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Immune checkpoint inhibitors: An emergency medicine focused review

Immune checkpoint inhibitors: An emergency medicine focused review | AntiNMDA | Scoop.it
Several novel cancer therapies have been developed, many of which focused on immune
system modulation. These include immune checkpoint inhibitors, modulators, T-cell
therapy, monoclonal antibodies, cytokines, oncolytic viruses, and vaccines.
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Long‐term cognitive outcome in anti‐NMDA receptor encephalitis - Heine - - Annals of Neurology

Long‐term cognitive outcome in anti‐NMDA receptor encephalitis - Heine - - Annals of Neurology | AntiNMDA | Scoop.it
Objective Cognitive dysfunction is a core symptom of NMDAR encephalitis, but detailed studies on prevalence, characteristics of cognitive deficits, and the potential for recovery are missing. Here,...
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PET coregistered with MRI imaging of anti-NMDAR encephalitis patient with SARS-CoV-2 infection

PET coregistered with MRI imaging of anti-NMDAR encephalitis patient with SARS-CoV-2 infection | AntiNMDA | Scoop.it
We report a case of Anti-N-methyl-d-aspartate receptor (Anti-NMDAR) encephalitis patient with SARS-CoV-2 infection. A 30 years-old female who was hospitalized on 17th March 2020, with agitation, dysarthria and hallucinations for 3 days. On 20th March 2020 patient started with a fever (>37.5 °C) and chills. A SARS-CoV-2 RT-PCR resulted positive. She was quarantined and treated with Hydroxychloroquine and Lopinavir/Ritonavir. Electroencephalogram showed left fronto-temporal lateralized epileptiform discharges and delta brush pattern. Cerebrospinal fluid (CSF) analysis show hyperproteinorraquia (54.5 mg/dl) and lymphocytic pleocytosis (leukocytes 44/μl with 90% lymphocytes). MRI acquired on April 2020 showed subtle hyperintensity of the left hippocampus on the Fluid-attenuated inversion recovery (FLAIR) sequence (Fig. 1 ). Two days later both CSF and blood test showed presence of NMDAR antibodies. Patient was treated with methylprednisolone, antiepileptic drugs and immunotherapy. Once cardiothoracic and neurologic symptomatology was stabilized, patient was discharged from the hospital on May 2020 with Rituximab and a neurorehabilitation program. On the follow-up, on September 2020, patient who showed new-onset mnesic cognitive impairment was studied with a brain 18F-FDG PET that showed a slight asymmetry on the left anterior temporal lobe and hypometabolism defects on the postero-medial left temporal lobe and in the right cerebellar hemisphere (Fig. 2 ). The corregistered imaging with the MRI acquired previously and PET imaging showed a concordance between an increase of signal intensity on the FLAIR image and hypometabolism defect. Patient continued with Rituximab, antiepileptic drugs and neurorehabilitation. On January 2021, a new MRI was performed and an infarction was observed in the right cerebellar hemisphere. Currently patient does not present epileptic seizures and she has mild cognitive impairment. PET quantification showed an asymmetry on left temporal anterior lobe corresponding to hypometabolism asymmetry (Fig. 3 ). Anti-NMDAR encephalitis is one of the most common types of autoimmune encephalitis characterized by antibodies against the GluN1 subunit of this receptor. NMDAR antibodies have a tropism on hippocampal neurons and from this biological effect derives its main clinical features. Patients are usually young adults, predominantly women, who develop progressive symptoms including abnormal behaviour, autonomic dysfunction, and seizures.1 Recognition of Anti-NMDAR encephalitis is important because, despite its severity, most patients respond to immunotherapy.2 Recently, COVID-19 has been described as a cause of autoimmune encephalitis including Anti-NMDAR encephalitis.1 In autoimmune encephalitis, SARS-CoV-2 virus causing COVID-19 disease leads to brain damage due to the cytokine storm mediated by interleukin mostly IL-2 and IL-6 in the CSF.2 This mechanism may be the cause of hypometabolism in PET related to cortical damage.3 Early hypermetabolism has been described in the mesial temporal areas and could be a marker of active inflammatory process of limbic encephalitis. On the contrary, the hypometabolism pattern including temporal, parietal and occipital areas was observed in the follow-up.3 In addition, MRI FLAIR signal abnormity has been described in autoimmune encephalitis caused by COVID-19 in the temporal lobe and in the basal ganglia.1 The regional infarct involving the right cerebellar cortex may be associated to cerebral thrombotic microangiopathy1, 2 as a complication in our case.
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Autoimmune Encephalitis Post-SARS-CoV-2 Infection: Case Frequency, Findings, and Outcomes | Neurology

Autoimmune Encephalitis Post-SARS-CoV-2 Infection: Case Frequency, Findings, and Outcomes | Neurology | AntiNMDA | Scoop.it
Results: Eighteen of the laboratory cohort (3%) were SARS-CoV-2 antibody positive (April-December 2020). Diagnoses were: AE, 2; post-acute sequelae of SARS CoV-2 infection [PASC], 3; toxic-metabolic encephalopathy during COVID-19 pneumonia, 2; diverse non-COVID-19 relatable neurological diagnoses, 9; unavailable, 2. Five of the encephalopathy cohort had AE (16%, including the 2 laboratory cohort cases which overlapped) representing 0.05% of 10,384 patients diagnosed and cared for with any COVID-19 illness at Mayo Clinic Rochester in 2020. The 5 patients met definite (n=1), probable (n=1), or possible (n=3) AE diagnostic criteria; median symptom onset age was 61 years (range, 46-63), 3 were women. All 5 were neural IgG negative and 4 tested were SARS-CoV-2 PCR/IgG index negative in CSF. Phenotypes (and accompanying MRI and EEG findings) were diverse (delirium [n=5], seizures [n=2], rhombencephalitis [n=1], aphasia [n=1], and ataxia [n=1]). No ADEM cases were encountered. The 3 patients with possible AE had spontaneously resolving syndromes. One with definite limbic encephalitis was immune therapy responsive but had residual mood and memory problems. One patient with probable autoimmune rhombencephalitis died despite immune therapy. The remaining 26 encephalopathy cohort patients had toxic-metabolic diagnoses.
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Autoimmune encephalitis: clinical spectrum and management | Practical Neurology

Autoimmune encephalitis: clinical spectrum and management | Practical Neurology | AntiNMDA | Scoop.it
In adult-onset NMDAR-antibody encephalitis, psychiatric features are typically the presenting complaint, with patients often needing mental health assessments before a neurology consultation. In our experience, relatively isolated psychiatric features occur in these patients only at disease onset. Subsequently, within a few days, they are rapidly accompanied by more traditional neurological abnormalities including delirium, amnesia and seizures. Nevertheless, careful consideration of the psychopathology can help in differentiating NMDAR-antibody encephalitis from primary psychiatric disease. NMDAR-antibody encephalitis often presents with a complex phenotype spanning classically distinct psychiatric diagnostic categories, including domains of mood, psychosis, behaviour and catatonia, the latter also seen with gamma aminobutyric acid A receptors (GABAAR)-antibodies.10 By contrast, early ‘transdiagnostic’ presentations are unusual in most primary psychiatric diseases. Overall, the complex psychiatric phenotype at onset combined with polysymptomatic neurological disease and a polymorphic movement disorder, discussed in detail later, creates a multifaceted presentation highly characteristic of NMDAR-antibody encephalitis. These features contrast markedly to the poorly circumscribed clinical syndrome of neuropsychiatric systemic lupus erythematosus, in which NMDAR-antibodies have also been reported. However, by contrast to antibodies which target native neuronal surface epitopes, those from patients with neuropsychiatric systemic lupus erythematosus have been found to show intrinsic ‘stickiness’, which is not NMDAR-specific, and hence have limited diagnostic value.11
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Anti-NMDAR Encephalitis: Multidisciplinary Development of a Clinical Practice Guideline | American Academy of Pediatrics

Anti-NMDAR Encephalitis: Multidisciplinary Development of a Clinical Practice Guideline | American Academy of Pediatrics | AntiNMDA | Scoop.it
The presentation and clinical course of anti-NMDAR encephalitis has been extensively described in the literature.10,11 The NMDAR is located on neuronal cell surfaces with high concentration in the limbic system, hypothalamus, and forebrain. When pathogenic antibodies to the ionotropic glutamate receptors subunit of the receptor are present in the cerebrospinal fluid (CSF), they bind and cause internalization of the receptors as well as disruption of the synaptic proteins and plasticity leading to synaptic dysfunction.12,13 The role of the NMDAR in complex neurologic and psychiatric processes accounts for the symptoms and clinical presentation. Initial symptoms at presentation vary on the basis of age of the patient. Large cohort studies have revealed that those aged >18 years present with behavioral, psychiatric, and/or memory issues ∼75% of the time. In the pediatric population of those aged <12 years, neurologic symptoms, including seizures and movement disorders (dyskinesia, chorea, dystonia) account for initial symptoms in 50% to 60% of patients.11,14 Specifically, in regards to movement disorders, orofacial dyskinesias are common in all ages, but children initially present with higher prevalence of chorea and other dyskinesias, whereas the majority of adults ultimately develop bradykinesia and catatonic symptoms (orofacial dyskinesia, echolalia, mutism, staring, …
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Anti-NMDA Receptor Encephalitis, Vaccination and Virus

Anti-NMDA Receptor Encephalitis, Vaccination and Virus | AntiNMDA | Scoop.it
Anti-N-methyl-d-aspartate (Anti-NMDA) receptor encephalitis is an acute autoimmune disorder. The symptoms range from psychiatric symptoms, movement disorders, cognitive impairment, and autonomic dysfunction.
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Early rituximab therapy effective for autoimmune encephalitis | iWeller.com

Early rituximab therapy effective for autoimmune encephalitis | iWeller.com | AntiNMDA | Scoop.it
October 13, 2021 @ All Health & Fitness Tips - Sumary of Early rituximab therapy effective for autoimmune encephalitis: Back to Healio Early and short-term rituximab may be an option to treat patients with certain forms of autoimmune encephalitis, according to study results published in Neurology:...
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Autoimmune Encephalitis versus Creutzfeldt-Jakob disease in a patient with typical Facio-brachial dystonic seizures: A case report with Diagnostic challenges

Autoimmune Encephalitis versus Creutzfeldt-Jakob disease in a patient with typical Facio-brachial dystonic seizures: A case report with Diagnostic challenges | AntiNMDA | Scoop.it
Autoimmune encephalitis mimicking CJD or vice versa is not a very commonly encountered phenomenon. This case discusses the clinical overlap of these two conditions and its diagnostic dilemmas.This case presented with typical LGI1 encephalitis and in spite of therapy with immunomodulators had a rapi...
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Frontiers | Clinical and Imaging Features of Patients With Encephalitic Symptoms and Myelin Oligodendrocyte Glycoprotein Antibodies | Immunology

Frontiers | Clinical and Imaging Features of Patients With Encephalitic Symptoms and Myelin Oligodendrocyte Glycoprotein Antibodies | Immunology | AntiNMDA | Scoop.it
BackgroundMyelin oligodendrocyte glycoprotein-antibody (MOG-ab)-associated disease (MOGAD) has highly heterogenous clinical and imaging presentations, in which encephalitis is an important phenotype. In recent years, some atypical presentations in MOG-ab-associated encephalitis (MOG-E) have been...
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Frontiers | Comprehensive B-Cell Immune Repertoire Analysis of Anti-NMDAR Encephalitis and Anti-LGI1 Encephalitis | Immunology

Frontiers | Comprehensive B-Cell Immune Repertoire Analysis of Anti-NMDAR Encephalitis and Anti-LGI1 Encephalitis | Immunology | AntiNMDA | Scoop.it
Anti-N-methyl-D-aspartate receptor encephalitis (anti-NMDARE) and anti-leucine-rich glioma-inactivated 1 encephalitis (anti-LGI1E) are the two most common types of antibody-mediated autoimmune encephalitis.
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Rituximab Treatment and Long-term Outcome of Patients With Autoimmune Encephalitis | Neurology Neuroimmunology & Neuroinflammation

