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Autoimmune encephalitis (AE) can present as first-episode psychosis (FEP) in children. An FEP diagnostic algorithm has been proposed, but how this algorithm applies to children is unknown. We assess the FEP diagnostic algorithm in children with FEP. The FEP algorithm was applied to a retrospective cohort of children with FEP without other neurological symptoms. Twenty-four patients were included, with five AE (anti- N -methyl-d-aspartate receptor encephalitis) and 19 non-AE patients (12 primary psychiatric, two headaches, mycoplasma-related encephalitis, post–coronavirus disease 2019 encephalitis, drug reaction with eosinophilia and systemic symptoms [DRESS] syndrome, cobalamin C deficiency, and two unknown). Some non-AE patients (five of 19 = 26%) received immunotherapies, with symptom resolution in one of five (20%) with immunotherapy and in four of 14 (29%) without immunotherapy. The FEP algorithm recommended cerebrospinal fluid (CSF) testing in all (five of five = 100%) patients with AE and in six of 19 (32%) non-AE patients, resulting in 100% sensitivity (95% confidence interval [CI]: 100% to 100%) and 45.5% specificity (95% CI: 16% to 75%), with a negative predictive value of 100% (95% CI: 100% to 100%). FEP can occur in children from different causes, including AE and metabolic conditions. Evaluation of FEP should be broad, especially without CSF evidence of inflammation. The FEP algorithm is useful to assess patients who would benefit from CSF testing and should be assessed in larger cohorts. [ABSTRACT FROM AUTHOR]

To evaluate the efficacy and safety of rituximab treatment for anti- N -methyl- d -aspartate receptor (NMDAR) encephalitis without tumor in children. Eighteen pediatric patients with NMDAR encephalitis treated with rituximab after failure of intravenous immunoglobulin (IVIG) and methylprednisolone treatment were analyzed retrospectively in terms of their medical history, clinical features, laboratory examination results, and treatments. The modified Rankin scale (mRS) score, peripheral blood CD19+ B cells, recurrence, and adverse events were used to evaluate the efficacy and safety of rituximab. The patients were treated with rituximab 3.2 ± 1.0 days after the end of IVIG and methylprednisolone treatment. After initial rituximab treatment for four weeks, the mRS score and number of CD19+ B cells in all patients were significantly lower than those before treatment (P < 0.05). At the last follow-up (44.1 months, 17.7 S.D.), all patients had recovered well (mRS ≤2), 14 patients (77.8%) recovered completely (mRS = 0), three patients had recurrent seizures, and one patient had mental and language impairment. Two patients had transient mild adverse events during infusion, and none of the other patients experienced severe adverse events during hospitalization or follow-up. Rituximab appears safe and may be effective for the treatment of anti-NMDAR encephalitis without tumor in children refractory to first-line agents. [ABSTRACT FROM AUTHOR]

Background: Combined first-line therapies have been frequently adopted for patients with anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis. Plasma exchange (PE) or immunoadsorption (IA) was used as an add-on option following initial immunotherapies, including high-dose steroids and intravenous immunoglobulin (IVIG). However, whether a shorter delay of PE or IA can improve the early recovery prognosis of patients with anti-NMDAR encephalitis remains largely unknown. Objective: To compare short-term clinical improvement between patients with early and late initiation of PE or IA in anti-NMDAR encephalitis. Design: A retrospective study was conducted for patients admitted with anti-NMDAR encephalitis between January 2015 and December 2023 (n = 29), including 21 patients who received PE or IA as synergistic therapies. Methods: The clinical prognosis was compared between the early PE/IA group and the late PE/IA group in the research. Primary outcome included changes in the Clinical Assessment Scale for Autoimmune Encephalitis (∆CASE) at 90 and 120 days after encephalitis onset. Secondary outcomes included changes in the modified Rankin scale (∆mRS) after 90 and 120 days from encephalitis onset, and the length of intensive care unit (ICU) stay for patients with severe anti-NMDAR encephalitis. Results: The ∆CASE scores after 90 and 120 days from encephalitis onset revealed a significant difference between patients with early and late initiation of PE or IA (p ⩽ 0.05). A significant difference in the ∆mRS was also found between patients with early and late initiation of PE or IA in severe encephalitis (p ⩽ 0.05). No significant difference was found in the length of ICU admission (p = 0.101). Conclusion: Our findings emphasize the importance of considering PE or IA as early as feasible for patients with anti-NMDAR encephalitis, even when steroids and IVIG are in use. [ABSTRACT FROM AUTHOR]

Objective: In adult anti‐N‐methyl‐d‐aspartate receptor (NMDAR) encephalitis, corticosteroids are commonly used as first‐line treatment. However, the optimal oral prednisone tapering (OPT) following intravenous methylprednisolone pulse therapy remains unclear. We aim to compare the efficacy and safety of different OPT courses in anti‐NMDAR encephalitis. Methods: The CHASE study, a multicenter prospective observational cohort study, enrolled patients with autoimmune encephalitis from October 2011 to March 2023. Patients were grouped based on oral prednisone tapering course: ≤3 months (Group ≤3 month), 3–6 months (Group 3–6 months, including 3 months), and >6 months (Group > 6 months). Kaplan–Meier plots were used to analyze time to relapse and time to total recovery within 2 years. Results: Among 666 screened patients, 171 (median [IQR] age 27 [21.0–36.5] years, 55.0% female) met selection criteria. Responders at 3 months were prevalent in Group ≤3 months (OR 7.251 [95% CI 2.252 to 23.344] and Group 3–6 months (OR, 3.857 [95% CI 1.107 to 13.440] than in Group >6 months. Clinical Assessment Scale for Autoimmune Encephalitis (CASE) scores at 12 months were higher in Group >6 months than in Group ≤3 months and Group 3–6 months (β, −2.329 [95% CI −3.784 to −.875]; β, −2.871 [95% CI −4.490, −1.253]). CASE seizures subscore was higher in Group >6 months than in Group 3–6 months (β, −.452 [95% CI −.788 to −.116]). No significant difference in seizure freedom rates among the groups. Adverse events were higher in Group 3–6 months and Group >6 months than in Group ≤3 months (OR 6.045 [95% CI 2.352 to 15.538]; OR 6.782 [95% CI 1.911 to 24.073]). Significance: Longer oral prednisone courses for adult patients with anti‐NMDAR encephalitis did not show superior effects compared to shorter courses in improving modified Rankin Scale (mRS) scores and CASE scores, reducing the risk of relapse within 2 years, or achieving seizure freedom. Instead, extended prednisone courses may lead to more side effects— particularly weight gain. This outcome recommends evaluating the possibility of shortening the duration of oral prednisone after a thorough patient assessment. [ABSTRACT FROM AUTHOR]

Background: Encephalitis associated with antibodies against the N-methyl-Daspartate receptor (NMDAR) results in a distinctive neuro-psychiatric syndrome. It has been reported that the serum phenylalanine-tyrosine (Phe/Tyr) ratio increases during infection. However, the connection between phenylalaninetyrosine metabolism and psychiatric symptoms remains unclear. Methods: We enrolled 24 individuals with anti-NMDAR encephalitis and 18 individuals with non-inflammatory neurological diseases (OND). Chromatography was used to measure serum levels of phenylalanine and tyrosine. Serum and cerebrospinal fluid (CSF) TNF-a levels were obtained from the clinical database. The modified Rankin Scale (mRS) score and Glasgow Coma Scale (GCS) score were recorded during the acute phase. The area under the curve (AUC) of the receiver operating characteristic curve was used to assess prediction efficacy. Results: In NMDAR patients, levels of serum Phe and the ratio of serum Phe/Tyr were higher compared to OND patients. The serum Phe/Tyr ratio was also elevated in NMDAR patients with psychiatric syndrome. Furthermore, serum Phe and Tyr levels were correlated with inflammatory indexes. Conclusion: The serum Phe/Tyr ratio is elevated in NMDAR patients with psychiatric syndrome and is associated with severity. Therefore, the serum Phe/Tyr ratio may serve as a potential prognostic biomarker. [ABSTRACT FROM AUTHOR]

