The Anti-NMDA Receptor Encephalitis Foundation Newsletter

Detection of neuronal surface antibodies (NSAb) is important for the diagnosis of autoimmune encephalitis (AE). Although most clinical laboratories use a commercial diagnostic kit (Euroimmun, Lübeck, Germany) based on indirect immunofluorescence on transfected cells (IIFA), clinical experience…

 




Abstract OBJECTIVES Patients with autoimmune encephalitis (AE) often present with symptoms that are broadly characterized as psychiatric or behavioral, yet little attention is given to the precise symptomatology observed. We sought to more fully define the psychiatric symptoms observed in patients with anti–N-methyl-D-aspartate receptor (NMDAR), anti–glutamic-acid-decarboxylase 65 (GAD65), and anti–voltage-gated-potassium-channel complex (VGKC) antibody-mediated AE using the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition nomenclature. METHODS We present a case series (n = 25) using a retrospective chart review of 225 patients evaluated for AE in a tertiary care academic medical center between 2014 and 2018. The included patients were ≤18 years old with anti-NMDAR AE (n = 13), anti-GAD65 AE (n = 7), or anti-VGKC AE (n = 5). The frequency of neuropsychiatric symptoms present at the onset of illness and time to diagnosis were compared across groups. RESULTS Psychiatric symptoms were seen in 92% of patients in our cohort. Depressive features (72%), personality change (64%), psychosis (48%), and catatonia (32%) were the most common psychiatric symptoms exhibited. On average, patients experienced impairment in ≥4 of 7 symptom domains. No patients had isolated psychiatric symptoms. The average times to diagnosis were 1.7, 15.5, and 12.4 months for anti-NMDAR AE, anti-GAD65 AE, and anti-VGKC AE, respectively (P < .001). CONCLUSIONS The psychiatric phenotype of AE in children is highly heterogenous. Involving psychiatry consultation services can be helpful in differentiating features of psychosis and catatonia, which may otherwise be misidentified. Patients presenting with psychiatric symptoms along with impairments in other domains should prompt a workup for AE, including testing for all known antineuronal antibodies. Copyright © 2021 by the American Academy of Pediatrics

 




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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N-methyl-D-aspartate antibody encephalitis: temporal progression of clinical and paraclinical observations in a predominantly non-paraneoplastic disorder of both sexes. Brain. 2010;133(pt 6):1655-1667.OpenUrlCrossRefPubMed 5.↵Hacohen Y, Absoud M, Hemingway C, et al. NMDA receptor antibodies associated with distinct white matter syndromes. Neurol Neuroimmunol Neuroinflamm. 2014;1(1):e2. 6.↵Byrne S, Walsh C, Hacohen Y, et al. Earlier treatment of NMDAR antibody encephalitis in children results in a better outcome. Neurol Neuroimmunol Neuroinflamm. 2015;2(4):e130. 7.↵Dale RC, Brilot F, Duffy LV, et al. Utility and safety of Rituximab in pediatric autoimmune and inflammatory CNS disease. Neurology. 2014;83(2):142-150.OpenUrlCrossRefPubMed 8.↵Gabilondo I, Saiz A, Galán L, et al. Analysis of relapses in anti-NMDAR encephalitis. Neurology. 2011;77(10):996-999.OpenUrlCrossRefPubMed 9.↵Nosadini M, Granata T, Matricardi S, et al. Relapse risk factors in anti-N-methyl-D-aspartate receptor encephalitis. Dev Med Child Neurol. 2019;61(9):1101-1107.OpenUrl 10.↵Bartolini L, Muscal E. Differences in treatment of anti-NMDA receptor encephalitis: results of a worldwide survey. J Neurol. 2017;264(4):647-653.OpenUrl 11.↵Kahn I, Helman G, Vanderver A, Wells E. Anti-N-methyl-d-aspartate (NMDA) receptor encephalitis. J Child Neurol. 2017;32(2):243-245.OpenUrl 12.↵Dalmau J, Lancaster E, Martinez-Hernandez E, Rosenfeld MR, Balice-Gordon R. Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis. Lancet Neurol. 2011;10(1):63-74.OpenUrlCrossRefPubMed 13.↵Nosadini M, Mohammad SS, Ramanathan S, Brilot F, Dale RC. Immune therapy in autoimmune encephalitis: a systematic review. Expert Rev Neurother. 2015;15(12):1391-1419.OpenUrlCrossRefPubMed 14.↵Lancaster E. The diagnosis and treatment of autoimmune encephalitis. J Clin Neurol. 2016;12(1):1-13.OpenUrlCrossRefPubMed 15.↵Dale RC, Gorman MP, Lim M. Autoimmune encephalitis in children: clinical phenomenology, therapeutics, and emerging challenges. Curr Opin Neurol. 2017;30(3):334-344.OpenUrlPubMed 16.↵Shin YW, Lee ST, Park KI, et al. Treatment strategies for autoimmune encephalitis. Ther Adv Neurol Disord. 2017;11:1756285617722347.OpenUrl 17.↵Zuliani L, Nosadini M, Gastaldi M, et al. Management of antibody-mediated autoimmune encephalitis in adults and children: literature review and consensus-based practical recommendations. Neurol Sci. 2019;40(10):2017-2030.OpenUrl 18.↵Dalmau J, Armangué T, Planagumà J, et al. An update on anti-NMDA receptor encephalitis for neurologists and psychiatrists: mechanisms and models. Lancet Neurol. 2019;18(11):1045-1057.OpenUrlCrossRefPubMed 19.↵Linstone HA, Turoff M, eds. The Delphi Method Techniques and Applications. Addison-Wesley; 1975. 20.↵Hasson F, Keeney S, McKenna H. Research guidelines for the Delphi survey technique. 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).

