personal compensation. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/cp.Appendix Authors<img height="1616" alt="Table" class="highwire-fragment fragment-image" src="https://cp.neurology.org/content/neurclinpract/13/3/e200151/T4.medium.gif"; width="599">FootnotesFunding information and disclosures are provided at the end of the article. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/cp.The Article Processing Charge was funded by the authors.Submitted and externally peer reviewed. The handling editor was Deputy Editor Kathryn Kvam, MD.Editorial, page e200155Received November 23, 2022.Accepted February 13, 2023.Copyright © 2023 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.References1.↵Budhram A, Dubey D, Sechi E, et al. Neural antibody testing in patients with suspected autoimmune encephalitis. Clin Chem. 2020;66(12):1496-1509. doi. 10.1093/clinchem/hvaa254.OpenUrlCrossRef2.↵Hacohen Y, Wright S, Waters P, et al. Paediatric autoimmune encephalopathies: clinical features, laboratory investigations and outcomes in patients with or without antibodies to known central nervous system autoantigens. J Neurol Neurosurg Psychiatry. 2013;84(7):748-755. doi. 10.1136/jnnp-2012-303807.OpenUrlAbstract/FREE Full Text3.↵Dubey D, Pittock SJ, Kelly CR, et al. 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Muscle Nerve. 2016;54(2):220-227. doi. 10.1002/mus.25027.OpenUrlCrossRefPubMed8.↵Budhram A, Freeman E, Bhayana V, Yang L. Positive predictive value of anti-GAD65 ELISA cut-offs for neurological autoimmunity. Can J Neurol Sci. 2022:1-3. doi. 10.1017/cjn.2022.276.OpenUrlCrossRef9.↵Flanagan EP, Hinson SR, Lennon VA, et al. Glial fibrillary acidic protein immunoglobulin G as biomarker of autoimmune astrocytopathy: Analysis of 102 patients. Ann Neurol. 2017;81(2):298-309. doi. 10.1002/ana.24881.OpenUrlCrossRefPubMed10.↵McKeon A, Shelly S, Zivelonghi C, et al. Neuronal intermediate filament IgGs in CSF: autoimmune axonopathy biomarkers. Ann Clin Transl Neurol. 2021;8(2):425-439. doi. 10.1002/acn3.51284.OpenUrlCrossRef11.↵Muniz-Castrillo S, Hedou JJ, Ambati A, et al. Distinctive clinical presentation and pathogenic specificities of anti-AK5 encephalitis. Brain. 2021;144(9):2709-2721. doi. 10.1093/brain/awab153.OpenUrlCrossRefPubMed12.↵Sabater L, Gaig C, Gelpi E, et al. A novel non-rapid-eye movement and rapid-eye-movement parasomnia with sleep breathing disorder associated with antibodies to IgLON5: a case series, characterisation of the antigen, and post-mortem study. Lancet Neurol. 2014;13(6):575-586. doi. 10.1016/s1474-4422(14)70051-1.OpenUrlCrossRefPubMed13.↵Luque FA, Furneaux HM, Ferziger R, et al. Anti-Ri: an antibody associated with paraneoplastic opsoclonus and breast cancer. Ann Neurol. 1991;29(3):241-251. doi. 10.1002/ana.410290303.OpenUrlCrossRefPubMed14.↵Mandel-Brehm C, Dubey D, Kryzer TJ, et al. Kelch-like protein 11 antibodies in seminoma-associated paraneoplastic encephalitis. N Engl J Med. 2019;381(1):47-54. doi. 10.1056/nejmoa1816721.OpenUrlCrossRefPubMed15.↵McKeon A, Pittock SJ, Lennon VA. CSF complements serum for evaluating paraneoplastic antibodies and NMO-IgG. Neurology. 2011;76(12):1108-1110. doi. 10.1212/wnl.0b013e318211c379.OpenUrlCrossRef16.↵Wingerchuk DM, Banwell B, Bennett JL, et al. International consensus diagnostic criteria for neuromyelitis optica spectrum disorders. Neurology. 2015;85(2):177-189. doi. 10.1212/wnl.0000000000001729.OpenUrlCrossRefPubMed17.↵Blackburn KM, Denney DA, Hopkins SC, Vernino SA. Low recruitment in a double-blind, placebo-controlled trial of ocrelizumab for autoimmune encephalitis: a case series and review of lessons learned. Neurol Ther. 2022;11(2):893-903. doi. 10.1007/s40120-022-00327-x.OpenUrlCrossRef18.↵Rodriguez A, Klein CJ, Sechi E, et al. LGI1 antibody encephalitis: acute treatment comparisons and outcome. J Neurol Neurosurg Psychiatry. 2022;93(3):309-315. doi. 10.1136/jnnp-2021-327302.OpenUrlAbstract/FREE Full Text19.↵Gabilondo I, Saiz A, Galan L, et al. Analysis of relapses in anti-NMDAR encephalitis. Neurology. 2011;77(10):996-999. doi. 10.1212/wnl.0b013e31822cfc6b.OpenUrlCrossRefPubMed20.↵Merwick A, Dalmau J, Delanty N. Bickerstaff encephalitis and atypical features–bickerstaff's papers revisited. J Neurol Sci. 2014;341(1-2):173. doi. 10.1016/j.jns.2014.03.050.OpenUrlCrossRef21.↵Dubey D, Wilson MR, Clarkson B, et al. Expanded clinical phenotype, oncological associations, and immunopathologic insights of paraneoplastic kelch-like protein-11 encephalitis. JAMA Neurol. 2020;77(11):1420. doi. 10.1001/jamaneurol.2020.2231.OpenUrlCrossRef22.↵McKeon A. Autoimmune encephalopathies and dementias. Continuum. 2016;22(2, Dementia):538-558. doi. 10.1212/con.0000000000000299.OpenUrlCrossRef23.↵Flanagan EP, McKeon A, Lennon VA, et al. Autoimmune dementia: clinical course and predictors of immunotherapy response. Mayo Clin Proc. 2010;85(10):881-897. doi. 10.4065/mcp.2010.0326.OpenUrlCrossRefPubMed24.↵Castillo P, Woodruff B, Caselli R, et al. Steroid-responsive encephalopathy associated with autoimmune thyroiditis. Arch Neurol. 2006;63(2):197-202. doi. 10.1001/archneur.63.2.197.OpenUrlCrossRefPubMed25.↵Valencia-Sanchez C, Pittock SJ, Mead-Harvey C, et al. Brain dysfunction and thyroid antibodies: autoimmune diagnosis and misdiagnosis. Brain Commun. 2021;3(2):fcaa233. doi. 10.1093/braincomms/fcaa233.OpenUrlCrossRef26.↵Dubey D, Pittock SJ, McKeon A. Antibody prevalence in epilepsy and encephalopathy score: increased specificity and applicability. Epilepsia. 2019;60(2):367-369. doi. 10.1111/epi.14649.OpenUrlCrossRefPubMed27.