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International Consensus Recommendations for the Treatment of Pediatric NMDAR Antibody Encephalitis | Neurology Neuroimmunology & Neuroinflammation

International Consensus Recommendations for the Treatment of Pediatric NMDAR Antibody Encephalitis | Neurology Neuroimmunology & Neuroinflammation | AntiNMDA | Scoop.it
From nn.neurology.org - July 26, 2021 3:20 PM
Abstract Objective To create an international consensus treatment recommendation for pediatric NMDA receptor antibody encephalitis (NMDARE). Methods After selection of a panel of 27 experts with representation from all continents, a 2-step Delphi method was adopted to develop consensus on relevant treatment regimens and statements, along with key definitions in pediatric NMDARE (disease severity, failure to improve, and relapse). Finally, an online face-to-face meeting was held to reach consensus (defined as ≥75% agreement). Results Corticosteroids are recommended in all children with NMDARE (pulsed IV preferred), with additional IV immunoglobulin or plasma exchange in severe patients. Prolonged first-line immunotherapy can be offered for up to 3–12 months (oral corticosteroids or monthly IV corticosteroids/immunoglobulin), dependent on disease severity. Second-line treatments are recommended for cases refractory to first-line therapies (rituximab preferred over cyclophosphamide) and should be considered about 2 weeks after first-line initiation. Further immunotherapies for refractory disease 1-3 months after second-line initiation include another second-line treatment (such as cyclophosphamide) and escalation to tocilizumab. Maintenance immune suppression beyond 6 months (such as rituximab redosing or mycophenolate mofetil) is generally not required, except for patients with a more severe course or prolonged impairments and hospitalization. For patients with relapsing disease, second-line and prolonged maintenance therapy should be considered. The treatment of NMDARE following herpes simplex encephalitis should be similar to idiopathic NMDARE. Broad guidance is provided for the total treatment duration (first line, second line, and maintenance), which is dictated by the severity and clinical course (i.e., median 3, 9 and 18 months in the best, average, and worst responders, respectively). Recommendations on the timing of oncologic searches are provided. Conclusion These international consensus recommendations for the management of pediatric NMDARE aim to standardize the treatment and provide practical guidance for clinicians, rather than absolute rules. A similar recommendation could be applicable to adult patients. Glossary HSE=herpes simplex virus encephalitis; IQR=interquartile range; IgG=immunoglobulin G; IVIg=IV immunoglobulin; NMDARE=NMDA receptor antibody encephalitis; TPE=therapeutic plasma exchange NMDA receptor antibody encephalitis (NMDARE) is one of the most common autoimmune encephalitides, characterized by a recognizable constellation of neurologic and psychiatric features alongside positive NMDAR antibodies.1,2 NMDARE mostly affects children and young adults, particularly females. It may be very severe in the acute phase with a mortality of about 5%, relapses occur in about 15% of patients, and the final physician-assessed functional outcome is generally favorable, although neuropsychological and psychiatric sequelae are relatively common.2,3 The use of immunotherapies has been shown to improve outcomes,2,4,-,6 especially with early administration.2,4,6,7 In addition, immunotherapies reduce the risk of relapses.2,8,9 However, several aspects of treatment remain incompletely clarified, and treatment strategies are still heterogeneous, especially with regard to second-line and long-term immunotherapies.10,11 Indeed, although a number of reviews have been published,12,-,18 no randomized controlled trials or consensus guidelines for the treatment of NMDARE are available. With support from the Autoimmune Encephalitis Alliance, we aimed to create a consensus recommendation for the treatment of pediatric NMDARE, which was pragmatic and relevant to a global community and could serve as a practical decision support tool for the clinician confronted with this rare and challenging condition. Notably, the present document is intended as a recommendation guideline rather than absolute rules, given the limited evidence supporting most treatment statements. Although this document is focused on immunotherapy and to some extent symptomatic management, there are multiple outstanding issues in the management of pediatric NMDARE, such as education around the diagnosis and rehabilitation of patients after the acute phase, which are beyond the scope of this current article. Methods Establishment of a Consensus Expert Panel A steering committee (R.C.D., M.L., T.T., M.N., and M.E.) carefully selected a panel of 27 experts with representation from all continents (later referred to as “the Panel”), and based on the individual: (1) being a specialist (usually pediatric neurologist or rheumatologist) with clinical and/or research expertise in pediatric NMDARE; these experts were identified as lead clinical researchers in the field based on the systematic review conducted before the consensus recommendations project (paper in preparation), or were nominated by national child neurology societies; (2) having a publication track record in the field of pediatric autoimmune encephalitis/CNS disease; (3) being committed to completing 2 Delphi studies (approximately 45 minutes each),19,20 and participating in a 2-hour face-to-face/online meeting to reach consensus. The 27 experts were pediatric neurologists (n = 23) or pediatric rheumatologists (n = 4), from North America (n = 9), South America (n = 1), Europe (n = 9), Asia (n = 6), Oceania (n = 1), and Africa (n = 1). In addition, patient representatives (parents, n = 2), a member of the Autoimmune Encephalitis Alliance (n = 1), and adult neurology experts in NMDARE (n = 2, J.D. and S.R.I.) were invited to provide input in the later stages of the process. Delphi Method A 2-step Delphi method was adopted to develop the consensus of relevant statements, similar to the method used by the European League Against Rheumatism.21 A document with key definitions in pediatric NMDARE (disease severity, failure to improve, and relapse) used in the Delphi statements was shared online with the Panel (January 2020) before the first Delphi questionnaire. A revised version of the modified Rankin Scale22 was used, to be more applicable in children. The first Delphi questionnaire (Delphi 1, eAppendix 1, links.lww.com/NXI/A530) included key statements on the treatment of pediatric NMDARE, which were created based on the steering committee's clinical practice and the available literature and was sent out to the Panel in February 2020 using a web-based survey tool (SurveyMonkey.com). The Panel members were asked to vote on each statement of the first Delphi questionnaire according to a 5-point Likert scale (strongly agree/agree/neither agree nor disagree/disagree/strongly disagree) and provide open text comments as appropriate. Consensus was defined as an agreement by at least 75% of the participants (i.e., ≥75% agree/strongly agree or ≥75% disagree/strongly disagree). Twenty-six of 27 experts completed Delphi 1; then, the statements were revised according to the Panel's responses and comments, and statements that reached consensus were collated into a second Delphi document (Delphi 2). In this second Delphi survey, time durations were added (i.e., total duration of immunotherapy in NMDARE or timing of treatment escalation), and median, interquartile range (IQR), and range were calculated. The Delphi 2 statements were shared with 2 adult experts (J.D. and S.R.I.), with the Autoimmune Encephalitis Alliance representative and family representatives for further input. Delphi 2 was completed by 26 of the 27 experts by online survey in May 2020 (eAppendix 1, links.lww.com/NXI/A530), and final drafted recommendations were created. Face-to-Face Meeting The drafted recommendations were then voted on during a 2-hour online consensus meeting via the platform Zoom (zoom.us) on November 3, 2020, and included 26 participants from the expert Panel, with representatives from all continents. Each recommendation was voted on via the platform sli.do with the outcomes agree, do not agree, or abstain. The definitions used in the recommendations and the drug regimens were also voted on for consensus. As before, consensus was defined as an agreement by at least 75% of the participants. The number of voters varied (22-26 panelists) for the statements due to connectivity issues during the meeting. The statements that reached consensus were collated and are presented. Data Availability The Delphi questionnaires used to create the consensus-based recommendations for the treatment of pediatric NMDARE are provided in eAppendix 1 (links.lww.com/NXI/A530). Results eAppendix 1 (links.lww.com/NXI/A530) provides the Delphi 1 and Delphi 2 questionnaires and answers. Only final recommendations that reached consensus at the final face-to-face meeting are presented in Tables 1–4 and the Figure. Table 1 shows the key definitions in pediatric NMDARE (disease severity, failure to improve, and relapse), which reached consensus support. In addition, to aid clinicians with less experience in the management of NMDARE, definitions for best, average, and poorest responders are described (Table 5). Tables 2 and 3 show the recommendations for the treatment of pediatric NMDARE and are subdivided into general management principles (Table 2, 2.1), treatment of first encephalitis event including first-line, second-line, and maintenance immunotherapy (Table 2, 2.2–2.4), overall duration of immunotherapy at first event (Table 2, 2.5), treatment at relapse (Table 3, 3.1), treatment of NMDARE triggered by preceding herpes simplex virus encephalitis (HSE) (Table 3, 3.2), symptomatic treatments (Table 3, 3.3), and oncologic searches (Table 3, 3.4). Table 4 shows the recommendations for immunotherapy doses and regimens.23,-,25 The Figure provides a therapeutic pathway for guidance. View inline View popup Table 1 Definitions Used in the Consensus Recommendations for the Treatment of Pediatric NMDAR Antibody Encephalitis (NMDARE) (Tables 2 and 3) View inline View popup Table 2 Consensus-Based Recommendations on the Treatment of First Event of Pediatric NMDAR Antibody Encephalitis (NMDARE): General Principles (2.1), First-Line Immunotherapy (2.2), Second-Line Immunotherapy (2.3), Maintenance Immune Suppression (2.4), and Overall Duration of Immunotherapy (2.5) View inline View popup Table 3 Consensus-Based Recommendations on the Treatment of Pediatric NMDAR Antibody Encephalitis (NMDARE): NMDARE Relapse (3.1), Herpes Simplex Virus Encephalitis Followed by NMDARE (3.2), Symptomatic Therapies (3.3), and Oncologic Searches (3.4) View inline View popup Table 4 Treatment Regimens and Doses for Pediatric NMDAR Antibody Encephalitis (NMDARE) (95% Agreement, 22 Voting—Final Face-to-Face Agreement) Figure International Consensus Recommendations for the Treatment of First Event of Pediatric NMDAR Antibody Encephalitis (NMDARE) View inline View popup Table 5 Definition of Responder to Immunotherapy Discussion Evidence on treatment of NMDARE is restricted to retrospective and some prospective descriptive studies. No consensus-based treatment guidelines have previously been proposed. Hence, our purpose was to create international consensus-based recommendations for the treatment of pediatric NMDARE, with expertise from an international group of clinical and academic pediatric neurologists and rheumatologists. Our vision was to have a global approach with applicability across all health care settings; therefore, the expert Panel included representatives from all continents. We also wanted this document to be useful for clinicians less experienced in the treatment of autoimmune encephalitis; hence, a practical and detailed approach was adopted wherever possible, including definitions of failure to respond, and timing of treatment escalation. Indeed, although the management of pediatric NMDARE should ideally be guided by a pediatric neurology team in a center with multidisciplinary expertise in NMDARE, this may not always be possible, particularly in the acute phase of the disease. Our recommendations begin with general management principles, highlighting the importance of early diagnosis and careful communication with the family (Table 2, 2.1). The importance of raising awareness of this disorder, which may present to psychiatrists and emergency physicians as well as neurologists, cannot be overemphasized, and the diagnostic criteria26 and modification for children,27 along with the distinctive clinical characteristics,12,28,29 may aid an expeditious diagnosis. Similarly, families need to be informed of the expected or potential disease evolution, the treatment possibilities, and the often long and demanding course of the illness. Understanding the timeline of the disease and the speed of recovery is one of the greatest challenges of this disease, and it is