 




Autoimmune encephalitis is most commonly caused by autoantibodies against N-methyl-D-aspartate (NMDA) receptors, and the malignancy most often associated with anti-NMDA receptor autoimmune encephalitis is an ovarian teratoma.

 




In May and June 2021, Mayo Clinic Laboratories announced three new tests along with numerous reference value changes, obsolete tests, […]…

 




Abstract Myelin oligodendrocyte glycoprotein antibody-associated disorders (MOGAD) are rare in both children and adults, and have been recently suggested to be an autoimmune neuroinflammatory group…

 










medRxiv – The Preprint Server for Health Sciences…

 




A case study describes a case of autoimmune anti-NMDAR encephalitis.

 




Our hope and that of our many followers lies in supporting research. In 2019 we introduced The Anti-NMDA Receptor Encephalitis Prize to support and empower …Read More…

 




Introduction In the first part of the Proposed Best Practice Recommendations, we covered diagnosis and acute immunotherapy for autoimmune encephalitis (AE). In this second part, we will cover symptomatic, bridging and maintenance immunotherapy of AE. The recommendations are based on literature review and an online survey of 68 members of the Autoimmune Encephalitis Alliance Clinicians Network (AEACN). The final manuscript was approved by all participating members after four rounds of revisions. Please refer to part-1 (Proposed Best Practice Recommendations for Diagnosis and Acute Management) for methodology details. Symptomatic therapy AE is often polysymptomatic. Symptoms start in the acute phase and may resolve or improve with acute immunotherapy alone or combined with targeted symptomatic treatment. However, many residual symptoms persist beyond the acute phase requiring long-term symptomatic therapy. In this section, we will review symptomatic therapy in both the acute phase of the disease and the long-term. A summary of symptomatic therapy recommendations is included in table 1. VIEW INLINE VIEW POPUP Table 1 Symptomatic management for autoimmune encephalitis Management of psychosis Often benzodiazepines are required in large doses for adequate sedation. Many patients with AE will need antipsychotics to control agitation and psychosis.1 One option is to avoid agents that lower seizure threshold (eg, clozapine and olanzapine)2 in patients with seizures or who are at increased seizure risk (eg, patients with limbic or cortical encephalitis or who have lateralised periodic discharges (LPDs) on electroencephalogram (EEG)). Antipsychotics that prolong the QT interval (eg, ziprasidone and IV haloperidol) should be used with caution or avoided in dysautonomic patients with symptomatic bradycardia or heart block. If an antipsychotic results in worsening of agitation or involuntary movements after initiation, it should be stopped and substituted with an alternative agent. In NMDAR-antibody encephalitis (see online supplemental appendix 1 for full names of neuronal autoantibodies (NAAs)), patients may be particularly sensitive to the extrapyramidal side effects of antipsychotics and may experience worsening of catatonia and other involuntary movement or even develop neuroleptic malignant syndrome.3 Second generation antipsychotics with the least potential for inducing seizures and extrapyramidal side effects (eg, quetiapine) may be preferred in patients with AE. Patients with manic symptoms in the setting of AE may be treated with mood stabilisers such as valproic acid especially in case of comorbid seizures.1 Elimination or dose reduction of certain medications may also improve behavioural symptoms in some patients (eg, steroids, benzodiazepines). It is important to instate safety measures (eg, padding, soft restraints, etc) for agitated patients to prevent self-injury and harm to others. Supplemental material Management of seizures In addition to immunotherapy, patients with AE with clinical or electrophysiological seizures may require treatment with antiseizure medications effective against focal seizures.4 However, in leucine-rich glioma inactivated-1 (LGI1)-antibody encephalitis, despite there being data showing sodium-channel blockers may be the most effective antiseizure medications,5 6 it is very clear that immunotherapy is far more effective than seizure medications in general. Hence, immunotherapies should be the antiseizure medication of choice in this condition.6–9 Patients with status-epilepticus may require standard status-epilepticus protocol with fast-acting intravenous benzodiazepines followed by intravenous loading of an appropriate antiseizure medication such as fosphenytoin, valproic acid or levetiracetam. Patients with new onset refractory status-epilepticus (NORSE) will require induced coma with midazolam, pentobarbital or propofol in an intensive care unit (ICU) setting.10 In super refractory status-epilepticus, effective seizure control may not be achieved until sufficient immunosuppression is in effect. In many patients, improvement of LPDs and other EEG abnormalities may be followed by improvement in mental status. Patients may not need long-term antiseizure medications after resolution of the acute attack. The nationwide retrospective study by de Bruijn and colleagues highlighted the central role of immunosuppression in controlling AE seizures and showed that almost all surviving patients with NMDAR, LGI1 and GABA-B-R-antibody encephalitis remained seizure-free and could be weaned off seizure medications successfully after immunosuppression and resolution of brain inflammation.6 Antiseizure medications have several side effects and weaning should be considered in recovered patients with normal brain MRI and EEG. Due to medical, social and driving privilege implications, data beyond 5 years of follow-up and from all AE subtypes is still needed before making definitive generalised recommendations regarding the optimal duration of antiseizure mediations following the initial AE attack. Clinicians should practice caution and consider several factors when making this decision including the type of antibody, the severity of the initial presentation, MRI and EEG findings, tolerability of the antiseizure agent, and local and national epilepsy guidelines. Patients who present initially with NORSE may be at a higher risk for chronic epilepsy. In the largest case