↵Steriade C, Britton J, Dale RC, et al. Acute symptomatic seizures secondary to autoimmune encephalitis and autoimmune-associated epilepsy: conceptual definitions. Epilepsia. 2020;61(7):1341-1351. doi. 10.1111/epi.16571.OpenUrlCrossRefPubMed28.↵Graus F. Towards a better recognition of paraneoplastic brainstem encephalitis. J Neurol Neurosurg Psychiatry. 2021;92(11):1141. doi. 10.1136/jnnp-2021-327386.OpenUrlFREE Full Text29.↵Orozco E, Guo Y, Chen JJ, et al. Clinical reasoning: a 43-year-old man with subacute onset of vision disturbances, jaw spasms, and balance and sleep difficulties. Neurology. 2022;99(9):387-392. doi. 10.1212/wnl.0000000000200950.OpenUrlCrossRef30.↵Kruse JL, Lapid MI, Lennon VA, et al. Psychiatric autoimmunity: N-Methyl-D-Aspartate receptor IgG and beyond. Psychosomatics. 2015;56(3):227-241. doi. 10.1016/j.psym.2015.01.003.OpenUrlCrossRefPubMed31.↵Kayser MS, Titulaer MJ, Gresa-Arribas N, Dalmau J. Frequency and characteristics of isolated psychiatric episodes in anti-N-methyl-d-aspartate receptor encephalitis. JAMA Neurology. 2013;70(9):1133-1139. doi. 10.1001/jamaneurol.2013.3216.OpenUrlCrossRefPubMed32.↵Pollak TA, Lennox BR, Muller S, et al. Autoimmune psychosis: an international consensus on an approach to the diagnosis and management of psychosis of suspected autoimmune origin. Lancet Psychiatry. 2020;7(1):93-108. doi. 10.1016/S2215-0366(19)30290-1.OpenUrlCrossRef33.↵Zoccarato M, Valeggia S, Zuliani L, et al. Conventional brain MRI features distinguishing limbic encephalitis from mesial temporal glioma. 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Predictive Value of Serum Neurofilament Light Chain Levels in Anti-NMDA Receptor Encephalitis | Neurology

Predictive Value of Serum Neurofilament Light Chain Levels in Anti-NMDA Receptor Encephalitis | Neurology | AntiNMDA | Scoop.it
AbstractBackground and Objectives Determinants of disease activity and prognosis are limited in anti-NMDA receptor (NMDAR) encephalitis. Neurofilament light chains (NfL) are markers of axonal damage and have been identified as valuable biomarkers for neurodegenerative and other neuroinflammatory disorders. We aimed to investigate serum NfL levels in patients with anti-NMDAR encephalitis as a biomarker for disease severity and outcome.Methods In this retrospective study, NfL values were measured in all available pretreatment serum and paired CSF samples of the nationwide anti-NMDAR encephalitis cohort. The values were analyzed in duplicate using single-molecule array and compared with measurements in healthy references. Follow-up sera were tested to analyze longitudinal responsiveness, if at least available from 2 time points after diagnosis. Serum NfL levels were compared with data on disease activity (seizures, MRI, and CSF findings), severity (modified Rankin Scale [mRS] score, admission days, and intensive care unit admission), and outcome (mRS score and relapses), using regression analysis.Results We have included 71 patients (75% female; mean age 31.4 years, range 0–85 years) of whom pretreatment serum samples were analyzed. Paired CSF samples were available of 33 patients, follow-up serum samples of 20 patients. Serum NfL levels at diagnosis were higher in patients (mean 19.5 pg/mL, 95% CI 13.7–27.7) than in references (mean 6.4 pg/mL, 95% CI 5.8–7.2, p < 0.0001). We observed a good correlation between serum and CSF NfL values (R = 0.84, p < 0.0001). Serum NfL levels and age correlated in patients (Pearson R = 0.57, p < 0.0001) and references (R = 0.62, p < 0.0001). Increased NfL values were detected in patients post–herpes simplex virus 1 encephalitis (mean 248.8 vs 14.1 pg/mL, p < 0.0001) and in patients with brain MRI lesions (mean 27.3 vs 11.1 pg/mL, p = 0.019). NfL levels did relate to the long-term follow-up (mRS score at 12 months; βNfL = 0.55, p = 0.013), although largely explained by the effect of age on NfL levels and prognosis. In serial samples, NfL values did roughly follow clinical disease activity, albeit with delay.Discussion Increased serum NfL levels reflect neuroaxonal damage in anti-NMDAR encephalitis. No relationship was identified with disease severity, whereas the association with outcome was confounded by age. The implied role of sampling timing on NfL levels also limits the applicability of NfL as a prognostic marker.GlossaryCoV=coefficient of variation; HSV=herpes simplex virus; ICU=intensive care unit; mRS=modified Rankin Scale; NfL=neurofilament light chain; NMDAR=NMDA receptorAnti-NMDA receptor (NMDAR) encephalitis is a complex immune-mediated disorder characterized by antibodies in the CSF against the ionotropic glutamate receptor type 1 subunit of the NMDAR. Clinical features include behavioral changes, cognitive impairment, seizures, language disorders, movement disorders, and autonomic dysfunctions. Anti-NMDAR encephalitis can occur as a paraneoplastic phenomenon (most often associated with ovarian teratomas), postinfectious after herpes simplex virus (HSV) encephalitis or sporadically.1 The disease is treatable by removing the trigger (if paraneoplastic) and administering immunotherapy. Still, patients might require admission to the intensive care unit (ICU) during the acute stage. Many patients experience persisting neurologic deficits, and 12% of cases relapse within 2 years.2 The outcome of anti-NMDAR encephalitis has previously been related to clinical factors like the requirement of ICU admission, treatment delay, and a lack of response to first-line immunotherapy.2,3 CSF leukocyte count and antibody titers correlate with outcome and clinical relapses.3,4 However, titers do not consistently reflect disease activity.5 