essential for clinicians and family members to appreciate that the typical course is of little change (or worsening) in the first weeks and slow improvements in the following months, and improvements may continue into the second year. As regards first-line immunotherapy (Table 2, 2.2), there was consensus that corticosteroids are the first agent to be used in pediatric NMDARE, with IV use (i.e., IV methylprednisolone) preferred over oral use (i.e., oral prednisone), although high-dose oral administration of corticosteroids is a good alternative, particularly if IV access is a problem. In high-income countries, therapeutic plasma exchange (TPE) and/or IV immunoglobulin (IVIg) are often used in conjunction with corticosteroids.30 Although some physicians use TPE or IVIg at the same time as corticosteroids, other administer them sequentially, with more severe patients often prompting a more aggressive combined treatment or rapid escalation. TPE was recommended for patients with severe disease, although it is recognized that TPE can be associated with more severe complications (e.g., central line infection) compared with IVIg.31,32 TPE was recommended over immunoadsorption, where there is less evidence.33,34 In general, ongoing corticosteroids are continued in the first months of disease, preferably as pulses, or alternatively oral tapers. Longer or repeated IVIg courses may be continued monthly for 3–6 months, depending on severity and availability, whereas monthly pulsed oral dexamethasone or IV methylprednisolone, or even ACTH, for 3-6 months may be used in resource-limited settings. In patients who are failing to improve (definition in Table 1) approximately 2 weeks after initiation of 2 or more first-line therapies, second-line treatment is recommended over further first-line therapies. Second-line treatments are recommended especially in patients with severe disease, with rituximab now generally preferred over cyclophosphamide (Table 2, 2.3). Rituximab dosing protocols were all equally accepted (Table 4) as there are no data to support one protocol over another. There is evidence suggesting that use of second-line immunotherapy improves outcome in patients failing to improve after first-line therapy2 and that second-line therapy reduces the risk of relapses.8,9,13 Moreover, earlier initiation of rituximab also seems more favorable compared with late treatment.7 The use of second-line immunotherapy is still variable globally and considerably less frequent in some countries. For instance, rituximab use is 0%–5.5% in Chinese cohorts35,-,37 and more variable in India (0%–61%),38,-,40 although with generally favorable outcomes, which suggests the outcomes described in the published literature may be affected by referral bias, publication bias, or ethnic vulnerability to worse outcomes.41 The specific approaches toward the use of second-line immunotherapy varied within the Panel, with some clinicians supporting the use of rituximab in all patients with NMDARE and others reserving it to cases with severe disease or failure to improve (Table 1). The consensus opinion was that second-line therapy is not needed in all patients, but only in patients with severe disease and those who fail to improve. One of the greatest challenges is deciding the timing of escalation after 1 second-line therapy. There was consensus that in the patient failing to improve 1-3 months (generally >6 weeks) following initiation of the first second-line immunotherapy, another second-line therapy such as cyclophosphamide if rituximab was used first can be considered. In the patient who fails rituximab, cyclophosphamide is generally recommended as an escalation agent, although some members of the Panel have increasing interest in tocilizumab as an alternative escalation therapy due to a more favorable perceived safety profile.42,-,44 Other escalation treatments have been reported in the literature, such as IV/intrathecal methotrexate with intrathecal corticosteroids and subcutaneous/IV bortezomib; these have more limited evidence, but can be used according to the local treating center's expertise.41,43,-,57 The patient who has severe disease and is failing to improve remains a major challenge. The clinician needs to balance the risk of severe disease (such as being on the intensive care unit) with the risk of treatment side effects, in the knowledge that NMDARE symptoms may take many weeks or months to improve.2,7 Indeed, unlike in acute disseminated encephalomyelitis, when treatment often results in rapid improvements within days, in NMDARE, the improvements are slow and continue for ≥24 months after the acute phase.2 Therefore, allowing treatments to have their effect, including their combined actions, is important to avoid hasty therapeutic decisions. In general, second-line agents such as rituximab or cyclophosphamide should be given 1-3 months before making judgment on effect, with 6 weeks being a broadly accepted guideline. The timing of escalation is very challenging and influenced by severity, age, risk-benefit ratio, treating center's experience, and access to treatments. Overall, for patients in the intensive care unit, where there may be multiple additional risk factors,7 earlier escalation seems reasonable. Anecdotal reports from our expert group of benefit of treatment with rituximab or tocilizumab years after onset suggest that in the patient who continues to have major impairments, further immunotherapies are warranted within reason, although there are likely to be diminishing returns when treatment is used later in the disease course. In the patient who has failed to improve a year or more after treatment, it is sometimes difficult to determine residual sequelae from ongoing inflammation. In this situation, CSF re-examination for ongoing neuroinflammation (i.e., persistent pleocytosis, intrathecal oligoclonal bands, elevated immunoglobulin G [IgG] index, or CSF neopterin)58 may help with decision making and the risk vs benefit consideration of an empiric retrial or immunotherapy (pulsed corticosteroid for 3 months, IVIg monthly, rituximab reinduction, or tocilizumab). CSF NMDAR antibody titers seem to correlate better with disease course compared with serum antibodies,59,60 but there is not a strong correlation between titer and clinical course in the individual patient, and antibodies can persist long after recovery.60,e1,e2 Although all stages of management of NMDARE may be challenging even for experienced physicians, this is especially true when dealing with a severe patient failing to improve, and a second opinion may be useful and help the clinician make further therapeutic decisions. Organizations such as the Autoimmune Encephalitis Alliance (aealliance.org/), the Encephalitis Society (encephalitis.info/), and the Anti NMDA Receptor Encephalitis Foundation Inc. (antinmdafoundation.org/) may help connect with experts. There was overall agreement that maintenance immune suppression beyond 6 months from onset is generally not needed (Table 2, 2.4), apart from patients with more severe course or prolonged impairments and hospitalization. Indeed, literature data show that early and adequate treatment, including use of second-line therapies when appropriate, is the priority,2 rather than prolonged maintenance immune suppression. Moreover, the relatively low relapse rate of NMDARE is in significant contrast with that of other disorders such as neuromyelitis optica, where chronic immune suppression is recommended from the first event. When giving immune suppression for more than 6 months, rituximab redosing was generally preferred, although mycophenolate mofetil is also used,9,36,e3-e5 and there is little evidence to suggest superiority of either. With regard to rituximab redosing, most experts recommend redosing when CD19 cells repopulate, in view of the variability in the time to B-cell repopulation between individuals.e6 An alternative approach is to redose rituximab at regular 6-month intervals similar to practice in adult patients with neuromyelitis optica.e7,e8 There was no consensus in the dosage and frequency of redosing, with some experts using the same dose/regimen used at induction and others using lower doses (Table 4). As regards mycophenolate mofetil, given its slow onset of efficacy, there should initially be overlap with other immunotherapies (i.e., oral corticosteroids) for 3-6 months after commencement.e3 Other maintenance agents, such as oral azathioprine and methotrexate, are sometimes used for maintenance immune suppression, although the paucity of experience precluded consensus recommendations from our expert group. In resource-poor countries, the Panel also agreed that prolonged first-line therapy (with IV pulsed methylprednisolone, dexamethasone, or IVIg) can be used as an alternative form of maintenance (>6 months) immunotherapy, if rituximab and mycophenolate mofetil are not available. There was agreement in the need for a more aggressive and prolonged treatment approach in patients with relapsing disease (Table 3, 3.1), with a lower threshold for second-line and maintenance treatments (rituximab or mycophenolate) and more prolonged overall immunotherapy duration. Indeed, the median overall duration of immunotherapy at first event of pediatric NMDARE was recommended to be about 3 months (IQR 3–6 months) in the best responders, 9 months (IQR 6–12 months) in the average responders, 18 months (IQR 12–24 months) in the poorest responders (Table 2, 2.5), and 12–24 months after a relapse, acknowledging patient severity and management variables (Table 3, 3.1). We acknowledge that the definition of “best,” “average,” and “poorest” is dependent on experience of the clinician; therefore, some guidance is provided in Table 5. Although not the focus of this work, the Panel acknowledges that infectious risk mitigation strategies are key to ensure the patients' safety while receiving immunotherapy, especially close monitoring for infections and adherence to hospital infection control protocols to prevent hospital acquired infection. In selected patients on prolonged high-dose corticosteroids, multiple second-line or escalation immunotherapies, prophylactic trimethoprim-sulfamethoxazole for Pneumocystis carinii pneumonia may be required. In patients with low IgG levels and recurrent infections despite prophylactic antibiotics, immunoglobulin supplementation may be required. As regards patients with relapse of neurologic symptoms after HSE (Table 3, 3.2), acyclovir should be administered promptly until HSE recurrence is excluded, while maintaining a high index of suspicion for an underlying autoimmune etiology. The Panel agreed that if autoimmune encephalitis is confirmed after HSE, immunotherapy should be used in a similar way to idiopathic/naive NMDARE.e9,e10 The Panel acknowledged that although immunotherapy is the therapeutic priority to treat the underlying disease, symptomatic management (such as antiseizure medications) is equally important (Table 3, 3.3). However, symptom management may be challenging and requires multidisciplinary expertise.e11 As stated in the recommendations, there was consensus on a preferred list of medications found to be useful in the treatment of behavior agitation and dyskinesia (full list of medications considered is detailed in eAppendix 1, links.lww.com/NXI/A530). Caution was also drawn to the observation that the use of antipsychotics in pediatric NMDARE may worsen dyskinesia or induce a neuroleptic malignant syndrome. Although paraneoplastic etiology is rare in prepubertal children and in boys,2,9,e12 oncologic searches for ovarian teratoma (and neural crest tumors in children aged <5 years) are mandatory in all children with NMDARE, should be performed early, and be completed in the first days-weeks after admission (Table 3, 3.4). Ultrasound or MRI of the abdomen and pelvis and CT or MRI of the chest are the recommended imaging modalities, and collaboration with local oncologists and radiologists will help guide the need for additional studies (e.g., PET scan) to optimize diagnostic yield in patients with severe disease or a failure to improve. The timely identification of a tumor and its subsequent removal may improve the outcome considerably, although the prognosis also depends on the type of tumor.2,e12 The Panel reached agreement on oncologic searches that should be performed in all patients, both at baseline and in patients who fail to improve or relapse, with particular focus on postpubertal females in whom ovarian teratoma screening and longitudinal surveillance for ovarian teratoma should be strongly pursued. Although not the main aim of this consensus document, the Panel acknowledged that adequate rehabilitation after the acute phase of NMDARE is essential and may improve outcomes. We strongly support the need for rehabilitation to be provided in a center familiar with rehabilitating young people with acquired brain injury such as encephalitis or traumatic brain injury, acknowledging that improvements may continue for up to 24 months. Rehabilitation often includes focus on cognitive and behavioral problems (including executive dysfunction and fatigue) post-NMDARE. In view