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.

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Summary Background Increasing evidence suggests that seizures and status epilepticus can be immune-mediated. We aimed to describe the clinical features of a new epileptic disorder, and to establish the target antigen and the effects of patients’ antibodies on neuronal cultures. Methods In this observational study, we selected serum and CSF samples for antigen characterisation from 140 patients with encephalitis, seizures or status epilepticus, and antibodies to unknown neuropil antigens. The samples were obtained from worldwide referrals of patients with disorders suspected to be autoimmune between April 28, 2006, and April 25, 2013. We used samples from 75 healthy individuals and 416 patients with a range of neurological diseases as controls. We assessed the samples using immunoprecipitation, mass spectrometry, cell-based assay, and analysis of antibody effects in cultured rat hippocampal neurons with confocal microscopy. Findings Neuronal cell-membrane immunoprecipitation with serum of two index patients revealed GABAA receptor sequences. Cell-based assay with HEK293 expressing α1/β3 subunits of the GABAA receptor showed high titre serum antibodies (>1:160) and CSF antibodies in six patients. All six patients (age 3–63 years, median 22 years; five male patients) developed refractory status epilepticus or epilepsia partialis continua along with extensive cortical-subcortical MRI abnormalities; four patients needed pharmacologically induced coma. 12 of 416 control patients with other diseases, but none of the healthy controls, had low-titre GABAA receptor antibodies detectable in only serum samples, five of them also had GAD-65 antibodies. These 12 patients (age 2–74 years, median 26·5 years; seven male patients) developed a broader spectrum of symptoms probably indicative of coexisting autoimmune disorders: six had encephalitis with seizures (one with status epilepticus needing pharmacologically induced coma; one with epilepsia partialis continua), four had stiff-person syndrome (one with seizures and limbic involvement), and two had opsoclonus-myoclonus. Overall, 12 of 15 patients for whom treatment and outcome were assessable had full (three patients) or partial (nine patients) response to immunotherapy or symptomatic treatment, and three died. Patients’ antibodies caused a selective reduction of GABAA receptor clusters at synapses, but not along dendrites, without altering NMDA receptors and gephyrin (a protein that anchors the GABAA receptor). Interpretation High titres of serum and CSF GABAA receptor antibodies are associated with a severe form of encephalitis with seizures, refractory status epilepticus, or both. The antibodies cause a selective reduction of synaptic GABAA receptors. The disorder often occurs with GABAergic and other coexisting autoimmune disorders and is potentially treatable. Funding The National Institutes of Health, the McKnight Neuroscience of Brain Disorders, the Fondo de Investigaciones Sanitarias, Fundació la Marató de TV3, the Netherlands Organisation for Scientific Rese...

Our study confirms GABABR as an autoantigen of paraneoplastic and nonparaneoplastic LE and expands the phenotype of GABABR antibodies to ataxia, OMS, and status epilepticus. The long-term prognosis is dictated by the presence of a tumor. Recognition of syndromes associated with GABABR antibodies is important because they usually respond to treatment.

Objective To report the clinical features of 20 pediatric patients with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. Study design Review of clinical data, long-term follow-up, and immunological studies performed in a single center in Spain in the last 4 years. Results The median age of the patients was 13 years (range, 8 months-18 years), 70% were female. In 12 patients (60%) the initial symptoms were neurologic, usually dyskinesias or seizures, and in the other 40% psychiatric. One month into the disease, all patients had involuntary movements and alterations of behavior and speech. All patients received steroids, intravenous immunoglobulin (IVIG) or plasma exchange, and 7 rituximab or cyclophosphamide. With a median follow up of 17.5 months, 85% had substantial recovery, 10% moderate or severe deficits, and 1 died. Three patients had previous episodes compatible with anti-NMDAR encephalitis, 2 of them with additional relapses after the diagnosis of the disorder. Ovarian teratoma was identified in two patients, one at onset of encephalitis and the other one year later. Two novel observations (one patient each) include, the identification of an electroencephalographic pattern (“extreme delta brush”) considered characteristic of this disorder, and the development of anti-NMDAR encephalitis after herpes simplex encephalitis (HSE). Conclusions The initial symptoms of pediatric anti-NMDAR encephalitis vary from those of the adults (more neurologic and less psychiatric in children), the development of a mono-symptomatic illness is extremely rare (except in relapses), and most patients respond to treatment. Our study suggests a link between post-HSE choreoathetosis and anti-NMDAR encephalitis.

Anti-N-methyl D-aspartate receptor (NMDAR) encephalitis is a severe neuropsychiatric disorder that associates with prominent memory and behavioural deficits. Patients' antibodies react with the N-terminal domain of the GluN1 (previously known as NR1) subunit of NMDAR causing in cultured neurons a selective and reversible internalization of cell-surface receptors. These effects and the frequent response to immunotherapy have suggested an antibody-mediated pathogenesis, but to date there is no animal model showing that patients' antibodies cause memory and behavioural deficits. To develop such a model, C57BL6/J mice underwent placement of ventricular catheters connected to osmotic pumps that delivered a continuous infusion of patients' or control cerebrospinal fluid (flow rate 0.25 µl/h, 14 days). During and after the infusion period standardized tests were applied, including tasks to assess memory (novel object recognition in open field and V-maze paradigms), anhedonic behaviours (sucrose preference test), depressive-like behaviours (tail suspension, forced swimming tests), anxiety (black and white, elevated plus maze tests), aggressiveness (resident-intruder test), and locomotor activity (horizontal and vertical). Animals sacrificed at Days 5, 13, 18, 26 and 46 were examined for brain-bound antibodies and the antibody effects on total and synaptic NMDAR clusters and protein concentration using confocal microscopy and immunoblot analysis. These experiments showed that animals infused with patients' cerebrospinal fluid, but not control cerebrospinal fluid, developed progressive memory deficits, and anhedonic and depressive-like behaviours, without affecting other behavioural or locomotor tasks. Memory deficits gradually worsened until Day 18 (4 days after the infusion stopped) and all symptoms resolved over the next week. Accompanying brain tissue studies showed progressive increase of brain-bound human antibodies, predominantly in the hippocampus (maximal on Days 13-18), that after acid extraction and characterization with GluN1-expressing human embryonic kidney cells were confirmed to be against the NMDAR. Confocal microscopy and immunoblot analysis of the hippocampus showed progressive decrease of the density of total and synaptic NMDAR clusters and total NMDAR protein concentration (maximal on Day 18), without affecting the post-synaptic density protein 95 (PSD95) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. These effects occurred in parallel with memory and other behavioural deficits and gradually improved after Day 18, with reversibility of symptoms accompanied by a decrease of brain-bound antibodies and restoration of NMDAR levels. Overall, these findings establish a link between memory and behavioural deficits and antibody-mediated reduction of NMDAR, provide the biological basis by which removal of antibodies and antibody-producing cells improve neurological function, and offer a model for testing experimental therapies in this and similar disorders.