Treatment decisions are currently based on clinical assessment since, despite several attempts, biomarkers for disease severity and prognosis are very limited.6Neurofilaments, and in particular the light chain subunit, are released from axons after acute damage. Neurofilament light chain (NfL) levels have therewith been identified as a useful biomarker for disease activity and prognosis in different neuroinflammatory and degenerative neurologic disorders.7 The strong correlation between CSF and serum NfL values and the high sensitivity of novel diagnostic techniques, allowing to quantify the lower levels detectable in serum, seem to expand the applicability of serum NfL as a biomarker.8 The preanalytical stability of NfL values (i.e., to delayed freezing and repeated thawing/freezing cycles) additionally raises the potential to investigate NfL as a biomarker.9 In this study, we investigate serum NfL levels at diagnosis and follow-up in patients with anti-NMDAR encephalitis to evaluate whether this biomarker of ongoing axonal damage correlates with disease severity and long-term outcome.MethodsStudy Participants and Sample SelectionAs the national referral center for autoimmune encephalitis of the Netherlands, accredited as the European Reference Network site (European Reference Network for Rare Immunodeficiency, Autoinflammatory and Autoimmune Diseases Network), we take note of all nationwide diagnoses of anti-NMDAR encephalitis. We have targeted all Dutch patients complying with the criteria for definite anti-NMDAR encephalitis,10 based on (1) the availability of a sufficient amount of serum from the time of diagnosis, (2) serum drawn before the start of immunotherapy, and (3) relevant clinical data of at least 4 months after diagnosis (eFigure 1, links.lww.com/WNL/C731). All eligible patients had previously consented to be in the nationwide anti-NMDAR encephalitis cohort and have been phenotyped clinically well (eTable 1).11 We compared the data with a healthy reference group (n = 61; 70% female; mean age 41.9 years, range 25–67 years) and with previously suggested age-based cutoff values.12,–,14 To correlate serum with CSF, we tested all available pretreatment CSF samples drawn within 48 hours from the serum sample. To investigate NfL longitudinally, we selected those patients of whom we had sufficient amounts of sera from at least 2 different time points after diagnosis.Clinical ParametersExtensive clinical data had been collected as part of our nationwide study.11 Age at onset, preceding HSV encephalitis, concomitant tumors, the presence of seizures or movement disorders, cerebral MRI abnormalities, and antibody titers were considered potentially relevant covariates for NfL levels. Maximum modified Rankin Scale (mRS) scores, duration of hospital admission, and the need for ICU admission were used as measures for disease severity. Short- and long-term outcomes were quantified as the mRS score at 4 and 12 months after diagnosis, respectively. A relapse was defined as the (re)emergence or worsening of clinical symptoms fitting the diagnostic criteria for anti-NMDAR encephalitis, after a period of at least 2 months of improvement or stabilization, combined with the confirmation of anti-NMDAR antibodies in CSF.2,11Procedures for NMDAR Antibody and NfL MeasurementsAnti-NMDAR antibodies were detected using cell-based assays (Euroimmun, AG, Lübeck, Germany) in CSF, and confirmed by immunohistochemistry, as described before.11 All patients had antibodies in CSF. NfL concentration in serum and CSF was measured in duplicate using single-molecule array NfL-light kit with SR-X immunoassay analyzer (Quanterix Corp., Billerica, MA), as previously described,15 by investigators blinded to clinical data. A Comparison was made with sera from 61 healthy controls. The mean intra-assay coefficient of variation (CoV) of duplicates and interassay CoV were 6.7% and 6.4%, respectively. Samples with CoV above 20% were reanalyzed.Standard Protocol Approvals, Registrations, and Patient ConsentsThis retrospective study was waived and declared non–complicit to the Medical Research Involving Humans Subjects Act by the Institutional Review Board of Erasmus MC. Written informed consent was obtained from all patients.StatisticsThe data on NfL values in serum and CSF were logarithmically transformed to adjust for skewness of the distribution. The descriptive statistics provided in this paper are centered around the geometric means. The correlation between NfL levels in serum and CSF was investigated by calculating Pearson correlation coefficient. A good correlation allowed serum NfL to be used as a surrogate biomarker. The serum NfL levels of the patients were compared with healthy adult references, as well as with age-based cutoff values from the literature, also including pediatric references.12,–,14 The known influence of age on NfL levels was confirmed by fitting a linear regression model. The rest of the analyses were corrected for this effect by the addition of age as a covariate. As the less extensively investigated effect of age on NfL in children does not seem strictly linear in the lowest age range, and the included healthy references were adults, we also performed all analyses in the subgroup of adult patients.The relationship between the independent variables tumor, preceding HSV1 infections, and visible MRI abnormalities and the dependent variable serum NfL and the relationship between serum NfL levels (independent variable) and duration of hospital admission were tested with variants of linear regression models, univariable and