of the relative rarity of this condition, any recommendation or guideline for the treatment of pediatric NMDARE is inevitably based on limited evidence; therefore, this document should be intended as a recommendation meant to provide guidance rather than absolute rules, and it should not be used to prevent access to therapies if these are recommended by a patient's physician. Moreover, by putting together international experts from very different settings, the present work highlighted heterogeneity in the management of this condition. The differences stimulated discussion and reflection, and there was still consensus around most aspects of pediatric NMDARE treatment. Although the experts included people with broad international expertise, the opinions remain vulnerable to anecdote and potential bias related to referral of complicated or atypical patients. Despite these limitations, we strove to create an international consensus-based recommendation aimed at supporting the clinician in the treatment of pediatric NMDARE, with a dedicated global approach for all health care settings. We hope that with the aid of recently released diagnostic criteria,26,27 the present treatment recommendation may contribute to a more systematic approach, resulting in more comparable data internationally, which may generate better quality evidence. Nonetheless, there are still major unresolved issues, which should represent the focus of future research. Study Funding There was funding commitment for the face to face meeting by the Autoimmune Encephalitis Alliance (AEA), which due to COVID-19 was not needed, as the face-to-face meeting was virtual. AEA has supported costs of open access for journal publication. M. Eyre is supported by Action Medical Research and the British Paediatric Neurology Association. T. Armangue is supported by research grants Instituto Carlos III/FEDER, Spain (PI18/00486) and Generalitat de Catalunya PERIS (SLT006/17/00362). S.R. Irani is supported by the Wellcome Trust (104079/Z/14/Z), the UCB-Oxford University Alliance, BMA Research Grants Vera Down grant (2013) and Margaret Temple (2017), Epilepsy Research UK (P1201), the Fulbright UK-US commission (MS-Society research award), and by the NIHR Oxford Biomedical Research Centre. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health). RCD is supported by NHMRC Investigator grant (Australia) and Petre Foundation. Disclosure M. Nosadini, T. Thomas, M. Eyre, B. Anlar, T. Armangue, S.M. Benseler, T. Cellucci, K. Deiva, and W. Gallentine report no disclosures relevant to the manuscript. G. Gombolay receives part-time salary support from the Centers for Disease Control and Prevention to review acute flaccid myelitis cases for surveillance. M.P. Gorman has received research funding from Pfizer and Roche for research unrelated to the current topic. Y. Hacohen, Y. Jiang, B.C. Lim, E. Muscal, and A. Ndondo report no disclosures relevant to the manuscript. R. Neuteboom participates in treatment studies in pediatric MS by Novartis and Sanofi-Genzyme and received consultation fees from Novartis, Zogenix, and Sanofi-Genzyme. K. Rostásy, H. Sakuma, and S. Sharma report no disclosures relevant to the manuscript. S.N. Tenembaum participates as member of the NMO Scientific Advisory Committee (Genentech-Roche Inc.) and chair of the NMO Relapse Adjudication Committee (Alexion Pharmaceuticals Inc.); she has received speaker honoraria from Biogen Idec Argentina, Merck Serono LATAM, Genzyme, Novartis Argentina, and Novartis Pharma Inc. H.A. Van Mater and E. Wells report no disclosures relevant to the manuscript. R. Wickstrom has received consultation fees from Roche, Novartis, and Octapharma. A.K. Yeshokumar reports no disclosures relevant to the manuscript. S.R. Irani is a coapplicant and receives royalties on patent application WO/210/046716 (U.K. patent no., PCT/GB2009/051441) entitled “Neurological Autoimmune Disorders” (the patent has been licensed for the development of assays for LGI1 and other VGKC-complex antibodies) and on an unlicensed patent to improve detection of autoantibodies. J. Dalmau reports no disclosures relevant to the manuscript. M. Lim has received consultation fees from CSL Behring, Novartis, and Octapharma; travel grants from Merck Serono; and was awarded educational grants to organize meetings by Novartis, Biogen Idec, Merck Serono, and Bayer. R.C. Dale reports no disclosures relevant to the manuscript. Go to Neurology.org/NN for full disclosures. Acknowledgment The authors thank Kimberley de Haseth from AEA and the De Vivero family for support and advice. Appendix Authors Footnotes Go to Neurology.org/NN for full disclosures. Funding information is provided at the end of the article. The Article Processing Charge was funded by Wellcome Trust. Received February 14, 2021. Accepted in final form May 21, 2021. Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. 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J Adv Nurs. 2000;32(4):1008-1015.OpenUrlCrossRefPubMed 21.↵ter Haar NM, Oswald M, Jeyaratnam J, et al. Recommendations for the management of autoinflammatory diseases. Ann Rheum Dis. 2015;74(9):1636-1644. 22.↵van Swieten JC, Koudstaal PJ, Visser MC, Schouten HJ, van Gijn J. Interobserver agreement for the assessment of handicap in stroke patients. Stroke. 1988;19(5):604-607. 23.↵Bertsias GK, Tektonidou M, Amoura Z, et al. Joint European League Against Rheumatism and European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations for the management of adult and paediatric lupus nephritis. Ann Rheum Dis. 2012;71(11):1771-1782. 24.↵Mina R, von Scheven E, Ardoin SP, et al. Consensus treatment plans for induction therapy of newly diagnosed proliferative lupus nephritis in juvenile systemic lupus erythematosus. Arthritis Care Res (Hoboken). 2012;64(3):375-383.OpenUrl 25.↵Stingl C, Cardinale K, Van Mater H. An update on the treatment of pediatric autoimmune encephalitis. Curr Treatm Opt Rheumatol. 2018;4(1):14-28.OpenUrl 26.↵Graus F, Titulaer MJ, Balu R, et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol. 2016;15(4):391-404.OpenUrlCrossRefPubMed 27.↵Cellucci T, Van Mater H, Graus F, et al. Clinical approach to the diagnosis of autoimmune encephalitis in the pediatric patient. Neurol Neuroimmunol Neuroinflamm. 2020;7(2):e663. 28.↵Al-Diwani A, Handel A, Townsend L, et al. The psychopathology of NMDAR-antibody encephalitis in adults: a systematic review and phenotypic analysis of individual patient data. Lancet Psychiatry. 2019;6(3):235-246.OpenUrl 29.↵Varley JA, Webb AJS, Balint B, et al. The Movement disorder associated with NMDAR antibody-encephalitis is complex and characteristic: an expert video-rating study. J Neurol Neurosurg Psychiatry. 2019;90(6):724-726.OpenUrlFREE Full Text 30.↵Suppiej A, Nosadini M, Zuliani L, et al. Plasma exchange in pediatric anti-NMDAR encephalitis: a systematic review. Brain Dev. 2016;38(7):613-622.OpenUrl 31.↵Eyre M, Hacohen Y, Barton C, Hemingway C, Lim M. Therapeutic plasma exchange in paediatric neurology: a critical review and proposed treatment algorithm. Dev Med Child Neurol. 2018;60(8):765-779.OpenUrlPubMed 32.↵Eyre M, Hacohen Y, Lamb K, et al. Utility and safety of plasma exchange in paediatric neuroimmune disorders. Dev Med Child Neurol. 2019;61(5):540-546.OpenUrl 33.↵Dogan Onugoren M, Golombeck KS, Bien C, et al. Immunoadsorption therapy in autoimmune encephalitides. Neurol Neuroimmunol Neuroinflamm. 2016;3(2):e207. 34.↵Heine J, Ly LT, Lieker I, et al. Immunoadsorption or plasma exchange in the treatment of autoimmune encephalitis: a pilot study. J Neurol. 2016;263(12):2395-2402.OpenUrl 35.↵Zhang M, Li W, Zhou S, et al. Clinical features, treatment, and outcomes among Chinese children with anti-methyl-D-aspartate receptor (anti-NMDAR) encephalitis. Front Neurol. 2019;10:596.OpenUrl 36.↵Xu X, Lu Q, Huang Y, et al. Anti-NMDAR encephalitis: a single-center, longitudinal study in China. Neurol Neuroimmunol Neuroinflamm. 2019;7(1):e633. 37.↵Mo Y, Wang L, Zhu L, et al. Analysis of risk factors for a poor prognosis in patients with anti-N-methyl-D-aspartate receptor encephalitis and construction of a prognostic composite score. J Clin Neurol. 2020;16(3):438-447.OpenUrl 38.↵Raha S, Gadgil P, Sankhla C, Udani V. Nonparaneoplastic anti-N-methyl-D-aspartate receptor encephalitis: a case series of four children. Pediatr Neurol. 2012;46(4):246-249.OpenUrlCrossRefPubMed 39.↵Nagappa M, Bindu PS, Mahadevan A, Sinha S, Mathuranath PS, Taly AB. Clinical features, therapeutic response, and follow-up in pediatric anti-N-methyl-D-aspartate receptor encephalitis: experience from a tertiary care university hospital in India. Neuropediatrics. 2016;47(1):24-32.OpenUrl 40.↵Nair A V, Menon J, Kuzhikkathukandiyil P. Clinical profile and neuropsychiatric outcome in children with anti-NMDAR encephalitis. Indian Pediatr. 2019;56(3):247-249.OpenUrl 41.↵Jones HF, Mohammad SS, Reed PW, et al. Anti-N-methyl-d-aspartate receptor encephalitis in Māori and Pacific Island children in New Zealand. Dev Med Child Neurol. 2017;59(7):719-724.OpenUrl 42.↵Lee WJ, Lee ST, Shin YW, et al. Teratoma removal, steroid, IVIG, rituximab and tocilizumab (T-SIRT) in anti-NMDAR encephalitis. Neurotherapeutics. 2021;18(1):474-487. doi: 10.1007/s13311-020-00921-7.OpenUrlCrossRef 43.↵Sveinsson O, Granqvist M, Forslin Y, Blennow K, Zetterberg H, Piehl F. Successful combined targeting of B- and plasma cells in treatment refractory anti-NMDAR encephalitis. J Neuroimmunol. 2017;312:15-18.OpenUrl 44.↵Jun JS, Seo HG, Lee ST, Chu K, Lee SK. Botulinum toxin treatment for hypersalivation in anti-NMDA receptor encephalitis. Ann Clin Transl Neurol. 2017;4(11):830-834.OpenUrl 45.↵Thomas A, Rauschkolb P, Gresa-Arribas N, Schned A, Dalmau JO, Fadul CE. Anti-N-methyl-D-aspartate receptor encephalitis: a patient with refractory illness after 25 months of intensive immunotherapy. JAMA Neurol. 2013;70(12):1566-1568.OpenUrl 46.↵DeSena AD, Greenberg BM, Graves D. Three phenotypes of anti-N-methyl-D-aspartate receptor antibody encephalitis in children: prevalence of symptoms and prognosis. Pediatr Neurol. 2014;51(4):542-549.OpenUrlPubMed 47.↵DeSena AD, Noland DK, Matevosyan K, et al. Intravenous methylprednisolone versus therapeutic plasma exchange for treatment of anti-N-methyl-D-aspartate receptor antibody encephalitis: a retrospective review. J Clin Apher. 2015;30(4):212-216.OpenUrlCrossRefPubMed 48.↵Tatencloux S, Chretien P, Rogemond V, Honnorat J, Tardieu M, Deiva K. Intrathecal treatment of anti-N-Methyl-D-aspartate receptor encephalitis in children. Dev Med Child Neurol. 2015;57(1):95-99.OpenUrl 49.↵Liba Z, Kayserova J, Elisak M, et al. Anti-N-methyl-D-aspartate receptor encephalitis: the clinical course in light of the chemokine and cytokine levels in cerebrospinal fluid. J Neuroinflammation. 2016;13(1):55.OpenUrl 50.↵Behrendt V, Krogias C, Reinacher-Schick A, Gold R, Kleiter I. Bortezomib treatment for patients with anti-N-methyl-d-aspartate receptor encephalitis. JAMA Neurol. 2016;73(10):1251-1253.OpenUrl 51.↵Mehr SR, Neeley RC, Wiley M, Kumar AB. Profound autonomic instability complicated by multiple episodes of cardiac asystole and refractory bradycardia in a patient with anti-NMDA encephalitis. Case Rep Neurol Med. 2016;2016:7967526.OpenUrl 52.↵Scheibe F, Prüss H, Mengel AM, et al. Bortezomib for treatment of therapy-refractory anti-NMDA receptor encephalitis. Neurology. 2017;88(4):366-370.OpenUrlCrossRefPubMed 53.↵Schroeder C, Back C, Koc Ü, et al. Breakthrough treatment with bortezomib for a patient with anti-NMDAR encephalitis. Clin Neurol Neurosurg. 2018;172:24-26.OpenUrl 54.↵Shin YW, Lee ST, Kim TJ, Jun JS, Chu K. Bortezomib treatment for severe refractory anti-NMDA receptor encephalitis. Ann Clin Transl Neurol. 2018;5(5):598-605.OpenUrl 55.↵Keddie S, Crisp SJ, Blackaby J, et al. Plasma cell depletion with bortezomib in the treatment of refractory NMDAR-antibody encephalitis. Rational developments in neuroimmunological treatment. Eur J Neurol. 2018;25(11):1384-1388.OpenUrlPubMed 56.↵Janmohamed M, Knezevic W, Needham M, Salman S. Primary lateral sclerosis-like picture in a patient with a remote history of anti-N-methyl-D-aspartate receptor (anti-NMDAR) antibody encephalitis. BMJ Case Rep. 2018;2018:bcr2017224060.OpenUrl 57.↵Yang XZ, Zhu HD, Ren HT, et al. Utility and safety of intrathecal methotrexate treatment in severe anti-N-methyl-D-aspartate receptor encephalitis: a pilot study. Chin Med J (Engl). 2018;131(2):156-160.OpenUrl 58.↵Dale RC, Brilot F, Fagan E, Earl J. Cerebrospinal fluid neopterin in paediatric neurology: a marker of active central nervous system inflammation. Dev Med Child Neurol. 2009;51(4):317-323.OpenUrlCrossRefPubMed 59.↵Frechette ES, Zhou L, Galetta SL, Chen L, Dalmau J. Prolonged follow-up and CSF antibody titers in a patient with anti-NMDA receptor encephalitis. Neurology. 2011;76(7 suppl):S64-S66.OpenUrlCrossRef 60.↵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.OpenUrlCrossRefPubMed 61.Additional references e1-e12 are available at eAppendix 2 (links.lww.com/NXI/A531).
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Josep Dalmau receives the “Scientific Breakthrough 2023” Award from the American Brain Foundation