Rituximab Treatment and Long-term Outcome of Patients With Autoimmune Encephalitis | Neurology Neuroimmunology & Neuroinflammation | AntiNMDA | Scoop.it
Abstract Background and Objectives To determine the real-world use of rituximab in autoimmune encephalitis (AE) and to correlate rituximab treatment with the long-term outcome. Methods Patients with NMDA receptor (NMDAR)-AE, leucine-rich glioma-inactivated-1 (LGI1)- AE, contactin-associated protein-like-2 (CASPR2)-AE, or glutamic acid decarboxylase 65 (GAD65) disease from the GErman Network for Research on AuToimmune Encephalitis who had received at least 1 rituximab dose and a control cohort of non–rituximab-treated patients were analyzed retrospectively. Results Of the 358 patients, 163 (46%) received rituximab (NMDAR-AE: 57%, CASPR2-AE: 44%, LGI1-AE: 43%, and GAD65 disease: 37%). Rituximab treatment was initiated significantly earlier in NMDAR- and LGI1-AE (median: 54 and 155 days from disease onset) compared with CASPR2-AE or GAD65 disease (median: 632 and 1,209 days). Modified Rankin Scale (mRS) scores improved significantly in patients with NMDAR-AE, both with and without rituximab treatment. Although being more severely affected at baseline, rituximab-treated patients with NMDAR-AE more frequently reached independent living (mRS score ≤2) (94% vs 88%). In LGI1-AE, rituximab-treated and nontreated patients improved, whereas in CASPR2-AE, only rituximab-treated patients improved significantly. No improvement was observed in patients with GAD65 disease. A significant reduction of the relapse rate was observed in rituximab-treated patients (5% vs 13%). Detection of NMDAR antibodies was significantly associated with mRS score improvement. A favorable outcome was also observed with early treatment initiation. Discussion We provide real-world data on immunosuppressive treatments with a focus on rituximab treatment for patients with AE in Germany. We suggest that early and short-term rituximab therapy might be an effective and safe treatment option in most patients with NMDAR-, LGI1-, and CASPR2-AE. Class of Evidence This study provides Class IV evidence that rituximab is an effective treatment for some types of AE. Glossary abs=antibodies; AE=autoimmune encephalitis; CA=cerebellar ataxia; CASPR2=contactin-associated protein-like-2; CBA=cell-based assay; GAD65=glutamic acid decarboxylase 65; GENERATE=GErman Network for Research on AuToimmune Encephalitis; IHC=immunohistochemistry; IVIG=IV immunoglobulin; LE=limbic/autoimmune encephalitis; LGI1=leucine-rich glioma-inactivated-1; mRS=Modified Rankin Scale; NMDAR=NMDA receptor; RIA=radioimmunoassay; SPS=stiff-person syndrome Autoimmune encephalitis (AE) is an umbrella term for an emerging spectrum of immune-mediated neuropsychiatric disorders often associated with antibodies (abs) against neuronal cell surface, synaptic, or intracellular proteins.1,2 Anti-NMDA receptor (NMDAR)-AE, anti–leucine-rich glioma-inactivated-1 (LGI1)-AE, anti–contactin-associated protein-like-2 (CASPR2)-AE, and anti–glutamic acid decarboxylase-65 (GAD65) disease together make up the majority of seropositive AE subtypes. NMDAR-AE affects young adults and children with female preponderance, is frequently associated with ovarian teratomas, and causes psychiatric symptoms, movement disorders, decreased consciousness, autonomic dysregulation, epileptic seizures, and central apnea.3,4 LGI1-AE affects middle-aged or elderly patients, causes short-term memory deficits, confusion, and epileptic seizures,5,6 and is sometimes preceded by faciobrachial dystonic or tonic seizures.7 CASPR2-AE predominantly affects elderly men and causes encephalitis and neuromyotonia, neuropathic pain, ataxia, myoclonus, autonomic dysfunction, or a combination thereof (e.g., Morvan syndrome).8,9 GAD65 disease is considerably more heterogeneous, affects predominantly women of all ages, and may cause cerebellar ataxia (CA), limbic/AE (LE), stiff-person syndrome (SPS), isolated temporal lobe epilepsy, and overlap forms of the aforementioned manifestations.10,-,13 Early diagnosis and prompt initiation of immunotherapy is crucial and often leads to substantial or complete recovery from these severe disorders.8 However, treatment data from randomized trials are scarce.14,15 Empiric treatment of AE usually consists of a step-wise escalation of immunotherapy including first-line therapy with steroids, plasma exchange, IV immunoglobulin (IVIG), or combinations, followed by second-line therapy with cyclophosphamide, rituximab, or combinations.2 Rituximab is a B cell–depleting monoclonal ab directed against CD20 with established efficacy in many neurologic autoimmune diseases including MS,16 and neuromyelitis optica spectrum disorders.17 Rituximab was shown to be effective in AE associated with different auto-abs.4,18,19 By contrast, 1 randomized placebo-controlled trial with rituximab did not show efficacy in patients with SPS.15 Detailed and comparative evaluations of rituximab use and the long-term outcome between AE subtypes in a real-world setting are missing. In this study, we evaluated demographic and clinical characteristics, laboratory findings, and immunotherapies in patients with NMDAR-, LGI1-, CASPR2-AE, or GAD65 disease in a cohort from the GErman NEtwork for Research on AuToimmune Encephalitis (GENERATE) registry and compared patients who had received at least 1 rituximab dose with non–rituximab-treated patients. In the rituximab cohort, we specifically correlated early, high-dose, or prolonged rituximab treatment with the long-term outcome. Methods Standard Protocol Approvals, Registrations, and Patient Consents All data were collected from the GENERATE registry, which is a noninterventional retrospective and prospective multicentric database for patients with AE in Germany, Austria, and Switzerland (generate-net.de). GENERATE was approved by the institutional review boards of all actively recruiting centers. Patients from participating centers entered into the registry until June 30, 2019, were analyzed. The study was performed according to the Declaration of Helsinki. All enrolled patients or their legal representatives gave written informed consent before enrollment in the registry. Study Population The following patients were included: (1) patients with detection of NMDAR-, LGI1-, CASPR2-, or GAD65 abs according to the ab criteria below; (2) clinical diagnosis of AE based on the consensus criteria published in reference 2, or for patients with GAD abs, alternatively diagnosis of CA or SPS; (3) any documented treatment with rituximab; and (4) available information on the number, dosage, and timing of rituximab infusions. In addition, a control cohort with consistent inclusion criteria except for rituximab treatment was included. Analysis of Clinical, Laboratory, and Immunotherapy Profiles Ab testing was performed in the respective GENERATE centers using cell-based assays (CBAs) and confirmation by immunofluorescence (commercial test kit panels Euroimmun, Lübeck) and/or immunohistochemistry (IHC) for NMDAR, LGI1, and CASPR2, and ELISA, radioimmunoassay (RIA), or CBA for GAD65. Patients fulfilling the following ab criteria in earliest available samples were included: NMDAR abs detected in serum by CBA confirmed by IHC (in the absence of confirmatory IHC in serum, only CBA serum titers of >1:500 were considered specific) and/or CSF positive; GAD abs >1:500 in CBA or >2000IE/mL in ELISA or RIA in serum and/or CSF positive; LGI1 abs at any titer in CSF and/or serum; CASPR2 abs >1:128 in serum and/or CSF positive.20 Only IgG abs were considered relevant. Data on any immunotherapy were recorded. First-line immunotherapy was defined as treatment with corticosteroids, plasma exchange/immunoabsorption, and IVIG; second-line therapy included rituximab in the rituximab cohort and all other immunotherapies except reapplied corticosteroids, IVIG, and plasma exchange in both cohorts. The occurrence of relapses during follow-up was based on the overall clinical impression of the treating physician. Functional status was assessed using the modified Rankin Scale (mRS) at the peak of disease and then throughout disease course. Side effects of rituximab treatment were queried from all participating centers. Primary Research Question Do rituximab-treated patients with NMDAR-AE, LGI1-AE, CASPR2-AE, and GAD65 disease have a better outcome than non–rituximab-treated patients? Classification of Evidence This study provides Class IV evidence that rituximab is an effective treatment for some types of AE. Statistics Statistical tests were performed using Prism Software (GraphPad). Normality testing was performed using the D'Agostino-Pearson omnibus test. Continuous variables with >2 subgroups were compared using the Kruskal-Wallis test followed by the Dunn multiple comparisons test and with 2 subgroups using the Mann-Whitney test. Ordinal variables were compared using the χ2 test or the Fisher exact test. The Benjamini-Hochberg procedure was performed to control for multiple testing. Multivariate analysis was performed by ordinal logistic fit using JMP software (Version 16, JMP, A Business Unit of SAS, Cary, NC). Data Availability No deidentified patient data will be shared. No study-related documents will be shared. Reasonable requests from any qualified investigator for anonymized data will be considered by the corresponding author. Results Patient Characteristics We identified 358 patients with NMDAR-AE, GAD65 disease, LGI1-AE, or CASPR2-AE. One hundred sixty-three patients (46%) were treated with rituximab. Based on the inclusion criteria, 14 patients in the rituximab cohort and 32 patients in the control cohort were excluded from further analysis (Figure 1, eFigure 1, links.lww.com/NXI/A595). Our final study cohort comprised 149 patients in the rituximab cohort (NMDAR-AE: n = 81, GAD65 disease: n = 31, LGI1-AE: n = 26, and CASPR2-AE: n = 11) and 163 patients in the control cohort (NMDAR-AE: n = 61, GAD65 disease: n = 53, LGI1-AE: n = 35, and CASPR2-AE: n = 14) (Figure 1). Overall, rituximab was administered most frequently in NMDAR-AE (57%), followed by CASPR2-AE (44%), LG1-1-AE (43%), and GAD65 disease (37%). Clinical characteristics as well as CSF and MRI parameters, as expected, varied considerably between the ab subgroups (Table 1). Differences between the rituximab cohort and the control cohort indicating severity bias were observed for patients with NMDAR-AE and GAD65 disease: patients with NMDAR-AE treated with rituximab had a significantly higher mRS score at peak of disease (rituximab cohort: median: 4.0; control cohort: median: 3.0) and a significantly higher frequency of decreased consciousness (Table 1). In patients with GAD65 disease, the mRS score at the peak of disease was also higher in the rituximab cohort (median: 3.0) compared with the control cohort (median: 2.0) (Table 1). Figure 1 Study Population Profile Patient numbers in the different study subpopulations are depicted. *Patients excluded because of insufficient data on rituximab dosing (n = 2), concomitant diagnosis of MS (n = 2), retraction of consent for the GENERATE registry (n = 1), or not fulfilling the ab criteria for inclusion (n = 9). **Patients excluded because of insufficient data on immunosuppressive treatment (n = 1) or not fulfilling the ab criteria for inclusion (n = 31). CA, cerebellar ataxia; CASPR2 = contactin-associated protein-like-2; Enc. = encephalitis; GAD65 = glutamic acid decarboxylase 65; GENERATE = GErman Network for Research on AuToimmune Encephalitis; LGI1 = leucine-rich glioma-inactivated-1; NMDAR = NMDA receptor; SPS = stiff-person syndrome. View inline View popup Table 1 Characterization of the Patient Cohort First-Line and Second-Line Treatments All patients with rituximab treatment received prior first-line immunotherapy. In the control cohort, 4 patients (7%) with NMDAR-AE, 5 patients (9%) with GAD65 disease, and 1 patient (7%) with CASPR2-AE had no prior first-line immunotherapy (Table 2). Time to initiation of first-line therapy was shortest in patients with NMDAR-AE, and the therapy was started significantly earlier in patients with NMDAR-AE treated with rituximab (median: 16 days) compared with patients with NMDAR-AE not receiving rituximab (median: 33 days) (Table 2). In all subgroups, the majority of patients received a combination of different first-line treatments with steroids and plasma exchange being the most frequent combination in the overall cohort (n = 103; 33%) (Figure 2, A–H). As expected, because of severity bias, patients in the rituximab cohort were treated significantly more often with combinations of first-line therapy (Figure 2, A–H). Physicians reported some improvement following first-line therapy in the majority of patients independent of the subgroup. Of interest, the frequency of this observation was similar between patients later receiving rituximab and patients who were treated differently (Table 2). View inline View popup Table 2 Immunotherapy and Follow-up of Patients Figure 2 Venn/Euler Diagrams Showing Applied Mono- and Combination First-Line and Second-Line Immunotherapies The numbers of patients treated with the respective prior first-line immunotherapies (A–H) and second-line immunotherapies (I–P) in the rituximab cohort (A–D) and in the control cohort (E–H) are depicted for the different ab subgroups (A, E, I, and M: NMDAR-AE; B, F, J, and N: GAD65 disease; C, G, K, and O: LGI1-AE; and D, H, L, and P: CASPR2-AE). Other second-line therapies included bortezomib (n = 6 in patients with NMDAR-AE treated with rituximab), daratumumab (n = 1 in patients with NMDAR-AE treated with rituximab), tacrolimus (n = 1 in patients with GAD65 disease treated with rituximab and n = 1 in patients with GAD65 disease not treated with rituximab), and basiliximab (n = 1 in patients with GAD65 disease treated with rituximab). Areas of Venn diagrams are proportional to the case numbers relative to the respective subgroup. (A–H) Proportions of combination first-line therapy relative to none/monotherapy were compared using the Fisher exact test. ***p < 0.001, **p < 0.01, and *p < 0.05. (I–P) Proportions of treatment with cyclophosphamide or other therapies relative to steroid-sparing therapies and no treatment were compared using the Fisher exact test. ***p < 0.001, **p < 0.01, and *p < 0.05. AZA = azathioprine; CASPR2 = contactin-associated protein-like-2; cyc = cyclophosphamide; GAD65 = glutamic acid decarboxylase 65; IVIG = IV immunoglobulin; MMF = mycophenolate mofetil; MTX = methotrexate; NMDAR = NMDA receptor; LGI1 = leucine-rich glioma-inactivated-1; PLEX = plasma exchange. Forty patients (25%) in the control cohort and 38 patients (26%) in the rituximab cohort received a second-line immunotherapy other than rituximab. The frequency of application of second-line immunotherapies other than rituximab did not differ between the rituximab cohort and the control cohort (Table 2). These second-line immunotherapies included cyclophosphamide, azathioprine, mycophenolate mofetil, methotrexate, bortezomib, daratumumab, tacrolimus, and basiliximab (Figure 2, I–P) and were applied before, parallel to, or after rituximab therapy. In patients with NMDAR-AE and GAD65 disease, more aggressive second-line therapies such as cyclophosphamide, bortezomib, or daratumumab were applied more frequently in the rituximab cohort compared with the control cohort (Figure 2, I–P). Other than this and the above-mentioned severity bias, we did not observe significant selection bias between patients treated with and without rituximab. Description of Rituximab Treatments A wide spectrum of rituximab treatment regimens was observed in our rituximab cohort. In detail, patients with GAD65 disease and CASPR2-AE received rituximab significantly later (GAD65: median 1,209 days, CASPR2: 632 days) than patients with NMDAR-AE (median: 54 days) and LGI1-AE (median: 155 days) (Figure 3A; Table 2). Time from initiation of first-line treatment to rituximab treatment was shortest in NMDAR-AE (median: 30 days) and longest in GAD65 disease (median: 141 days) (Figure 3B; Table 2). Sixteen (20%) patients with NMDAR-AE received rituximab very early within 2 weeks after first-line immunotherapy. The median number of infusions and total rituximab dose did not differ significantly among the subgroups (Figure 3C, D; Table 2). The duration of rituximab treatment, defined as the time from first to last infusion, was shortest in NMDAR-AE (median: 24 days) and longest in GAD65 disease (median: 454 days) (Figure 3E and Table 2). The percentage of patients who received only induction therapy defined as time between first to last rituximab treatment of less than 6 months was highest in patients with NMDAR-AE (54%) and lowest in patients with GAD65 abs (27%); patients with LGI1- and CASPR2-AE were in between (35% and 46%, respectively) (Figure 3F; Table 2). Side effects after rituximab treatment were rare (n = 5, 3.4%); however, they were not systematically registered in this study. In detail, we observed n = 2 infusion-related reactions (n = 1: urticaria with, however, simultaneous IVIG application; n = 1: tremor, tachycardia, and fear); n = 1 lymphopenia leading to a reduction of the rituximab dose; n = 1 frequent infections; and n = 1 unknown side effect. Figure 3 Rituximab Regimens Used in Patients With AE and the Outcome According to Subtypes of AE (A–F) In different subgroups (NMDAR-AE, GAD65 disease, LGI1-AE, and CASPR2-AE), the duration in days from disease onset to initiation of rituximab treatment (A), the duration in days from initiation of first-line therapy to initiation of rituximab treatment (B), the number of rituximab infusions (C), the total cumulative rituximab dose (D), the duration in days from the first to the last rituximab infusion (E), and the number of patients receiving induction therapy (rituximab treatment <6 months) or induction + maintenance therapy (rituximab treatment ≥6 months) (F) are depicted. Bars indicate the median. Normality testing was performed using the D'Agostino-Pearson omnibus test. Continuous variables were compared using the Kruskal-Wallis test followed by the Dunn multiple comparisons test, and ordinal variables were compared using the Fisher exact test. ****p<0.0001 ***p < 0.001, **p < 0.01, and *p < 0.05. (G) mRS scores in the different ab subgroups were compared in the rituximab cohort and in the control cohort. The distribution of mRS scores is depicted at 4 time points: I, maximal mRS at symptom onset; II, mRS at initiation of rituximab treatment (from −2 months to +4 months from rituximab onset); III, mRS 4–12 months after initiation of rituximab treatment; IV, mRS at last follow-up with at least >12 months after rituximab treatment. The line represents the change in mRS scores dividing favorable mRS scores (0–2) and nonfavorable mRS scores (≥3). The ordinal χ2 test was applied to compare the distribution of mRS scores. ****p<0.0001 ***p < 0.001, **p < 0.01, and *p < 0.05. CASPR2, contactin-associated protein-like-2; GAD65 = glutamic acid decarboxylase 65; mRS = modified Rankin Scale; NMDAR = NMDA receptor; LGI1 = leucine-rich glioma-inactivated-1. Follow-up and Treatment Response Follow-up data were available for 282 patients (90%) with a median follow-up duration of 41 months with no significant differences between rituximab-treated patients and controls regarding follow-up data availability and duration (Table 2). The distribution of mRS scores at the peak of disease and at last follow-up improved significantly in patients with NMDAR-AE and in patients with LGI1-AE both in the rituximab cohort and in the control cohort. In patients with CASPR2-AE, a significant improvement was observed only in the rituximab cohort, but not in the control cohort. No significant improvement was observed in patients with GAD65 disease (Figure 3G). In addition, in patients with GAD65 disease, no significant improvement was observed when mRS scores were analyzed in the different disease subentities (encephalitis/overlap syndrome, CA, and SPS) (eFigure 2A, links.lww.com/NXI/A596). Although patients with NMDAR-AE treated with rituximab were affected more severely at baseline (Table 1), at final follow-up, 94% of rituximab-treated patients compared with 88% of nontreated patients had reached independent living (mRS score ≤2, p = 0.33). Patients with LGI1-AE reached independent living in 83% of cases treated with rituximab and in 78% of cases without rituximab treatment (p = 0.74). In CASPR2-AE, independent living was observed in 80% of cases treated with rituximab vs 57% of cases who did not receive B-cell depletion (p = 0.60). In contrast, patients with GAD65 disease treated with rituximab, who were more severely affected at baseline, continued to have a lower rate of independent living compared with the non–rituximab-treated control cohort at last follow-up (52% vs 75%, p = 0.07). When we analyzed the mRS scores in the rituximab cohort throughout follow-up in more detail, we found patients with NMDAR-AE to improve significantly already before rituximab initiation (Figure 3, G.a I-II), presumably because of first-line treatments. After initiation of rituximab treatment, patients continued to improve significantly (Figure 3G.a II-III). No significant difference in the mRS score was observed in patients with NMDAR-AE exhibiting a tumor compared with those without a tumor both regarding mRS score at worst status and mRS score at last follow-up (eFigure 2B, links.lww.com/NXI/A596). In LGI1 patients, a significant improvement was also already observed before rituximab treatment was initiated (Figure 3G.c I-II). After initiation of rituximab treatment, the mRS scores continued to drop; however, this improvement did not reach statistical significance (Figure 3G.c II-IV). In patients with CASPR2-AE, mRS scores decreased after initiation of rituximab treatment (Figure 3G.d II-IV) without reaching significance presumably because of small patient numbers. Nineteen relapses (14%) were reported during follow-up in the rituximab cohort (NMDAR-AE: n = 13, 19%; LGI1-AE: n = 5, 20%; and CASPR2-AE: n = 1, 11%). Of note, only 6 relapses (5%) in the rituximab cohort occurred after rituximab treatment was started (NDMAR-AE: n = 3, 4%; LGI1-AE: n = 3; 12%) (Table 2). The other 13 relapses occurred before rituximab initiation. In the control cohort, 19 relapses (13%) occurred (NMDAR-AE: n = 7, 13%; LGI1-AE: n = 10, 31%; CASPR2-AE: n = 2, 14%), which was more frequent than those observed in the rituximab group after initiation of rituximab (p = 0.02) (Table 2). Finally, we performed a multivariate analysis for the rituximab cohort to identify factors associated with the extent of improvement as measured by the change in the mRS score from baseline to last follow-up. Most significantly, the AE subtype (NMDAR-AE) was associated with mRS score improvement, whereas rituximab dosage and duration were not significantly associated with an improved mRS score (Table 3). MRS score improvement was also observed for early initiation of rituximab treatment (≤60 days after initiation of first-line treatment), and a trend was observed for early initiation of first-line treatment (≤30 days after symptom onset). View inline View popup Table 3 Multivariate Analysis of the Outcome Discussion This study describes real-world data on rituximab usage in a large German cohort of patients with the most common AE subtypes. We confirm the following: (1) Rituximab is the most frequent second-line immunotherapy that is used in nearly half of all patients with AE in Germany. (2) Rituximab usage differs within AE subtypes with patients with NMDAR-AE most frequently and patients with GAD65 disease least frequently receiving rituximab. Treatment was in all cases initiated following prior first-line immunotherapy. Patients with NMDAR-AE and GAD65 disease were more likely to be treated with rituximab if they presented with more severe disease (decreased levels of consciousness and higher mRS). (3) Patients with NMDAR-AE were treated earlier and more often (54%) received a short-term rituximab treatment (<6 months) without repeated maintenance reinfusion than other AE subgroups. (4) The long-term outcome in patients with NMDAR-, LGI1-, and CASPR2-AE in the overall cohort was favorable with 91%, 80%, and 63% of the patients being able to function independently at last follow-up, respectively. (5) Although comparison of patients with and without rituximab treatment is prone to severity bias, we found some hints of a better outcome and fewer relapses in the former group: patients with NMDAR-AE treated with rituximab more often reached independent living at last follow-up although being affected more severely at baseline; patients with CASPR2-AE improved significantly better under rituximab treatment; patients with NMDAR-E and LGI1-AE experienced fewer relapses if treated with rituximab. (6) No significant improvement during follow-up of patients with GAD65 disease was observed both in the rituximab cohort and in the control cohort. However, although we did not observe a group effect in GAD65 disease, some individuals showed a remarkable response associated with B cell–depleting treatment. In NMDAR-AE, treatment with rituximab is widely accepted. It has been used empirically since the first description of NMDAR-AE, and a large prospective case series4 and a systematic review21 could add further evidence that early second-line immunotherapy in patients not responding sufficiently to first-line immunotherapy was associated with better outcomes and fewer relapses. Recently, a meta-analysis of 14 retrospective and prospective case series summarizing 277 patients with AE (88.8% NMDAR-AE) concluded that rituximab is an effective second-line agent with an acceptable toxicity profile.19 Our data confirm and extend these observations. We found patients with NMDAR-AE treated with rituximab to have a favorable outcome. As patients treated with induction or maintenance therapy did not significantly differ in the outcome, our data support the notion that in many patients with NMDAR-AE, short-term rituximab treatment might be sufficient to control the disease. In a recent position paper by the Autoimmune Encephalitis Alliance Clinicians Network,22 this is reflected by the recommendation to consider long-term rituximab treatment mainly in relapsing disease. Compared with NMDAR-AE, considerably less information on long-term immunosuppression and especially rituximab is available in other AE subtypes. For LGI1-AE, early initiation of any immune therapy was associated with better outcomes in studies with 297 and 13 patients,23 respectively. Only few patients were treated with rituximab in retrospective case series19,24,25 and a small open-label trial.26 In our cohort, we observed a surprisingly favorable outcome in patients with LGI1-AE, with 80% reaching independent living (mRS score ≤2) (83% in the rituximab cohort and 78% in the control cohort). A systematic review21 showed full recovery or an mRS score of 0 in 27.8% of patients, with 8% of patients treated with rituximab and 18% of patients receiving second-line treatment. In light of these findings, we believe that rituximab treatment can be considered early in patients with LGI1-AE as 1 possible immunosuppressive treatment, although the duration of therapy is unclear. Relapses occurred in 16% of patients with NMDAR-AE and 26% with LGI1-AE in our overall cohort. Previously, relapses were reported in 11.2% (85/758) of patients with NMDAR-AE and 18.8% (16/85) with LGI1-AE.21 However, we did observe a reduced rate of relapses in patients with NMDAR-AE and LGI1-AE treated with rituximab compared with patients without (independent of other second-line immunotherapies) suggesting better efficacy of rituximab in preventing relapses compared with other regimens. Nevertheless, this should be interpreted with caution because absolute patient numbers are small and controlled studies missing. For the treatment of CASPR2-AE, even less evidence exists. In our series, 44% of patients with CASPR2-AE (n = 11) were treated with rituximab albeit considerably later than patients with NMDAR-AE. We could show significant improvement in patients with CASPR2-AE treated with rituximab, which was not observed in the control group. Although patient numbers were small, our results suggest an effect of rituximab treatment in CASPR2-AE but also indicate the need for larger numbers. Immunotherapeutic strategies for GAD65-AE remain highly controversial.27 Most patients are considered to require immunotherapy, and early immunotherapy has been found to be associated with a better outcome.10,28 However, the different neurologic manifestations of SPS, CA, and LE appear to respond differently to treatments.27 Treatment of SPS with IVIG has been examined in a small crossover placebo-controlled trial in 16 patients with SPS11 and showed efficacy in approximately 80% of patients. The use of plasma exchange and corticosteroids was linked to ambiguous clinical responses,29,30 and immunosuppressive agents such as azathioprine, methotrexate, cyclophosphamide, and mycophenolate mofetil are currently used in clinical practice, however, with insufficient evidence from larger clinical trials.30,31 Rituximab was examined in a randomized, placebo-controlled trial in 24 patients with GAD65-SPS yet surprisingly did not show significant effects, possibly because of the long disease duration at the time of treatment initiation (8.0 years).15 The long-term outcome in SPS in general was poor, with 40% of patients not responding to immunotherapy.32 Although small case series show a benefit from immunotherapy including rituximab in GAD65-CA in 41%–48% of cases,33,34 the long-term outcome is poor in approximately 65% of patients.10 Similarly, most patients with GAD65-LE continue to have seizures with or without immunotherapy.35,36 Our data are in line with these observations. Rituximab treatment was initiated very late after onset of symptoms in our patients, and we did not find a significant association with a better outcome in these patients. Yet, the functional level was better than expected with 67% of patients being able to live independently (mRS score ≤2) (52% in the rituximab group and 75% in the control group). In summary, our data support the notion that long-standing GAD65 disease does not respond to rituximab therapy. However, patients in early disease stages might be more likely to respond to rituximab treatment; however, response is difficult to predict, and a lack of response should trigger benefit-risk reevaluation of rituximab therapy. We analyzed data acquired by the GENERATE network, a multicenter registry for AE in Germany. Of note, all participating centers had experience in treatment of AE, and thus, our study is not necessarily representative for nonexpert centers or centers outside Germany. Further limitations of our study are the observational character going along with a severity bias when patients with and without rituximab treatment are compared and the difficulty to differentiate rituximab treatment effects from spontaneous improvements or improvements due to concomitant treatments, the incomplete follow-up data with potential selection bias, and the lack of clinical criteria defining response to first-line therapies. Nevertheless, because randomized trials are difficult to conduct in rare diseases such as AE, real-world data from registries add important information on treatment profiles and sequences and may lead to standardized treatment protocols. In addition, single-center bias is unlikely due to the multicenter approach. Analysis of auto-ab levels, B-cell counts, and biomarkers like serum neurofilament light chain concentration throughout treatment course could add to future studies investigating the response to rituximab treatment in AE. In addition, safety data should be captured systematically. Our results support the efficacy of early rituximab treatment in NMDAR-, LGI1-, and CASPR2-AE and suggest that short-term therapy could be a treatment option. They also suggest that patients with long-standing GAD65 disease are less likely to benefit from B-cell depletion than the other AE subgroups. Nevertheless, future controlled, randomized, and prospective studies in addition to national and supranational registries with collaborative research efforts are in dire need in the field of AE. As an example of such collaborative research, the multicentric, double-blinded, and placebo-controlled phase II study GENERATE-BOOST is currently investigating the response to bortezomib in patients with severe AE. Study Funding This work was supported by the Else Kröner Fresenius Stiftung (2011_A154), the Gemeinnützige Hertie Stiftung, the Bundesministerium für Bildung und Forschung (CONNECT-GENERATE, 01GM1908), and the Munich Cluster for Systems Neurology (SyNergy). Disclosure The authors report no disclosures relevant to the manuscript. Go to Neurology.org/NN for full disclosures. Acknowledgment The authors thank the patients and relatives contributing by donating their pseudonymized data and biomaterials to the GENERATE network. Appendix 1 Authors Appendix 2 Coinvestigators Footnotes Go to Neurology.org/NN for full disclosures. Funding information is provided at the end of the article. F. Leypoldt and T. Kümpfel contributed equally to this work as co–senior authors. German Network for Research on Autoimmune Encephalitis (GENERATE) coinvestigators are listed in Appendix 2 at the end of the article. The Article Processing Charge was funded by the authors. Class of Evidence: NPub.org/coe Received February 12, 2021. Accepted in final form August 23, 2021. Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. References 1.↵Leypoldt F, Armangue T, Dalmau J. Autoimmune encephalopathies. Ann N Y Acad Sci. 2015;1338(1):94-114.OpenUrlCrossRefPubMed 2.↵Graus F, Titulaer MJ, Balu R, et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol. 2016;15(4):391-404.OpenUrlCrossRefPubMed 3.↵Dalmau J, Gleichman AJ, Hughes EG, et al. Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies. 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Autoimmune encephalitis: clinical presentation, investigation and treatment | SpringerLink