Background: Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an autoimmune disorder with a variety of clinical manifestations. It has been established that anti-NMDAR encephalitis may be related to ovarian teratoma in female patients. However, a considerable number of patients have no obvious evidence of ovarian teratoma during the onset of the disease. Case: A 25-year-old previously-healthy female experienced a series of acute symptoms within two days, including confusion, disorientation, short-term memory loss, auditory hallucinations, abnormal behavior, refractory status epilepticus, etc. Her brain MRI and abdominal imaging showed no definite abnormality while her electroencephalogram exhibited the presence of low to moderate amplitude sharp, spike, and multi-spike waves. Serum and cerebrospinal fluid tests yielded positive results for anti-NMDAR antibodies. However, an ultrasound scan failed to identify an ovarian teratoma. Consequently, the diagnosis of anti-NMDAR encephalitis without teratoma was made after 4 days onset. After the plasma exchange and immunoglobulin therapy, her neurological symptoms improved and obtained a clinical cure. In the next eight months of follow-up, the patient accidentally touched a lump in the lower abdomen without any symptoms, and abdominal ultrasound and CT scan revealed a left ovarian tumor. Then she underwent left ovarian teratoma resection surgery and histopathology showed a mature cystic teratoma with neural components. The patient continued to receive five years of follow-up, and her condition remained stable without any recurrence, except that there had been a low titer of anti-NMDAR antibody in her serum. Conclusion: Our case demonstrated the importance of long-term follow-up for female patients with anti-NMDAR encephalitis, since anti-NMDAR encephalitis-associated ovarian teratomas may develop in a delayed manner, even without any symptoms. [ABSTRACT FROM AUTHOR]

A rare autoimmune disease called anti-NMDAR encephalitis usually affects young people and frequently manifests as cognitive deterioration, seizures, and psychiatric symptoms. The diagnostic challenge and the importance in recognizing the clinical features and employing appropriate laboratory and imaging techniques for accurate and timely diagnosis will be discussed. We describe the example of an 8-year-old girl who suddenly began exhibiting strange behavioral and speech problems. Anti-NMDAR encephalitis was diagnosed after further investigation. This casee illustrates how different clinical presentations can lead to a delay in the disorder's diagnosis. Healthcare practitioners continue to have difficulties in diagnosing heterogeneous clinical manifestations of anti-NMDAR encephalitis, particularly in the juvenile age range. [ABSTRACT FROM AUTHOR]

Isolated psychiatric symptoms can be the initial symptom of pediatric anti- N -methyl-d-aspartate (NMDA) receptor autoimmune encephalitis (pNMDARE). Here we report on the prevalence of isolated psychiatric symptoms in pNMDARE. We also assess whether initial neurodiagnostic tests (brain magnetic resonance imaging [MRI], electroencephalography [EEG], and/or cerebrospinal fluid [CSF] white blood cell count) are abnormal in children with isolated psychiatric symptoms and pNMDARE. This multicenter retrospective cohort study from CONNECT (Conquering Neuroinflammation and Epilepsies Consortium) from 14 institutions included children under age 18 years who were diagnosed with pNMDARE. Descriptive statistics using means, medians, and comparisons for continuous versus discrete data was performed. Of 249 children included, 12 (5%) had only psychiatric symptoms without other typical clinical features of autoimmune encephalitis at presentation. All but one (11 of 12 = 92%) had at least one abnormal finding on initial ancillary testing: eight of 12 (67%) had an abnormal EEG, six of 12 (50%) had an abnormal MRI, and five of 12 (42%) demonstrated CSF pleocytosis. The single patient with a normal MRI, EEG, and CSF profile had low positive CSF NMDA antibody (titer of 1:1), and symptoms improved without immunotherapy. Isolated first-episode psychiatric symptoms in pNMDARE are uncommon, and the majority of children will exhibit additional neurodiagnostic abnormalities. Delaying immunotherapy in a child with isolated psychiatric symptoms and normal neurodiagnostic testing may be warranted while awaiting confirmatory antibody testing. [ABSTRACT FROM AUTHOR]

Abstract Background Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an autoimmune disorder with a variety of clinical manifestations. It has been established that anti-NMDAR encephalitis may be related to ovarian teratoma in female patients. However, a considerable number of patients have no obvious evidence of ovarian teratoma during the onset of the disease. Case A 25-year-old previously-healthy female experienced a series of acute symptoms within two days, including confusion, disorientation, short-term memory loss, auditory hallucinations, abnormal behavior, refractory status epilepticus, etc. Her brain MRI and abdominal imaging showed no definite abnormality while her electroencephalogram exhibited the presence of low to moderate amplitude sharp, spike, and multi-spike waves. Serum and cerebrospinal fluid tests yielded positive results for anti-NMDAR antibodies. However, an ultrasound scan failed to identify an ovarian teratoma. Consequently, the diagnosis of anti-NMDAR encephalitis without teratoma was made after 4 days onset. After the plasma exchange and immunoglobulin therapy, her neurological symptoms improved and obtained a clinical cure. In the next eight months of follow-up, the patient accidentally touched a lump in the lower abdomen without any symptoms, and abdominal ultrasound and CT scan revealed a left ovarian tumor. Then she underwent left ovarian teratoma resection surgery and histopathology showed a mature cystic teratoma with neural components. The patient continued to receive five years of follow-up, and her condition remained stable without any recurrence, except that there had been a low titer of anti-NMDAR antibody in her serum. Conclusion Our case demonstrated the importance of long-term follow-up for female patients with anti-NMDAR encephalitis, since anti-NMDAR encephalitis-associated ovarian teratomas may develop in a delayed manner, even without any symptoms.

Abstract Objective Herpes simplex virus (HSV) encephalitis can be associated with many secondary neurological complications, but having multiple episodes of recurrent neurological complications is rare in an individual. Understanding the course of each complication can reduce time to diagnosis and adequate treatment. Additionally, we postulate the role of RNF213 mutation in HSV susceptibility. Methods We describe a unique presentation of HSV‐1 encephalitis in an infant with a pathogenic RNF213 mutation who went on to develop multiple rare neurological complications over the course of her illness. Results Our patient was first diagnosed with neonatal HSV‐1 encephalitis at age 2 weeks. She had recurrence of HSV encephalitis (HSE) with associated vasculopathy that led to right middle cerebral artery and posterior cerebral artery infarctions at 13 months, and then later developed post‐HSE anti‐N‐methyl‐ d‐aspartate receptor encephalitis. All of this occurred concomitant with RNF213 mutation. Interpretation This patient demonstrates that, though rare, multiple neurological complications can occur in a single person, thus highlighting the importance of close surveillance of patients with a history of neonatal HSE and pursuing a broad differential in patients with subtle or recurrent symptoms. Furthermore, we propose a potential role of RNF213 mutation in the pathogenesis of our patient's multiple medical conditions.