From www.clinicbarcelona.org - May 23, 2023 2:38 PM
The accolade recognises the commitment of this Clínic Barcelona-IDIBAPS researcher to deepening our understanding of autoimmune neurological diseases such...
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IDIBAPS creates three multidisciplinary research programs to encourage collaboration among its groups

From www.clinicbarcelona.org - September 5, 2023 11:21 AM
They are the Translational cancer research program, the Synaptic autoimmunity in neurology, psychiatry and cognitive neuroscience program and the Lymphoid...
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ExTINGUISH: A Beacon of Hope for NMDAR Encephalitis

From youtu.be - August 6, 2023 7:10 PM
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MR Imaging Findings in a Large Population of Autoimmune Encephalitis | American Journal of Neuroradiology

MR Imaging Findings in a Large Population of Autoimmune Encephalitis | American Journal of Neuroradiology | AntiNMDA | Scoop.it
From www.ajnr.org - July 27, 2023 11:18 AM
Research ArticleAdult Brain MR Imaging Findings in a Large Population of Autoimmune Encephalitis S. Gillon, M. Chan, J. Chen, E.L. Guterman, X. Wu, C.M. Glastonbury and Y. Li American Journal of Neuroradiology July 2023, 44 (7) 799-806; DOI: https://doi.org/10.3174/ajnr.A7907 ArticleFigures & DataInfo & MetricsReferences PDF 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 PURPOSE: Autoimmune encephalitis is a rare condition in which autoantibodies attack neuronal tissue, causing neuropsychiatric disturbances. This study sought to evaluate MR imaging findings associated with subtypes and categories of autoimmune encephalitis.MATERIALS AND METHODS: Cases of autoimmune encephalitis with specific autoantibodies were identified from the medical record (2009–2019). Cases were excluded if no MR imaging of the brain was available, antibodies were associated with demyelinating disease, or >1 concurrent antibody was present. Demographics, CSF profile, antibody subtype and group (group 1 intracellular antigen or group 2 extracellular antigen), and MR imaging features at symptom onset were reviewed. Imaging and clinical features were compared across antibody groups using χ2 and Wilcoxon rank-sum tests.RESULTS: Eighty-five cases of autoimmune encephalitis constituting 16 distinct antibodies were reviewed. The most common antibodies were anti-N-methyl-D-aspartate (n = 41), anti-glutamic acid decarboxylase (n = 7), and anti-voltage-gated potassium channel (n = 6). Eighteen of 85 (21%) were group 1; and 67/85 (79%) were group 2. The median time between MR imaging and antibody diagnosis was 14 days (interquartile range, 4–26 days). MR imaging had normal findings in 33/85 (39%), and 20/33 (61%) patients with normal MRIs had anti-N-methyl-D-aspartate receptor antibodies. Signal abnormality was most common in the limbic system (28/85, 33%); 1/68 (1.5%) had susceptibility artifacts. Brainstem and cerebellar involvement were more common in group 1, while leptomeningeal enhancement was more common in group 2.CONCLUSIONS: Sixty-one percent of patients with autoimmune encephalitis had abnormal brain MR imaging findings at symptom onset, most commonly involving the limbic system. Susceptibility artifact is rare and makes autoimmune encephalitis less likely as a diagnosis. Brainstem and cerebellar involvement were more common in group 1, while leptomeningeal enhancement was more common in group 2.ABBREVIATIONS:AIEautoimmune encephalitisanti-Gq1banti-ganglioside Q1banti-LGI1anti-leucine-rich glioma inactivated 1CASPR2contactin-associated protein-like 2GABAgamma-aminobutyric acidGADglutamic acid decarboxylaseGFAPglial fibrillary acidic proteinNMDAN-methyl-D-aspartatePD-1programmed cell death protein 1VGCCvoltage gated calcium channelVGKCvoltage-gated potassium channel© 2023 by American Journal of NeuroradiologyView Full Text Log in using your username and password Username * Password * Forgot your user name or password? PreviousNext Back to top In this issue American Journal of Neuroradiology Vol. 44, Issue 7 1 Jul 2023 Table of ContentsIndex by authorComplete Issue (PDF) Print Download PDF Email Article Citation Tools Share Tweet WidgetFacebook LikeGoogle Plus One Purchase Related ArticlesNo related articles found.PubMedGoogle Scholar Cited By...No citing articles found.CrossrefGoogle Scholar More in this TOC Section Cost-Effectiveness Analysis of 68Ga-DOTATATE PET/MRI in Radiotherapy Planning in Patients with Intermediate-Risk Meningioma Choroid Plexus Calcification Correlates with Cortical Microglial Activation in Humans: A Multimodal PET, CT, MRI Study Show more ADULT BRAIN Similar Articles
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Elevated blood and cerebrospinal fluid biomarkers of microglial activation and blood‒brain barrier disruption in anti-NMDA receptor encephalitis | Journal of Neuroinflammation | Full Text

Elevated blood and cerebrospinal fluid biomarkers of microglial activation and blood‒brain barrier disruption in anti-NMDA receptor encephalitis | Journal of Neuroinflammation | Full Text | AntiNMDA | Scoop.it
From jneuroinflammation.biomedcentral.com - July 27, 2023 11:01 AM
Background Anti-NMDA receptor (NMDAR) encephalitis is an autoimmune disease characterized by complex neuropsychiatric syndrome and cerebrospinal fluid (CSF) NMDAR antibodies. Triggering receptor expressed on myeloid cells 2 (TREM2) has been reported to be associated with inflammation of the...
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Anti-N-methyl-d-aspartate receptor encephalitis and positive human herpesvirus-7 deoxyribonucleic acid in cerebrospinal fluid: a case report | Journal of Medical Case Reports | Full Text