multivariable with age as a covariate. Because of the reported effect of an HSV1 encephalitis on both NfL levels and prognosis of anti-NMDAR encephalitis,16,17 we have left these patients out of the analyses to determine the prognostic value of serum NfL in anti-NMDAR encephalitis (eFigure 1, links.lww.com/WNL/C731). Logistic regression analysis was applied to investigate the relationship between serum NfL at diagnosis and the need for ICU admission, as measures of disease severity. The predictive value of early NfL levels for maximum disease severity (maximum mRS score), outcome (mRS score at 4 and 12 months after disease onset), and time to recovery (improving to an mRS score ≤2) was explored with ordinal regression analysis. Patients with an mRS score >2 before disease onset were excluded from the latter analyses as we would not be able to determine the outcome specifically related to the anti-NMDAR encephalitis (eFigure 1).Data AvailabilityAny data not published within this article are available at the Erasmus University Medical Center. Patient-related data will be shared on reasonable request from any qualified investigator, maintaining anonymity of the individual patients.ResultsWe included 71 patients with anti-NMDAR encephalitis (75% female; mean age 31.4 years, range 0–85 years; Table 1), representative of the complete national cohort (eTable 1, links.lww.com/WNL/C731).View inline View popup Table 1 Patient Characteristics of the Included Patients With Anti-NMDAR EncephalitisNfL Levels and Associated Clinical FactorsThe serum NfL concentration at diagnosis was higher in patients with anti-NMDAR encephalitis (mean 19.5 pg/mL, 95% CI 13.7–27.7) than in healthy controls (mean 6.4 pg/mL, 95% CI 5.8–7.2, p < 0.0001). Serum NfL values increased with increasing age at sampling in both patients (Pearson R = 0.57, p < 0.0001) and healthy controls (R = 0.62, p < 0.0001; Figure 1A). Serum and CSF NfL levels (n = 33) showed a good correlation (Pearson R = 0.84, p < 0.0001; Figure 1B). Patients with post-HSV1 anti-NMDAR encephalitis had higher serum NfL values than those without a preceding infection (mean 248.8 vs 14.1 pg/mL, p < 0.0001; Figure 2). Serum NfL levels were significantly higher in patients with cerebral MRI lesions compared with patients without (mean 27.3 vs 11.1 pg/mL, p = 0.019, patients with post-HSV1 encephalitis were not included in this analysis; Figure 2). These effects were similar when age was added to the analysis as a covariable (βHSV = 2.7, p < 0.0001, βMRI = 0.70, p = 0.012; Table 2). Analyzing these results in a slightly different way, using dichotomous age-based cutoff values, confirmed these results: patients with increased serum NfL levels (n = 39 [55%]) more frequently had a preceding HSV1 encephalitis (21% vs 0%, p = 0.019) and more frequently had MRI abnormalities (54% vs 16%, p = 0.002), compared with patients with serum NfL levels below the cutoff (eTable 2, links.lww.com/WNL/C731).<img height="440" width="327" alt="Figure 1" class="highwire-fragment fragment-image" src="https://n.neurology.org/content/neurology/100/21/e2204/F1.medium.gif">Download figure Open in new tab Download powerpoint Figure 1 Serum NfL Correlation With Age and CSFNfL levels in serum correlate positively with age (A) and CSF (B). NfL = neurofilament light chain; NMDARE = NMDA receptor encephalitis.<img class="highwire-fragment fragment-image" alt="Figure 2" height="390" width="440" src="https://n.neurology.org/content/neurology/100/21/e2204/F2.medium.gif">Download figure Open in new tab Download powerpoint Figure 2 Serum NfL Related to Radiologic FindingsPatients with anti-NMDAR encephalitis with MRI abnormalities had higher NfL levels in serum (p = 0.019; geographic means of patients with and without MRI abnormalities are represented by the black horizontal lines). Patients with a preceding HSV1 encephalitis (depicted in blue; all with MRI abnormalities) had even higher NfL levels in serum compared with patients without preceding a preceding HSV1 encephalitis (p < 0.0001; the geographic means of patients with and without a preceding HSV1 encephalitis are represented by the blue and red dotted horizontal lines, respectively). HSV = herpes simplex virus; NfL = neurofilament light chain; NMDAR = NMDA receptor.View inline View popup Table 2 Analyses With and Without Age CorrectionThe presence of concomitant tumors, seizures, and movement disorders, the delay between symptom onset and sample drawing, and serum and CSF antibody titers did not significantly relate to NfL levels, with or without age as covariable (Table 2 and eFigures 2–4, links.lww.com/WNL/C731). A subgroup analysis of only the adult patients (n = 59), to account for different behavior of NfL as serum biomarker in children, did not provide different results (eTable 3, links.lww.com/WNL/C731).The Prognostic Value of NfL for Disease Severity and OutcomeNfL levels at diagnosis did not associate with markers for disease severity: it did not significantly differ between patients who needed ICU admission or not and did not relate to the maximum mRS score over the course of the disease (eFigure 5, links.lww.com/WNL/C731) nor the duration of hospital admission (eFigure 6). Similarly, no relation was noted between NfL levels at diagnosis and disability (mRS score) 4 months after disease onset (eFigure 7).In univariable analysis, NfL serum levels at diagnosis were related to the outcome after 12 months (βNfL = 0.55, p = 0.013) and the time until recovery (to an mRS score ≤2; βNfL = 0.31, p = 0.050), although this seemed largely attributed to the effect of age at disease onset (βNfL = 0.38, p = 0.14 and βAge = 0.018, p = 0.26 for outcome after 12 months, Figure 3A; βNfL = 0.18, p = 0.31 and βAge = 0.020, p = 0.15 for recovery time, Figure 3B; Table 2). These findings were confirmed when applying dichotomous age-based cutoff values (p = 0.069 for outcome after 12 months, p = 0.14 for recovery time; eTable 2, links.lww.com/WNL/C731), and a subgroup analysis of the adult patients showed no different results either (eTable 3).