Objective: The alterations of the functional network (FN) in anti-N-methyl-Daspartate receptor (NMDAR) encephalitis have been recognized by functional magnetic resonance imaging studies. However, few studies using the electroencephalogram (EEG) have been performed to explore the possible FN changes in anti-NMDAR encephalitis. In this study, the aim was to explore any FN changes in patients with anti-NMDAR encephalitis. Methods: Twenty-nine anti-NMDAR encephalitis patients and 29 age- and gender-matched healthy controls (HC) were assessed using 19-channel EEG examination. For each participant, five 10-second epochs of resting state EEG with eyes closed were extracted. The cortical source signals of 84 Brodmann areas were calculated using the exact low resolution brain electromagnetic tomography (eLORETA) inverse solution by LORETA-KEY. Phase Lag Index (PLI) matrices were then obtained and graph and relative band power (RBP) analyses were performed. Results: Compared with healthy controls, functional connectivity (FC) in the delta, theta, beta 1 and beta 2 bands significantly increased within the 84 cortical source signals of anti-NMDAR encephalitis patients (p < 0.05) and scalp FC in the alpha band decreased within the 19 electrodes. Additionally, the anti-NMDAR encephalitis group exhibited higher local efficiency and clustering coefficient compared to the healthy control group in the four bands. The slowing band RBP increased while the fast band RBP decreased in multiple-lobes and some of these changes in RBP were correlated with the modified Rankin Scale (mRS) and Mini-mental State Examination (MMSE) in anti-NMDAR encephalitis patients. Conclusions: This study further deepens the understanding of related changes in the abnormal brain network and power spectrum of anti-NMDA receptor encephalitis. The decreased scalp alpha FC may indicate brain dysfunction, while the increased source beta FC may indicate a compensatory mechanism for brain function in anti-NMDAR encephalitis patients. These findings extend understanding of how the brain FN changes from a cortical source perspective. Further studies are needed to detect correlations between altered FNs and clinical features and characterize their potential value for the management of anti-NMDAR encephalitis. [ABSTRACT FROM AUTHOR]

Introduction: This study was designed to analyze clinical and radiographic features of adult patients coexisting with NMDAR-IgG and MOG-IgG. Methods: Eleven adult patients coexisting with NMDAR-IgG and MOG-IgG were collected from Xiangya Hospital, Central South University, between June 2017 and December 2021. Fifty-five patients with anti-NMDAR encephalitis and 49 with MOG-AD were served as controls. Results: Onset age was 27 (IQR 20–34) years old. Seizures and psychotic symptoms were prominent symptoms. Ten of eleven patients presented abnormal T2/FLAIR hyperintensity, mainly involving the cortex, brainstem, and optic nerve. Compared with the NMDAR IgG (+)/MOG IgG (−) group, the NMDAR IgG (+)/MOG IgG (+) group showed more ataxia symptoms (27.3% vs. 3.6%, P = 0.037), while more T2/FLAIR hyperintensity lesions were found in the brainstem (54.5% vs. 7.3%, P < 0.001) and optic nerve (27.3% vs. 1.8%, P = 0.011) with more abnormal MRI patterns (90.9% vs. 41.8%, P = 0.003). In comparison with the NMDAR IgG (−)/MOG IgG (+) group, the NMDAR IgG (+)/MOG IgG (+) group had more seizures (72.7% vs. 24.5%, P = 0.007) and mental symptoms (45.5% vs. 0, P < 0.001). The NMDAR IgG (+)/MOG IgG (+) group tended to be treated with corticosteroids alone (63.6% vs. 20.0%, P = 0.009), more prone to recur (36.5% vs. 7.3%, P = 0.028) and lower mRS score (P = 0.036) at the last follow-up than pure anti-NMDAR encephalitis. Conclusion: The symptoms of the NMDAR IgG (+)/MOG IgG (+) group were more similar to anti-NMDAR encephalitis, while MRI patterns overlapped more with MOG-AD. Detecting both NMDAR-IgG and MOG-IgG maybe warranted in patients with atypical encephalitis symptoms and demyelinating lesions in infratentorial regions. [ABSTRACT FROM AUTHOR]

Patients with autoimmune encephalitis (AE) often developed psychiatric features during the disease course. Many studies focused on the psychiatric characteristic in anti-NMDAR encephalitis (NMDAR-E), but anti-LGI1 encephalitis (LGI1-E) had received less attention regarding the analysis of psychiatric features, and no study compared psychiatric characteristic between these two groups. The clinical data of AE patients (62 NMDAR-E and 20 LGI1-E) who developed psychiatric symptoms were analyzed in this study. In NMDAR-E, the most common higher-level feature was "behavior changes" (60/62, 96.8%) and the lower-level feature "incoherent speech" was observed in 33 patients (33/62, 53.2%), followed by "agitation" (29/62, 46.8%) and "incongruent laughter/crying" (20/62, 32.3%). Similar to NMDAR-E, "behavior changes" was most common in LGI1-E (17/20, 85.0%), but the features of suicidality, eating, and obsessive–compulsive were not reported. The top three lower-level features were visual hallucinations (9/20, 45.0%), incoherent speech (8/20, 40.0%), and mood instability (7/20, 35.0%). The comparative study found that "incongruent laughter/crying", in lower-level features, was more frequently observed in NMDAR-E (32.3% vs. 0%, p = 0.002). Moreover, the Bush Francis Catatonia Rating Scale (BFCRS) assessing the catatonic symptoms in NMDAR-E were higher than LGI1-E, but the 18 item-Brief Psychiatric Rating Scale (BPRS-18) showed no difference in the two groups. In summary, both NMDAR-E and LGI1-E often developed psychiatric symptoms. In contrast with LGI1-E, the psychiatric feature "incongruent laughter/crying" was more frequently associated with NMDAR-E, and catatonic symptoms were more severe in NMDAR-E. [ABSTRACT FROM AUTHOR]

Introduction: Genetic predisposition to autoimmune encephalitis with antibodies against N-methyl-D-aspartate receptor (NMDAR) is poorly understood. Given the diversity of associated environmental factors (tumors, infections), we hypothesized that human leukocyte antigen (HLA) and killer-cell immunoglobulin-like receptors (KIR), two extremely polymorphic gene complexes key to the immune system, might be relevant for the genetic predisposition to anti-NMDAR encephalitis. Notably, KIR are chiefly expressed by Natural Killer (NK) cells, recognize distinct HLA class I allotypes and play a major role in anti-tumor and anti-infection responses. Methods: We conducted a Genome Wide Association Study (GWAS) with subsequent control-matching using Principal Component Analysis (PCA) and HLA imputation, in a multi-ethnic cohort of anti-NMDAR encephalitis (n=479); KIR and HLA were further sequenced in a large subsample (n=323). PCAcontrolled logistic regression was then conducted for carrier frequencies (HLA and KIR) and copy number variation (KIR). HLA-KIR interaction associations were also modeled. Additionally, single cell sequencing was conducted in peripheral blood mononuclear cells from 16 cases and 16 controls, NK cells were sorted and phenotyped. Results: Anti-NMDAR encephalitis showed a weak HLA association with DRB1*01:01~DQA1*01:01~DQB1*05:01 (OR=1.57, 1.51, 1.45; respectively), and DRB1*11:01 (OR=1.60); these effects were stronger in European descendants and in patients without an underlying ovarian teratoma. More interestingly, we found increased copy number variation of KIR2DL5B (OR=1.72), principally due to an overrepresentation of KIR2DL5B*00201. Further, we identified two allele associations in framework genes, KIR2DL4*00103 (25.4% vs. 12.5% in controls, OR=1.98) and KIR3DL3*00302 (5.3% vs. 1.3%, OR=4.44). Notably, the ligands of these KIR2DL4 and KIR3DL3, respectively, HLA-G and HHLA2, are known to act as immune checkpoint with immunosuppressive functions. However, we did not find differences in specific KIR-HLA ligand interactions or HLA-G polymorphisms between cases and controls. Similarly, gene expression of CD56dim or CD56bright NK cells did not differ between cases and controls. Discussion: Our observations for the first time suggest that the HLA-KIR axis might be involved in anti-NMDAR encephalitis. While the genetic risk conferred by the identified polymorphisms appears small, a role of this axis in the pathophysiology of this disease appears highly plausible and should be analyzed in future studies. [ABSTRACT FROM AUTHOR]