Anti-N-methyl-d-aspartate receptor encephalitis and positive human herpesvirus-7 deoxyribonucleic acid in cerebrospinal fluid: a case report | Journal of Medical Case Reports | Full Text | AntiNMDA | Scoop.it
From jmedicalcasereports.biomedcentral.com - July 14, 2023 2:17 PM
Background Anti-N-methyl-d-aspartate receptor encephalitis is a neuroautoimmune syndrome typically presenting with seizures, psychiatric symptoms, and autonomic dysfunction. Human herpesvirus-7 is often found with human herpesvirus-6 and infects leukocytes such as T-cells, monocytes–macrophages,...
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We have a winner! - The Anti-NMDA Receptor Encephalitis Foundation Prize, 2023

We have a winner! - The Anti-NMDA Receptor Encephalitis Foundation Prize, 2023 | AntiNMDA | Scoop.it
From www.antinmdafoundation.org - June 25, 2023 2:58 PM
It’s that time of year again, when the Foundation is delighted to offer its annual Anti-NMDA Receptor Encephalitis Foundation Prize to a promising neurology trainee ...Read More...
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Antibodies Associated With Autoimmune Encephalitis in Patients With Presumed Neurodegenerative Dementia | Neurology Neuroimmunology & Neuroinflammation

Antibodies Associated With Autoimmune Encephalitis in Patients With Presumed Neurodegenerative Dementia | Neurology Neuroimmunology & Neuroinflammation | AntiNMDA | Scoop.it
From nn.neurology.org - June 19, 2023 9:45 PM
AbstractBackground & Objectives Autoimmune encephalitis (AIE) may present with prominent cognitive disturbances without overt inflammatory changes in MRI and CSF. Identification of these neurodegenerative dementia diagnosis mimics is important because patients generally respond to immunotherapy. The objective of this study was to determine the frequency of neuronal antibodies in patients with presumed neurodegenerative dementia and describe the clinical characteristics of the patients with neuronal antibodies.Methods In this retrospective cohort study, 920 patients were included with neurodegenerative dementia diagnosis from established cohorts at 2 large Dutch academic memory clinics. In total, 1,398 samples were tested (both CSF and serum in 478 patients) using immunohistochemistry (IHC), cell-based assays (CBA), and live hippocampal cell cultures (LN). To ascertain specificity and prevent false positive results, samples had to test positive by at least 2 different research techniques. Clinical data were retrieved from patient files.Results Neuronal antibodies were detected in 7 patients (0.8%), including anti-IgLON5 (n = 3), anti-LGI1 (n = 2), anti-DPPX, and anti-NMDAR. Clinical symptoms atypical for neurodegenerative diseases were identified in all 7 and included subacute deterioration (n = 3), myoclonus (n = 2), a history of autoimmune disease (n = 2), a fluctuating disease course (n = 1), and epileptic seizures (n = 1). In this cohort, no patients with antibodies fulfilled the criteria for rapidly progressive dementia (RPD), yet a subacute deterioration was reported in 3 patients later in the disease course. Brain MRI of none of the patients demonstrated abnormalities suggestive for AIE. CSF pleocytosis was found in 1 patient, considered as an atypical sign for neurodegenerative diseases. Compared with patients without neuronal antibodies (4 per antibody-positive patient), atypical clinical signs for neurodegenerative diseases were seen more frequently among the patients with antibodies (100% vs 21%, p = 0.0003), especially a subacute deterioration or fluctuating course (57% vs 7%, p = 0.009).Discussion A small, but clinically relevant proportion of patients suspected to have neurodegenerative dementias have neuronal antibodies indicative of AIE and might benefit from immunotherapy. In patients with atypical signs for neurodegenerative diseases, clinicians should consider neuronal antibody testing. Physicians should keep in mind the clinical phenotype and confirmation of positive test results to avoid false positive results and administration of potential harmful therapy for the wrong indication.GlossaryAD=Alzheimer dementia; AIE=autoimmune encephalitis; CBA=cell-based assays; DLB=dementia with Lewy bodies; IHC=immunohistochemistry; LN=live hippocampal cell cultures; PPA=primary progressive aphasia; PSP=progressive supranuclear palsy; RPD=rapidly progressive dementia; VGCC=voltage-gated calcium channelCognitive dysfunction can be the presenting and most prominent symptom in patients with autoimmune encephalitis (AIE).1,2 In contrast to neurodegenerative diseases, patients with antibody-mediated encephalitis might benefit from immunotherapy and improve considerably.3,4 The presence of neuronal antibodies has been reported predominantly in rapidly progressive dementia (RPD).5,6 However, AIE can present less fulminantly and is therefore potentially missed, resulting in diagnosis and treatment delay or even misdiagnosis.7,8 We hypothesized that a small—but not insignificant—part of dementia syndromes is indeed caused by antibody-mediated encephalitis and underdiagnosed, withholding these patients' available treatments. The wish to diagnose every single patient with autoimmune encephalitis is in opposition with the risk for false positive tests.9 Therefore, we strictly adhere to confirmation of positive test results with 2 different test techniques. In this study, we describe the frequency of neuronal antibodies in a cohort of patients diagnosed with various dementia syndromes in a memory clinic. In addition, we present clues to improve clinical recognition of AIE in dementia syndromes.MethodsPatients and Laboratory StudiesIn this retrospective multicenter study, we tested for the presence of neuronal antibodies in serum and CSF samples from patients diagnosed with neurodegenerative dementia diagnosis, included earlier prospectively in established cohorts at 2 large Dutch academic memory clinics (Erasmus University Medical Center, Amsterdam University Medical Centers, location VUmc)10 between 1998 and 2016 (84% last 10 years). All patients fulfilled the core clinical criteria for dementia, as defined by the National Institutes of Aging-Alzheimer Association workgroups.11 Patients were classified into 4 subgroups (based on diagnostic criteria): Alzheimer dementia (AD), frontotemporal dementia (FTD; both behavioral variant and primary progressive aphasia [PPA]), dementia with Lewy bodies (DLB), and other dementia syndromes.11,-,14 Rapidly progressive dementia was defined as dementia within 12 months or death within 2 years after the appearance of the first cognitive symptoms.15 Patients with vascular dementia were not included. Clinic information was retrieved from the prospectively collected data. A subacute deterioration was defined as a marked progression of symptoms in 3 months and a fluctuating course as a disease course fluctuating over a longer period (e.g., weeks to months; different from the fluctuations within a day as seen in some patients with DLB). Dementia markers were scored according to the reference values (per year and per center; included in Table 1).View inline View popup Table 1 Patient Characteristics of Auto-antibody Positive PatientsAll samples, stored in both cohorts' biobanks, were screened for immunoreactivity with immunohistochemistry (IHC), as previously described.16 Preferably, paired serum and CSF were tested for optimal sensitivity and specificity. Samples that were showing a positive or questionable staining pattern were tested more extensively using validated commercial cell-based assays (CBA) and in-house CBA (eTable 1, links.lww.com/NXI/A869). In addition, these samples were tested with live hippocampal cell cultures (LN).16,17 To ascertain specificity, only samples that could be confirmed by CBA or LN were scored as positive because there is a higher risk for false-positive test results in this population with a low a priori chance to have encephalitis.9,18 If IHC was suggestive for antibodies against intracellular (paraneoplastic) targets, this was explored by a different IHC technique.19 Anti-thyroid peroxidase (TPO), voltage-gated calcium channel (VGCC), or low titer glutamic acid decarboxylase antibodies were not tested for because these are generally nonspecific at these ages and are not associated with dementia syndromes.Antibody-positive patients were described exploratory and compared with a randomly selected antibody-negative group (ratio 1:4) matched for memory clinic, dementia subtype, sex, and age (±5 years). For these comparisons, medical records were additionally assessed for both the antibody-positive and antibody-negative patients. All antibody-positive patients were reviewed by a panel consisting of neurologists specialized in neurodegenerative (F.J., H.S., J.S.) or autoimmune diseases (J.V., P.S.S., M.T.), and a consensus classification of AIE vs AIE with a neurodegenerative dementia comorbidity was reached.Statistical AnalysisWe used IBM SPSS 25.0 (SPSS Inc) and Prism 8.4.3 (GraphPad) for statistical analysis. Baseline characteristics were analyzed using the Fisher exact test, the Fisher-Freeman-Halton test, or the Kruskal-Wallis test, when appropriate. For group comparisons, encompassing categorical data, we used the Pearson χ2 test or the Fisher-Freeman-Halton test, when appropriate. Continuous data were analyzed using the Mann-Whitney U test. All p-values were two-sided and considered statistically significant when below 0.05. We applied no correction for multiple testing, and therefore, p values between 0.05 and 0.005 should be interpreted carefully.Standard Protocol Approvals, Registrations, and Patient ConsentsThe study was approved by The Institutional Review Boards of Erasmus University Medical Center Rotterdam and Amsterdam University Medical Center, location VUmc. Written informed consent was obtained from all patients.Data AvailabilityAny data not published within this article are available at the Erasmus MC University Medical Center. Patient-related data will be shared on reasonable request from any qualified investigator, maintaining anonymization of the individual patients.ResultsIn total, 1,398 samples from 920 patients were tested (Figure; in 478, both CSF and serum [52%]). Three-hundred fifty-eight patients were classified as AD (39%), 283 FTD (31%), and 161 DLB (17%). The fourth subgroup with other dementia syndromes consisted of 118 patients (13%), including progressive supranuclear palsy (n = 48, 5%) and corticobasal syndrome (n = 29, 3%). The median age at disease onset was 62 years (range 16–90 years). Male patients were overrepresented (n = 542, 59%), and 60 patients (7%) fulfilled the criteria for rapidly progressive dementia (RPD; eTable 2, links.lww.com/NXI/A869).