series of NORSE (all aetiologies) to date, 37% of patients later developed chronic epilepsy and 92% of survivors remained on antiseizure medications.11 Management of movement disorders Mild movement disorders in the setting of AE do not require specific symptomatic therapy as they may improve with immunotherapy alone. Severe, dangerous or disabling movement disorders will require phenomenology-directed treatment.12 Severe dystonia may be treated with anticholinergics or muscle relaxants (eg, trihexyphenidyl, baclofen, respectively); myoclonus, stiff person syndromeand progressive encephalomyelitis with rigidity and myoclonus can be treated with benzodiazepines; catatonia may respond to intravenous lorazepam and/or electroconvulsive therapy although the relapse rate and cognitive impact of the latter is unknown in patients with AE.1 12 Severe chorea, athetosis and ballism can be treated with a cautious use of dopamine-blockers or depleters (eg, risperidone, tetrabenazine, respectively) while carefully watching for any paradoxical worsening of other involuntary movements. Dopaminergic treatment with dopamine agonists or carbidopa/levodopa may be tried in patients with acquired parkinsonism or severe akinetic-rigid syndrome.12 Management of dysautonomia In most cases, supportive therapy with continuous monitoring in an ICU setting along with immunotherapy is all that is needed in dysautonomic patients. However, on rare occasions, symptomatic treatment with non-selective beta-blockers, alpha-2 agonists and/or acetylcholinesterase inhibitors may be required to ameliorate sympathetic overactivity. Patients with severe symptomatic postural hypotension may require midodrine, fludrocortisone or droxidopa in addition to good hydration and compressive stocking usage. Temporary pacing may be required in patients with acquired heart block or severe arrhythmias. In addition to symptomatic pharmacotherapy, patients with severe gastrointestinal dysmotility may require temporary total parenteral nutrition, and those with urinary retention often require indwelling catheters. Patients with central hypoventilation require artificial ventilation. Management of sleep dysfunction Improved sleep facilitates control over agitation, seizures and psychosis. Improving the sleep cycle is imperative in patients with AE and should be among the priorities of symptomatic therapy. The use of environmental conditioning and sleep hygiene, along with pharmacological measures such as melatonin, sedating benzodiazepines (eg, clonazepam or diazepam) and/or non-benzodiazepine hypnotics (eg, zopiclone) should be considered as appropriate for patients with AE with sleep dysfunction.3 MANAGEMENT OF ASSOCIATED NEOPLASM IF PRESENT When a paraneoplastic aetiology is confirmed, treatment of the neoplasm may result in neurological improvement or remission in some cases with or without immunotherapy.13 In cases associated with classical onconeuronal antibodies, tumour resection may be the intervention with the highest therapeutic benefit since neurological symptoms tend to be immunotherapy-resistant in many of those patients.14 In inoperable tumours, debulking surgery or palliative radiotherapy or chemotherapy may result in neurological improvement by reducing the abnormal immune drive.15 Of note, the Karnofsky Performance Status score may be poor due to the paraneoplastic syndrome rather than the direct effect of cancer so low scores should not hinder aggressive oncological management. Neurologists should consult with the appropriate oncology service and advocate for timely oncological intervention in order to expedite neurological recovery and prevent permanent neurological disability. For antibodies against neuronal surface antigens in the presence of a neoplasm, AE tends to be responsive to immounomodualting therapy but tumour treatment is still necessary for neurological improvement. For example, along with immunotherapy, resection of ovarian or testicular teratoma may accelerate remission in NMDAR-antibody encephalitis.4 Studies have shown a germinal centre-like histology of the ovarian teratomas, with intramural NMDAR-specific B-cells that can cross the blood brain and evolve into antibody-producing intrathecal plasmablasts.16–18 This suggests a plausible biological basis for the observed improvement after tumour resection. The same goes for other neuronal surface antibodies associated with various benign or malignant neoplasms like AMPA-R (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) and GABA/BR antibodies. In addition to conventional antineoplastic treatments via surgical resection, chemotherapy and radiotherapy, the recent introduction of cancer-directed immune checkpoint inhibitors adds a new layer of complexity to the management of paraneoplastic AE. Although anticancer treatment usually contributes to neurological improvement, the use of ICIs is likely to trigger new paraneoplastic reactions or exacerbate pre-existing paraneoplastic AE due to the ‘unchecked’ immune response against tumour (and neuronal) antigens.19 Fortunately, the symptoms of paraneoplastic AE in the setting of ICIs are usually steroid-responsive.19 Per the recommendations of the European Society of Medical Oncology guidelines, steroids should be initiated and ICIs should be interrupted for moderate neurological side effects (grade-2) and permanently discontinued in severe cases (grade-3).20 The National Comprehensive Cancer Network guidelines consider meningitis and encephalitis as moderate or severe ICI neurotoxicity.21 If there are no other alternatives for oncological therapy, or based on patient preferences, rechallenge with ICIs may be carefully considered in selected cases after sufficient corticosteroid treatment and resolution of neurological symptoms. BRIDGING IMMUNOTHERAPY ON DISCHARGE After acute treatment, it is important to avoid abrupt discontinuation of immunotherapy to prevent early recurrence.22–24 Therefore, a bridging strategy should be implemented followed by slow weaning or initiation of long-term immunotherapy, if indicated. A common strategy is to start oral prednisone 1–2 mg/kg/day immediately after completing acute therapy followed by a gradual taper over weeks to months overlapping with long-term immunotherapy if indicated. The rate of taper varies according to the clinical syndrome, clinical