Anti-N-methyl D-aspartate receptor (anti-NMDAR) encephalitis is an autoimmune disorder characterized by IgG antibodies targeting NMDAR. The prevalence is remarkably higher in women and some develop the condition during pregnancy. While immunotherapies have shown good outcomes for pregnant mothers and their infants, the impact on early neurodevelopment remains elusive. This study investigates the effects of anti-NMDAR antibody on the development of primary cortical cultures. Anti-NMDAR antibody was administered to the cultures at day in vitro 5 for the following 5 days to assess dendritic branching and arbor complexity, and at day in vitro 14 for measuring the expression of brain-derived neurotrophic factor (BDNF) and synaptic proteins. Immature cultured neurons treated with anti-NMDAR antibody exhibited impaired dendritic branching and arbor complexity. Interestingly, BDNF expression was unaffected in mature neurons. Additionally, GluN1 expression, a mandatory NMDAR subunit, was significantly reduced, while no significant alterations were observed in PSD-95, gephyrin and synaptophysin expression. These findings shed light on the structural and synaptic impacts of anti-NMDAR antibody on immature neurons, providing evidence for their consequences in early neuronal development. [ABSTRACT FROM AUTHOR]

Introduction: Neuroinfection is associated with the deposition of amyloid-beta (Aβ) peptides, and subsequent decrease in cerebrospinal fluid (CSF) amyloid levels. However, whether autoimmune encephalitis involves extracellular deposition of Aβ peptides in the brain is unreported. Methods: We examined CSF amyloid and tau values in adults with anti-N-methyl-D-aspartate receptor encephalitis (NMDAR-E). Forty-two patients with NMDAR-E, 35 patients with viral and bacterial neuroinfections, and 16 controls were included. We measured CSF Aβ1–42 (cAβ1–42), Aβ1–40 (cAβ1–40), t-Tau (ct-Tau), and p-Tau181 (cp-Tau181) levels and assessed their efficacies regarding differential diagnosis and predicting prognosis. Results: NMDAR-E patients had lower cAβ1–42 levels; however, they were higher than those of patients with bacterial meningitis. ct-Tau levels in NMDAR-E patients were lower than those in patients with neuroinfections. No changes were observed in controls. cAβ1–42 and ct-Tau were combined as an excellent marker to distinguish NMDAR-E from neuroinfections. cAβ1–42 levels in NMDAR-E patients were positively correlated with Montreal Cognitive Assessment scores. We observed an inverse relationship between cAβ1–42 levels and modified Rankin Scale scores. Patients with poor outcomes exhibited low cAβ1–42 levels and high levels of several blood parameters. cAβ1–42 was the highest quality biomarker for assessing NMDAR-E prognosis. Correlations were found between cAβ1–42 and some inflammatory indicators. Conclusion: cAβ1–42 was decreased in NMDAR-E patients. cAβ1–42 levels indicated NMDAR-E severity and acted as a biomarker for its prognosis. Combining cAβ1–42 and ct-Tau levels could serve as a novel differential diagnostic marker for NMDAR-E. [ABSTRACT FROM AUTHOR]

Objective: Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis is frequently associated with ovarian teratomas. The diverse clinical presentations and several stages of disease development pose a significant diagnostic challenge for clinicians. The main objective of this research was to show the prevalence of neuropsychiatric symptoms of ovarian-teratoma-associated anti-NMDAR encephalitis and to highlight the importance of multidisciplinary collaboration in the diagnosis, treatment, and prevention of disease progression. Methods: Literature searches were carried out using PubMed, Scopus, and Web of Science Core Collection. The following data were retrieved: authors' names, year of publication, type of study, number and age of patients included, diagnostic methods of disease evaluation, prevalence of anti-NMDAR antibodies, psychiatric manifestations, other symptoms, initial diagnosis, treatment strategies, and histopathology results. Data analyses were performed and considered statistically significant when p

Abstract Background The pathway involving PTEN-induced putative kinase 1 (PINK1) and PARKIN plays a crucial role in mitophagy, a process activated by artesunate (ART). We propose that patients with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis exhibit insufficient mitophagy, and ART enhances mitophagy via the PINK1/PARKIN pathway, thereby providing neuroprotection. Methods Adult female mice aged 8–10 weeks were selected to create a passive transfer model of anti-NMDAR encephalitis. We conducted behavioral tests on these mice within a set timeframe. Techniques such as immunohistochemistry, immunofluorescence, and western blotting were employed to assess markers including PINK1, PARKIN, LC3B, p62, caspase3, and cleaved caspase3. The TUNEL assay was utilized to detect neuronal apoptosis, while transmission electron microscopy (TEM) was used to examine mitochondrial autophagosomes. Primary hippocampal neurons were cultured, treated, and then analyzed through immunofluorescence for mtDNA, mtROS, TMRM. Results In comparison to the control group, mitophagy levels in the experimental group were not significantly altered, yet there was a notable increase in apoptotic neurons. Furthermore, markers indicative of mitochondrial leakage and damage were found to be elevated in the experimental group compared to the control group, but these markers showed improvement following ART treatment. ART was effective in activating the PINK1/PARKIN pathway, enhancing mitophagy, and diminishing neuronal apoptosis. Behavioral assessments revealed that ART ameliorated symptoms in mice with anti-NMDAR encephalitis in the passive transfer model (PTM). The knockdown of PINK1 led to a reduction in mitophagy levels, and subsequent ART intervention did not alleviate symptoms in the anti-NMDAR encephalitis PTM mice, indicating that ART’s therapeutic efficacy is mediated through the activation of the PINK1/PARKIN pathway. Conclusions At the onset of anti-NMDAR encephalitis, mitochondrial damage is observed; however, this damage is mitigated by the activation of mitophagy via the PINK1/PARKIN pathway. This regulatory feedback mechanism facilitates the removal of damaged mitochondria, prevents neuronal apoptosis, and consequently safeguards neural tissue. ART activates the PINK1/PARKIN pathway to enhance mitophagy, thereby exerting neuroprotective effects and may achieve therapeutic goals in treating anti-NMDAR encephalitis.

Abstract Background Persistent somatoform pain disorder (PSPD) is often the initial diagnosis in patients seeking treatment in psychiatric departments, making it challenging to consider organic nervous system diseases. However, autoimmune encephalitis can present with atypical initial symptoms, leading to misdiagnosis or missed diagnosis. Lumbar puncture, with antibody support, plays a crucial role in diagnosing autoimmune encephalitis. Case presentation This report describes a 40-year-old male adult patient who was initially diagnosed with persistent somatoform pain disorder in 2022. The patient reported a reduction in pain while resting on his back. There were no fever or relevant medical history. Despite 8 months of symptomatic treatment, the symptoms did not improve. Moreover, the patient developed confusion, gibberish speech, non-cooperation during questioning, and increased frequency and amplitude of upper limb convulsions. Lumbar puncture revealed elevated protein levels and protein-cell dissociation. The autoimmune encephalitis antibody NMDAR (+) was detected, leading to a diagnosis of autoimmune encephalitis (NMDAR). Conclusion Autoimmune encephalitis (NMDAR), starting with persistent somatoform pain (PSPD), often presents with atypical symptoms and can be easily misdiagnosed. Therefore, it is important to consider the possibility of organic nervous system disease in time, and to test serum or cerebrospinal fluid antibodies to rule out organic nervous system disease after symptomatic treatment of mental disorders is ineffective. This approach facilitates the early diagnosis of autoimmune encephalitis and other underlying organic neurological disorders.