<img class="highwire-fragment fragment-image" alt="Figure" width="440" height="305" src="https://nn.neurology.org/content/nnn/10/5/e200137/F1.medium.gif">Download figure Open in new tab Download powerpoint Figure Flowchart of Patient Inclusion With Antibody ResultsIn total, 920 patients (1,398 samples) with a presumed neurodegenerative dementia syndrome were tested for the presence of neuronal antibodies in serum and CSF. Neuronal antibodies were detected in 7 patients (0.8%, 95% CI 0.2–1.3); five among the 358 Alzheimer disease patients. Subclassification of the ‘other’ group is provided in supplementary table eTable 2 (links.lww.com/NXI/A869). AD = Alzheimer disease; DLB = diffuse Lewy body dementia; DPPX = dipeptidyl aminopeptidase-like protein 6; FTD = frontotemporal dementia; IgLON5 = Ig-like domain-containing protein family member 5; LGI1 = leucin-rich glioma inactivated protein 1; NMDAR = N-methyl-d-aspartate receptor; S = serum.Neuronal antibodies were detected in 7 patients (0.8%; 5 in the AD group: 1.4%; Figure), including anti-IgLON5 (n = 3), anti-LGI1 (n = 2), anti-DPPX (n = 1), and anti-NMDAR antibodies (n = 1; Table 1). Among these 7, 4 patients were diagnosed retrospectively with an exclusive diagnosis of AIE, while 3 patients were classified to have AIE (anti-IgLON5 [n = 2] and anti-NMDAR antibodies [n = 1]) with a neurodegenerative dementia comorbidity. No patients with antibodies fulfilled the criteria for RPD, yet a subacute deterioration later in the disease was reported in 3 patients. Atypical clinical signs for neurodegenerative diseases were present in 7 of 7 antibody-positive patients (100% vs 21% in antibody-negative patients, p = 0.0003; Table 2). These included a subacute deterioration (n = 3), myoclonus (n = 2), a fluctuating disease course over months (n = 1), a history of autoimmune disease (n = 2), and epileptic seizures (n = 1; Table 1). Brain MRI of none of the patients demonstrated abnormalities suggestive for active AIE, in particular no hippocampal swelling nor increased T2-signal intensity. CSF pleocytosis was found in 1 patient. CSF biomarkers (t-tau, p-tau, and Aβ42) were tested in 5 of 7 patients, and t-tau and p-tau were increased in 4, while a low Aβ42 was seen in 2. Of note, only 1 patient had the combination of reduced Aβ42 and increased p-tau/t-tau, and was diagnosed with a comorbid AD. No patient received immunotherapy. Two patients still alive (1 anti-LG1, 1 anti-DPPX positive) were contacted but refused to visit our clinic to try very delayed immunotherapy trials. It is of interest that the patient with anti-DPPX antibodies showed spontaneous improvement of cognitive disturbances, atypical for a pure neurodegenerative disease.View inline View popup Table 2 Comparisons Between Patients With Neuronal Auto-antibodies and Antibody-Negative PatientsCompared with the patients without neuronal antibodies, subacute cognitive deterioration or fluctuating course was present more frequently (4/7 [57%] vs 2/28 [7%], p = 0.009). Although movement disorders (myoclonus) and autoimmune disorders were present in 2 of 7 patients each, this did not reach significance (Table 2).DiscussionIn this large, multicenter, cohort study consisting of patients with a presumed neurodegenerative dementia diagnosis, we show that a small, but clinically relevant proportion (0.8%) have neuronal antibodies. In this particular group, 4 of 7 antibody-positive patients presented with an atypical clinical course (subacute deterioration or fluctuating disease course), which is considered as a clinical clue (‘red flag’) for an antibody-mediated etiology of dementia.4 It is important that a fluctuating disease course was observed over a longer period (e.g., weeks or months) in AIE and should not be confused with shorter fluctuations of cognition or alertness (over the day) in DLB. Other known red flags, which we observed in these 7 patients, were myoclonus, epilepsy, pleocytosis, or a history of autoimmune disorders, as described earlier.1,4,-,6 Compared with antibody-negative patients, no significant difference was found related to these symptoms alone, probably due to the low number of positive patients and related low power. However, atypical clinical signs for neurodegenerative diseases together were seen significantly more frequently in the antibody-positive group. Within this cohort mostly devoid of patients with RPD, none of the antibody-positive patients fulfilled the criteria for RPD, nor ancillary testing showed specific signs for AIE in most patients. This implicates that AIE can resemble more protracted, progressive neurodegenerative dementia syndromes, as we reported earlier.1Three antibody-positive patients had IgLON5 antibodies, which is a very rare and known to have heterogeneous (chronic) clinical manifestations, including pronounced sleep problems, cognitive dysfunction, and movement disorders.20,21 Misdiagnosis with progressive supranuclear palsy (PSP) is reported, mainly associated with the preceding movement disorders. In addition, half of the patients have cognitive impairment of whom 20% fulfilled clinical criteria for dementia.21 It is of interest that IgLON5 disease shares features with neurodegeneration because autopsy studies showed tau deposits.22 However, there is a strong HLA association,20 and studies show that antibodies directly bind to surface IgLON5 on neurons and directly alter neuronal function and structure,23 suggesting a primary inflammatory disease.In previous research, a notably higher frequency (14%) of neuronal antibodies in patients with dementia was reported by Giannocaro et al.24 The discrepancy with our test results is probably explained by differences in patient selection and antibody testing methodology. First, 30% of the patients in the cohort described by Giannocaro et al. demonstrated CSF inflammatory abnormalities, indicating a relatively high pretest probability of antibody-positivity compared with our study.24 A lack of CSF pleocytosis probably better represents the population of memory clinics. Second, the previous study exclusively tested serum by cell-based assay without confirmatory tests nor testing antibodies in CSF.24 We only considered antibody test results positive when confirmed by additional techniques to avoid suboptimal specificity and false-positive test results.9Previous studies, including our own, suggested RPD as a relevant red flag for AIE,1,4,9,25 but we cannot determine this from our study based on the design of our study. We included patients at tertiary memory clinics without overt signs or symptoms suggestive for encephalitis. Therefore, the amount of patients with RPD included was very limited (7%), comparable with other large dementia cohort studies, as was the amount of patients with abnormal ancillary testing suggestive for AIE because this would have prompted a different approach than referral to a tertiary memory clinic. These patients with RPD and ancillary testing suggestive of AIE were not included in our study. Inclusion of those patients would have likely increased our rate of positivity.The strength of our study is the large number of paired samples (serum and CSF combined) from a cohort with various presumed neurodegenerative diseases without AIE suspicion, representative for academic memory clinics. A limitation is the lack of neuropathologic data to support our findings and make diagnoses of neurodegeneration or inflammation definite. To confirm if the symptoms are related to the presence of antibodies, we tried to overcome this concern in different ways. First, the presence of antibodies in serum and CSF was confirmed by different techniques (cell-based assay, tissue immunohistochemistry, and cultured live neurons), indicating optimal test specificity. Second, afterward patients were thoroughly reviewed by a panel of neurologists specialized in neurodegenerative or autoimmune disease to detect atypical signs and symptoms related to AIE. This is a very large cohort of patients with dementia examined for the presence of neuronal antibodies. Nevertheless, an important limitation of this study is the small number of antibody-positive patients, underpowering the probability to identify significant differences between antibody-positive and antibody-negative patients. The low number of patients with RPD has probably added to this small number, and a prospective study including patients with RPD is recommended. Nevertheless, several probable red flags could be identified. Diagnosing AIE in patients with dementia is highly relevant because these patients might respond to immunotherapy. Therefore, clinicians should test for neuronal antibody in patients demonstrating red flags suggestive for an autoimmune etiology, if possible early in disease course. When profound temporal lobe atrophy already has developed, little effect is to be expected. Red flags identified in this study are subacute deterioration or fluctuating course. Other red flags described previously, we also see reflected in our study, are autoimmune disorders, myoclonus, seizures, and pleocytosis,1,4,-,6 Preferably, both serum and CSF should be tested and confirmed by additional techniques. Always consider the possibility of a false positive test result, especially when only using a single technique (like the commercial cell-based assay). If the clinical phenotype is atypical, confirmation in a research laboratory should be mandatory. The use of antibody panels is discouraged, especially including the paraneoplastic blots, because these are associated with higher risks of lack of clinical relevance.26 This caution is even more warranted for tests not associated with neurodegenerative syndromes, but with a history of nonspecificity, including VGKC (in the absence of LGI1 or CASPR2), VGCC, anti-TPO, and low-titer anti-GAD65.27,-,30 Further research should focus on improving clinical recognition of AIE in patients with dementia determining the effect of immunotherapy in this specific patient category and assessing the frequency of AIE in RPD.In conclusion, we have shown that a clinically relevant, albeit small proportion of patients with a suspected neurodegenerative disease and nonrapidly progressive course have neuronal antibodies indicative of AIE.Study FundingM.J. Titulaer was supported by an Erasmus MC fellowship and has received funding from the Netherlands Organization for Scientific Research (NWO, Veni incentive), ZonMw (Memorabel program), the Dutch Epilepsy Foundation (NEF 14-19 & 19-08), Dioraphte (2001 0403), and E-RARE JTC 2018 (UltraAIE, 90030376505). F. Leypoldt has received funding from the German Ministry of Education and Research (01GM1908A) and the Era-Net funding program (LE3064/2-1).DisclosureA.E.M. Bastiaansen reports no disclosures. R.W. van