context, relapse risk, and treatment response and tolerability. However, this approach may not be suitable for patients with ongoing behavioural issues or who have contraindications to maintenance corticosteroid therapy. An alternative strategy is to give periodic intravenous methyl-prednisolone (IVMP) or intravenous immunoglobulins (IVIg) as a maintenance therapy for the same duration.25 If a second-line agent such as rituximab is used during the acute attack, it may serve as a bridging therapy in itself given its long-term effects.22–24 However, corticosteroid overlap may still be needed with the initial rituximab dose to avoid possible treatment-related relapses, in alignment with reports in patients with neuromyelitis optica spectrum disorder (NMOSD)26 although AE and NMOSD are substantially different conditions. When using prednisone for extended periods of time, it is important to mitigate corticosteroids toxicity by cotreatment with proton pump inhibitors, vitamin D supplements and antibiotic prophylaxis against Pneumocystis jiroveci pneumonia when indicated. It is also important to ensure good control of blood pressure and blood glucose while on corticosteroids. On our AEACN survey (see online supplemental appendix 2 for details), the most popular bridging therapy was oral prednisone taper chosen by 38% of clinicians with 28% choosing to taper over months and 10% choosing to taper over days to weeks. This was followed by periodic IVIg (28%), rituximab alone or with oral prednisone (16%), and weekly or monthly IVMP (12%) including an approach of gradually increasing the intervals between infusions. Supplemental material SECTION 3: LONG-TERM MANAGEMENT OF AE Perhaps one of the most understudied aspects of AE is its long-term outpatient management following the initial attack. A major obstacle is identifying a clinician with expertise and interest in the long-term management of AE. Possible solutions include the integration of formal AE training in clinical neuroimmunology and MS fellowships or developing dedicated autoimmune neurology fellowships focusing on AE and related conditions (mirroring the limited autoimmune neurology programmes that are currently available in select institutions). Teleneurology and virtual visits may be another option to connect patients in remote areas to experts in academic centres. The long-term management of AE entails several equally important components as detailed later. Interpretation of NAA panel results Unlike acute management, the long-term management of AE is highly influenced by the presence and type of NAAs.27 In some cases, the results of the NAAs panel become available after the patient has been discharged although in patients with prolonged hospitalisation (eg, NMDAR-antibody encephalitis), the results become available while the patient is still hospitalised and can influence acute management. It is important to select a laboratory that uses the best available method for antibody detection. Cell-based-assay is the preferred method for neuronal surface antibodies while indirect tissue immunofluorescence and immunohistochemistry followed by Western blot confirmation is the standard for antibodies against intracellular antigens.25 Proper case selection for testing increases the likelihood of a positive test.28 Predicting scores such as the Antibody Prevalence in Epilepsy score (table 2) can help in case selection for NAAs testing factoring in the clinical presentation, cerebrospinal fluid (CSF) and MRI findings, and cancer history.28 A score greater than 3 predicts a high likelihood of identifying a neuronal specific antibody. Furthermore, it has been proposed that this scale could be used in the diagnostic criteria of AE in that a score greater than 3 with positive neuronal specific antibody is antibody positive AE and a score greater than 6 is probable AE. VIEW INLINE VIEW POPUP Table 2 Antibody prevalence in epilepsy and encephalopathy (APE2 score) When interpreting the NAAs panel, four possible results may be encountered. The first possibility is positivity for an antibody against intracellular antigens. These antibodies are highly specific and usually predictive of a paraneoplastic aetiology and a recognisable paraneoplastic syndrome in most cases especially those with typical clinical phenotype.29 A recent study evaluating the diagnostic yield of commercial onconeuronal antibodies in France found a low cancer predictability rate in a cohort of patients with frequent non-classical clinical presentations and questionable laboratory results (confirmed by another technique in only 30% of cases).30 The second possibility is positivity for one of the highly clinically relevant antibodies against neuronal surface antigens such as NMDAR or LGI1-antibodies. These antibodies are highly specific with reasonable positive predictive value for neurological autoimmunity and are known to be clinically relevant when present in the proper clinical setting.27 They can be associated with idiopathic or paraneoplastic forms of AE. Paraneoplastic cases are most frequently associated with NMDAR, AMPAR and GABA/BR antibodies.25 27 The third possibility is positivity for an antibody against neuronal surface antigens with limited clinical relevance such as VGCC, non-LGI1 non-CASPR2 ‘double negative’ VGKC and ganglionic AChR antibodies (table 1, part-1). These antibodies may or may not be relevant to the patient’s presentation depending on the clinical picture, and their presence should not preclude thorough exclusion of other potential causes of the neurological presentation.31–33 The antibody level (for some antibodies like GAD65-antibody), clinical presentation, disease course, CSF findings and smoking or cancer history are factors that can be used to determine the clinical relevance of the positive antibody.33–35 The NAAs confidence scale is one suggested tool to increase the confidence in the clinical relevance of these less specific antibodies (table 3).33 VIEW INLINE VIEW POPUP Table 3 Neuronal Autoantibody Confidence Scale* This scale has a 77% sensitivity, 94% specificity, 87% positive predictive value and 89% negative predictive value for clinical relevance of the positive NAAs. If the score is greater than 1, it is likely that the antibody is clinically relevant. Conversely, if the score is less than 1, it is likely that the antibody is