Background Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an autoimmune disorder in which the use of immunotherapy and the long-term outcome have not been defined. Methods In this multi-institutional observational study (2007-2012), all patients with GluN1 antibodies were assessed at symptom onset and 4, 8, 12, 18, and 24 months using the modified Rankin Scale (mRS). Treatment included first-line immunotherapy (steroids, intravenous immunoglobulin, plasmapheresis), second-line immunotherapy (rituximab, cyclophosphamide), and tumor removal. Predictors of outcome were determined at the Universities of Pennsylvania and Barcelona using generalized linear mixed models with binary distribution. Results 577 patients (1-85 years, median 21) were studied, 212 were children (<18 years). Treatment effects and outcome were assessable in 501 (median follow-up 24 months): 472 (94%) underwent first-line immunotherapy or tumor removal, resulting in improvement within four weeks in 251 (53%). Of 221 patients who failed first-line therapy, 125 (57%) received second-line immunotherapy resulting in better outcome than those who did not (OR 2·69, CI 1·24-5·80, p=0·012). During the first 24 months, 394/501 reached good outcome (mRS 0-2; median 6 months), and 30 died. At 24 month follow-up 204/252 (81%) had good outcome. Outcomes continued to improve for up to 18 months after symptom onset. Predictors of good outcome were early treatment (OR 0·62, CI 0·50-0·76, p<0·0001) and lack of ICU admission (OR 0.12, CI 0·06-0·22,p<0·0001). 45 patients had one or multiple relapses (representing a 12% risk within 2 years); 46/69 (67%) relapses were milder than previous episodes (p<0·0001). In 177 children, predictors of good outcome and the magnitude of effect of second-line immunotherapy were comparable to those of the entire cohort. Conclusions Patients with anti-NMDAR encephalitis respond to immunotherapy. Second-line immunotherapy is usually effective when first-line therapies fail. Recovery can take more than 18 months.

Encephalitis is a severe inflammatory disorder of the brain with many possible causes and a complex differential diagnosis. Advances in autoimmune encephalitis research in the past 10 years have led to the identification of new syndromes and biomarkers that have transformed the diagnostic approach to these disorders. However, existing criteria for autoimmune encephalitis are too reliant on antibody testing and response to immunotherapy, which might delay the diagnosis. We reviewed the literature and gathered the experience of a team of experts with the aims of developing a practical, syndrome-based diagnostic approach to autoimmune encephalitis and providing guidelines to navigate through the differential diagnosis. Because autoantibody test results and response to therapy are not available at disease onset, we based the initial diagnostic approach on neurological assessment and conventional tests that are accessible to most clinicians. Through logical differential diagnosis, levels of evidence for autoimmune encephalitis (possible, probable, or definite) are achieved, which can lead to prompt immunotherapy.

Summary Background We aimed to assess the sensitivity/specificity of serum and CSF antibody-testing in patients with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, and the correlation between titers, relapses, outcome, and epitope repertoire. Methods In this observational study, brain immunohistochemistry and cell-based assays (CBA) with fixed and live NMDAR-expressing cells were used to determine the sensitivity/specificity of antibody-testing in paired serum/CSF obtained at diagnosis of 250 patients with anti-NMDAR encephalitis and 100 control subjects. A patient was considered antibody-positive if either serum or CSF tested positive with both immunohistochemistry and CBA; titers were determined with serial sample dilution using brain immunohistochemistry. Samples from 45 patients (25 good-outcome: modified Rankin Scale [mRS] 0–2; 10 poor-outcome: mRS 3–6; 10 relapses) were examined at ≥3 disease time points. Epitope repertoire was determined with CBA expressing GluN1-NMDAR mutants Findings All 250 patients had NMDAR-antibodies in CSF but only 214/250 had antibodies in serum (sensitivity 100% [98.5–100%] versus 85.6% [80.7–89.4%], p<0.0001). Serum immunohistochemistry-testing was more often in agreement with CBA with fixed than live cells (77/108 versus 63/108, p=0.0056). In multivariable analysis, CSF and serum titers were higher in patients with poor-outcome than in those with good-outcome (CSF dilution 340 versus 129, difference 211, [95%-CI 1.1–421], p=0.049; serum 7370 versus 1243, difference 6127 [2369–9885], p=0.0025), and in patients with teratoma than in those without (CSF 395 versus 110, difference 285 [134–437], p=0.0079; serum 5515 versus 1644, difference 3870 [548–7193], p=0.024). Over time there was a decrease of antibody-titers regardless of outcome (from diagnosis to last follow-up: CSF 614 to 76, difference 538 [288–788]; serum 5460 to 1564, difference 3896 [2428–5362], both p<0.0001). Relapses correlated better with the titer-change in CSF than that in serum (14/19 versus 7/16, p=0.037). After recovery, 24/28 CSF and 17/23 serum from patients remained antibody-positive. Patients’ antibodies targeted a main epitope region at GluN1 aa369; the epitope repertoire did not differ between patients with different outcomes, and did not change during relapses. Interpretation NMDAR antibody-testing is more sensitive in CSF than serum. Antibody-titers in CSF and serum are higher in patients with poor-outcome or teratoma. The titer-change in CSF correlates better with relapses than that of serum. Funding The Dutch Cancer Society, the National Institute of Health, the McKnight Neuroscience of Brain Disorders award, the Fondo de Investigaciones Sanitarias, Erasmus MC fellowship and Fundació la Marató de TV3.