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Objective: Diagnosing autoimmune encephalitis (AIE) is difficult in patients with less fulminant diseases such as epilepsy. However, recognition is important, as patients require immunotherapy. This study aims to identify antibodies in patients with focal epilepsy of unknown etiology, and to create a score to preselect patients requiring testing. Methods: In this prospective, multicenter cohort study, adults with focal epilepsy of unknown etiology, without recognized AIE, were included, between December 2014 and December 2017, and followed for 1 year. Serum, and if available cerebrospinal fluid, were analyzed using different laboratory techniques. The ACES score was created using factors favoring an autoimmune etiology of seizures (AES), as determined by multivariate logistic regression. The model was externally validated and evaluated using the Concordance (C) statistic. Results: We included 582 patients, with median epilepsy duration of 8 years (interquartile range = 2–18). Twenty patients (3.4%) had AES, of whom 3 had anti–leucine‐rich glioma inactivated 1, 3 had anti–contactin‐associated protein‐like 2, 1 had anti–N‐methyl‐D‐aspartate receptor, and 13 had anti–glutamic acid decarboxylase 65 (enzyme‐linked immunosorbent assay concentrations >10,000IU/ml). Risk factors for AES were temporal magnetic resonance imaging hyperintensities (odds ratio [OR] = 255.3, 95% confidence interval [CI] = 19.6–3332.2, p < 0.0001), autoimmune diseases (OR = 13.31, 95% CI = 3.1–56.6, p = 0.0005), behavioral changes (OR 12.3, 95% CI = 3.2–49.9, p = 0.0003), autonomic symptoms (OR = 13.3, 95% CI = 3.1–56.6, p = 0.0005), cognitive symptoms (OR = 30.6, 95% CI = 2.4–382.7, p = 0.009), and speech problems (OR = 9.6, 95% CI = 2.0–46.7, p = 0.005). The internally validated C statistic was 0.95, and 0.92 in the validation cohort (n = 128). Assigning each factor 1 point, an antibodies contributing to focal epilepsy signs and symptoms (ACES) score ≥ 2 had a sensitivity of 100% to detect AES, and a specificity of 84.9%. Interpretation: Specific signs point toward AES in focal epilepsy of unknown etiology. The ACES score (cutoff ≥ 2) is useful to select patients requiring antibody testing. ANN NEUROL 2021;89:698–710 [ABSTRACT FROM AUTHOR]

Objectives: Anti-N-methyl-D-aspartate receptor encephalitis (anti-NMDARE) is a severe, but treatable disease. This study aims to give a detailed description of electroencephalogram (EEG) results in paediatric and adult patients to improve disease recognition, and analyses the predictive value of the first EEG for the final clinical outcome.Methods: This nationwide cohort study includes patients with N-methyl-D-aspartate receptor antibodies confirmed with cell-based assay and immunohistochemistry in serum and cerebrospinal fluid. EEG recordings were re-evaluated by two experienced neurophysiologists, mixed with control EEGs for blinding. Initial EEG as well as follow-up registrations were analysed.Results: 35 adults and 18 children were included. Only two patients (4%) had a normal EEG. During the first recording, the majority of the patients had normal posterior rhythm (71%), which was associated with better modified Rankin Scale at final outcome (OR 4.74; 95% CI 1.56 to 14.47; p=0.006). In addition, EEGs showed focal (73%) or diffuse (67%) slowing. The first EEG was severely abnormal in 26%. However, 8 of 14 patients with a severely abnormal first EEG still had a favourable outcome. During the course of the disease, extreme delta brushes (EDBs) were present in 6 of 53(11%)patients.Conclusions: The first EEG commonly shows normal posterior rhythm with focal or diffuse slowing. Although the sensitivity of an abnormal EEG is high (96%), normal EEG does not exclude anti-NMDARE. EDBs are only present in severely affected patients. The first EEG recording is predictive of the final clinical outcome. [ABSTRACT FROM AUTHOR]