Background: Recently, cases of overlapping encephalitis caused by anti-N-methyl-D-aspartate receptor (anti-NMDAR) and anti-myelin oligodendrocyte glycoprotein (MOG) antibodies have been reported, and their clinical characteristics are gradually becoming clear. Acute-phase treatment typically involves the use of steroids, and although some studies have suggested that steroids can be effective, the extent of their efficacy has not yet been fully explored. Case presentation: We present the case of a 25-year-old man with anti-NMDAR and anti-MOG antibody overlapping encephalitis who showed considerable improvement after steroid treatment. To gain a deeper understanding of the efficacy of steroids in managing this condition, we conducted a literature review of cases of anti-NMDAR and anti-MOG antibody double-positive encephalitis that were treated with steroids during the acute phase. Thirteen cases were analyzed, including a new case diagnosed at our hospital. All patients showed improvement after receiving steroid treatment in the acute phase. Ten patients did not have any sequelae, and nine of them showed a rapid or major response during the acute phase. In contrast, three patients experienced sequelae (mild cognitive decline, visual impairment, and memory impairment, respectively), with their response to steroids in the acute phase being slow or limited. Relapses occurred in five patients, in one patient during steroid tapering, and in another two patients after cessation of steroids. Conclusion: Steroid therapy can be effective in the acute stage of anti-NMDAR and anti-MOG antibody overlapping encephalitis. A positive prognosis may be expected in patients who experience substantial improvement with steroid therapy during the acute phase. [ABSTRACT FROM AUTHOR]

We described a challenging case of anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis in a young girl. Despite enduring months of reduced consciousness with ongoing antibody presence, she ultimately exhibited remarkable improvement within a 5-year follow-up period. Additionally, we conducted a concise review of relevant literature on anti-NMDAR encephalitis, with a specific focus on anti-NMDAR antibodies. Our findings enhance the clinical comprehension of anti-NMDAR encephalitis and offer valuable insights to clinicians for its management. [ABSTRACT FROM AUTHOR]

With the increase in the number of cases of autoimmune encephalitis (AE), the cerebrospinal fluid (CSF) of people living with HIV (PLWH) showing abnormal behavior, cognitive impairment or abnormal movements should be actively screened for the antibody panel of AE. Early recognition and treatment can prevent severe seizures or coma and markedly improve the prognosis of patients. The first-line immunotherapy for AE includes intravenous methylprednisolone and immunoglobulin. However, whether long-time immunosuppressive maintenance therapy is needed is debated. For PLWH, immunosuppressive therapy and even steroids could be more challenging. Here, we review and summarize the clinical characteristics often reported cases and report one case from our center to improve the diagnosis and treatment of anti-N-methyl-d-aspartate receptor encephalitis in PLWH. [ABSTRACT FROM AUTHOR]

Cerebellar ataxia is an uncommon and atypical manifestation of anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, often accompanied by seizures, psychiatric symptoms, and cognitive deficits. Previous cases of isolated brainstem-cerebellar symptoms in patients with anti-NMDAR encephalitis have not been documented. This report presents a case of anti-NMDAR encephalitis in which the patient exhibited cerebellar ataxia, nystagmus, diplopia, positive bilateral pathological signs, and hemiparesthesia with no other accompanying symptoms or signs. The presence of positive CSF anti-NMDAR antibodies further supports the diagnosis. Other autoantibodies were excluded through the use of cell-based assays. Immunotherapy was subsequently administered, leading to a gradual recovery of the patient. [ABSTRACT FROM AUTHOR]

Background: Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a severe autoimmune encephalitis due to immune production of anti-NMDAR antibodies against the NR1 subunit of the NMDA receptor which is present throughout the central nervous system. This condition had been reported to be prevalent in patients with certain medical conditions; however so far, there have been limited systematic reviews and meta-analyses on the prevalence and factors associated. Objective: This study was to determine the prevalence and factors associated with anti-NMDAR encephalitis among affected patients. Material and Methods: The protocol of this study has been registered (2019: CRD42019142002) with the International Prospective Register of Systematic Reviews (PROSPERO). The primary outcome was the incidence or prevalence of anti-NMDAR encephalitis and secondary outcomes were factors associated with anti-NMDAR encephalitis. Results: There were 11 studies and a total of 873 million patients taken from high-risk populations across 11 countries that were included in the primary analysis. The overall pooled prevalence of anti-NMDAR encephalitis among patients with medical conditions was 7.0% (95% CI = 4.4, 9.6). Those with first episode of psychosis or schizophrenia were at a higher risk of developing anti-NMDAR encephalitis with an odds ratio of 5.976 (95% CI = 1.122, 31.825). Conclusion: We found that almost one-tenth of patients with medical conditions had anti-NMDAR encephalitis; particularly those with first episode of psychosis or schizophrenia were among the high-risk medical conditions. [ABSTRACT FROM AUTHOR]

Background: Persistent somatoform pain disorder (PSPD) is often the initial diagnosis in patients seeking treatment in psychiatric departments, making it challenging to consider organic nervous system diseases. However, autoimmune encephalitis can present with atypical initial symptoms, leading to misdiagnosis or missed diagnosis. Lumbar puncture, with antibody support, plays a crucial role in diagnosing autoimmune encephalitis. Case presentation: This report describes a 40-year-old male adult patient who was initially diagnosed with persistent somatoform pain disorder in 2022. The patient reported a reduction in pain while resting on his back. There were no fever or relevant medical history. Despite 8 months of symptomatic treatment, the symptoms did not improve. Moreover, the patient developed confusion, gibberish speech, non-cooperation during questioning, and increased frequency and amplitude of upper limb convulsions. Lumbar puncture revealed elevated protein levels and protein-cell dissociation. The autoimmune encephalitis antibody NMDAR (+) was detected, leading to a diagnosis of autoimmune encephalitis (NMDAR). Conclusion: Autoimmune encephalitis (NMDAR), starting with persistent somatoform pain (PSPD), often presents with atypical symptoms and can be easily misdiagnosed. Therefore, it is important to consider the possibility of organic nervous system disease in time, and to test serum or cerebrospinal fluid antibodies to rule out organic nervous system disease after symptomatic treatment of mental disorders is ineffective. This approach facilitates the early diagnosis of autoimmune encephalitis and other underlying organic neurological disorders. [ABSTRACT FROM AUTHOR]

IntroductionGenetic predisposition to autoimmune encephalitis with antibodies against N-methyl-D-aspartate receptor (NMDAR) is poorly understood. Given the diversity of associated environmental factors (tumors, infections), we hypothesized that human leukocyte antigen (HLA) and killer-cell immunoglobulin-like receptors (KIR), two extremely polymorphic gene complexes key to the immune system, might be relevant for the genetic predisposition to anti-NMDAR encephalitis. Notably, KIR are chiefly expressed by Natural Killer (NK) cells, recognize distinct HLA class I allotypes and play a major role in anti-tumor and anti-infection responses.MethodsWe conducted a Genome Wide Association Study (GWAS) with subsequent control-matching using Principal Component Analysis (PCA) and HLA imputation, in a multi-ethnic cohort of anti-NMDAR encephalitis (n=479); KIR and HLA were further sequenced in a large subsample (n=323). PCA-controlled logistic regression was then conducted for carrier frequencies (HLA and KIR) and copy number variation (KIR). HLA-KIR interaction associations were also modeled. Additionally, single cell sequencing was conducted in peripheral blood mononuclear cells from 16 cases and 16 controls, NK cells were sorted and phenotyped.ResultsAnti-NMDAR encephalitis showed a weak HLA association with DRB1*01:01~DQA1*01:01~DQB1*05:01 (OR=1.57, 1.51, 1.45; respectively), and DRB1*11:01 (OR=1.60); these effects were stronger in European descendants and in patients without an underlying ovarian teratoma. More interestingly, we found increased copy number variation of KIR2DL5B (OR=1.72), principally due to an overrepresentation of KIR2DL5B*00201. Further, we identified two allele associations in framework genes, KIR2DL4*00103 (25.4% vs. 12.5% in controls, OR=1.98) and KIR3DL3*00302 (5.3% vs. 1.3%, OR=4.44). Notably, the ligands of these KIR2DL4 and KIR3DL3, respectively, HLA-G and HHLA2, are known to act as immune checkpoint with immunosuppressive functions. However, we did not find differences in specific KIR-HLA ligand interactions or HLA-G polymorphisms between cases and controls. Similarly, gene expression of CD56dim or CD56bright NK cells did not differ between cases and controls.DiscussionOur observations for the first time suggest that the HLA-KIR axis might be involved in anti-NMDAR encephalitis. While the genetic risk conferred by the identified polymorphisms appears small, a role of this axis in the pathophysiology of this disease appears highly plausible and should be analyzed in future studies.

