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Background Anti-N-methyl-D-aspartate-receptor (NMDAR) encephalitis is a severe autoimmune condition, which typically affects young females. The long-term clinical consequences and brain morphology changes after anti-NMDAR encephalitis are not well known. Case presentation We present clinical and neuroimaging follow-up data on a 25-year female patient with typically presenting anti-NMDAR encephalitis. Longitudinal analyses of brain morphology were done using 3 T structural magnetic resonance imaging (sMRI) and Freesurfer analysis at the time of diagnosis and after symptomatic remission. The presented case attained good functional recovery after standard immunoglobulin-corticosteroid treatment but elevated serum NMDAR antibody levels persisted. The patient had no symptomatic relapses during a 3-year clinical follow-up. In the baseline brain sMRI scan there were no marked volume changes. However, a follow-up sMRI after 9 months indicated clear volume reductions in frontal cortical regions compared to matched controls with identical sMRI scans. Conclusions This case report of anti-NMDAR encephalitis suggests that despite clinical recovery long-term brain morphological changes can develop in the frontal cortex. Longer clinical and imaging follow-up studies are needed to see whether these frontocortical alterations are fully reversible and if not, can they result in trait vulnerabilities for e.g. neuropsychiatric disorders.

•There are few reports where NMDAR encephalitis attacked pregnant women.•Serial examinations of anti-NMDAR antibodies of a pregnant woman who had uncomplicated healthy newborn were performed.•Serum antibodies became negative within 2nd trimester of the gestation with immunotherapies.•These serial change of serum but not CSF antibodies titers are well correlated with having healthy newborn.•This study demonstrated the importance of negative serum antibodies for having healthy baby from NMDAR encephalitis mother.

Anti-NMDA receptor (NMDAR) encephalitis is an autoimmune disorder in which the use of immunotherapy and the long-term outcome have not been defined. We aimed to assess the presentation of the disease, the spectrum of symptoms, immunotherapies used, timing of improvement, and long-term outcome. In this multi-institutional observational study, we tested for the presence of NMDAR antibodies in serum or CSF samples of patients with encephalitis between Jan 1, 2007, and Jan 1, 2012. All patients who tested positive for NMDAR antibodies were included in the study; patients were assessed at symptom onset and at months 4, 8, 12, 18, and 24, by use of the modified Rankin scale (mRS). Treatment included first-line immunotherapy (steroids, intravenous immunoglobulin, plasmapheresis), second-line immunotherapy (rituximab, cyclophosphamide), and tumour removal. Predictors of outcome were determined at the Universities of Pennsylvania (PA, USA) and Barcelona (Spain) by use of a generalised linear mixed model with binary distribution. We enrolled 577 patients (median age 21 years, range 8 months to 85 years), 211 of whom were children (<18 years). Treatment effects and outcome were assessable in 501 (median follow-up 24 months, range 4–186): 472 (94%) underwent first-line immunotherapy or tumour removal, resulting in improvement within 4 weeks in 251 (53%). Of 221 patients who did not improve with first-line treatment, 125 (57%) received second-line immunotherapy that resulted in a better outcome (mRS 0–2) than those who did not (odds ratio [OR] 2·69, CI 1·24–5·80; p=0·012). During the first 24 months, 394 of 501 patients achieved a good outcome (mRS 0–2; median 6 months, IQR 2–12) and 30 died. At 24 months’ follow-up, 203 (81%) of 252 patients had good outcome. Outcomes continued to improve for up to 18 months after symptom onset. Predictors of good outcome were early treatment (0·62, 0·50–0·76; p<0·0001) and no admission to an intensive care unit (0·12, 0·06–0·22; p<0·0001). 45 patients had one or multiple relapses (representing a 12% risk within 2 years); 46 (67%) of 69 relapses were less severe than initial episodes (p<0·0001). In 177 children, predictors of good outcome and the magnitude of effect of second-line immunotherapy were similar to those of the entire cohort. Most patients with anti-NMDAR encephalitis respond to immunotherapy. Second-line immunotherapy is usually effective when first-line treatments fail. In this cohort, the recovery of some patients took up to 18 months. The Dutch Cancer Society, the National Institutes of Health, the McKnight Neuroscience of Brain Disorders award, The Fondo de Investigaciones Sanitarias, and Fundació la Marató de TV3.