Background and Objectives: Anti-NMDA receptor (anti-NMDAR) encephalitis generally manifests in young adults. Although 80%-90% returns to independence, the majority experience persistent cognitive and psychosocial difficulties. Studies have demonstrated that cognitive recovery may continue for years; the temporal trajectory is largely unknown, as are factors influencing cognitive/psychosocial recovery. Objectives were to (1) describe the cognitive recovery trajectory, (2) assess self-reported outcomes, (3) identify factors relating to outcome, and (4) explore the relation between cognitive and self-reported outcomes, and participation., Methods: We performed a large-scale cross-sectional and prospective cohort study. We addressed our nationwide cohort, provided they were (1) older than 16 years, (2) independent preillness, and (3) able to perform cognitive tests and/or self-report. Patients completed Patient-Reported Outcome Measures and neuropsychological assessments (memory, language, perception and construction, and attention and executive functions), and functional outcomes were established (modified Rankin Scale [mRS] score and return-to-work/-education). Outcomes were compared with references and between groups based on clinical characteristics and functional outcomes ( T -tests for normalized data and nonparametric tests for patient-reported data). Recovery was visualized by plotting outcomes against time-of-assessment., Results: We included 92 patients (age 29 ± 2 years; 77% female). Cognitive scores improved with time-of-assessment, up to 36 months after diagnosis ( R = 0.35, p = 0.022), with the most enhanced improvement in the first 6 months. This result could be reproduced in prospective patients (n = 12). Beyond 36 months (n = 44), 34% of patients had a persistent impairment ( z -score <-1.5 SD) and 65% scored below-average (<-1 SD) in 1 or more cognitive domains, despite a "favorable" outcome measured by mRS (≤2) in the majority (91%). Most affected were memory (mean -0.67 ± 0.89 SD, p = 0.25) and language (-0.75 ± 1.06 SD, p = 0.23). Self-reported complaints remained in emotional well-being (mean 72 ± 25 SD vs norm 82 ± 33 SD, p < 0.001), social functioning (73 ± 26 SD vs 84 ± 22 SD, p < 0.001), energy levels (57 ± 19 SD vs 69 ± 19 SD, p < 0.001), and quality of life (0.85 ± 0.14 SD vs 0.93 ± 0.11 SD, p < 0.001). Many patients did not resume school/work (30%) or needed adjustments (18%). Resuming school/work related to processing speed (-0.14 ± 0.78 SD vs -0.84 ± 1.05 SD, p = 0.039) and well-being (EuroQol 5 Dimensions 5 Levels median 0.90 vs 0.81, p = 0.016)., Discussion: Recovery from anti-NMDAR encephalitis may continue for 3 years, with risk of persisting cognitive deficits, notably in memory and language, and sequelae in social functioning, energy levels, and well-being. The frequently applied outcome measure mRS does not fully capture outcomes. Almost half of patients struggled resuming school/work, associated with cognitive deficits and well-being.

Background and Objectives: Determinants of disease activity and prognosis are limited in anti-NMDA receptor (NMDAR) encephalitis. Neurofilament light chains (NfL) are markers of axonal damage and have been identified as valuable biomarkers for neurodegenerative and other neuroinflammatory disorders. We aimed to investigate serum NfL levels in patients with anti-NMDAR encephalitis as a biomarker for disease severity and outcome., Methods: In this retrospective study, NfL values were measured in all available pretreatment serum and paired CSF samples of the nationwide anti-NMDAR encephalitis cohort. The values were analyzed in duplicate using single-molecule array and compared with measurements in healthy references. Follow-up sera were tested to analyze longitudinal responsiveness, if at least available from 2 time points after diagnosis. Serum NfL levels were compared with data on disease activity (seizures, MRI, and CSF findings), severity (modified Rankin Scale [mRS] score, admission days, and intensive care unit admission), and outcome (mRS score and relapses), using regression analysis., Results: We have included 71 patients (75% female; mean age 31.4 years, range 0-85 years) of whom pretreatment serum samples were analyzed. Paired CSF samples were available of 33 patients, follow-up serum samples of 20 patients. Serum NfL levels at diagnosis were higher in patients (mean 19.5 pg/mL, 95% CI 13.7-27.7) than in references (mean 6.4 pg/mL, 95% CI 5.8-7.2, p < 0.0001). We observed a good correlation between serum and CSF NfL values ( R = 0.84, p < 0.0001). Serum NfL levels and age correlated in patients (Pearson R = 0.57, p < 0.0001) and references ( R = 0.62, p < 0.0001). Increased NfL values were detected in patients post-herpes simplex virus 1 encephalitis (mean 248.8 vs 14.1 pg/mL, p < 0.0001) and in patients with brain MRI lesions (mean 27.3 vs 11.1 pg/mL, p = 