Steenhoven reports no disclosures. Research programs of Wiesje van der Flier have been funded by ZonMW, now, EUFP7, EU-JPND, Alzheimer Nederland, Hersenstichting CardioVascular Onderzoek Nederland, Health∼Holland, Topsector Life Sciences & Health, stichting Dioraphte, Gieskes-Strijbis fonds, stichting Equilibrio, Edwin Bouw fonds, Pasman stichting, stichting Alzheimer & Neuropsychiatrie Foundation, Philips, Biogen MA Inc, Novartis-NL, Life-MI, AVID, Roche BV, Fujifilm, and Combinostics. W.M. van der Flier holds the Pasman chair. W.M. van der Flier is recipient of ABOARD, which is a public-private partnership receiving funding from ZonMW (#73305095007) and Health Holland, Topsector Life Sciences & Health (PPP-allowance; #LSHM20106). All funding is paid to her institution. WF has performed contract research for Biogen MA Inc and Boehringer Ingelheim. All funding is paid to her institution. W.M. van der Flier has been an invited speaker at Boehringer Ingelheim, Biogen MA Inc, Danone, Eisai, WebMD Neurology (Medscape), and Springer Healthcare. All funding is paid to her institution. W.M. van der Flier is consultant to Oxford Health Policy Forum CIC, Roche, and Biogen MA Inc. All funding is paid to her institution. W.M. van der Flier participated in advisory boards of Biogen MA Inc and Roche. All funding is paid to her institution. W.M. van der Flier is a member of the steering committee of PAVE and Think Brain Health. W.M. van der Flier was an associate editor of Alzheimer, Research & Therapy in 2020/2021. W.M. van der Flier is an associate editor at Brain. Research of C. Teunissen was supported by the European Commission (Marie Curie International Training Network, Grant Agreement No. 860197 (MIRIADE)), Innovative Medicines Initiatives 3TR (Horizon 2020, Grant No. 831434), EPND (IMI 2 Joint Undertaking (JU) under Grant Agreement No. 101034344) and JPND (bPRIDE), National MS Society (Progressive MS alliance) and Health Holland, the Dutch Research Council (ZonMW), Alzheimer Drug Discovery Foundation, The Selfridges Group Foundation, Alzheimer Netherlands, and Alzheimer Association. C. Teunissen is recipient of ABOARD, which is a public-private partnership receiving funding from ZonMW (#73305095007) and Health∼Holland, Topsector Life Sciences & Health (PPP-allowance, #LSHM20106). ABOARD also receives funding from Edwin Bouw Fonds and Gieskes-Strijbisfonds. C. Teunissen has a collaboration contract with ADx Neurosciences, Quanterix, and Eli Lilly, performed contract research or received grants from AC-Immune, Axon Neurosciences, Bioconnect, Bioorchestra, Brainstorm Therapeutics, Celgene, EIP Pharma, Eisai, Grifols, Novo Nordisk, PeopleBio, Roche, Toyama, and Vivoryon. She serves on editorial boards of Medidact Neurologie/Springer, Alzheimer Research and Therapy, and Neurology: Neuroimmunology & Neuroinflammation and is an editor of a Neuromethods book Springer. She had speaker contracts for Roche, Grifols, and Novo Nordisk. E. de Graaff holds a patent for the detection of anti-DNER antibodies. M.M.P. Nagtzaam reports no disclosures. M. Paunovic reports no disclosures. S. Franken reports no disclosures. M.W.J. Schreurs reports no disclosures. F. Leypoldt has received speakers honoraria from Grifols, Roche, Novartis, Alexion, and Biogen and serves on an advisory board for Roche and Biogen. He works for an academic institution (University Hospital Schleswig-Holstein) which offers commercial autoantibody testing. P.A.E. Sillevis Smitt holds a patent for the detection of anti-DNER and received research support from Euroimmun. J.M. de Vries reports no disclosures. H. Seelaar reports no disclosures. J.C. van Swieten reports no disclosures. F.J. de Jong reports no disclosures. Y.A.L. Pijnenburg Research of Alzheimer center Amsterdam is part of the neurodegeneration research program of Amsterdam Neuroscience. Alzheimer Center Amsterdam is supported by Stichting Alzheimer Nederland and Stichting VUmc fonds. The chair of Wiesje van der Flier is supported by the Pasman stichting. M.J. Titulaer has filed a patent, on behalf of the Erasmus MC, for methods for typing neurologic disorders and cancer, and devices for use therein, and has received research funds for serving on a scientific advisory board of Horizon Therapeutics, for consultation at Guidepoint Global LLC, for consultation at UCB, for teaching colleagues by Novartis. MT has received an unrestricted research grant from Euroimmun AG and from CSL Behring. Go to Neurology.org/NN for full disclosure.AcknowledgmentThe authors thank all patients for their participation. The authors also thank Esther Hulsenboom and Ashraf Jozefzoon-Aghai for their technical assistance. M.W.J. Schreurs, F. Leypoldt, 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; HCP Erasmus MC and University Hospital Schleswig-Holstein). H. Seelaar, J.C. van Swieten, and F.J. de Jong of this publication are members of the European Reference Network for Rare Neurological Diseases—Project ID 73910. Research of the VUmc Alzheimer center is part of the neurodegeneration research program of Amsterdam Neuroscience. The Alzheimer Center VUmc is supported by Alzheimer Nederland and Stichting VUmc Fonds. The clinical database structure was developed with funding from Stichting Dioraphte.Appendix Authors<img class="highwire-fragment fragment-image" alt="Table" src="https://nn.neurology.org/content/nnn/10/5/e200137/T3.medium.gif"; width="599" height="2531">FootnotesGo to Neurology.org/NN for full disclosures. Funding information is provided at the end of the article.The Article Processing Charge was funded the authors.Submitted and externally peer reviewed. The handling editor was Editor Josep O. Dalmau, MD, PhD, FAAN.Received December 8, 2022.Accepted in final form May 8, 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.↵Bastiaansen AEM, van Steenhoven RW, de Bruijn M, et al. Autoimmune encephalitis resembling dementia syndromes. Neurol Neuroimmunol Neuroinflamm. 2021;8(5):e1039.OpenUrlAbstract/FREE Full Text2.↵Lancaster E, Lai M, Peng X, et al. Antibodies to the GABA(B) receptor in limbic encephalitis with seizures: case series and characterisation of the antigen. Lancet Neurol. 2010;9(1):67-76.OpenUrlCrossRefPubMed3.↵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.OpenUrlCrossRefPubMed4.↵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.OpenUrlCrossRefPubMed5.↵Geschwind MD, Tan KM, Lennon VA, et al. Voltage-gated potassium channel autoimmunity mimicking creutzfeldt-jakob disease. Arch Neurol. 2008;65(10):1341-1346.OpenUrlCrossRefPubMed6.↵Grau-Rivera O, Sanchez-Valle R, Saiz A, et al. Determination of neuronal antibodies in suspected and definite Creutzfeldt-Jakob disease. JAMA Neurol. 2014;71(1):74-78.OpenUrl7.↵Titulaer MJ, McCracken L, Gabilondo I, et al. Late-onset anti-NMDA receptor encephalitis. Neurology. 2013;81(12):1058-1063.OpenUrlAbstract/FREE Full Text8.↵Gaig C, Graus F, Compta Y, et al. Clinical manifestations of the anti-IgLON5 disease. Neurology. 2017;88(18):1736-1743.OpenUrlAbstract/FREE Full Text9.↵Bastiaansen AEM, de Bruijn M, Schuller SL, et al. Anti-NMDAR encephalitis in The Netherlands, focusing on late-onset patients and antibody test accuracy. Neurol Neuroimmunol Neuroinflamm. 2022;9(2):e1127.OpenUrl10.↵van der Flier WM, Scheltens P. Amsterdam dementia cohort: performing research to optimize care. J Alzheimers Dis. 2018;62(3):1091-1111.OpenUrl11.↵McKhann GM, Knopman DS, Chertkow H, et al. The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 2011;7(3):263-269.OpenUrlCrossRefPubMed12.↵Rascovsky K, Hodges JR, Knopman D, et al. Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia. Brain. 2011;134(Pt 9):2456-2477.OpenUrlCrossRefPubMed13.↵Gorno-Tempini ML, Hillis AE, Weintraub S, et al. Classification of primary progressive aphasia and its variants. Neurology. 2011;76(11):1006-1014.OpenUrlAbstract/FREE Full Text14.↵McKeith IG, Boeve BF, Dickson DW, et al. Diagnosis and management of dementia with Lewy bodies: fourth consensus report of the DLB Consortium. Neurology. 2017;89(1):88-100.OpenUrlAbstract/FREE Full Text15.↵Geschwind MD. Rapidly progressive dementia. Continuum (Minneap Minn). 2016;22(2 Dementia):510-537.OpenUrl16.↵Ances BM, Vitaliani R, Taylor RA, et al. Treatment-responsive limbic encephalitis identified by neuropil antibodies: MRI and PET correlates. Brain. 2005;128(Pt 8):1764-1777.OpenUrlCrossRefPubMed17.↵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.OpenUrlCrossRefPubMed18.↵Martinez-Martinez P, Titulaer MJ. Autoimmune psychosis. Lancet Psychiatry. 2020;7(2):122-123.OpenUrl19.↵van Coevorden-Hameete MH, Titulaer MJ, Schreurs MW, et al. Detection and characterization of autoantibodies to neuronal cell-surface antigens in the central nervous system. Front Mol Neurosci. 2016;9:37.OpenUrl20.↵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.OpenUrlCrossRefPubMed21.↵Gaig C, Compta Y, Heidbreder A, et al. Frequency and characterization of movement disorders in anti-IgLON5 disease. Neurology. 2021;97(14):e1367–e1381.OpenUrlAbstract/FREE Full Text22.↵Gelpi E, Hoftberger R, Graus F, et al. Neuropathological criteria of anti-IgLON5-related tauopathy. Acta Neuropathol. 2016;132(4):531-543.OpenUrlCrossRefPubMed23.↵Landa J, Gaig C, Plaguma J, et al. Effects of IgLON5 antibodies on neuronal cytoskeleton: a link between autoimmunity and neurodegeneration. Ann Neurol. 2020;88(5):1023-1027.OpenUrlCrossRefPubMed24.↵Giannoccaro MP, Gastaldi M, Rizzo G, et al. Antibodies to neuronal surface antigens in patients with a clinical diagnosis of neurodegenerative disorder. Brain Behav Immun. 2021;96:106-112.OpenUrl25.↵Hermann P, Zerr I. Rapidly progressive dementias - aetiologies, diagnosis and management. Nat Rev Neurol. 2022;18(6):363-376.OpenUrl26.↵Dechelotte B, Muniz-Castrillo S, Joubert B, et al. Diagnostic yield of commercial immunodots to diagnose paraneoplastic neurologic syndromes. Neurol Neuroimmunol Neuroinflamm. 2020;7(3):e701.OpenUrlAbstract/FREE Full Text27.↵van Sonderen A, Schreurs MW, de Bruijn MA, et al. The relevance of VGKC positivity in the absence of LGI1 and Caspr2 antibodies. Neurology. 2016;86(18):1692-1699.OpenUrlCrossRefPubMed28.↵Muñoz Lopetegi A, Boukhrissi S, Bastiaansen A, et al. Neurological syndromes related to anti-GAD65: clinical and serological response to treatment. Neurol Neuroimmunol Neuroinflamm. 2020;7(3):e696.OpenUrlAbstract/FREE Full Text29.↵Mattozzi S, Sabater L, Escudero D, et al. Hashimoto encephalopathy in the 21st century. Neurology. 2020;94(2):e217-e224.OpenUrlAbstract/FREE Full Text30.↵Flanagan EP, Geschwind MD, Lopez-Chiriboga AS, et al. Autoimmune encephalitis misdiagnosis in adults. JAMA Neurol. 2023;80(1):30-39.OpenUrl
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Research study - can you help?