<img alt="Figure 3" height="440" class="highwire-fragment fragment-image" src="https://n.neurology.org/content/neurology/100/21/e2204/F3.medium.gif"; width="424">Download figure Open in new tab Download powerpoint Figure 3 NfL, Age, and Long-term OutcomeHigher NfL levels in serum were correlated with a worse outcome (higher mRS score) after 12 months (A) and a longer time to recovery (B). As can be seen by the colored dots, this was largely influenced by the age at onset. Correction for age at onset negated the significant association. mRS = modified Rankin Scale; NfL = neurofilament light chain.NfL in Longitudinal Follow-up SeraWe included a total of 58 follow-up samples of 20 patients, of whom 10 had had at least 1 relapse of encephalitis (Figure 4A), and 10 had a monophasic course. When monitoring NfL levels over time, we noted that NfL values often increased considerably in the weeks after onset, especially while on the ICU, and had a subsequent decrease over time, more pronounced in patients discharged from the ICU (Figure 4, B and C, eFigures 8 and 9, links.lww.com/WNL/C731). Of interest, in an illustrative patient with a relapse, the main increase of NfL was seen only after the onset of symptoms (both in the initial episode and at relapse; Figure 4B). The suggestion of increase at the moment of onset of the relapse was similar to another patient who did not experience a relapse (Figure 4C). When focusing on the repeated serum measurements within the first months after disease onset, we see an increase of NfL levels up to 4–6 weeks (Figure 5A). This is in line with the observation that the majority of serum NfL measurements within the first weeks fall within the range of the healthy references, as opposed to the measurements after 2–4 weeks (Figure 5B).<img src="https://n.neurology.org/content/neurology/100/21/e2204/F4.medium.gif"; height="440" width="417" class="highwire-fragment fragment-image" alt="Figure 4">Download figure Open in new tab Download powerpoint Figure 4 Longitudinal NfL Levels in SerumIn all patients with a relapse (A), marked by the arrowheads. In 2 exemplary patients (B and C), we see an increase in NfL while admitted to the ICU (ICU admission annotated in red). The increase measured at the moment of relapse in patient B is similar to the one in the still-improving patient (C), without a relapse. The considerable increase is only seen later during the relapse. The treatment regime is represented by the colored squares at the top of the figure; IV methylprednisolone courses in light blue, immunoglobulins in dark blue, rituximab in light green, and cyclophosphamide in dark green. ICU = intensive care unit; mRS = modified Rankin Scale; NfL = neurofilament light chain.<img class="highwire-fragment fragment-image" src="https://n.neurology.org/content/neurology/100/21/e2204/F5.medium.gif"; width="440" alt="Figure 5" height="243">Download figure Open in new tab Download powerpoint Figure 5 Details on Timing of NfL MeasurementsIn all patients with multiple serum samples in the first 2 months after diagnosis, we see that the second measurements, starting at 28 days after diagnosis, exceed the normal range (A). The majority of all samples taken within the first 2 weeks after onset fall in the range of the healthy references (annotated with the green square; B). NfL = neurofilament light chain.DiscussionIn this study, we have investigated serum NfL as a biomarker in a large cohort of well-characterized patients with anti-NMDAR encephalitis. We demonstrate several important aspects: (1) although serum NfL levels are increased in patients with anti-NMDAR encephalitis, these do not provide independent prognostic value at diagnosis, neither for maximum severity nor for long-term outcome, and (2) serum NfL can be used to monitor the activity of disease in the chronic phase. However, the timing of serum NfL sampling has an influence on the values found, complicating the use as a biomarker to identify relapses early.We have first established that serum NfL levels are increased in patients with anti-NMDAR encephalitis compared with the general population. Identified associations between NfL levels and age, a preceding HSV1 encephalitis, and radiologic signs of tissue damage are all in line with what we would expect, NfL being a marker of tissue injury associated with neuroaxonal damage.8,17We identified no association between NfL levels at diagnosis and measures of maximum disease severity. In serial samples of patients admitted to the ICU, NfL levels increased within the first weeks; however, the initial values at diagnosis had no predictive value for ICU admission. Using univariable analysis, an association between serum NfL values and outcome after a year seemed to be present. As we and others have identified age as a factor associated both with higher NfL levels and with longer time to recovery, correction for age at onset was warranted.11 This explained at least the larger part of the difference in NfL levels, and no independent relationship between NfL and outcome at 12 months was identified.These findings correspond partly with the