clinically irrelevant, whereas a score of 1 is not predictive. If an alternative diagnosis was found during workup (eg, neurosarcoidosis, nutritional deficiency) then the positivity of one of these less specific antibodies should be considered a clinically irrelevant result not necessitating repeat cancer screening or addition or change of immunotherapy.33 34 It is to be noted that the clinical relevance of some of these antibodies is higher for peripheral neurological disorders as in the case of VGCC antibody with Lambert-Eaton myasthenic syndrome, and ganglionic AChR antibody with autoimmune autonomic ganglionopathy. Therefore, it is important to always correlate the clinical presentation to the positive antibody and question the clinical relevance of the test result if there is clinical-serological discordance. More recent NAAs panels emphasise the importance of clinical correlation and are based on clinical presentation (movement disorders vs epilepsy vs encephalopathy, etc) as opposed to aetiology (paraneoplastic vs idiopathic). As our knowledge and understanding of autoimmune neurology expands, antibodies with limited clinical relevance are expected to become obsolete or limited to specific panels. The fourth possibility is negativity for all commercially available antibodies. In that situation, it is important to determine whether the patient meets criteria for definite autoimmune limbic encephalitis or probable seronegative AE (online supplemental boxes 1 and 2).27 Patients with probable or definite seronegative AE should be tested for novel antibodies in research neuroimmunology laboratories if access to one is available (examples include Mayo Clinic, Pennsylvania, Oxford, Erasmus and Barcelona universities). If a patient was treated empirically for possible AE in the acute setting but tested negative for NAAs and did not meet criteria for definite or probable seronegative AE, it is very important that the diagnosis is challenged and workup for other potential diagnoses is initiated or repeated, especially if the response to immunotherapy was limited (figure 1). Supplemental material Supplemental material Figure 1 Interpretation of the neuronal autoantibody panel. *Anti-Hu (ANNA-1), anti-Ri (ANNA-2), ANNA-3, anti-SOX1 (AGNA), anti-amphiphysin, anti-CRMP-5 (anti-CV2), anti-Yo (PCA-1), PCA-2, high-titre anti-GAD65. **Anti-NMDA-R, anti-LGI1, anti-CASPR2, anti-AMPA-R, anti-GABA-A/B, PCA-Tr, anti-DPPX, anti-mGluR1, anti-mGluR2, anti-mGluR5, anti-IgLON5, anti-AQP4, anti-MOG. ***Non-LGI1 non-CASPR2 anti-VGKC, anti-P/Q VGCC, anti-N VGCC, Ach-b, Ach-M, Ach-G, Striational. Low-titre anti-GAD65 is an antibody against cytoplasmic antigen but is of questionable clinical significance. Adapted with permission from George et al.40 Determining the need for long-term immunosuppression As mentioned previously, it is important to initiate bridging immunosuppression after acute therapy in the hospital followed by a gradual taper. The more difficult task is selecting patients for long-term immunosuppression. The recurrence rate is highest in conditions associated with clinically relevant neuronal surface antibodies and much lower in conditions associated with antibodies against intracellular antigens, which tend to follow a relentless progressive course rather than a relapsing one but may remit after cancer treatment in some patients.25 27 Determining what constitutes a recurrence is itself a difficult task. Fluctuation of cognition, breakthrough seizures and other transient worsening of residual symptoms after the initial attack are common and do not necessarily represent a recurrence of the autoimmune inflammation. In some AE types, relapses tend to be phenotypically identical to the initial attack as in LGI1-antbiody encephalitis36 or similar but milder in severity as in NMDAR-antibody encephalitis.36 In other AE subtypes, relapses can present differently from the initial attack, as is the case of CASPR2-antibody encephalitis.37 In all cases, getting supportive objective information from MRI, EEG and/or CSF can help confirm a true relapse. Recurrence rates in AE associated with neuronal surface antibodies range from 10% to 35% based on retrospective observational studies but these rates are confounded by short follow-up periods in most of the reported case series and review articles.13 22 24 38 On the other hand, suspecting AE and testing the antibody panel may sometimes happen only after a relapse of encephalopathy so the true rates of monophasic disease may also be underestimated.38 The recurrence rate is unknown in seronegative AE. With this uncertainty and the low recurrence rates in seropositive cases, it is difficult to justify prolonged immunosuppression though in some cases a few to several years of maintenance immunosuppression may be indicated. Decisions regarding long-term immunosuppression should take in consideration published relapse rates for each specific clinical syndrome as well as severity of the initial attack and individual risks related to immunosuppression. Relapse rates and the value of long-term immunosuppression are among the key areas in need for further future research. In the meantime, any decision regarding maintenance immunosuppression in patients with AE should carefully weigh the risks versus potential benefits and incorporate evolving data about relapse risk for each specific clinical syndrome. Patients who experience a definite clinical relapse based on high clinical suspicion and supported by objective evidence of ancillary tests (eg, MRI or EEG) should start long-term immunosuppression after relapse treatment.23 Although azathioprine and mycophenolate mofetil (MMF) have been used in this setting, the use of rituximab may have the added benefit of a potentially faster onset of action (second-line acute therapy) and less carcinogenic potential with prolonged use compared with other agents.23 24 Rituximab can be used as both a second-line agent for acute immunosuppression and as a long-term immunosuppressant for recurrent cases. Rituximab, however, does not deplete the antibody-secreting cells which are typically CD20-negative. In these conditions, rituximab may work by deleting the antigen-specific memory B-cell populations and hence preventing the formation of new plasmablasts which secrete the pathogenic antibodies.17 The use of other