Abstract With the increase in the number of cases of autoimmune encephalitis (AE), the cerebrospinal fluid (CSF) of people living with HIV (PLWH) showing abnormal behavior, cognitive impairment or abnormal movements should be actively screened for the antibody panel of AE. Early recognition and treatment can prevent severe seizures or coma and markedly improve the prognosis of patients. The first-line immunotherapy for AE includes intravenous methylprednisolone and immunoglobulin. However, whether long-time immunosuppressive maintenance therapy is needed is debated. For PLWH, immunosuppressive therapy and even steroids could be more challenging. Here, we review and summarize the clinical characteristics often reported cases and report one case from our center to improve the diagnosis and treatment of anti-N-methyl-d-aspartate receptor encephalitis in PLWH.

Introduction: Mature cystic teratoma (MCT) is a common type of ovarian tumors that can, in rare cases, undergo malignant transformation. It has been discovered that MCT patients may experience psychiatric symptoms due to the presence of anti-N-methyl-D-aspartate receptor (NMDAR) antibodies, which is the underlying cause of autoimmune encephalitis. Here, we present the first documented case of a patient with anti-NMDAR encephalitis who also had a morphology of low-grade glioma within MCT. Case Report: A 45-year-old woman presented with seizures, altered consciousness, abnormal NMDAR antibody IgG titers, and abnormal brain MRI findings confirm the diagnosis of anti-NMDAR encephalitis. Physical examination revealed an oval mixed echo mass measuring 54 × 37 mm in the left adnexal area on ultrasound of the uterine appendage. The patient underwent laparoscopic left ovarian and fallopian tube resection. The pathological gross examination revealed a pile of grayish-red cystic and solid fragmented tissue measuring 7 × 6 × 2.2 cm. Histological examination revealed characteristic components of MCT. Furthermore, the solid component of the gross tissue showed proliferative and densely arranged astrocytes with cellular atypia, which were positive for GFAP and Olig-2, negative for IDH1 and EMA. And the Ki67 index was approximately 10%, suggesting the presence of low-grade glioma lesions. The patient was diagnosed with malignant transformation of MCT into a morphology of low-grade glioma, not otherwise specified. After the removal of the ovarian tumor, the patient’s psychiatric symptoms improved. Conclusions: Low-grade glioma within MCT is a rare occurrence, and the presence of this malignant transformation in patients with anti-NMDAR encephalitis is even more uncommon.

Objective: Movement disorders (MDs) are common in anti-N-methyl-Daspartate receptor (NMDAR) encephalitis but are poorly studied. This study aimed to investigate the clinical characteristics of MDs and the clinical differences between patients with and without MDs in anti-NMDAR encephalitis. Methods: A retrospective study was conducted on patients with anti-NMDAR encephalitis who were first diagnosed and treated in the First People's Hospital of Yunnan Province from January 2017 to September 2022. According to the presence or absence of MDs, all patients were divided into two groups, and the clinical manifestations, auxiliary examinations, and prognosis of the two groups were compared. Patients in the MDs group were further subgrouped by different ages (<12 years, 12-17 years, and ≥ 18 years) and genders, and the prevalence of each MD was compared in different age and gender groups. Results: (1) In our study there were 64 patients, of whom 76.6% (49/64) presented with MDs; the median age of onset in patients with MDs was 21 (15,35) years and 65.3% (32/49) were female. The three most common MDs were orofacial dyskinesia (OFLD) (67.3%), dystonia (55.1%), and stereotypies (34.7%). Patients <12 years were more likely to experience chorea than patients in other age groups (p = 0.003). (2) Compared with the non-MDs group, patients in the MDs group showed higher rates of prodromal manifestations, autonomic dysfunction, consciousness disorders, as well as pulmonary infection and gastrointestinal dysfunction (all p < 0.05). Peripheral blood neutrophil to lymphocyte ratio (NLR) (p = 0.014), the proportion of cerebrospinal fluid (CSF) NMDAR antibody titers ≥1:32 (p = 0.047), ICU admission rate (p = 0.04), length of stay (p = 0.007), maximum mRS score in the course of disease (p = 0.001) and mRS score at discharge (p = 0.006) in the MDs group were significantly higher than the non-MDs group. Conclusion: MDs associated with anti-NMDAR encephalitis were predominantly hyperkinetic. Chorea occurred more commonly in patients aged <12 years. Patients with MDs were prone to autonomic dysfunction, consciousness disorders, pulmonary infection, and gastrointestinal dysfunction; they had more intense inflammation, more severe disease, and a poorer short-term prognosis. [ABSTRACT FROM AUTHOR]

Introduction: The cases of MOG-AD (MOG antibody-associated disorder) and anti-NMDAR encephalitis overlapping syndrome (MNOS) are rare, especially among pediatric patients, and their clinical understanding is limited. This study aimed to investigate the clinical manifestations, imaging findings, treatments, and prognosis of Chinese pediatric patients who tested positive for anti-NMDAR and MOG antibodies. Methods: This retrospective study enrolled 10 MNOS pediatric patients, 50 MOGAD (anti-NMDAR antibody-negative), and 81 anti-NMDAR encephalitis (MOG antibody-negative) pediatric patients who were admitted from July 2016 to June 2022 and used their clinical data for comparison. Results: The MNOS patients had a significantly lower incidence of psychobehavioral abnormalities and involuntary movements than anti-NMDAR antibody (+)/MOG antibody (-) patients and had a significantly higher incidence of sleep disorders, seizures, and psycho-behavioral abnormalities than MOG antibody (+)/anti-NMDAR antibody (-) patients. The MNOS patients had a significantly higher incidence of MRI abnormalities than the anti-NMDAR antibody (+)/MOG antibody (-) patients, while there was no significant difference in the incidence between the MNOS patients and the MOG antibody (+)/anti-NMDAR antibody (-) patients. No significant difference was seen in the initial mRS score between the three groups of patients. The anti-NMDAR antibody (+)/MOG antibody (-) patients had a higher rate of admission to the ICU, a longer length of in-hospital stay, and a higher rate of introduction to second-line treatment than the other two groups of patients. No significant difference was seen in the mRS score at the last follow-up and in the disease recurrence rate between the three groups. All these patients respond well to immunosuppressive therapy. Discussion: In the presence of psycho-behavioral abnormalities, sleep disorders, and frequent seizures in MOG-AD patients or demyelinating symptoms of the central nervous system or demyelinating lesions on head MRI in anti-NMDAR encephalitis patients, the coexistence of MOG and anti-NMDAR antibodies should be considered and would suggest a diagnosis of MNOS for these patients. Immunotherapy is effective among these patients and should be given possibly earlier. [ABSTRACT FROM AUTHOR]