literature. Whereas other studies also negate the association between initial NfL levels, albeit in CSF, and disease severity,15,18 2 studies do associate NfL levels with disease severity (i.e., ICU admission).19,20 The referred samples in one were of the moment of determining severity and did not precede or predict disease severity (i.e., at diagnosis).19 Two of the mentioned studies, in homogeneous cohorts of patients with anti-NMDAR encephalitis, also described no applicability of NfL levels in CSF or serum as a biomarker for outcome.18,20 Two other studies found a correlation between NfL levels in diagnostic CSF samples and long-term outcome, even after (partial) correction for age, albeit in heterogeneous cohorts of patients with autoimmune encephalitis or paraneoplastic syndromes with diverse pathophysiologic mechanisms (not limited to anti-NMDAR encephalitis).21,22The observed NfL increase in the weeks after symptom onset was previously observed in a cohort of patients with anti-NMDAR encephalitis.19 This might suggest that axonal damage is not a hyperacute initial feature of the disease causing clinical symptoms; rather, serum NfL levels likely reflect an integral measure of antecedent and ongoing neuronal damage. This additionally discourages the deployment of NfL as a biomarker, as the timing of sampling largely affects the values found. Although the longitudinal data are limited, we provide some data to suggest that the same delay in increase hampers the use of serum NfL as a marker to predict relapses. As serum levels do often increase, a delayed NfL measurement may be used as a marker to differentiate between a relapse, pseudorelapse (i.e., due to infection), or persisting neurologic symptoms. As serum NMDAR antibodies are not very reliable,4 and CSF NMDAR antibody titers at remission are often not available, this could still be very valuable to decide on escalation of treatment or installment of maintenance immunotherapy.Our study has limitations, mainly related to the sample size and retrospective design. Although we have included all available pretreatment samples of our nationwide cohort, anti-NMDAR encephalitis is a rare disease, and the consequentially moderate sample size limits the power of our analyses. The retrospective study design did not allow us to monitor NfL values at regulated time points, and the longitudinal analysis is based on a limited subgroup only. In addition, follow-up was relatively short, and we did not perform regular imaging at consistent intervals, so we were unable to correlate NfL levels with lesion load and brain volume loss over time. Last, we used the mRS to quantify disability and outcome, which, despite being the most commonly used scale, is crude and not specific for this condition. More sensitive (cognitive) measures might yield different results correlating NfL values and disability. Prospective, structured follow-up could solve the majority of these limitations in the future.In conclusion, axonal damage is a feature of active anti-NMDAR encephalitis, and measuring serum NfL might prove helpful in clinical practice to identify active disease and monitor recovery. NfL levels are no independent predictors for disease severity or outcome. As the timing of sampling seems to have a large effect on NfL values, the use of single values in prediction of disease severity, outcome, or relapses is complicated.Study FundingThis study has received funding from Dioraphte (2001 0403) and is supported by ZonMw (Memorabel program).DisclosureJ. Brenner reports no disclosures relevant to the manuscript. S. Mariotto has received support for attending scientific meetings by Merck and Euroimmun and received speaker honoraria from Biogen and Novartis. A.E.M. Bastiaansen and M. Paunovic report no disclosures relevant to the manuscript. S. Ferrari received support for attending scientific meetings by Shire, Sanofi Genzyme, and Euroimmun and received a speaker honorarium from Lundbeck. D. Alberti, M.A.A.M. de Bruijn, Y.S. Crijnen, M.W.J. Schreurs, R.F. Neuteboom, J.G.M.C. Damoiseaux, and J.M. de Vries report no disclosures relevant to the manuscript. M.J. Titulaer has received research funds for serving on a scientific advisory board of MedImmune LLC and UCB, has filed a patent for methods and devices for typing neurologic disorders and cancer, and has received research funds for consultation at Guidepoint Global LLC and unrestricted research grants from CSL Behring and Euroimmun AG. M.J. Titulaer is supported by an Interlaken Leadership Award, an E-RARE 3 grant (UltraAIE), and the Dutch Epilepsy Foundation (NEF 14-19 and 19-08). Go to Neurology.org/N for full disclosures.AcknowledgmentThe authors thank all patients for their participation and all referring physicians. They thank Suzanne Franken, Mariska Nagtzaam, and Sanae Boukhrissi for their technical assistance. M.W.J. Schreurs, R.F. Neuteboom, P.A.E. Sillevis Smitt, J.M. de Vries, and M.J. Titulaer of this publication are members of the European Reference Network for Rare Immunodeficiency, Autoinflammatory and Autoimmune Diseases—Project ID No. 739543 (ERN-RITA).Appendix Authors<img height="1893" alt="Table" width="599" class="highwire-fragment fragment-image" src="https://n.neurology.org/content/neurology/100/21/e2204/T3.medium.gif">FootnotesGo to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.The Article Processing Charge was funded by Erasmus University.Submitted and externally peer reviewed. The handling editors were Brad Worrall, MD, MSc, FAAN, and Amy Kunchok, MBBS, MMed, FRACP.Editorial, page 991Received June 30, 2022.Accepted in final form February 9, 2023.Copyright © 2023 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 License 4.0 (CC BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.References1.