0.019). NfL levels did relate to the long-term follow-up (mRS score at 12 months; β NfL = 0.55, p = 0.013), although largely explained by the effect of age on NfL levels and prognosis. In serial samples, NfL values did roughly follow clinical disease activity, albeit with delay., Discussion: Increased serum NfL levels reflect neuroaxonal damage in anti-NMDAR encephalitis. No relationship was identified with disease severity, whereas the association with outcome was confounded by age. The implied role of sampling timing on NfL levels also limits the applicability of NfL as a prognostic marker., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background and Objectives: To describe the clinical features of anti-NMDAR encephalitis, emphasizing on late-onset patients and antibody test characteristics in serum and CSF., Methods: Nationwide observational Dutch cohort study, in patients diagnosed with anti-NMDAR encephalitis between 2007 and 2019., Results: One hundred twenty-six patients with anti-NMDAR encephalitis were included with a median age of 24 years (range 1-86 years). The mean annual incidence was 1.00/million (95% CI 0.62-1.59). Patients ≥45 years of age at onset (19%) had fewer seizures (46% vs 71%, p = 0.021), fewer symptoms during disease course (3 vs 6 symptoms, p = 0.020), and more often undetectable serum antibodies compared with younger patients ( p = 0.031). In the late-onset group, outcome was worse, and all tumors were carcinomas (both p < 0.0001). CSF was more accurate than serum to detect anti-NMDAR encephalitis (sensitivity 99% vs 68%, p < 0.0001). Using cell-based assay (CBA), CSF provided an unconfirmed positive test result in 11/2,600 patients (0.4%); 6/11 had a neuroinflammatory disease (other than anti-NMDAR encephalitis). Patients with anti-NMDAR encephalitis, who tested positive in CSF only, had lower CSF antibody titers ( p = 0.003), but appeared to have an equally severe disease course., Discussion: Anti-NMDAR encephalitis occurs at all ages and is less rare in the elderly patients than initially anticipated. In older patients, the clinical phenotype is less outspoken, has different tumor association, and a less favorable recovery. Detection of antibodies in CSF is the gold standard, and although the CBA has very good validity, it is not perfect. The clinical phenotype should be leading, and confirmation in a research laboratory is recommended, when in doubt., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Objective: This nationwide cohort study evaluates seizure responses to immunotherapy and antiepileptic drugs (AEDs) in patients with anti-leucine-rich glioma-inactivated 1 (LGI1), anti-NMDA receptor (NMDAR), and anti-gamma-aminobutyric-acid B receptor (GABA B R) encephalitis., Methods: Anti-LGI1, anti-NMDAR, and anti-GABA B R encephalitis patients with new-onset seizures were included. Medical information about disease course, AEDs and immunotherapies used, effects, and side effects were collected. Outcome measures were (1) seizure freedom while using AEDs or immunotherapy, (2) days to seizure freedom from start of AEDs or immunotherapy, and (3) side effects., Results: Of 153 patients with autoimmune encephalitis (AIE) (53 LGI1, 75 NMDAR, 25 GABA B R), 72% (n = 110) had epileptic seizures, and 89% reached seizure freedom. At least 53% achieved seizure freedom shortly after immunotherapy, and 14% achieved seizure freedom while using only AEDs ( p < 0.0001). This effect was similar in all types ( p = 0.0001; p = 0.0005; p = 0.013, respectively). Median time to seizure freedom from AEDs start was 59 days (interquartile range [IQR] 27-160), and 28 days from start of immunotherapy (IQR 9-71, p < 0.0001). Side effects were psychotic behavior and suicidal thoughts by the use of levetiracetam, and rash by the use of carbamazepine. Carbamazepine was more effective than levetiracetam in reducing seizures in anti-LGI1 encephalitis ( p = 0.031). Only 1 patient, of 86 surviving patients, developed epilepsy after resolved encephalitis., Conclusion: Epilepsy after resolved encephalitis was rare in our cohort of patients with AIE treated with immunotherapy. In addition, seizure freedom is achieved faster and more frequently after immunotherapy. Therefore, AEDs should be considered as add-on treatment, and similar to treatment of other encephalitis symptoms, immunotherapy is crucial., (Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)