Anti-N-methyl-D-aspartate receptor encephalitis (anti-NMDARE) is a complex neuropsychiatric syndrome known for its diverse neurological manifestations, often involving psychiatric symptoms and seizures that elevate the risk of suicidal ideation and behavior. We present a case illustrating the potentially lethal nature of anti-NMDARE, wherein an unexpected suicide attempt occurred 10 days after the onset of seizures in a 21-year-old man. Upon arrival at the emergency room, immediate interventions addressed hypovolemic shock, followed by subsequent neurosurgical and orthopedic procedures. Six days after cessation of sedation, the patient exhibited atypical focal seizures, behavioral arrest, psychotic responses, and delusions. Despite normal brain magnetic resonance imaging and cerebrospinal fluid (CSF) analysis results, a high CSF immunoglobulin G index and posterior hypometabolism on brain F-fluorodeoxyglucose positron emission tomography raised suspicion of autoimmune encephalitis. Steroids and intravenous immunoglobulins were administered. A comprehensive evaluation ruled out other conditions. Serum and CSF tests confirmed the presence of anti-NMDAR antibodies. This case highlights the potential lethality of the acute stage of anti-NMDARE, emphasizing the absence of apparent psychiatric symptoms before a suicide attempt. Further studies on suicidality associated with anti-NMDARE are crucial, underscoring the importance of vigilance in cases involving newly diagnosed seizures or psychoses. [ABSTRACT FROM AUTHOR]

Introduction: Mature cystic teratoma (MCT) is a common type of ovarian tumors that can, in rare cases, undergo malignant transformation. It has been discovered that MCT patients may experience psychiatric symptoms due to the presence of anti-N-methyl-D-aspartate receptor (NMDAR) antibodies, which is the underlying cause of autoimmune encephalitis. Here, we present the first documented case of a patient with anti-NMDAR encephalitis who also had a morphology of low-grade glioma within MCT. Case Report: A 45-year-old woman presented with seizures, altered consciousness, abnormal NMDAR antibody IgG titers, and abnormal brain MRI findings confirm the diagnosis of anti-NMDAR encephalitis. Physical examination revealed an oval mixed echo mass measuring 54 × 37 mm in the left adnexal area on ultrasound of the uterine appendage. The patient underwent laparoscopic left ovarian and fallopian tube resection. The pathological gross examination revealed a pile of grayish-red cystic and solid fragmented tissue measuring 7 × 6 × 2.2 cm. Histological examination revealed characteristic components of MCT. Furthermore, the solid component of the gross tissue showed proliferative and densely arranged astrocytes with cellular atypia, which were positive for GFAP and Olig-2, negative for IDH1 and EMA. And the Ki67 index was approximately 10%, suggesting the presence of low-grade glioma lesions. The patient was diagnosed with malignant transformation of MCT into a morphology of low-grade glioma, not otherwise specified. After the removal of the ovarian tumor, the patient's psychiatric symptoms improved. Conclusions: Low-grade glioma within MCT is a rare occurrence, and the presence of this malignant transformation in patients with anti-NMDAR encephalitis is even more uncommon. [ABSTRACT FROM AUTHOR]

Cerebellar ataxia is an uncommon and atypical manifestation of anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, often accompanied by seizures, psychiatric symptoms, and cognitive deficits. Previous cases of isolated brainstem-cerebellar symptoms in patients with anti-NMDAR encephalitis have not been documented. This report presents a case of anti-NMDAR encephalitis in which the patient exhibited cerebellar ataxia, nystagmus, diplopia, positive bilateral pathological signs, and hemiparesthesia with no other accompanying symptoms or signs. The presence of positive CSF anti-NMDAR antibodies further supports the diagnosis. Other autoantibodies were excluded through the use of cell-based assays. Immunotherapy was subsequently administered, leading to a gradual recovery of the patient.

Background: The development of anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis following viral encephalitis, such as Japanese encephalitis, has received increasing attention in recent years. However, the mechanism of anti-NMDAR antibody production following Japanese encephalitis has not been explored. Methods: A peptide from the Japanese encephalitis virus (JEV), which shares a similar amino acid sequence with GluN1, was identified by sequence comparison. We then explored whether active subcutaneous immunization with the JEV peptide could induce the production of anti-NMDAR antibodies and related pathophysiological and behavioral changes in mice. In addition, a published active immune model of anti-NMDAR encephalitis using a GluN1 peptide was used as the positive control. Results: A 6-amino-acid sequence with 83 % similarity between the envelope protein of the JEV (HGTVVI) and GluN1 (NGTHVI) was identified, and the sequence included the N368/G369 region. Active immunization with the JEV peptide induced a substantial and specific immune response in mice. However, anti-NMDAR antibodies were not detected in the serum of mice immunized with the JEV peptide by ELISA, CBA, and TBA. Moreover, mice immunized with the JEV peptide presented no abnormities related to anti-NMDAR antibodies according to western blotting, patch clamp, and a series of behavioral tests. In addition, active immunization with a recently reported GluN1 peptide failed to induce anti-NMDAR antibody production in mice. Conclusions: In this study, the attempt of active immunization with the JEV peptide to induce the production of anti-NMDAR antibodies via molecular mimicry failed. The pathogenesis of anti-NMDAR encephalitis following Japanese encephalitis remains to be elucidated.

Anti N-methyl-D-aspartate receptor (NMDAR) encephalitis is an autoimmune disease that often presents with various neurological and neuropsychiatric symptoms. Although most reported cases occur in children, only a limited number of studies on children are available. The subject of this case report is an 8-month-old female who presented with fever, vomiting, and seizure. She was diagnosed with encephalitis and treated with acyclovir. After 21 days, she showed irritability, seizure, orolingual-facial dyskinesias, choreodystonic movements, hemiparesis, dysphagia, strabismus, lack of interest in light and objects. Clinical signs, neuroimaging findings, and serum analysis of anti-NMDAR antibodies confirmed the diagnosis of anti-NMDAR encephalitis. After the first line of treatment, she showed full recovery. We update the infants with anti-NMDAR encephalitis in the literature. Clinical outcomes suggest that patients with anti-NMDAR encephalitis are mostly poor in the infants, excluding our case. We propose that early and appropriate treatments are critical for timely diagnosis and rapid improvement. [ABSTRACT FROM AUTHOR]

The disruption of the blood–brain barrier (BBB) is hypothesized to be involved in the progression of anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis, but its mechanism is still unclear. Recently, the phosphatidylinositol 3-kinase (PI3K)/threonine kinase (Akt) pathway is involved in the regulation of the BBB in various diseases. This study is aimed to investigate the mechanism of BBB damage and neurobehavior changes in anti-NMDAR encephalitis mice. Female C57BL/6J mice were actively immunized to establish an anti-NMDAR encephalitis mouse model and evaluate the neurobehavior changes of mice. To study its potential mechanism, LY294002 (PI3K inhibitor, 8 mg/kg) and Recilisib (PI3K agonist, 10 mg/kg) were treated by intraperitoneal injection, respectively. Anti-NMDAR encephalitis mice showed neurological deficits, increased BBB permeability, open endothelial tight junctions (TJs), and decreased expression of TJ-related proteins zonula occludens (ZO)-1 and Claudin-5. However, administration of PI3K inhibitor significantly reduced the expression of p-PI3K and p-Akt, improved neurobehavior function, decreased BBB permeability, and upregulated the expressions of ZO-1 and Claudin-5. Furthermore, PI3K inhibition reversed the decline of NMDAR NR1 in the membranes of hippocampal neurons, which reduced the loss of neuron-specific nucleoprotein (NeuN) and microtubule-associated protein 2 (MAP2). In contrast, administration of the PI3K agonist Recilisib showed a tendency to exacerbate BBB breakdown and neurological deficits. Our results showed that the activation of PI3K/Akt, along with the changes in TJ-related proteins ZO-1 and Claudin-5, may be closely related to BBB damage and neurobehavior changes in anti-NMDAR encephalitis mice. PI3K inhibition attenuates BBB disruption and neuronal damage in mice, thereby improving neurobehavior. [ABSTRACT FROM AUTHOR]