Autoimmune encephalitis: clinical presentation, investigation and treatment | SpringerLink | AntiNMDA | Scoop.it
Autoimmune encephalitis is an immune-mediated condition traditionally presenting with cognitive decline, seizures, psychiatric symptoms, and movement disorders. Despite an increasing number of implicated antibodies, the diagnosis of autoimmune encephalitis remains challenging because of the clinical overlap with a broad range of other neurological conditions. This month’s journal club explores three papers relating to clinical presentation, investigation and treatment options for refractory autoimmune encephalitis. The first paper is a cohort study evaluating resemblance in clinical presentation and ancillary testing between autoimmune encephalitis and neurodegenerative syndromes. The second paper is a multicentre retrospective review of patients with autoimmune encephalitis who underwent continuous EEG monitoring and propose the presence of a signature EEG pattern for NMDA encephalitis. The third paper describes the use of a Janus kinase inhibitor in the management of refractory cases of autoimmune encephalitis. Autoimmune encephalitis resembling dementia syndromes Autoimmune encephalitis can mimic neurodegenerative dementia syndromes, which may result in misdiagnosis and delayed immunotherapy. The aim of this study was to evaluate dementia symptoms in confirmed cased of autoimmune encephalitis and identify red flag features for autoimmune encephalitis in middle-aged and elderly patients. In this observational cohort study, patients with anti-leucine-rich glioma-inactivated 1 (LGI1), anti-N-Methyl-D-aspartic acid receptor (NMDA-R), anti-gamma-aminobutyric acid B receptor (GABA-B-R) or anti-contactin-associated protein-like 2 (CASPR-2) encephalitis were included. The authors state that these are the most common antibodies causing autoimmune encephalitis, with cognition frequently affected in these subtypes. Patients were identified between 1999 and 2019 through the department of neurology of the Erasmus University Centre in Denmark, which is the national referral site for patients with autoimmune encephalitis. Patients diagnosed with autoimmune encephalitis over the age of 45, who fulfilled internationally accepted dementia criteria (2011 NINCDS-ADRDA), and had no prominent seizures early in the disease course, were invited to participate (n = 67). Data were obtained regarding the clinical phenotype, diagnostic workup, and where possible, CSF biomarkers relating to neurodegenerative syndromes. Of the 67 patients included in the study, 42 had anti-LGI1 encephalitis, 13 anti-NMDA-R encephalitis, 8 anti-GABA-B-R encephalitis, and 4 anti-CASPR-2 encephalitis. Patient with CASPR-2 encephalitis were excluded from statistical analysis and described exploratively due to the small number. 98% of 63 (n = 62) patients had cognitive deterioration, and 87% (n = 55) had behavioural changes. There was a rapidly progressive deterioration of cognitive symptoms in 76% (n = 48) of patients. A neurodegenerative syndrome was suspected in 52% (n = 33) of cases. Patients with anti-LGI1 and anti-GABA-R demonstrated impairment of visuospatial and executive functions, while patients with anti-NMDA-R encephalitis exhibited impaired language function, behavioural change and movement disorders. 64% (n = 40) of patients developed seizures during the disease course. Of those, 28% had developed subtle seizures which were missed in the first weeks of disease onset; the most subtle seizures were seen in anti-LGI-1 encephalitis. Normal routine CSF results and an absence of mesial temporal lobe abnormality was found in 53% and 54% of patients respectively. CSF was most frequently normal in LGI1 encephalitis (76%, p ˂ 0.0001). 14 patients were considered to have a CSF biomarker profile in keeping with Alzheimer’s disease or Creutzfeldt–Jakob disease. Comment. This study highlights the prominence of dementia symptoms in several subtypes of autoimmune encephalitis. Investigation in autoimmune encephalitis can often be normal and CSF biomarkers in autoimmune encephalitis can closely resemble a dementia syndrome. Rapidly progressive cognitive decline, seizures and evidence of neuroinflammation in ancillary testing were identified as ‘red flag’ features for autoimmune encephalitis. Subtle brachio-facial-dystonic seizures were commonly missed in early anti-LGI1 encephalitis. Strengths of this study include the national recruitment of a broad range of encephalitis subtypes, and availability of CSF data. A larger study looking at antibody prevalence and response to immunotherapy in patients with presumed dementia may consolidate these findings. Bastiaansen et al. (2021) Neur Neurimmunol Nuroinflamm. https://doi.org/10.1212/NXI.0000000000001039 Continuous EEG findings in autoimmune encephalitis Seizures are a common clinical feature of autoimmune encephalitis. This study describes the findings of continuous EEG monitoring in autoimmune encephalitis. This was a retrospective review of 400 patients identified through a code search for the diagnosis “encephalitis”. Adult patients who presented to hospital with symptoms consistent with autoimmune encephalitis and underwent at least 6 h of continuous EEG monitoring were recruited. The decision to perform EEG monitoring was made by the treating team. Patients with known central nervous system infection, malignancy, brain injury or known seizure disorder were excluded from the study. Of 64 patients, 43 had antibody-proven autoimmune encephalitis with subtypes as follows: NMDA (n = 17, 27%), voltage-gated potassium channel (VGKC) (n = 16, 25%), glutamic acid decarboxylase (GAD) (N = 6, 9%) and other (n = 4, 6%). The remaining patients were classed as probable antibody-negative autoimmune encephalitis (n = 11, 17%), definite antibody-negative limbic encephalitis (n = 2, 3%) and Hashimoto’s encephalopathy (n = 8, 13%). The diagnosis of antibody-negative autoimmune encephalitis was made using previously published criteria. EEG reports were reviewed retrospectively and noted for the presence of periodic or rhythmic patterns, focal or generalised seizure activity, seizure type, and the presence of new onset refractory status. EEG patterns were coded according to the American Clinical Neurophysiology Society critical care EEG nomenclature. There were no statistically significant differences between autoimmune encephalitis subtypes with regards to demographics, clinical features, radiographic findings, CSF findings, rates of non-convulsive status or outcomes at discharge. There was a high incidence (54%) of electrographic seizures in the study group. New onset refractory status epilepticus was seen in 19% of all patients. Generalised rhythmic delta activity (GDRA) was identified significantly more often in anti-NMDA receptor encephalitis (p = 0.0001), in fact anti-NMDA receptor encephalitis was the only subtype that demonstrated GRDA plus fast (GDRA + F) subtype (p = 0.0001). No specific EEG findings were identified in association with any other antibody causing autoimmune encephalitis. The presence of non-convulsive status conferred the highest risk of a poor outcome. The presence of GDRA did not correlate to a poor outcome in this study. Comment. The authors suggest that GRDA + F is synonymous with the extreme delta brush (EDB) pattern previously reported as characteristic of NMDA encephalitis and conclude that this pattern is a useful biomarker for NMDA encephalitis. Limitations of this study include the small numbers of autoimmune encephalitis subtypes, and unclear definitions of some antibody-negative subtypes. EEG review was also retrospective, and a limited range of EEG outcomes were assessed, and assessment of interrater reliability was not available. Moise et al. (2021) J Clin Neurophysiol. https://doi.org/10.1097/WNP.0000000000000654 Tofacitinib treatment for refractory autoimmune encephalitis Tofacitinib is a Janus kinase inhibitor with effective penetration of the blood–brain barrier, already in use in refractory rheumatoid arthritis and ulcerative colitis. This paper describes outcomes in eight patients with refractory autoimmune neurological syndromes treated with Tofacitinib who did not previously respond to conventional immunotherapy. A total of eight patients were treated with Tofacitinib. Two patients had NMDA-R antibodies, one had anti-GAD antibodies and one had myelin-oligodendrocyte glycoprotein (MOG) antibodies. Four patients had no detectable antibodies. The clinical syndromes for these patients comprised limbic encephalitis (n = 4), rhombencephalitis (n = 2), stiff-person syndrome (n = 1) and non-convulsive status (n = 1). All patients previously had an unclear response to steroids, immunoglobulin therapy, and a range of steroid-sparing agents. Tofacitinib was administered at 5 mg twice daily. Patient outcomes were assessed using a number of assessment tools including the modified Rankin scale. The treatment efficacy of Tofacitinib was assessed as good in two patients and partial in three patients. There was no response in three patients. The two patients with favourable responses are described. One patient had a chronic meningoencephalitis refractory to steroids, immunoglobulin therapy and steroid-sparing agents, which responded clinically and radiologically to Tofacitinib administered over a month. The second case of non-convulsive status with MOG antibodies refractory to anti-epileptic therapy and immunotherapy responded to Tofacitinib with cessation of epileptiform discharge 16 days post-administration. In the patients with partial response, Tofacitinib stopped the progression of active disease. Tofacitinib was well tolerated in six patients. One patient reported nausea, another had transient neutropenia necessitating withdrawal of Tofacitinib. Comment. This study describes a small case series of patients with a range of refractory neurological syndromes. Overall, Tofacitinib was well tolerated in seven out of eight patients, and six patients demonstrated a partial or good response. This is a promising initial report for the use of JAK inhibitors in a range of refractory autoimmune neurological conditions. Further studies with larger numbers of patients with confirmed antibody-mediated encephalitis would be helpful in determining optimal doses and duration of treatment. Jang et al. (2021) Epilepsia. https://doi.org/10.1111/epi.16848 Conclusion The three papers described in this month’s journal club allow us to improve our understanding of the presentation and management of autoimmune encephalitis, which should be considered early in cases of rapidly progressive dementia with seizures. Furthermore, EEG signatures may be characteristic of autoimmune encephalitis subtypes, with encouraging reports emerging for targeted immune treatment strategies. Author information Affiliations Department of Neurology, University Hospital of Wales, Heath Park, Cardiff, CF14 4XN, UK A. Al-Ansari Department of Neurology, Division of Psychological Medicine and Clinical Neuroscience, Cardiff University, University Hospital of Wales, Heath Park, Cardiff, CF14 4XN, UK N. P. Robertson Authors A. Al-Ansari View author publications You can also search for this author in PubMedGoogle Scholar N. P. Robertson View author publications You can also search for this author in PubMedGoogle Scholar Corresponding author Correspondence to N. P. Robertson. Rights and permissions Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. Reprints and Permissions About this article Cite this article Al-Ansari, A., Robertson, N.P. Autoimmune encephalitis: clinical presentation, investigation and treatment. J Neurol 268, 3935–3937 (2021). https://doi.org/10.1007/s00415-021-10800-6 Download citation Accepted11 August 2021 Published21 September 2021 Issue DateOctober 2021 DOIhttps://doi.org/10.1007/s00415-021-10800-6
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Autoimmune encephalitis: clinical spectrum and management | Practical Neurology