B-cell therapies (eg, humanised anti-CD20 and anti-CD19 monoclonal antibodies) may be worth exploring in future research. Overlapping with oral corticosteroids is needed for 3–6 months when using azathioprine or MMF due to their delayed onset of action. On our AEACN survey, in response to a question in the check-all-that-apply format, 70% of responders indicated they would start long-term immunosuppression in AE associated with antibodies against neuronal surface antigens after a second attack while 50% indicated they would start after the first attack. As for seronegative AE, 61% indicated they would start long-term immunosuppression after a second attack and only 10.4% indicated they would start after the first attack. However, these generalised survey results should be treated with caution since clinicians’ practice is influenced by the specific AE subtype they see most frequently. In addition, many clinical specifics influence the decision regarding long-term immunosuppression as mentioned earlier. For patients with antibodies against intracellular antigens in whom the associated tumour has been treated, shorter bridging therapy may be considered. This is because recurrence rates are low after tumour treatment and since the response to immunotherapy is generally limited in those patients.23 24 29 In patients with antibodies against intracellular antigens in whom no tumour was found, a shorter course of bridging therapy is also advisable especially if they have not had a robust response to acute immunotherapy since prolonged immunosuppression may increase the risk of progression of the presumed underlying tumour. Long-term immunosuppression should generally be used with caution in those patients for the same reasons. This concept was reflected in the AEACN survey results as only 29% of responders indicated they would start long-term immunosuppression after treatment of the coexisting tumour for AE associated with antibodies against intracellular antigens and only 46% indicated they would start long-term immunosuppression if a tumour was not found. Patients with ongoing progression of neurological disability may be selected for immunosuppression with careful and frequent cancer screening. On the AEACN survey, the most popular choice for long-term immunosuppression for relapsing AE was rituximab chosen by 46% of responders, followed by azathioprine (15%), MMF (12%), maintenance corticosteroids (6%) and maintenance IVIg (4%). Some clinicians (12%) indicated that their choice of the long-term immunosuppressive agent depends on the antibody type with rituximab being preferred for antibodies against neuronal surface antigens (humoral autoimmunity) and other agents such as azathioprine or MMF preferred for antibodies against intracellular antigens and for seronegative AE (for presumed cellular autoimmunity). Some responders stressed the importance of patients’ comorbidities and preferences in making this decision. The optimal duration of maintenance therapy in relapsing forms of AE is unknown but published empiric approaches suggest initial maintenance period of 3 years followed by re-evaluation and attempt at withdrawal of immunosuppression.22–25 This suggested duration of long-term immunotherapy is arbitrary and not evidence-based. Retrospective studies in NMDAR-antibody encephalitis showed a small rate of recurrence within a 2-year duration but patients who received second-line immunotherapy (predominantly rituximab) had lower recurrence rates.22 Patients who have more than one relapse while on immunosuppression or while being weaned should be considered for extended immunosuppression.23 On the AEACN survey, the most popular choice for the duration of long-term immunosuppression in relapsing AE was 3 years selected by 44% of responders followed by 2 years (19%), 1 year (13%), lifelong (7%) and 6 months (3%). Of note, 13% of survey responders indicated that the duration of immunosuppression would depend on multiple factors including severity of prior attacks, tolerability of the immunosuppressive agents, antibody type and patient’s comorbidities and cancer risk. The best long-term preventive therapy for relapsing AE depends on the specific immunopathology of each AE subtype. The current empiric approaches are expected to improve as the specific pathogenic mechanism of each serological and/or clinical AE subtype is refined. A tailored approach with more selective immunomodulation to each specific syndrome will likely improve outcomes and limit unnecessary side effects. The value of non-cell-depleting immunotherapies (eg, complement or cytokine inhibitors) is yet to be fully explored in the long-term management of AE. The use of interleukein-6 inhibitors as second-line rescue therapy has already been discussed in part-1 but their use as maintenance therapy for recurrent AE is yet to be evaluated. The rarity of individual AE subtypes hinder large-scale clinical trials but this can possibly be overcome through international multicentre collaborations similar to the recent NMOSD trials. Consolidation of AE subtypes with similar pathogenic mechanisms could be considered to facilitate recruitment and expedite the advancement of evidence-based medicine in AE. Determining the need for and frequency of periodic cancer screening Initial cancer screening should be considered for most adult patients with AE at the time of presentation and at the time of any definite relapse.39 In patients in whom a tumour was found and treated, recommendations for periodic screening are dictated by established guidelines for each cancer type. In patients in whom a tumour is not found initially, periodic tumour screening every 6–12 months for an average of 4 years should be considered for patients with antibodies against intracellular antigens given their strong association with tumours.39 As for antibodies against neuronal surface antigens, tumour association is less frequent and is variable from one antibody to another. There is currently no clear guidelines for the optimal frequency and duration for cancer screening in adult patients with AE with antibodies against neuronal surface antigens, which can understandably vary depending on the specific antibody. The importance of early tumour detection should be weighed against the risks of frequent and prolonged cancer screening including increased cost