Anti-N-methyl-d-aspartate (NMDA) receptor encephalitis is a severe but treatable autoimmune disorder which diagnosis depends on sensitive and specific antibody testing. We aimed to assess the sensitivity and specificity of serum and CSF antibody testing in patients with anti-NMDA receptor encephalitis, and the relation between titres, relapses, outcome, and epitope repertoire. In this observational study, we used rat brain immunohistochemistry and cell-based assays (CBA) with fixed or live NMDA receptor-expressing cells to determine the sensitivity and specificity of antibody testing in paired serum and CSF samples. Samples were obtained at diagnosis from patients with anti-NMDA receptor encephalitis and from control participants worldwide. We deemed a patient to be antibody positive if their serum, their CSF, or both tested positive with both immunohistochemistry and CBA techniques; we determined titres with serial sample dilution using brain immunohistochemistry. We examined samples from 45 patients (25 with good outcome [modified Rankin Scale, mRS 0–2], ten with poor outcome [mRS 3–6], and ten with relapses) at three or more timepoints. We determined the epitope repertoire in the samples of 23 patients with CBA expressing GluN1-NMDA receptor mutants. We analysed samples from 250 patients with anti-NMDA receptor encephalitis and 100 control participants. All 250 patients had NMDA receptor antibodies in CSF but only 214 had antibodies in serum (sensitivity 100·0% [98·5–100·0%] vs 85·6% [80·7–89·4%], p<0·0001). Serum immunohistochemistry testing was more often in agreement with CBA with fixed cells (77 [71%] of 108) than with CBA with live cells (63 [58%] of 108, p=0·0056). In multivariable analysis, CSF and serum titres were higher in patients with poor outcome than in those with good outcome (CSF dilution 340 vs 129, difference 211, [95% CI 1–421], p=0·049; serum dilution 7370 vs 1243, difference 6127 [2369–9885], p=0·0025), and in patients with teratoma than in those without teratoma (CSF 395 vs 110, difference 285 [134–437], p=0·0079; serum 5515 vs 1644, difference 3870 [548–7193], p=0·024). Over time there was a decrease of antibody titres in the 35 patients with good or poor outcome and samples followed at three timepoints 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 were associated with a change in titre more often in CSF than in serum (14 of 19 vs seven of 16, p=0·037). After recovery, 24 of 28 CSF samples and 17 of 23 serum samples from patients remained antibody positive. Patients' antibodies targeted a main epitope region at GluN1 aminoacid 369; the epitope repertoire did not differ between patients with different outcomes, and did not change during relapses. The sensitivity of NMDA receptor antibody testing is higher in CSF than in serum. Antibody titres in CSF and serum were higher in patients with poor outcome or teratoma than in patients with good outcome or no tumour. The titre change in CSF was more closely related with relapses than was that in serum. These findings emphasise the importance of including CSF in antibody studies, and that antibody titres can complement clinical assessments. Dutch Cancer Society, National Institutes of Health, McKnight Neuroscience of Brain Disorders award, the Fondo de Investigaciones Sanitarias, ErasmusMC fellowship, and Fundació la Marató de TV3.

Objective The aim of this study was to analyze the clinical characteristics of adult patients with anti- N -methyl- d -aspartate receptor (NMDAR) encephalitis combined with anti-myelin oligodendrocyte glycoprotein (MOG) antibodies. Methods This was a non-randomized controlled study. Clinical data were collected from 17 patients with anti-NMDAR encephalitis combined with anti-MOG antibodies admitted to Xuanwu Hospital, Capital Medical University, from January 2020 to August 2024. As controls, 20 patients with NMDAR(+)/MOG(−) and 27 patients with MOG(+)/NMDAR(−) were selected. Results The mean age of onset in the double-positive group was 33.47 ± 1.065 years, with a male-to-female ratio of 14:3. Significant differences were observed between the NMDAR(+)/MOG(+) group and the NMDAR(+)/MOG(−) group in terms of headache, lumbar puncture pressure, and cerebrospinal fluid (CSF) leukocyte counts ( P  < 0.05). Comparing the NMDAR(+)/MOG(+) group with the MOG(+)/NMDAR(−) group revealed significant differences in gender, headache, mental and behavioral abnormalities, limb twitching, loss of consciousness, cognitive impairment, speech impairment, visual impairment, limb numbness, cortical/sub-cortical white matter, brainstem lesions, OB type II, and CSF leukocyte counts ( P  < 0.05). No statistically significant differences were found in the comparison of CSF and serum antibody titers among the three groups ( P  > 0.05). Conclusion NMDAR and MOG antibodies can coexist in patients with autoimmune diseases, with a predominance of young male patients. The double-positive group exhibited more severe intracranial viral infections and a higher rate of intrathecal immunoglobulin synthesis in the central tissues. Compared to the double-positive group, NMDAR encephalitis alone presented with more similar clinical manifestations, while MOG-related disease demonstrated a higher likelihood of brainstem involvement.