Autoimmune encephalitis: clinical spectrum and management | Practical Neurology | AntiNMDA | Scoop.it
Introduction Autoimmune encephalitis comprises a group of disorders in which the host immune system targets self-antigens expressed in the central nervous system (CNS).1 Some of the best-characterised diseases are associated with autoantibodies that target neuroglial antigens (table 1). These autoantibodies are considered pathogenic because they are directed against the extracellular—and hence in vivo exposed—domains of their target antigens.2–4 This fundamental property has led to much interest and excitement surrounding this rapidly expanding field, with new autoantibody targets described most years. Many established antigens are key synaptic proteins, ion channels or receptors, meaning that the extracellular domain-targeting autoantibodies are likely to directly modulate critical physiological processes. VIEW INLINE VIEW POPUP Table 1 Demographic, clinical and paraclinical features of neuronal autoantibody syndromes This field is of major clinical importance to all neurologists because these patients present with a wide variety of neurological features and typically respond to immunotherapies. Therefore, these conditions are often considered ‘not to miss’ diagnoses, with defined pathogenic agents that can present to cognitive, movement disorder, epilepsy, psychiatry and peripheral nerve clinics. In this pragmatic review, which reflects our experience of managing >200 cases with surface-directed autoantibodies, we highlight key clinical features to help identify these patients, outline immunological findings that inform laboratory testing and describe the clinically relevant disease biology of relevance to treatment decisions. Autoimmune encephalitis is not rare Until the discovery of neuroglial surface autoantibodies, infections were the most common known causes of encephalitis. However, over the last 20 years, the description of multiple autoantibodies targeting the extracellular domains of neuroglial proteins in patients with encephalitis has shifted this balance. For example, the California Encephalitis Project found that among persons under 30 years of age, N-methyl-D-aspartate receptor (NMDAR)-antibody encephalitis was more common than any individual infectious cause of encephalitis.5 Also, autoimmune causes of encephalitis have been reported to be at least as common as viral causes in Olmsted County, USA.6 Interestingly, the incidence of autoimmune encephalitis rose in the second 10-year epoch of this study, likely owing to growing awareness of these disorders and more widespread diagnostic capacities. Nevertheless, as fever, focal neurological deficits and cerebrospinal fluid (CSF) lymphocytosis remain inclusion criteria for many ‘all cause encephalitis’ studies, such approaches likely continue to underestimate the prevalence of autoimmune causes, which often lack these features.7 In future, we predict that unbiased surveys in patients with encephalitis will show that the growing range of autoimmune causes significantly exceed those of infectious causes in developed countries. Distinctive clinical manifestations of individual autoimmune encephalitides While the clinical features of these disorders span the spectrum of neurological symptomatology, for patients with autoantibodies against any individual target there is often a characteristic set of core phenotypic manifestations, which may relate to the regional expression, function and relative susceptibility of the target protein. Table 1 summarises the most common such syndromes on a ‘per target’ basis. By way of generalisation, autoantibody-mediated disorders often present rapidly, over a few days to weeks. However, we have observed more chronic courses, of between 1 and 5 years, particularly in leucine-rich glioma-inactivated protein 1 (LGI1)-antibody, contact-associated protein 2 (CASPR2)-antibody and immunoglobulin-like cell-adhesion molecule 5 (IgLON5)-antibody syndromes. These findings mean that time to disease nadir is often outside of the 3-month duration which appears in diagnostic guidelines.8 In our clinical experience, these more insidious courses—which are sometimes more akin to neurodegenerative presentations than florid encephalitis syndromes—often lead to a delayed diagnosis, and hence late commencement of immunotherapy. In patients with more acute-onset, dramatic presentations the diagnosis tends to be considered early but immunotherapy may still be delayed while excluding differentials and awaiting autoantibody test results. While tumours, prion disease and metabolic disorders are often in the differential diagnosis, a pragmatic trial of immunotherapy may only be absolutely contraindicated in the setting of some infections. Yet, observational data show that corticosteroids may be beneficial in some forms of herpes simplex virus (HSV) encephalitis, suggesting this may not be a universal contraindication.9 To encourage earlier immunotherapy administration to these patients, we have set out below some ‘identifying’ clinical findings that we find valuable in everyday autoimmune neurology practice (figure 1). Some features are so characteristic of certain antibody syndromes that they serve as essentially pathognomonic clues to the underlying autoantibody. Later, we describe the dominant presenting features, and relate these to individual syndromes. Figure 1 Classic syndromes and characteristic features of neuronal autoantibodies. Listed in an estimated order of descending frequency. AMPAR, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; CASPR2, contact-associated protein 2; DPPX, dipeptidyl peptidase-like protein 6; GABAA/BR, gamma aminobutyric acid; IgLON5, immunoglobulin-like cell-adhesion molecule 5; LGI1, leucine-rich glioma inactivated protein 1; NMDAR, N-methyl-D-aspartate receptor; MOG, myelin-oligodendrocyte glycoprotein. Psychiatric/behavioural Psychiatric symptoms such as aggression, irritability, mood lability, hallucinations and marked disturbance in sleep/wake cycles may occur in many of these patients across the spectrum of autoimmune encephalitis, and are especially notable in NMDAR-antibody and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor-antibody syndromes. In adult-onset NMDAR-antibody encephalitis, psychiatric features are typically the presenting complaint, with patients often needing mental health assessments before a neurology consultation. In our experience, relatively isolated psychiatric features occur in these patients only at disease onset. Subsequently, within a few days, they are rapidly accompanied by more traditional neurological abnormalities including delirium, amnesia and seizures. Nevertheless, careful consideration of the psychopathology can help in differentiating NMDAR-antibody encephalitis from primary psychiatric disease. NMDAR-antibody encephalitis often presents with a complex phenotype spanning classically distinct psychiatric diagnostic categories, including domains of mood, psychosis, behaviour and catatonia, the latter also seen with gamma aminobutyric acid A receptors (GABAAR)-antibodies.10 By contrast, early ‘transdiagnostic’ presentations are unusual in most primary psychiatric diseases. Overall, the complex psychiatric phenotype at onset combined with polysymptomatic neurological disease and a polymorphic movement disorder, discussed in detail later, creates a multifaceted presentation highly characteristic of NMDAR-antibody encephalitis. These features contrast markedly to the poorly circumscribed clinical syndrome of neuropsychiatric systemic lupus erythematosus, in which NMDAR-antibodies have also been reported. However, by contrast to antibodies which target native neuronal surface epitopes, those from patients with neuropsychiatric systemic lupus erythematosus have been found to show intrinsic ‘stickiness’, which is not NMDAR-specific, and hence have limited diagnostic value.11 Cognition In the acute phase, many patients with encephalitis show disorientation, confusion, confabulation and amnesia, features that may relate to the dense expression of many autoantigens in limbic structures, particularly the hippocampus. Patients with LGI1-antibody and NMDAR-antibody syndromes, and other forms of limbic encephalitis, often experience a dense amnesia for the period of acute hospitalisation, especially the nadir of their disease. Some patients and relatives consider this fortuitous due to several, inevitably distressing, events typical of their hospital stays. In LGI1-antibody encephalitis, the amnesia characteristically affects both anterograde memories plus a loss of autobiographical retrograde epochs.12 13 Comparative neuropsychological analyses are pending in the other forms of autoimmune encephalitis. Seizures Seizures occur in most autoimmune encephalitis syndromes and are a common factor that triggers neurological attention. The types and frequencies of seizure vary between autoantibody-mediated diseases and may help pinpoint the individual autoantibody. In LGI1-antibody encephalitis, the seizure profile is especially well-characterised. These patients, typically men in their fifth to eighth decades, have very frequent focal events with multiple semiologies and only rare generalised seizures. The pathognomonic faciobrachial dystonic seizures are frequent, brief events with posturing of the ipsilateral face and arm that often occur hundreds of times per day.14 15 Also, the leg may be involved and the sudden leg spasms often precipitate falls. In addition, patients with LGI1-antibodies may have short-lived, and again frequent, piloerection seizures and experience paroxysmal dizziness spells.16 From our experience, paroxysmal dizziness spells are likely ictal events characterised by frequent, intense episodic dizziness without vertigo or electroencephalographic correlates. In these patients, other focal seizure semiologies include more classical temporal lobe events, with rising epigastric phenomenon, sudden onset fear or panic, and déjà-vu or jamais-vu. As many of these are very short lived, they may be subtle and their detection often requires direct questioning of patients and relatives. Although not as well-characterised as the seizures associated with LGI1-antibodies, CASPR2-antibody encephalitis is also associated with frequent focal seizures and rare generalised seizures.16 However, we have not observed faciobrachial dystonic seizures and paroxysmal dizziness spells in the CASPR2-antibody patients, whose seizure semiology awaits further characterisation. Myelin oligodendrocyte glycoprotein (MOG) antibodies are associated with relapsing syndromes involving brainstem or cortical encephalitis, sometimes with optic neuritis and transverse myelitis, which particularly involve children and young adults. Seizures may present as the index event and the syndrome can evolve to a more diffuse encephalitis, including one which radiologically mimics classical acute disseminated encephalomyelitis. Patients typically respond well to corticosteroid therapies, although the duration of their administration remains controversial as relapses are common.17–19 This presentation is rare; in our practice, we have seen one case of MOG-antibody related encephalitis alongside >200 other patients with autoimmune encephalitis. Status epilepticus may occur in autoimmune encephalitis and is most frequent in patients with antibodies to the GABAAR/GABABR. Patients with GABAAR-antibody encephalitis frequently have distinctive neuroimaging with cortical and subcortical T2/FLAIR signal on MRI affecting two or more brain regions.20 21 In our experience, these multiple ‘fluffy’ lesions appear to be a characteristic feature; their presence consistently associated with GABAAR-antibody positivity. Patients with GABABR-antibodies are typically in around their sixth decade of life and commonly present with an acute limbic encephalitis. More rarely, they have a prolonged time course, characterised as a rapidly progressive dementia.22 Detection of GABABR-antibodies should prompt a search for malignancy, with tumours in ~50% of patients (most commonly small cell lung cancer). Although patients with NMDAR-antibody encephalitis often have few seizures, it is sometimes an ictal event that prompts consideration of diagnoses outside the realm of primary psychiatric disease. One important question is whether testing these autoantibodies benefits a broader population of people with epilepsy. To date, studies have yielded highly divergent positivity rates for autoantibodies in a variety of patients with seizures. However, only recently have studies combined accurate clinical phenotyping with the autoantibody results in unselected populations.23 24 These largely concur with our routine clinical experience: patients who have unselected new-onset seizures, neuronal surface autoantibodies and an immunotherapy-responsive syndrome typically have mild features of autoimmune encephalitis, such as cognitive and mood features, specific seizure semiologies, dysautonomia and limbic MRI changes. This clinically-driven assessment approach aims to limit unfruitful or equivocal immunotherapy trials in patients attending epilepsy clinics. Movement disorders The autoimmune encephalitis syndromes may show a diverse spectrum of movement disorder phenomenologies. In keeping with the complex nature of NMDAR-antibody encephalitis, the associated movement disorder is typically polymorphic, defying classification into classical movement disorder taxonomies.25 26 Most characteristically, patients have combinations of chorea, stereotypies and dystonia, with limited tremor, which affect all limbs and—most characteristically—the face and mouth. Encephalitis syndromes associated with both glycine receptor (GlyR) and dipeptidyl peptidase-like protein 6 (DPPX) antibodies are characterised by hyperekplexia and myoclonus;27 28 however, accompanying features, such as marked rigidity and falls in GlyR-antibody encephalitis and prominent diarrhoea in DPPX-antibody encephalitis, can usually differentiate these entities. Although not typically associated with a movement disorder, chorea is rare in LGI1-antibody encephalitis.29 Gait disturbances are frequent in CASPR2- and IgLON5-antibody syndromes.30–32 IgLON5-antibody disease is associated with a polymorphic sleep disturbance plus progressive supranuclear palsy-like picture with axial rigidity and gait freezing, whereas CASPR2-antibody disease typically has a gait disturbance secondary to episodic or persistent ataxia. Indeed, ataxia helps to differentiate CASPR2- from LGI1-antibody syndromes but, as with psychiatric features and seizures, is rarely the sole clinical manifestation. Dysautonomia Dysautonomia is a common feature to many of these disorders. These symptoms are typically progressive through the initial disease course and can be life-threatening, requiring close monitoring. Particularly in NMDAR-antibody encephalitis, wide fluctuations in blood pressure and tachy-arrhythmias or brady-arrhythmias are key features that often prompt us to consult with colleagues in intensive care and cardiology. Occasionally, temporary pacing is appropriate. Other autonomic involvement includes orthostatic hypotension, constipation and abnormal sudomotor function. Pain In our experience, pain is under-recognised in the autoimmune encephalitis syndromes particularly in patients with autoantibodies to CASPR2. In this disease, ~60% of patients report pain.16 30 It can occur in the context of a peripheral nerve hyperexcitability syndrome (neuromyotonia, fasciculations, cramps and myokymia) but—more commonly—develops without peripheral motor nerve involvement (Ramanathan, Uy, Bennett and Irani, in revisions). Pain is also less common with LGI1-antibodies.16 33 In addition, patients with GlyR-antibodies often complaint of allodynia, dysaesthesia and prominent pruritus.28 In all these groups, our experience is that pain may respond partially to immunotherapy but often persists. This area merits more detailed future studies. Differential diagnoses Clinicians need to consider a broad differential diagnosis to reflect the spectrum of neurological phenomenology in autoimmune encephalitis. Here we outline a few considerations that apply in each of several clinical situations. Infectious encephalitis (most commonly HSV): often presents with seizures as well as fever, focal neurology and more extensive imaging changes than in autoimmune encephalitis. Temporal lobe glioma in cases with mesial temporal swelling: semiologies can overlap but autoimmune encephalitis usually has a less abrupt onset and interval imaging swelling on imaging typically resolves with treatment on interval imaging. Creutzfeldt-Jakob disease and other rapid dementias: often remain a differential in more chronic cases, especially patients with LGI1-antibodies. However, in practice, the differences in clinical features, CSF and imaging mean that distinguishing these is usually straightforward. Post-ictal MRI changes in patients with frequent seizures can often mimic autoimmune encephalitis in the acute phase. Metabolic encephalopathies: usually delirium dominates the clinical picture. Hashimoto’s encephalopathy: fundamentally a difficult diagnosis to make as definitions remain unclear. New autoantibody discoveries may better describe many cases once termed ‘Hashimoto’s’.34 Clinical management Symptomatic considerations In addition to treatment of the underlying immunological process, it is often necessary to consider management of seizures, movement disorders, behaviour, pain, sleep and autonomic disturbance, and mood disorders. We do not discuss this substantial topic comprehensively here but rather we focus on special considerations relevant to the two most common forms of autoimmune encephalitis: NMDAR-antibody and LGI1-antibody encephalitis. The overlap in clinical features between NMDAR-antibody encephalitis and neuroleptic malignant syndrome has led some to hypothesise that patients with NMDAR-antibody encephalitis have hypersensitivity to neuroleptic agents, with an increased risk of developing neuroleptic malignant syndrome.35–38 Hence, we judiciously use antipsychotic medications for behavioural symptom management, injury prevention and to facilitate care, often once daily olanzapine 10 mg. Alternatively, we find benzodiazepines are effective, although often at high doses (sometimes up to 180 mg/day of diazepam), for treating both behavioural symptoms and some dyskinesias.39 We frequently liaise closely with neuropsychiatry colleagues to manage behavioural features. As discussed earlier, seizures are a common presenting feature among the autoimmune encephalitis syndromes. However, from 103 patients with LGI1-antibody encephalitis, antiseizure medications alone stopped faciobrachial dystonic seizures in only 10%. By contrast, faciobrachial dystonic seizures stopped within 30 days of starting immunotherapy in 51%, rising to 88% by 90 days.40 The same principle appears increasingly true for seizures associated with multiple forms of autoimmune encephalitis.41 Thus, it is imperative for appropriate and timely treatment to recognise an underlying autoimmune encephalitis syndrome. Furthermore, patients with LGI1-antibody disease are at higher risk of cutaneous reactions and Stevens-Johnson syndrome with antiseizure medications. Therefore, not only is antiseizure medication use likely to be ineffective but may also result in iatrogenic adverse events. Whenever possible, we prioritise optimisation of immunotherapy in these patients and increasingly reserve antiseizure medications only for generalised convulsions or instances where the seizure semiology is likely to cause injury. After improvements on immunotherapy, discussed later, patients often ask about the risk of ongoing seizures. Indeed, epilepsy is defined as a tendency to enduring seizures. So, it is of interest that few patients in recent autoimmune encephalitis cohorts developed epilepsy after the acute illness.41 42 This observation suggests lifelong antiseizure therapy may not be necessary in many cases. In seizure-free patients keen to stop antiseizure medications, we discuss a trial of weaning including the possible complications of long-term antiseizure medications (eg, osteoporosis, patient choice) and implications for driving. Early immunotherapy improves outcomes The importance of early recognition and diagnosis in autoimmune encephalitis is paramount to the ultimate goal of optimal immunotherapy. Although there are no specific data available for all autoantibody-mediated encephalitis syndromes, the two most common forms of autoimmune encephalitis are clear exemplars where improved patient outcomes associate with early immunotherapy. In LGI1-antibody encephalitis, ~80% of patients noticed that faciobrachial dystonic seizures typically precede onset of marked cognitive impairment. Given that immunotherapy is more effective than antiseizure medications in treating LGI1-antibody-associated seizures, early treatment with immunotherapy has shown great promise for preventing otherwise incipient cognitive impairment and functional disability.40 In NMDAR-antibody encephalitis, early treatment independently predicted good outcome (modified Rankin score ≤ 2) whereas delays in immunotherapy of >4 weeks were associated with poor functional outcomes at 1 year.43 44 In NMDAR-antibody encephalitis, teratoma removal is a key step in both acute treatment and relapse prevention.43 It is considered of equivalent efficacy to other individual first-line immunotherapies, likely because the teratoma is a germinal centre harbouring NMDAR-reactive B cells.45 Men and children tend to have non-paraneoplastic disease. Half of adult female patients are diagnosed with ovarian teratomas. So, especially in these cases, pelvic imaging should be performed, and small or equivocal findings carefully followed up and investigated thoroughly. Repeat serial imaging may be considered in cases where a teratoma is suspected and a clinical relapse should certainly prompt re-investigation. We are familiar with patients in whom the teratoma has been radiologically (mis-)interpreted as a luteal or haemorrhagic cyst. However, overall, most patients do not have a detectable teratoma, meaning that in all cases immunotherapy should not be delayed. Also, in our experiences, empirical oophorectomy is low yield for a microscopic teratoma. There are several