Research study - can you help? | AntiNMDA | Scoop.it
From www.encephalitis.info - June 19, 2023 9:38 PM
Researchers at Kings College London are looking for young people to travel to London and help with an encephalitis study...
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Sociocultural Influences in Autoimmune Encephalitis Without Neurologic Symptoms

Sociocultural Influences in Autoimmune Encephalitis Without Neurologic Symptoms | AntiNMDA | Scoop.it
From www.psychiatrist.com - June 19, 2023 9:33 PM
This complex case highlights barriers to identifying autoimmune encephalitis when no neurologic symptoms are present, which are normally central to disease detection.
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Anti N-Methyl-D-Aspartate receptor antibody associated Acute Demyelinating Encephalomyelitis in a patient with COVID-19: a case report | Journal of Medical Case Reports | Full Text

Anti N-Methyl-D-Aspartate receptor antibody associated Acute Demyelinating Encephalomyelitis in a patient with COVID-19: a case report | Journal of Medical Case Reports | Full Text | AntiNMDA | Scoop.it
From jmedicalcasereports.biomedcentral.com - June 19, 2023 9:27 PM
Background Anti N-Methyl-D-Aspartate (NMDA) receptor antibody associated ADEM is a diagnosis that was first described relatively recently in 2007 by Dalmau et al. The recent COVID-19 pandemic has resulted in multiple neurological complications being reported.
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Autoimmune Encephalitis Consensus Criteria | Neurology Clinical Practice

Autoimmune Encephalitis Consensus Criteria | Neurology Clinical Practice | AntiNMDA | Scoop.it
From cp.neurology.org - June 14, 2023 7:42 PM
June 2023; 13 (3) Editorial Autoimmune Encephalitis Consensus CriteriaLessons Learned From Real-World Practice View ORCID ProfileJeffrey M. Gelfand, Chu-Yueh Guo First published April 25, 2023, DOI: https://doi.org/10.1212/CPJ.0000000000200155 Full PDF Citation Permissions Make Comment See Comments Downloads133 Share Article 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. Autoimmune encephalitis (AE) encompasses a spectrum of neurologic disorders caused by brain inflammation, a subset of which is associated with autoantibodies to neuronal cell-surface antigens such as anti-N-methyl-d-aspartate (NMDA) receptor AE or anti-leucine-rich glioma-inactivated 1 (LGI1) AE.1 Up to half of patients with AE, however, do not have abnormal neuronal or glial autoantibodies identified and are classified as having “seronegative” AE.2 Clinical antibody testing can take several days to result, a time in which clinicians caring for patients with suspected AE may wish to initiate empiric immunosuppressive therapy. Antibody testing is also not readily accessible in some health care settings and, even when technically available, may require time-consuming advocacy with local clinical laboratories to justify relatively costly send-out testing. To add further complexity, some patients with immunoreactive (e.g., laboratory true-positive) antibodies do not have clinical AE, and over-reliance and misapplication of antibody testing were identified as important contributors to AE misdiagnosis in a 2023 multicenter analysis.3FootnotesFunding 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.See page e200151© 2023 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 Safety and Efficacy of Tenecteplase and Alteplase in Patients With Tandem Lesion Stroke: A Post Hoc Analysis of the EXTEND-IA TNK Trials Dr. Nicole Sur and Dr. Mausaminben Hathidara ► Watch Related Articles Autoimmune Encephalitis Criteria in Clinical Practice Topics Discussed All Clinical Neurology Autoimmune diseases Encephalitis Alert Me Alert me when eletters are published
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Predictive Value of Serum Neurofilament Light Chain Levels in Anti-NMDA Receptor Encephalitis

Predictive Value of Serum Neurofilament Light Chain Levels in Anti-NMDA Receptor Encephalitis | AntiNMDA | Scoop.it
From pubmed.ncbi.nlm.nih.gov - June 14, 2023 7:41 PM
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...
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Frontiers | The MOG antibody associated encephalitis preceded by COVID-19 infection; a case study and systematic review of the literature

Frontiers | The MOG antibody associated encephalitis preceded by COVID-19 infection; a case study and systematic review of the literature | AntiNMDA | Scoop.it
From www.frontiersin.org - September 5, 2023 11:22 AM
BackgroundNew neurological complications of COVID-19 infection have been reported in recent research. Among them, the spectrum of anti-MOG positive diseases, defined as anti-MOG antibody associated disease (MOGAD), is distinguished, which can manifest as optic neuritis, myelitis, or various forms...
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Enceph-IG Study - Institute of Infection, Veterinary and Ecological Sciences - University of Liverpool

Enceph-IG Study - Institute of Infection, Veterinary and Ecological Sciences - University of Liverpool | AntiNMDA | Scoop.it
From www.liverpool.ac.uk - August 6, 2023 7:27 PM
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A Rare Presentation of Steroid-responsive Encephalopathy Associated with Autoimmune Thyroiditis with Neuropsychiatric Symptoms: A Case Report

A Rare Presentation of Steroid-responsive Encephalopathy Associated with Autoimmune Thyroiditis with Neuropsychiatric Symptoms: A Case Report | AntiNMDA | Scoop.it
From touchneurology.com - July 27, 2023 11:22 AM
A 42-year-old woman presented in the emergency department with acute onset whole-body myoclonic jerks for 1 day.On enquiry, the patient’s parents advised...
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Pioneering Research in Autoimmune Neurology: Vanda Lennon, M.D., Ph.D.

Pioneering Research in Autoimmune Neurology: Vanda Lennon, M.D., Ph.D. | AntiNMDA | Scoop.it
From news.mayocliniclabs.com - July 27, 2023 11:05 AM
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New center to spotlight neurological autoimmune disorders

New center to spotlight neurological autoimmune disorders | AntiNMDA | Scoop.it
From bioengineer.org - July 14, 2023 2:19 PM
How do neurological disorders arise that are caused, triggered, or influenced by antibodies? What better possibilities are there for diagnosis – and above all for treatment? These are the questions addressed by the new Clinical Research Unit “BecauseY” headed by Charité – Universitätsmedizin Berlin.
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Progressive alliance advances science through patient-powered research

Progressive alliance advances science through patient-powered research | AntiNMDA | Scoop.it
From news.mayocliniclabs.com - July 14, 2023 2:16 PM
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ENCEPH-IG Trial: The Challenges Of Running A Rare Disease Trial - Centre for Trials Research

ENCEPH-IG Trial: The Challenges Of Running A Rare Disease Trial - Centre for Trials Research | AntiNMDA | Scoop.it
From blogs.cardiff.ac.uk - June 19, 2023 9:46 PM
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30 neurological disorders every doctor should know about –

30 neurological disorders every doctor should know about – | AntiNMDA | Scoop.it
From theneurologylounge.com - June 19, 2023 9:42 PM
Neurology is a jungle of disorders and syndromes. This creates a challenge for doctors and medical students... What to prioritise for learning and practice? *** To solve this conundrum... We combed the extensive database of Neurochecklists...
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A score that predicts 1-year functional status in patients with anti-NMDA receptor encephalitis

A score that predicts 1-year functional status in patients with anti-NMDA receptor encephalitis | AntiNMDA | Scoop.it
From pubmed.ncbi.nlm.nih.gov - June 19, 2023 9:34 PM
The NEOS score accurately predicts 1-year functional status in patients with anti-NMDAR encephalitis. This score could help estimate the clinical course following diagnosis and may aid in identifying patients who could benefit from novel therapies.
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Canadian Blood Services needs thousands more donors to roll up their sleeves | CBC News

Canadian Blood Services needs thousands more donors to roll up their sleeves | CBC News | AntiNMDA | Scoop.it
From www.cbc.ca - June 19, 2023 9:28 PM
Canadian Blood Services is looking to fill 150,000 appointments for people willing to donate their blood or plasma to tackle a shortage.
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A catatonic woman awakened after 20 years. Her story may change psychiatry – My Health CRM

A catatonic woman awakened after 20 years. Her story may change psychiatry – My Health CRM | AntiNMDA | Scoop.it
From myhealthcrm.com - June 14, 2023 7:43 PM
New research suggests that a subset of patients with psychiatric conditions such as schizophrenia may actually have autoimmune disease that attacks the brain...
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Case Report: Paroxysmal weakness of unilateral limb as an initial symptom in anti-LGI1 encephalitis: a report of five cases

Case Report: Paroxysmal weakness of unilateral limb as an initial symptom in anti-LGI1 encephalitis: a report of five cases | AntiNMDA | Scoop.it
From pubmed.ncbi.nlm.nih.gov - June 14, 2023 7:41 PM
Anti-leucine-rich glioma-inactivated 1 (LGI1) encephalitis is the second most common kind of autoimmune encephalitis following anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis.Anti-LGI1 encephalitis is characterized by cognitive impairment or rapid progressive dementia, psychiatric disorders...
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Medical Moment: The signs of ‘brain-on-fire’ disease

Medical Moment: The signs of ‘brain-on-fire’ disease | AntiNMDA | Scoop.it
From www.wndu.com - June 14, 2023 7:40 PM
(WNDU) - Imagine being totally fine one day, then the next, you’re having hallucinations, seizures, memory loss, and even trouble talking.It’s called “brain-on-fire” disease or anti-NMDA receptor encephalitis. It’s a rare neurological disorder that can cause inflammation in the brain.It occurs when the body’s immune system mistakenly attacks the NMDA receptors in the brain, which are responsible for regulating communication between nerve cells. Brain-on-fire disease is often misdiagnosed as other neurological disorders or psychiatric illnesses because its symptoms are similar to those of many other conditions.However, a blood or cerebrospinal fluid test can help diagnose the disease by detecting the presence of antibodies that attack the NMDA receptors in the brain. The disease is rare as it affects one in 1.5 million people a year.Katie Miller would be one of those people.Hunting, mountain biking, horseback riding - you name it, Katie Miler would do it... until she couldn’t.“I just didn’t feel like myself, like normal,” Katie recalled.“Katie said, ‘Mom, I feel like my brain snapped,’” said Colleen Miller, Katie’s mother.Local doctors admitted Katie into a psychiatric ward, but what was happening to Katie wasn’t mental; it was physical.“What happens is you’re perfectly normal one day, and suddenly overnight, this person can become paranoid, can start having visual hallucinations, auditory hallucinations,” explained Stacy Clardy, MD, PhD, an autoimmune neurologist at the University of Utah.Anti-NMDA receptor encephalitis is misdiagnosed as a psychiatric disorder in up to 40% of patients.“So, for many of the females, especially after puberty, they can develop what’s called an ovarian dermoid cyst or an ovarian teratoma,” Dr. Clardy said.These cysts often have hair and teeth in them. The immune system sees it as foreign and attacks it, but...“In these cysts, there is a component of tissue that really is brain tissue,” Dr. Clardy continued.Within four days, Katie was catatonic and needed a ventilator to breathe. There is no single approved treatment. That’s why a five-year, nationwide clinical trial is testing whether a drug called Inebilizumab will stop the assault on the brain. It has the potential to improve outcomes for patients who are not responding to other treatments and may also lead to fewer long-term neurological effects.Katie had her cyst removed; she can’t remember three months of her life. But now, with various medications, Katie is on her way to recovery.Up to 50% of patients can suffer long-term consequences, especially cognitive and mood symptoms.Copyright 2023 WNDU. All rights reserved.
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jack henry's curator insight, April 2, 7:35 AM


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