ObjectiveThere are now a large number of requests for N-methyl-d-aspartate receptor autoantibody (NMDAR-Ab) tests, and it is important to assess the clinical relevance of all results, particularly when they are reported as ‘Low Positive’.MethodsThe clinical data of 56 patients found Positive or Low Positive by the Oxford live cell-based assay were reviewed. An autoimmune basis for the condition was assigned as ‘Definite’, ‘Possible’ or ‘Unlikely’. The number of core features (encephalopathy, psychiatric, cognitive, epileptic, extrapyramidal and inflammatory cerebrospinal fluid (CSF)) was tabulated.ResultsTwenty-five (44.6%) patients had a Definite NMDAR-Ab encephalitis (eight ovarian teratomas, one Hodgkin's lymphoma), 18 (32.1%) a Possible NMDAR-Ab encephalitis and 13 (23.2%) an Unlikely autoimmune syndrome. Serum NMDAR-Ab levels were higher in patients with tumours. Positive NMDAR-Abs were found not only in patients with three or more core features and a Definite syndrome, but also in five patients classified as Possible. Conversely, Low Positive NMDAR-Abs were present in 7 Definite cases as well as in 13 Possible cases. Unlikely patients had mainly Low Positive antibodies and fewer core features. CSF NMDAR-Abs, only available in 11 pairs and at varying time points, broadly related to serum levels and were Positive in 3/3 patients with tumours but in only 2/5 Definite patients, and none of the Possible or Unlikely cases.InterpretationUsing live cell-based assays, Positive and Low Positive antibodies can be of clinical significance. The number of core clinical features should help to select those patients in whom an immunotherapy intervention might be considered, irrespective of the antibody level.

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is potentially lethal, but it is also a treatable autoimmune disorder characterized by prominent psychiatric and neurologic symptoms. It is often accompanied with teratoma or other neoplasm, especially in female patients. Anti-NMDAR antibodies in cerebrospinal fluid (CSF) and serum are characteristic features of the disease, thereby suggesting a pathogenic role in the disease. Here, we summarize recent studies that have clearly documented that both clinical manifestations and the antibodies may contribute to early diagnosis and multidisciplinary care. The clinical course of the disorder is reversible and the relapse could occur in some patients. Anti-NMDAR encephalitis coexisting with demyelinating disorders makes the diagnosis more complex; thus, clinicians should be aware of the overlapping diseases.

Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis (NMDARE) is an autoimmune neurological disorder associated with anti-NMDAR antibodies (NMDAR-Ab), leading to synaptic dysfunction. While the effect of NMDAR-Ab on receptor internalization is well documented, its effect on dendritic protrusion morphology remains unclear. To investigate how NMDAR-Ab alters dendritic protrusion size and the associated molecular mechanisms using patient-derived sera. Cultured hippocampal neurons were treated with sera from patients with NMDARE. Protrusion size and the phosphorylation of cofilin, a regulator of actin dynamics, were also assessed. Exposure to NMDAR-Ab significantly decreased dendritic protrusion width and length while increasing protrusion density. Mechanistically, NMDAR-Ab decreased cofilin phosphorylation in dendritic protrusions. The reduction in spine size was partially reversible upon discontinuation of antibody treatment, except for the reduction in phosphorylated cofilin levels. NMDAR-Ab induced changes in dendritic protrusion size, along with alterations in actin dynamics, which may contribute to the cognitive and behavioral symptoms of NMDARE.