options for acute and long-term immunotherapies in both the inpatient and outpatient settings (table 2). Initial inpatient therapy often involves corticosteroids, intravenous immunoglobulins and/or plasma exchange. While awaiting autoantibody results, we start first-line immunotherapy when we are clinically confident of the diagnosis. Second-line therapies include rituximab, cyclophosphamide and other corticosteroid-sparing agents. Choice of initial therapy should balance the risk profile of the intervention and the severity/trajectory of the individual patient’s disease course. VIEW INLINE VIEW POPUP Table 2 Immunotherapeutic options for treatment of autoimmune encephalitis In our experience, intravenous corticosteroids are generically highly effective agents, so relative contraindications (eg, pre-existing diabetes or psychiatric diseases) are often carefully managed in the acute phase but rarely considered absolute contraindications. We also find plasma exchange to be very effective, often used if patients show a limited or inadequate response to corticosteroids, or for patients with a rapid deterioration whose trajectory may otherwise be intensive care unit admission. While intravenous immunoglobulin is the only immunotherapy with randomised data to support its use,46 in practice it appears the least effective of the three conventional first-line interventions. This observation is supported by the minimal effect size observed in this inaugural randomised control trial. Below, we discuss our more specific management approaches to the two most common autoantibody-mediated syndromes. NMDAR-antibody encephalitis Due to its associated high-morbidity and mortality, potential for months of hospitalisation and high rate of relapses, we favour early aggressive therapy in patients with NMDAR-antibody encephalitis. Teratoma removal and first-line immunotherapies are routine interventions: typically, 3–5 days of 1 g intravenous methylprednisolone daily, plus plasma exchange. Second-line immunotherapies reduce the relapse risk and, from our clinical observations, expedite recoveries and time to discharge.43 Our threshold to escalate to second-line therapy is increasingly low, with >70% of our patients receiving cyclophosphamide or rituximab if awareness and behaviour have not improved within 2 weeks. As outpatients, we tend not to employ a prolonged course of oral corticosteroids, especially if second-line therapy or tumour removal appears to be having the desired effect. This approach appears to associate with a <5% rate of relapses, to date. If second-line immunotherapy is not administered during initial episode, it should be strongly considered in relapses. LGI1-antibody encephalitis For this condition, we favour first-line treatment with high-dose intravenous or oral corticosteroids. We have an increasingly low threshold for plasma exchange at disease onset, particularly in patients with greater degrees of impairment. In our experience, oral prednisolone should be maintained for around 24–36 months, as shorter durations of corticosteroids are often associated with relapses.14 We typically taper oral prednisolone from 50 to 60 mg for the first 2–4 months to around 20–30 mg by 12 months, with a slow taper thereafter. In elderly patients, this approach does inevitably induce some glucocorticoid side effects that need to be carefully considered. However, in our experience, despite corticosteroid-sparing agents (mainly mycophenolate mofetil) more rapid steroid tapers tend to result in relapse. A few patients who require cyclophosphamide show variable outcomes. By contrast, rituximab appears more effective but longer-term follow-up is awaited. Molecular discoveries provide clinical insights The ability to detect CNS-directed autoantibodies that target the extracellular domains of neuroglial proteins has revolutionised our ability to diagnose and classify this nascent group of autoantibody-mediated disorders. The confident detection of a causative autoantibody has implications for the treatment regimen and may help focus a search for associated malignancies or surveillance for associated complications. Moreover, an understanding of the basic immunobiology helps to appreciate nuances around diagnostic testing, suspected mechanisms of pathogenesis and offer a rationale for administration of therapies. As these diseases are associated with pathogenic autoantibodies, a focus on the B cell immunobiology may be the key to understanding autoimmune encephalitis. A full discussion of the underlying immunopathology is beyond the scope of this review and have been described elsewhere.2 Here, we discuss select concepts with the greatest clinical relevance. Therapeutic insights Autoantigen-specific B cells are probably first established peripherally before migrating into the CNS, as the pathogenic neuronal autoantibodies typically have ~50-fold higher concentrations in the serum than in CSF.2 Interestingly, this ratio holds true for patients in whom an infectious encephalitis (HSV encephalitis) is followed by an autoimmune form (NMDAR-antibody encephalitis). Therefore, even with a brain-specific trigger, the autoimmunity probably begins outside the CNS. Hence, the peripheral B cells that carry these self-reactivities need to evade tolerance checkpoints, a potential avenue for therapeutic interventions. Also, the B lineage cells that secrete these autoantibodies in the periphery are themselves a key therapeutic target. For example, studies that implicate CD20− long lived plasma cells as dominant producers of autoantibodies imply drugs such as bortezomib—by acting on the proteosome, which is especially active in plasma cells—may be effective treatments.47 Alternatively, emerging evidence suggests autoantibodies secreted by CD20+ B cells that have undergone recent germinal centre reactions may be a key source of these autoantibodies45 48: if this mechanism were dominant, rituximab administration might logically prove to be an especially effective option. A key factor in generating the mature antigen-specific B cells is their interaction with antigen-specific T cells. This occurs via the engagement of human leucocyte antigen (HLA) with the T-cell receptor. Hence, it remains of biological interest that >90% of patients with LGI1-antibodies carry the HLA-DRB1*07:01 allele, and that ~70% of the patients with CNS diseases and CASPR2-antibodies carry the HLA-DRB1*11:01 allele.49 T-cell directed therapies may be a future avenue for treatment in these patients. In addition, these findings may be of value in clinical practice: we have found the absence of these alleles as a useful adjunctive investigation to identify the few patients with LGI1-antibodies or CASPR2-antibodies who do not have an immunotherapy-responsive syndrome. Hence, genetic testing may become a reflexive test in these conditions. After B cell autoreactivities originate in the periphery, autoantibody access to the CNS is likely to play a major role in pathogenesis. Of course, fundamentally, the autoantibodies must gain access to the brain. But it remains poorly addressed as to whether they cross the blood–brain barrier as soluble immunoglobulins or are predominantly secreted by intrathecal B cells that have crossed the blood–brain barrier. In beginning to address this, recent studies show these patients have an enrichment of autoantigen-reactive B cells in the CSF, providing direct evidence of intrathecal autoantibody production.50 51 Hence, drugs that prevent lymphocyte transmigration into the CNS may yet be effective agents in these disorders. Diagnostics insights In addition, the biology around roles of peripheral and central compartments also has implications for diagnostic testing. Autoantibodies can be detected in both CSF and serum, and—put simply—both samples should be sent in all patients, wherever possible. However, there are important nuances between conditions. For example, LGI1-antibodies are not detected in around 50% of patient CSF samples.33 By contrast, NMDAR-antibodies are consistently detected in the CSF of patients and said to be absent in ~20% of serum samples. Finding autoantibodies in the CSF but not the serum does not seem biologically intuitive given the immunological response likely begins in the periphery, perhaps most clearly in patients with (systemic) ovarian teratomas. By comparison to serum, CSF has a ~500-fold lower total IgG concentration and hence offers a sample with inherently lower backgrounds in diagnostic assays, which may explain the above finding. Yet, in some patients, for example, those who are irritable, not suitable for sedation and in young children, serum may be the only pragmatic sample source. However, serum NMDAR-antibodies occur at ~3% rates in healthy and disease controls and hence so called ‘clinically irrelevant’ serum NMDAR-antibody results are not infrequent, again supporting the use of CSF for detecting NMDAR-antibodies. For these reasons, in this condition, the absence of CSF positivity is considered to indicate a lack of direct autoantibody pathogenicity. However, as described above, the opposite is true for LGI1-antibodies. Therefore, whenever possible, paired CSF-serum should be tested. When sending and interpreting results for CNS autoantibody testing, it is important to emphasise the clinical hypothesis. Clinicians interpreting these results should also take into account differences in sensitivity and specificity of individual autoantibody tests (figure 2). For example, several clinical laboratories use commercially available ‘fixed’ cell-based assay kits. These kits have limitations as they inherently alter the native antigens with fixation, creating non-physiological autoantigens.3 By contrast, live cell-based assays detect autoantibodies against the closest resemblance of the targets that would be encountered in vivo. Live cell-based assays are often more sensitive than fixed ones52–54; therefore, in the setting of an appropriate clinical syndrome, a negative test on fixed cell-based assay should raise suspicion of a false-negative result and clinicians should consider having these samples re-tested at a reference laboratory. Figure 2 Neuronal surface antibody detection methods. Current research and diagnostic methods expose the test sample to neuronal antigens which differ in the properties of the antigens. Cell-based assays aim largely to expose a single known antigen, by its expression in mammalian cells. Conversely, neurone-based assays and tissue-based assays expose multiple endogenous antigens, both those known to be targets of pathogenic antibodies and as yet unknown antigens. Additionally, the assays vary on whether the antigen was fixed before incubation with the patient sample (serum or cerebrospinal fluid) and whether the cell membrane is intact (‘live’). Live cell-based assays and live neurone-based assays neither fix the surface antigen nor permeabilise the membrane before exposure to the patient’s sample. By contrast, in fixed permeabilised cell-based assays and tissue-based assays, target antigens are potentially altered by fixation and cell membrane integrity is lost. Figure modified from Ramanathan et al.3 CBA, cell-based assay. ‘I’m sure this patient has an autoantibody’ We continue to see several patients with no known autoantibody, but a clinical syndrome compatible with autoimmune encephalitis. In these so called ‘seronegative’ cases, where there is a clinical suspicion of an autoantibody but no identified defined autoantigenic target, we aim to begin early immunotherapy whenever possible given that autoimmune encephalitis is a treatable syndrome. In parallel, we continue to re-evaluate possible alternative diagnoses but escalate therapy when autoimmune encephalitis is considered the likeliest cause. Various research-level tests can offer greater diagnostic clarity (figure 2).3 The patient sera/CSF can be applied to rodent brain sections to identify neuroglial reactivity and, perhaps, a distinctive binding pattern. This approach has been used in several instances as an initial step in target identification, but is also a valuable technique to simply diagnose a brain reactive autoantibody.55 As this method exposes patient autoantibodies to both intracellular and extracellular domains of neuroglial proteins, it does not exclusively detect pathogenic species. To define these, it is possible to assess reactivity of serum or CSF IgGs against the surface of cultured neurones or astrocytes. While time consuming to perform, binding patterns have provided valuable information for many patients with suspected autoantibody-mediated syndromes who were negative on available clinical assays. These tests are available on request from research laboratories. Closing remarks The recognition of neuronal surface autoantibodies as a cause of encephalitis has had far-reaching implications. It has helped to define a group of immunotherapy-responsive disorders, describe their pathogenesis, and develop therapies informed by these pathogenic mechanisms. Further, the scope of autoantibody-mediated diseases has expanded beyond the initial limbic encephalitis picture to include other polysymptomatic immunotherapy-responsive syndromes. Clinical suspicion of these disorders remains the cornerstone to their detection and there are now many clinically recognisable syndromes described. Interpretation of autoantibody results should similarly be in the context of this clinical picture. Earlier recognition, treatment and escalation of immunotherapy in many of these syndromes can lead to improved outcomes and reduced disability. Further reading Graus F, Titulaer MJ, Balu R, etal. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol 2016;15:391–404. doi:10.1016/S1474-4422(15)00401-9.A. Ramanathan S, Al-Diwani A, Waters P, etal. The autoantibody-mediated encephalitides: from clinical observations to molecular pathogenesis. J Neurol 2019;1–19. doi:10.1007/s00415-019-09590-9. SunB, Ramberger M, O’Connor KC, etal. The B cell immunobiology that underlies CNS autoantibody-mediated diseases. Nat Rev Neurol 2020;16:481–92. doi:10.1038/s41582-020-0381-z. Key points Autoimmune causes of encephalitis are at least as common as infectious causes and should be considered early. Several characteristic core phenotypic manifestations may strongly suggest an underlying autoantibody-mediated encephalitis; this should raise the consideration of empiric immunotherapy once infectious causes are reasonably excluded. Early immunotherapy improves outcomes in patients with autoimmune encephalitis. Whenever possible, paired cerebrospinal fluid and serum should be tested, and clinicians should emphasise the clinical hypothesis when interpreting the results. Brain sections and neuronal cultures are valuable methods to detect autoantibodies in patients who have a suspected autoimmune condition despite negative antigen-specific results. Ethics statements Patient consent for publication Obtained. References ↵ Dalmau J , Graus F . Antibody-Mediated encephalitis. N Engl J Med 2018;378:840–51.doi:10.1056/NEJMra1708712 pmid:http://www.ncbi.nlm.nih.gov/pubmed/29490181 OpenUrlCrossRefPubMed ↵ Sun B , Ramberger M , O'Connor KC , et al . The B cell immunobiology that underlies CNS autoantibody-mediated diseases. Nat Rev Neurol 2020;16:481–92.doi:10.1038/s41582-020-0381-z pmid:http://www.ncbi.nlm.nih.gov/pubmed/32724223 OpenUrlPubMed ↵ Ramanathan S , Al-Diwani A , Waters P , et al . The autoantibody-mediated encephalitides: from clinical observations to molecular pathogenesis. J Neurol 2021;268:1689–707.doi:10.1007/s00415-019-09590-9 pmid:http://www.ncbi.nlm.nih.gov/pubmed/31655889 OpenUrlPubMed ↵ Varley J , Taylor J , Irani SR . Autoantibody-mediated diseases of the CNS: structure, dysfunction and therapy. Neuropharmacology 2018;132:71–82.doi:10.1016/j.neuropharm.2017.04.046 pmid:http://www.ncbi.nlm.nih.gov/pubmed/28476644 OpenUrlPubMed ↵ Gable MS , Sheriff H , Dalmau J , et al . The frequency of autoimmune N-methyl-D-aspartate receptor encephalitis surpasses that of individual viral etiologies in young individuals enrolled in the California encephalitis project. Clin Infect Dis 2012;54:899–904.doi:10.1093/cid/cir1038 pmid:http://www.ncbi.nlm.nih.gov/pubmed/22281844 OpenUrlCrossRefPubMed ↵ Dubey D , Pittock SJ , Kelly CR , et al . Autoimmune encephalitis epidemiology and a comparison to infectious encephalitis. Ann Neurol 2018;83:166–77.doi:10.1002/ana.25131 pmid:http://www.ncbi.nlm.nih.gov/pubmed/29293273 OpenUrlCrossRefPubMed ↵ Granerod J , Ambrose HE , Davies NW , et al . Causes of encephalitis and differences in their clinical presentations in England: a multicentre, population-based prospective study. Lancet Infect Dis 2010;10:835–44.doi:10.1016/S1473-3099(10)70222-X pmid:http://www.ncbi.nlm.nih.gov/pubmed/20952256 ↵ Graus F , Titulaer MJ , Balu R , et al . A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol 2016;15:391–404.doi:10.1016/S1474-4422(15)00401-9 OpenUrlCrossRefPubMed ↵ Kamei S , Sekizawa T , Shiota H , et al . Evaluation of combination therapy using aciclovir and corticosteroid in adult patients with herpes simplex virus encephalitis. J Neurol Neurosurg Psychiatry 2005;76:1544–9.doi:10.1136/jnnp.2004.049676 pmid:http://www.ncbi.nlm.nih.gov/pubmed/16227548 ↵ 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;6:235–46.doi:10.1016/S2215-0366(19)30001-X pmid:http://www.ncbi.nlm.nih.gov/pubmed/30765329 OpenUrlPubMed ↵ Varley JA , Andersson M , Grant E , et al . Absence of neuronal autoantibodies in neuropsychiatric systemic lupus erythematosus. Ann Neurol 2020;88:1244–50.doi:10.1002/ana.25908 pmid:http://www.ncbi.nlm.nih.gov/pubmed/32951275 OpenUrlPubMed ↵ Miller TD , Chong TT-J , Aimola Davies AM , et al . Focal CA3 hippocampal subfield atrophy following LGI1 VGKC-complex antibody limbic encephalitis. Brain 2017;140:1212–9.doi:10.1093/brain/awx070 pmid:http://www.ncbi.nlm.nih.gov/pubmed/28369215 OpenUrlCrossRefPubMed ↵ Miller TD , Chong TT-J , Aimola Davies AM , Davies AMA , et al . Human hippocampal CA3 damage disrupts both recent and remote episodic memories. Elife 2020;9:1–47.doi:10.7554/eLife.41836 pmid:http://www.ncbi.nlm.nih.gov/pubmed/31976861 OpenUrlCrossRefPubMed ↵ Irani SR , Stagg CJ , Schott JM , et al . Faciobrachial dystonic seizures: the influence of immunotherapy on seizure control and prevention of cognitive impairment in a broadening phenotype. Brain 2013;136:3151–62.doi:10.1093/brain/awt212 pmid:http://www.ncbi.nlm.nih.gov/pubmed/24014519 ↵ Irani SR , Michell AW , Lang B , et al . Faciobrachial dystonic seizures precede LGI1 antibody limbic encephalitis. Ann Neurol 2011;69:892–900.doi:10.1002/ana.22307 pmid:http://www.ncbi.nlm.nih.gov/pubmed/21416487 ↵ Gadoth A , Pittock SJ , Dubey D , et al . Expanded phenotypes and outcomes among 256 LGI1/CASPR2-IgG-positive patients. Ann Neurol 2017;82:79–92.doi:10.1002/ana.24979 pmid:http://www.ncbi.nlm.nih.gov/pubmed/28628235 OpenUrlCrossRefPubMed ↵ Hamid SHM , Whittam D , Saviour M , et al . Seizures and encephalitis in myelin oligodendrocyte glycoprotein IgG disease vs aquaporin 4 IgG disease. JAMA Neurol 2018;75:65–71.doi:10.1001/jamaneurol.2017.3196 pmid:http://www.ncbi.nlm.nih.gov/pubmed/29131884 OpenUrlPubMed ↵ Ramanathan S , O'grady GL , Malone S , et al . Isolated seizures during the first episode of relapsing myelin oligodendrocyte glycoprotein antibody-associated demyelination in children. Dev Med Child Neurol 2019;61:610–4.doi:10.1111/dmcn.14032 pmid:http://www.ncbi.nlm.nih.gov/pubmed/30221764 OpenUrlPubMed ↵ Waters P , Fadda G , Woodhall M , et al . Serial anti-myelin oligodendrocyte glycoprotein antibody analyses and outcomes in children with demyelinating syndromes. JAMA Neurol 2020;77:82–93.doi:10.1001/jamaneurol.2019.2940 pmid:http://www.ncbi.nlm.nih.gov/pubmed/31545352 OpenUrlPubMed ↵ Petit-Pedrol M , Armangue T , Peng X , et al . Encephalitis with refractory seizures, status epilepticus, and antibodies to the GABAA receptor: a case series, characterisation of the antigen, and analysis of the effects of antibodies. Lancet Neurol 2014;13:276–86.doi:10.1016/S1474-4422(13)70299-0 pmid:http://www.ncbi.nlm.nih.gov/pubmed/24462240 ↵ Spatola M , Petit-Pedrol M , Simabukuro MM , Castro FJ , et al . Investigations in GABAA receptor antibody-associated encephalitis. Neurology 2017;88:1012–20.doi:10.1212/WNL.0000000000003713 pmid:http://www.ncbi.nlm.nih.gov/pubmed/28202703 OpenUrlPubMed ↵ Lancaster E , Lai M , Peng X , et al . 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Acta Neurol Scand 2020;141:263–70.doi:10.1111/ane.13207 pmid:http://www.ncbi.nlm.nih.gov/pubmed/31853949 OpenUrlPubMed ↵ Van SA , Thijs RD , Coenders EC . Anti-Lgi1 encephalitis: clinical sydrome and long-term follow-up. Neurology 2016;87:1149–456.OpenUrl ↵ Valencia-Sanchez C , Pittock SJ , Mead-Harvey C , et al . Brain dysfunction and thyroid antibodies: autoimmune diagnosis and misdiagnosis. Brain Commun 2021:fcaa233. doi:10.1093/braincomms/fcaa233 ↵ Wang H-Y , Li T , Li X-L , et al . Anti-N-methyl-D-aspartate receptor encephalitis mimics neuroleptic malignant syndrome: case report and literature review. Neuropsychiatr Dis Treat 2019;15:773–8.doi:10.2147/NDT.S195706 pmid:http://www.ncbi.nlm.nih.gov/pubmed/31040676 OpenUrlPubMed ↵ Caroff SN , Campbell EC . Risk of neuroleptic malignant syndrome in patients with NMDAR encephalitis. Neurol Sci 2015;36:479–80.doi:10.1007/s10072-014-2022-z pmid:http://www.ncbi.nlm.nih.gov/pubmed/25480349 OpenUrlPubMed ↵ Lejuste F , Thomas L , Picard G , et al . Neuroleptic intolerance in patients with anti-NMDAR encephalitis. Neurol Neuroimmunol Neuroinflamm 2016;3:e280.doi:10.1212/NXI.0000000000000280 pmid:http://www.ncbi.nlm.nih.gov/pubmed/27606355 ↵ Rozier M , Morita D , King M . Anti-N-Methyl-D-Aspartate receptor encephalitis: a potential mimic of neuroleptic malignant syndrome. Pediatr Neurol 2016;63:71–2.doi:10.1016/j.pediatrneurol.2016.03.023 pmid:http://www.ncbi.nlm.nih.gov/pubmed/27590992 OpenUrlPubMed ↵ Shin H-R , Jang Y , Shin Y-W , et al . High-Dose diazepam controls severe dyskinesia in anti-NMDA receptor encephalitis. Neurology 2020:10.1212/CPJ.0000000000001001. doi:10.1212/CPJ.0000000000001001 ↵ Thompson J , Bi M , Murchison AG , et al . The importance of early immunotherapy in patients with Faciobrachial dystonic seizures. 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Clinical Features and Outcomes in Pediatric Autoimmune Encephalitis Associated With CASPR2 Antibody