↵Dalmau J, Armangué T, Planagumà J, et al. An update on anti-NMDA receptor encephalitis for neurologists and psychiatrists: mechanisms and models. Lancet Neurol. 2019;18(11):1045-1057. doi:10.1016/S1474-4422(19)30244-3OpenUrlCrossRefPubMed2.↵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(2):157-165. doi:10.1016/S1474-4422(12)70310-1OpenUrlCrossRefPubMed3.↵Balu R, McCracken L, Lancaster E, Graus F, Dalmau J, Titulaer MJ. A score that predicts 1-year functional status in patients with anti-NMDA receptor encephalitis. Neurology. 2019;92(3):e244-e252. doi:10.1212/WNL.0000000000006783OpenUrlAbstract/FREE Full Text4.↵Gresa-Arribas N, Titulaer MJ, Torrents A, et al. Antibody titres at diagnosis and during follow-up of anti-NMDA receptor encephalitis: a retrospective study. Lancet Neurol. 2014;13(2):167-177. doi:10.1016/S1474-4422(13)70282-5OpenUrlCrossRefPubMed5.↵Hansen HC, Klingbeil C, Dalmau J, Li W, Weißbrich B, Wandinger KP. Persistent intrathecal antibody synthesis 15 years after recovering from anti-N-methyl-D-aspartate receptor encephalitis. JAMA Neurol. 2013;70(1):117-119. doi:10.1001/jamaneurol.2013.585OpenUrlCrossRefPubMed6.↵Leypoldt F, Höftberger R, Titulaer MJ, et al. Investigations on CXCL13 in anti-N-methyl-D-aspartate receptor encephalitis: a potential biomarker of treatment response. JAMA Neurol. 2015;72(2):180-186. doi:10.1001/jamaneurol.2014.2956OpenUrlCrossRefPubMed7.↵Khalil M, Teunissen CE, Otto M, et al. Neurofilaments as biomarkers in neurological disorders. Nat Rev Neurol. 2018;14(10):577-589. doi:10.1038/s41582-018-0058-zOpenUrlCrossRefPubMed8.↵Mariotto S, Sechi E, Ferrari S. Serum neurofilament light chain studies in neurological disorders, hints for interpretation. J Neurol Sci. 2020;416:116986. doi:10.1016/j.jns.2020.116986OpenUrlCrossRef9.↵Altmann P, Leutmezer F, Zach H, et al. Serum neurofilament light chain withstands delayed freezing and repeated thawing. Sci Rep. 2020;10(1):19982. doi:10.1038/s41598-020-77098-8OpenUrlCrossRef10.↵Graus F, Titulaer MJ, Balu R, et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol. 2016;15(4):391-404. doi:10.1016/S1474-4422(15)00401-9OpenUrlCrossRefPubMed11.↵Bastiaansen AEM, de Bruijn MAAM, Schuller SL, et al. Anti-NMDAR encephalitis in the Netherlands, focusing on late-onset patients and antibody test accuracy. Neurol Neuroimmunol Neuroinflamm. 2021;9(2):e1127. doi:10.1212/NXI.0000000000001127OpenUrlAbstract/FREE Full Text12.↵Valentino P, Marnetto F, Martire S, et al. Serum neurofilament light chain levels in healthy individuals: a proposal of cut-off values for use in multiple sclerosis clinical practice. Mult Scler Relat Disord. 2021;54:103090. doi:10.1016/j.msard.2021.103090OpenUrlCrossRef13.↵Hviid CVB, Knudsen CS, Parkner T. Reference interval and preanalytical properties of serum neurofilament light chain in Scandinavian adults. Scand J Clin Lab Invest. 2020;80(4):291-295. doi:10.1080/00365513.2020.1730434OpenUrlCrossRef14.↵Jin J, Cui Y, Hong Y, et al. Reference values for plasma neurofilament light chain in healthy Chinese children. Clin Chem Lab Med. 2021;60(1):e10-e12. doi:10.1515/cclm-2021-0804OpenUrlCrossRef15.↵Mariotto S, Gajofatto A, Zuliani L, et al. Serum and CSF neurofilament light chain levels in antibody-mediated encephalitis. J Neurol. 2019;266(7):1643-1648. doi:10.1007/s00415-019-09306-zOpenUrlCrossRefPubMed16.↵Armangue T, Leypoldt F, Málaga I, et al. Herpes simplex virus encephalitis is a trigger of brain autoimmunity. Ann Neurol. 2014;75(2):317-323. doi:10.1002/ana.24083OpenUrlCrossRefPubMed17.↵Westman G, Aurelius E, Ahlm C, et al. Cerebrospinal fluid biomarkers of brain injury, inflammation and synaptic autoimmunity predict long-term neurocognitive outcome in herpes simplex encephalitis. Clin Microbiol Infect. 2021;27(8):1131-1136. doi:10.1016/j.cmi.2020.09.031OpenUrlCrossRefPubMed18.↵Day GS, Yarbrough MY, Körtvelyessy PM, et al. Prospective quantification of CSF biomarkers in antibody-mediated encephalitis. Neurology. 2021;96(20):e2546-e2557. doi:10.1212/WNL.0000000000011937. Erratum in: Neurology. 2021;97(16):795.OpenUrlAbstract/FREE Full Text19.↵Macher S, Zrzavy T, Höftberger R, et al. Longitudinal measurement of cerebrospinal fluid neurofilament light in anti-N-methyl-D-aspartate receptor encephalitis. Eur J Neurol. 2021;28(4):1401-1405. doi:10.1111/ene.14631OpenUrlCrossRef20.↵Guasp M, Martín-Aguilar L, Sabater L, et al. Neurofilament light chain levels in anti-NMDAR encephalitis and primary psychiatric psychosis. Neurology. 2022;98(14):e1489-e1498. doi:10.1212/WNL.0000000000200021OpenUrlAbstract/FREE Full Text21.↵Constantinescu R, Krýsl D, Andrén K, et al. Cerebrospinal fluid markers of neuronal and glial cell damage in patients with autoimmune neurologic syndromes with and without underlying malignancies. J Neuroimmunol. 2017;306:25-30. doi:10.1016/j.jneuroim.2017.02.018OpenUrlCrossRef22.↵Nissen MS, Ryding M, Nilsson AC, et al. CSF-neurofilament light chain levels in NMDAR and LGI1 encephalitis: a national cohort study. Front Immunol. 2021;12:719432. doi:10.3389/fimmu.2021.719432OpenUrlCrossRef
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Epilepsy: A Spectrum Disorder - PMC

Epilepsy, a disorder of unprovoked seizures is a multifaceted disease affecting individuals of all ages with a particular predilection for the very young and old. In addition to seizures, many patients often report cognitive and psychiatric problems associated ...