To analyze the clinical characteristics of an overlapping syndrome, MNOS, of anti-myelin oligodendrocyte glycoprotein antibody (MOG-Ab) coexisting with anti-N-methyl-D-aspartate receptor encephalitis (NMDARE) in children. We included patients with NMDARE at Children’s Hospital of Chongqing Medical University between 2018 and 2022 and conducted a comparison between NMDARE with and without MOG-Ab. Among 163 patients with NMDARE, 15 individuals tested positive for MOG-Ab. The median age of MNOS was 11 years (IQR 8–13). Furthermore, 10 out of 15 were female. More than half of MNOS experienced a prior history of encephalitis or demyelinating disorders. Among ten patients with low MOG-Ab titers, two met the diagnostic criteria for MOGAD. All five patients with high MOG-Ab titers satisfied the criteria for MOGAD. A total of seven patients diagnosed with MOGAD presented with acute disseminated encephalomyelitis. The proportion of prodromal symptoms and brain lesions, the neutrophil counts, and the frequency of mycophenolate mofetil administration were significantly higher in MNOS compared to NMDARE patients without MOG-Ab ( p  < 0.05). The outcomes of MNOS were favorable and comparable to those observed in NMDARE. Nevertheless, MNOS demonstrated a higher tendency to relapse, with rates of 60.0% compared to 3.1% ( p  < 0.001). Conclusion : Pediatric MNOS exhibited a high prevalence among females, particularly those with a prior history of MOGAD or encephalitis. MNOS had a favorable prognosis but with a high relapse rate. Coexisting MOG-Ab in pediatric MNOS may be pathogenic or a bystander, potentially correlating with antibody titers. What is Known: • Pediatric anti-N-methyl-D-aspartate receptor encephalitis (NMDARE) coexisting with anti-myelin oligodendrocyte glycoprotein antibody (MOG-Ab) generally has a favorable prognosis, albeit with a tendency to relapse. • Pediatric NMDARE coexisting with MOG-Ab may exhibit imaging features indicative of demyelination. What is New: • Pediatric patients of MOG-Ab coexisting with NMDARE overlapping syndrome (MNOS) were predominantly observed in females, particularly those with a history of MOG-Ab-associated disorder (MOGAD) or encephalitis. • Compared with NMDARE patients, pediatric MNOS patients had higher neutrophil counts and more frequently exhibited abnormal MRI findings in the basal ganglia, insular lobe, temporal lobe, thalamus, and cerebellum. Graphical abstract

Anti-N-methyl-D-aspartate receptor (NMDA-R) encephalitis is a neuropsychiatric disorder with additional psychiatric features caused by NMDA-R immunoglobulin G (IgG) antibodies in cerebrospinal fluid (CSF). This report presents the follow-up of a patient in whom we assumed mild NMDA-R encephalitis in the first psychotic episode. A patient with a prior episode of an acute polymorphic psychotic syndrome relapsed five and a half years later following a severe COVID-19 infection. Serum NMDA-R antibodies were again detected with a titer of max. 1:320 using fixed-cell-based assays, but conventional magnetic resonance imaging (MRI), electroencephalography (EEG), and CSF findings were largely normal. NMDA-R antibody levels in serum decreased to 1:80 after approximately one month without immunotherapy. [ F]fluorodeoxyglucose positron emission tomography (FDG-PET) still revealed pronounced metabolism of the association cortices (clearly more pronounced in the first episode with an encephalitis-like pattern at that time). Advanced MRI analyses including diffusion microstructure imaging (DMI) showed frontal and thalamic microstructural alterations compatible with edematization (but also far less accentuated than in the first episode). Further advanced antibody tests of CSF (approx. 1 month after symptom onset) using a live-cell-based and different tissue-based assays were negative for NMDA-R IgG antibodies. Research mass spectrometry of the CSF identified neurotransmitter-precursor shortages, increased turnover of tryptophan into quinolinic acid, and low-glucose/lactate levels. Immunotherapy (performed after the initial assumption of an autoimmune cause) with steroids led to clinical improvement of residual symptoms. After approximately three months, NMDA-R IgG serum antibodies were no longer detectable; however, FDG-PET/DMI follow-up revealed no relevant changes. The international consensus criteria for a probable/definite diagnosis of NMDA-R encephalitis or autoimmune psychosis were not fulfilled, especially as no NMDA-R IgG antibodies were identified in CSF using different antibody assays and EEG/CSF routine findings were inconspicuous. NMDA-R encephalitis was therefore not diagnosed (as initially suspected). Independent of the NMDA-R IgG antibodies, there were possible signs of an autoimmune process. For a better understanding of similar patients, multimodal diagnostic approaches including complementary antibody tests could be promising.