and the potential for incidental findings and subsequent unnecessary investigations or interventions. On our AEACN survey (figure 2), the majority of responders (49%) opted to cancer screening for 4 years in those patients with half the responders choosing semiannual screening and half choosing annual screening during that period. Screening yearly for 2 years was chosen by 18% of responders while only 6% indicated that no periodic cancer screen is necessary after the initial screen. Some clinicians (18%) indicated that the frequency and duration of cancer screening must be tailored according to published rates of cancer association for each specific antibody. However, it should also be noted that many patients with these conditions would never have a tumour discovered. Figure 2 Autoimmune Encephalitis Alliance Clinicians Network survey results for periodic cancer screening. AE, autoimmune encephalitis. *Excluding immune checkpoint inhibitors. The value of periodic cancer screening in patients with seronegative AE is unknown but should be considered in patients with relapsing disease and those with definite limbic encephalitis in whom the connection to cancer is expected to be higher than other neuroanatomical variants.29 39 On the AEACN survey, 46% of responders indicated they would perform cancer screening every 6–12 months for 4 years in patients with seronegative limbic encephalitis while 20% chose yearly screening for 2 years and 21% indicated that no periodic cancer screening is necessary after the initial screen. As for other seronegative neuroanatomical variants (eg, cortical, brainstem), fewer clinicians felt the need to screen patients for 4 years (36%) than in the case of limbic encephalitis and relatively more clinicians chose screening for 2 years (24%) or no screening (24%). Some clinicians (10%) indicated that the frequency and duration of cancer screening in seronegative AE would depend on each patient’s demographics and social habits (eg, age, smoking, etc). In patients with AE in the setting of ICI cancer treatment, cancer monitoring will be dictated by the oncologist according to established guidelines for each cancer type. When AE occurs in the setting of other immunomodulating therapies (eg, TNF-alpha inhibitors, daclizumab) or other well-known triggers (eg, post-herpetic), periodic cancer screening may not be as imperative since a paraneoplastic aetiology is less likely in the presence of an established trigger. On our AEACN survey, this concept was reflected in the answers addressing cancer screening following post-herpetic AE as 65% of responders indicated that there is no need for periodic screening following the initial screen. However, in iatrogenic AE in the setting of immumodulating therapies other than ICIs, only 39.3% of responders opted not to perform periodic cancer screening after the initial one indicating less confidence in the aetiological relationship between these agents and AE development especially in patients with cancer risk factors. Nevertheless, most clinicians selected less stringent cancer screening protocols in patients with iatrogenic AE (only 25% recommended cancer screening for a duration of 4 years). Whole body FDG-PET is a single test that may be used for periodic screening in addition to recommended age appropriate screening tests (eg, mammograms, colonoscopy).39 An initial first-line screening study (eg, CT) may be required prior to approval of FDG-PET, although approval policies vary by insurer. FDG-PET can detect tumours that are missed by CT making it a higher yield test in paraneoplastic conditions since associated tumours are usually in early development.39 Medical insurance providers should allow FDG-PET coverage in patients with paraneoplastic syndromes and/or positive NAAs as discussed in part-1. FDG-PET is not ideal for seminoma/teratoma detection so periodic pelvic/scrotal ultrasound should be considered in case of AE serological or phenotypical subtypes suggestive of these tumours (eg, anti-NMDR or anti-Ma2 encephalitis or their phenotypes). A more targeted periodic cancer screening can also be considered for certain antibodies with specific cancer associations (eg, pelvic ultrasound and mammogram/breast MRI for anti-Yo antibody). Physical and neuropsychological rehabilitation Patients with ataxia, spasticity and other mobility issues may benefit from physical therapy and neurorehabilitation. More importantly, patients with short-term memory impairment and other cognitive deficits should undergo neuropsychological evaluation to identify those in need for neuropsychological rehabilitation programmes. The value of cognitive and neuropsychological rehabilitation in AE has not been investigated in a systematic manner but clinical experience supports a pivotal role in recovery after the acute phase. Response to neuropsychological rehabilitation may vary according to patient’s age, comorbidities and extent/location of permanent brain damage if any. It is unknown if antibody type influences responsiveness to neuropsychological rehabilitation. Studies on cognitive outcomes of AE and the role of neuropsychological rehabilitation is among the most pressing needs in AE research. Some patients may require modification of their house or workplace. Many patients may need formal functional capacity evaluations to determine their ability to go back to the workforce, and most will need aggressive management of vascular risk factors and promotion of healthy lifestyle to avoid further cognitive decline. DISCUSSION AND SUMMARY In this two-part project, we analysed each step in AE management in a real-life chronological order that covers the first neurological presentation, diagnostic workup, acute management, bridging therapy, and long-term management and monitoring. We focused on practical management questions and used published research and expert opinion to provide broad recommendations to clinicians. We understand that AE is a heterogeneous disease and that treatment strategies may differ from one antibody-related syndrome and/or one clinical subtype to another. However, individual AE syndromes are rare and information on the specific antibody is usually lacking at the time of presentation. This makes it necessary to establish a common general approach to AE to guide initial management until the specific antibody is