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Autoimmune encephalitis: recent clinical and biological advances.

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Our Actively Enrolling Clinical Trials | International Clinical Trials Day 2023

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Improving Early Recognition of Creutzfeldt-Jakob Disease Mimics | Neurology Clinical Practice

December 2022; 12 (6) Research Article Improving Early Recognition of Creutzfeldt-Jakob Disease Mimics Evelyn B. Lazar, Amanda L. Porter, Christian C. Prusinski, S. Richard Dunham, A. Sebastian Lopez-Chiriboga, M. Bakri Hammami, Divyanshu Dubey, Gregory S. Day First published October 12, 2022, DOI: https://doi.org/10.1212/CPJ.0000000000200097 Full PDF Citation Permissions Make Comment See Comments Downloads242 Share Article Figures & Data Info & Disclosures This article requires a subscription to view the full text. If you have a subscription you may use the login form below to view the article. Access to this article can also be purchased. AbstractBackground and Objectives Diagnostic criteria emphasize the use of sensitive and disease-specific tests to distinguish patients with rapidly progressive dementia (RPD) due to Creutzfeldt-Jakob disease (CJD) vs other causes (mimics). These tests are often performed in specialized centers, with results taking days to return. There is a need to leverage clinical features and rapidly reporting tests to distinguish patients with RPD due to CJD from those due to other causes (mimics) early in the symptomatic course.Methods In this case-control series, clinical features and the results of diagnostic tests were compared between mimics (n = 11) and patients with definite (pathologically proven, n = 33) or probable CJD (with positive real-time quaking-induced conversion [RT-QuIC], n = 60). Patients were assessed at Mayo Clinic Enterprise or Washington University from January 2014 to February 2021. Mimics were enrolled in prospective studies of RPD; mimics met the diagnostic criteria for probable CJD but did not have CJD.Results Mimics were ultimately diagnosed with autoimmune encephalitis (n = 6), neurosarcoidosis, frontotemporal lobar degeneration with motor neuron disease, dural arteriovenous fistula, cerebral amyloid angiopathy with related inflammation, and systemic lupus erythematous with polypharmacy. Age at symptom onset, sex, presenting features, and MRI and EEG findings were similar in CJD cases and mimics. Focal motor abnormalities (49/93, 11/11), CSF leukocytosis (4/92, 5/11), and protein >45 mg/dL (39/92, 10/11) were more common in mimics (p < 0.01). Positive RT-QuIC (77/80, 0/9) and total tau >1149 pg/mL (74/82, 2/10) were more common in CJD cases (all p < 0.01). Protein 14-3-3 was elevated in 64/89 CJD cases and 4/10 mimics (p = 0.067). Neural-specific autoantibodies associated with autoimmune encephalitis were detected within the serum (5/9) and CSF (5/10) of mimics; nonspecific antibodies were detected within the serum of 9/71 CJD cases.Discussion Immune-mediated, vascular, granulomatous, and neurodegenerative diseases may mimic CJD at presentation and should be considered in patients with early motor dysfunction and abnormal CSF studies. The detection of atypical features—particularly elevations in CSF leukocytes and protein—should prompt evaluation for mimics and consideration of empiric treatment while waiting for the results of more specific tests.FootnotesFunding information and disclosures are provided at the end of the article. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/cp.Submitted and externally peer reviewed. The handling editor was Associate Editor Jack W. Tsao, MD, DPhil, FAAN.Received March 21, 2022.Accepted September 15, 2022.© 2022 American Academy of NeurologyView Full Text AAN Members We have changed the login procedure to improve access between AAN.com and the Neurology journals. If you are experiencing issues, please log out of AAN.com and clear history and cookies. (For instructions by browser, please click the instruction pages below). After clearing, choose preferred Journal and select login for AAN Members. You will be redirected to a login page where you can log in with your AAN ID number and password. When you are returned to the Journal, your name should appear at the top right of the page. Google Safari Microsoft Edge Firefox Click here to login AAN Non-Member Subscribers Click here to login Purchase access For assistance, please contact: AAN Members (800) 879-1960 or (612) 928-6000 (International) Non-AAN Member subscribers (800) 638-3030 or (301) 223-2300 option 3, select 1 (international) Sign Up Information on how to subscribe to Neurology and Neurology: Clinical Practice can be found here Purchase Individual access to articles is available through the Add to Cart option on the article page. Access for 1 day (from the computer you are currently using) is US$ 39.00. Pay-per-view content is for the use of the payee only, and content may not be further distributed by print or electronic means. The payee may view, download, and/or print the article for his/her personal, scholarly, research, and educational use. Distributing copies (electronic or otherwise) of the article is not allowed. You May Also be Interested in Back to top RELATED MULTIMEDIA Listen Now: Dr. Justin Abbatemarco talks with Dr. Gregg Day, about patients with rapidly progressive dementia due to Creutzfeldt-Jakob disease versus other causes Podcast Download MP3 Morphologic and Molecular Patterns of Polymyositis With Mitochondrial Pathology and Inclusion Body Myositis Dr. Steven Greenberg and Dr. Erika Williams ► Watch Related Articles No related articles found. Alert Me Alert me when eletters are published
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Autoimmune encephalitis | Great Ormond Street Hospital

Autoimmune encephalitis | Great Ormond Street Hospital | AntiNMDA | Scoop.it
Autoimmune encephalitis is a group of rare neurological condition causing inflammation of the brain. This page from Great Ormond Street Hospital (GOSH) explains the causes, symptoms and treatment of autoimmune encephalitis and where to get help.
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