Clinical Features and Outcomes in Pediatric Autoimmune Encephalitis Associated With CASPR2 Antibody | AntiNMDA | Scoop.it
Background: Contactin-associated protein-like 2 (CASPR2) neurological autoimmunity has been associated with various clinical syndromes involving central and peripheral nervous system. CASPR2 antibody-associated autoimmune encephalitis is mostly reported ...
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Autoimmune epilepsy due to N-methyl-d-aspartate receptor antibodies in a child: a case report | Journal of Medical Case Reports | Full Text

Autoimmune epilepsy due to N-methyl-d-aspartate receptor antibodies in a child: a case report | Journal of Medical Case Reports | Full Text | AntiNMDA | Scoop.it
Introduction Seizures of autoimmune etiology may occur independent of or predate syndromes of encephalitis. We report a child with “pure” autoimmune epilepsy followed up for 7 years to highlight long-term effects of this epilepsy and the importance of early initiation and appropriate escalation of...
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Differentiation of viral and autoimmune central nervous system inflammation by kynurenine pathway - Luo - - Annals of Clinical and Translational Neurology

Differentiation of viral and autoimmune central nervous system inflammation by kynurenine pathway - Luo - - Annals of Clinical and Translational Neurology | AntiNMDA | Scoop.it
Abstract Objective To determine whether the metabolites of Kynurenine pathway (KP) could serve as biomarkers for distinguishing between viral CNS infections and autoimmune neuroinflammatory disease...
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Genome-wide Association Study Identifies 2 New Loci Associated With Anti-NMDAR Encephalitis | Neurology Neuroimmunology & Neuroinflammation