revealed. Moreover, many cases of AE are not linked to any of the commercially available antibodies, which adds to the importance of having a common approach. In addition, many AE syndromes have common clinical and pathogenic features making standardisation of certain aspects of both acute and long-term management possible for some of these syndromes. A major limitation to our survey questionnaire is generalisation. When addressing a diverse clinical entity like AE with a wide spectrum of clinical phenotypes and patient demographics/comorbidities, it is difficult to develop specific questions for every possible clinical scenario. Therefore, our recommendations may not be suitable for all patients and clinicians will still need to make individual decisions based on each patient’s unique circumstances. Our AEACN survey results highlight the diversity of practice across institutions when it comes to AE management and emphasise the need for development of standards of care. Although no consensus was reached for most of the survey questions, the survey results showed which approaches are most popular among AE clinicians and which steps in AE management are most divisive and therefore require more research. More formal consensus techniques like the Delphi method were not implemented to avoid misinterpretation of our recommendations as firm treatment guidelines. A major goal of this paper was to showcase both agreements and disagreements in AE management in order to inform future observational and interventional studies. In this evolving field, presenting firm consensus guidelines in the absence of strong scientific evidence can have a negative impact on future research efforts. On the other hand, translating practice patterns into management recommendations remains a major limitation to this paper. However, the recommendations did not rely solely on survey results and incorporated available evidence from several AE subtypes and related immune-mediated disorders. The inclusion of multiple subspecialties and several countries in the survey enriched the results and made our recommendations applicable to a larger audience. However, this diversity in specialty and geographical locations inevitably introduced a degree of responder bias given the difference in practice per specialty (eg, paediatric vs adult neurologists) and location (eg, some therapeutic and diagnostic interventions are not readily available in some countries/institutions). Our recommendations are meant to serve as a general guidance for clinicians until better quality evidence becomes available for each AE subtype and are expected to evolve over time as more data emerge in the future. A summary of the recommendations for acute management was presented after part-1. Box 1 includes a summary of the recommendations for long-term management. Box 1 Best practice recommendations summary for long-term management of autoimmune encephalitis Positive antibody against intracellular antigen (classical onconeuronal antigens) and typical clinical picture: refer to oncology for treatment and surveillance of tumour if one was found. If no tumour was found, initiate semiannual to annual cancer screening for at least 4 years. Treat neurological relapses with intravenous methyl-prednisolone and/or cyclophosphamide as necessary but avoid long-term immunosuppression. Positive antibody against neuronal surface antigen with high clinical relevance and typical clinical picture: consider periodic tumour screening based on the type of antibody and each patient’s cancer risk factors. Some neuronal surface antibodies with higher rates of tumour association may require more frequent screening as in gamma-Aminobutyric acid-B receptor (GABABR)-antibody encephalitis and some may require less frequent screening as in leucine-rich glioma inactivated-1-antibody encephalitis. Consider initiating at least annual cancer screening for an average of 2–4 years based on antibody type. A more selective screening approach could be considered for antibodies with specific tumour associations. Consider long-term immunosuppression preferably with rituximab (based on presumed antibody-mediated immunity and on N-methyl-D-aspartate receptor (NMDAR)-antibody encephalitis studies) after a second attack. May consider starting long-term immunosuppression after the first attack in patients with severe initial presentation or risk factors for relapse (eg, persistently positive oligoclonal bands). Overlap with short-term oral corticosteroids after initiation of long-term agent. The duration of long-term immunosuppression depends on relapse rate, relapse severity and tolerability of the immunosuppressive agent. Positive antibody against neuronal surface antigen with low clinical relevance to the clinical presentation: evaluate confidence in the clinical relevance of the positive antibody based on clinical and ancillary data. Evaluate for alternative aetiologies. If the diagnosis of autoimmune encephalitis (AE) is felt to be probable and no other aetiology found then follow recommendation 2. Seronegative AE: confirm the diagnosis according to published criteria and exclude alternative causes. May consider initiating annual cancer screening for an average of 4 years for seronegative definite autoimmune limbic encephalitis and may consider periodic screening for an average of 2 years for all other neuroanatomical variants. Start long-term immunosuppression with rituximab, mycophenolate mofetil or azathioprine after a second attack. Overlap with short-term corticosteroids after initiation of long-term agent. The duration of long-term immunosuppression depends on relapse rate, relapse severity and tolerability of the immunosuppressive agent. Recommendations for seronegative AE are particularly anecdotal and more research is needed for this subtype of AE. For all AE subtypes: treat residual symptoms including seizures, movement disorders, psychiatric symptoms, spasticity, sleep dysfunction and dysautonomia. Also start de-escalation of symptomatic medications when appropriate. Start physical, occupational and speech therapy depending on residual deficits. Strongly consider neuropsychological rehabilitation although the value behind this intervention is in need for further research to establish scientific evidence.

 




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