Genome-wide Association Study Identifies 2 New Loci Associated With Anti-NMDAR Encephalitis | Neurology Neuroimmunology & Neuroinflammation | AntiNMDA | Scoop.it
We used PLINK v.1.9,7 R v.3.6.3,8 and the Illumina GenomeStudio for genotype quality control. First, we excluded all nonoverlapping variants between the 2 different versions of the GSA chip, variants with multicharacter allele codes, insertions, deletions, duplicated markers, and ambiguous A/T and G/C variants. We determined genotyping sex by the X-chromosome inbreeding coefficients, with F < 0.2 being female and F > 0.8 being male, and excluded samples with discordance between reported and imputed sex. After that, we filtered first variants and then individuals with a relaxed threshold for a call rate of less than 85%, followed by a stringent threshold of 98%. We applied a minor allele frequency (MAF) filter of 1%, as well as filters for significant deviation from Hardy-Weinberg equilibrium (HWE; p < 1 × 10−6) in controls, informative missingness (p < 1 × 10−5), and outlying heterozygosity rate (mean ± 3 SDs). To determine duplicated or cryptically related individuals, we used pairwise genome-wide estimates of the proportion of identity by descent (IBD) on a pruned data set containing only markers in low linkage disequilibrium (LD) regions (pairwise r2 < 0.2) and excluded those more closely related than third-degree relatives (IBD > 0.125). Of each identified sample pair, we kept the individual with a higher call rate. To identify ethnic outliers, we used a procedure similar to the one suggested in the R package plinkQC9: we combined the genotype data with the samples of the publicly available 1000 Genomes Project10 and performed a principal component (PC) analysis on the merged data set. A European center was determined by the first 2 PCs of known European samples, and the Euclidean distance from this center determined the ethnical assignment with samples more than 1.5 times the maximal European Euclidean distance away from the center being excluded. The remaining individuals were used for preliminary association analysis based on which we visually inspected the cluster plots of all variants with a p value < 10–4 and discarded variants without adequate cluster separation. To overcome issues with population stratification, we matched controls by ancestry and sex to cases with the R package PCAmatchR,11 leading to 590 control samples for the analysis and approximately 3 controls per case. An exact match on sex was used because there were significantly more female samples in the case samples than in the control samples.
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Autism Associated With Anti-NMDAR Encephalitis: Glutamate-Related Therapy

Autism Associated With Anti-NMDAR Encephalitis: Glutamate-Related Therapy | AntiNMDA | Scoop.it
The purpose of this review is to correlate autism with autoimmune dysfunction in the absence of an explanation for the etiology of autism spectrum disorder. The anti-N-methyl-D-aspartate receptor (anti-NMDAR) autoantibody is a typical synaptic protein ...
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Stream episode Autoimmune encephalitis: clinical spectrum and management by BMJ talk medicine podcast | Listen online for free on

As the number of people with dementia worldwide approaches 50 million, the need for early and accurate diagnosis is more urgent than ever.However, the biggest challenge is often suspecting dementia i...
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Virus reactivation after immunotherapy of anti-NMDAR encephalitis secondary to herpes simplex encephalitis: A case report

Virus reactivation after immunotherapy of anti-NMDAR encephalitis secondary to herpes simplex encephalitis: A case report | AntiNMDA | Scoop.it
Herpes simplex encephalitis is the most common cause of sporadic fatal encephalitis. More than half of patients with herpes simplex encephalitis will die and the vast majority of survivors have severe neurologic sequelae without effective antiviral therapy.
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Multimodal electrophysiological analyses reveal that reduced synaptic excitatory neurotransmission underlies seizures in a model of NMDAR antibody-mediated encephalitis

Multimodal electrophysiological analyses reveal that reduced synaptic excitatory neurotransmission underlies seizures in a model of NMDAR antibody-mediated encephalitis | AntiNMDA | Scoop.it
Sukhvir Wright et al. present a NMDAR antibody-induced model of encephalitis in rats and use in vitro, in vivo, and in silico electrophysiology to examine alterations in neural circuit behavior. Their results suggest that reduction of NMDARs leads to increased excitability and seizure activity,...
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NN111 ExTINGUISH | NeuroNEXT

NN111 ExTINGUISH | NeuroNEXT | AntiNMDA | Scoop.it
A Phase-2b, Double-Blind, Randomized Controlled Trial to Evaluate the Activity and Safety of Inebilizumab in Anti-N-methyl-D-aspartate receptor (NMDAR) Encephalitis and Assess Markers of Disease...
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Understanding Seizures and Prognosis of the Extreme Delta Brush Pattern in Anti-N-Methyl-D-Aspartate (NMDA) Receptor Encephalitis: A Systematic Review

Understanding Seizures and Prognosis of the Extreme Delta Brush Pattern in Anti-N-Methyl-D-Aspartate (NMDA) Receptor Encephalitis: A Systematic Review | AntiNMDA | Scoop.it
Anti-N-methyl-d-aspartate (NMDA) receptor encephalitis (ANMDARE) is an autoimmune disorder with neurological and psychiatric features. The disease presents with a viral prodrome, followed by psychiatric manifestations.
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A Story That Begins Too Soon: A case of a girl with untreated Anti–N-methyl-d-aspartate receptor encephalitis for fourteen years | Canadian Journal of Neurological Sciences

A Story That Begins Too Soon: A case of a girl with untreated Anti–N-methyl-d-aspartate receptor encephalitis for fourteen years | Canadian Journal of Neurological Sciences | AntiNMDA | Scoop.it
A Story That Begins Too Soon: A case of a girl with untreated Anti–N-methyl-d-aspartate receptor encephalitis for fourteen years...
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Autoimmune encephalitis and seizures, cerebrospinal fluid, imaging, and EEG findings: a case series | SpringerLink

Autoimmune encephalitis and seizures, cerebrospinal fluid, imaging, and EEG findings: a case series | SpringerLink | AntiNMDA | Scoop.it
Antibody-mediated encephalitides constitute a group of inflammatory brain diseases characterized by prominent neuropsychiatric symptoms and are associated with antibodies against neuronal cell-surface proteins, ion channels, or receptors.
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