Anti–N-methyl-D-aspartate receptor (NMDAR) encephalitis is an autoimmune encephalitis caused by antibodies (Ab) against the GluN1 subunit of the NMDAR. The disease typically presents with a combination of psychiatric and neurological symptoms. Presentation solely with psychiatric symptoms is rare, especially in childhood. After treatment substantial recovery with mild or no residual symptoms is seen in most cases in both children and adults. Relapse occurs in 10%–25% of patients, with recurrent episodes presenting less severe than initial presentation in most cases. We herein describe a child with a pure psychiatric presentation of anti-NMDAR encephalitis. Diagnosis and treatment was delayed because of the atypical presentation. The child relapsed several times and severe residual psychiatric symptoms persisted after recovery. This case illuminates the need to consider the diagnosis of anti-NMDAR encephalitis in both adults and children with an atypical psychiatric presentation. It also demonstrates the need for a multidisciplinary approach and brings attention to the possible severe impact of the disease on long-term psychosocial functioning. [ABSTRACT FROM AUTHOR]

As of December 2020, millions of people have been immunized using vaccines against SARS-CoV-2. A wide range of neurological adverse effects of SARS-CoV-2 vaccines have been reported so far. Here, we report a 23-year-old male who experienced psychiatric symptoms, loss of consciousness, language disintegration, and incontinency that happened 10 days after the first dosage of the COVID-19 AstraZeneca vaccine. Anti-NMDAR Encephalitis was diagnosed based on the results of the autoimmune panel. The patient responded to intravenous dexamethasone very well and experienced no other complications in 6 months of follow-up. Scientific reports of neurological side effects such as anti-NMDAR encephalitis after vaccination are necessary to optimize the safety and effectiveness of SARS-CoV-2 vaccines. [ABSTRACT FROM AUTHOR]

Introduction: Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a common autoimmune encephalitis, and it is associated with psychosis, dyskinesia, and seizures. Anti-NMDAR encephalitis (NMDARE) in juveniles and adults presents different clinical charactreistics. However, the pathogenesis of juvenile anti-NMDAR encephalitis remains unclear, partly because of a lack of suitable animal models. Methods: We developed amodel of juvenile anti-NMDAR encephalitis using active immunization with an amino terminal domain peptide from the GluN1 subunit (GluN1356-385) against NMDARs in 3-week-old female C57BL/6J mice. Results: Immunofluorescence staining suggested that autoantibody levels in the hippocampus increased, and HEK-293T cells staining identified the target of the autoantibodies as GluN1, suggesting that GluN1-specific immunoglobulin G was successfully induced. Behavior assessment showed that the mice suffered significant cognition impairment and sociability reduction, which is similar to what is observed in patients affected by anti-NMDAR encephalitis. The mice also exhibited impaired long-term potentiation in hippocampal CA1. Pilocarpine-induced epilepsy was more severe and had a longer duration, while no spontaneous seizures were observed. Conclusion: The juvenile mouse model for anti-NMDAR encephalitis is of great importance to investigate the pathological mechanism and therapeutic strategies for the disease, and could accelerate the study of autoimmune encephalitis. [ABSTRACT FROM AUTHOR]

Abstract Background Anti-N-methyl-d-aspartate receptor encephalitis is a neuroautoimmune syndrome typically presenting with seizures, psychiatric symptoms, and autonomic dysfunction. Human herpesvirus-7 is often found with human herpesvirus-6 and infects leukocytes such as T-cells, monocytes–macrophages, epithelial cells, and central nervous system cells. The pathogenicity of human herpesvirus-7 is unclear. Cases of anti-N-methyl-d-aspartate receptor encephalitis with human herpesvirus-7 present in cerebrospinal fluid have been documented, but the clinical significance of this finding remains unclear. Case presentation An 11-year-old Caucasian boy was admitted to hospital after a generalized tonic–clonic seizure. Generalized tonic seizures repeated three more times during the day of hospitalization. Blood tests showed minor ongoing inflammation, while brain computed tomography yielded normal results. Brain magnetic resonance imaging showed hyperintense focal alterations in both temporal lobes, hippocampi, and at the base of the right frontal lobe. Positive anti-N-methyl-d-aspartate receptor antibodies were found in both serum and cerebrospinal fluid. Positive novel coronavirus 2 (severe acute respiratory syndrome coronavirus 2) immunoglobulin G antibodies were found in serum. Polymerase chain reaction test for severe acute respiratory syndrome coronavirus 2 was negative. Furthermore, positive human herpesvirus-7 deoxyribonucleic acid was found in cerebrospinal fluid. The patient was treated with acyclovir, human immunoglobulin, and methylprednisolone. The seizures did not repeat, and no psychiatric symptoms were present. The patient made a full recovery. Conclusions We present a pediatric case of anti-N-methyl-d-aspartate receptor encephalitis with atypical clinical presentation. The role of human herpesvirus-7 in neurological disorders remains unclear in immunocompetent patients.

Zhuowei Gong, Dayuan Lao, Fang Huang, Sirao Lv, Fengping Mao, Wen Huang Department of Neurology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, People’s Republic of ChinaCorrespondence: Wen Huang, Department of Neurology, The First Affiliated Hospital of Guangxi Medical University, No. 6 Shuangyong Road, Nanning, Guangxi, 530021, People’s Republic of China, Tel +86-771-5356504, Email hwen1229@163.comPurpose: Disturbance of consciousness is common in patients with severe anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. However, little is known about it. This study aimed to analyze the clinical manifestations and prognostic factors of anti-NMDAR encephalitis with disturbance of consciousness.Methods: In this retrospective study, the clinical features, treatment results, and long-term outcomes of anti-NMDAR encephalitis patients with disturbance of consciousness were analyzed, and multivariate logistic regression was used to analyze the factors affecting their prognosis.Results: In the group with disturbance of consciousness, the incidences of seizures, involuntary movements, pulmonary infection, mechanical ventilation, intensive care unit (ICU) admission, neutrophil-lymphocyte ratio (NLR), abnormal cerebrospinal fluid index, plasma exchange, and immunosuppressive therapy were higher than those in the group without disturbance of consciousness (all P< 0.05). During the follow-up period (median: 36 months, range: 12– 78 months), the modified Rankin scale (mRS) score, the maximum mRS score during hospitalization, the mRS score at discharge, and the mRS score at 12 months after discharge were higher in the disturbance of consciousness group (all P < 0.001). However, there was no significant difference in long-term outcomes and recurrence between the two groups. Multivariate logistic regression analysis showed that mechanical ventilation, elevated IgG index, and delayed immunotherapy were independent risk factors for poor outcomes in patients with anti-NMDAR encephalitis with disturbance of consciousness at 12 months (odds ratio: 22.591, 39.868, 1.195). The receiver operating characteristics (ROC) curve analysis showed that the area under the curve (AUC) of mechanical ventilation, elevated IgG index, and delayed immunotherapy was 0.971 (95% CI=0.934– 1.000, P< 0.001).Conclusion: Mechanical ventilation, elevated IgG index, and delayed immunotherapy may be the influencing factors of poor prognosis of anti-NMDAR encephalitis patients with disturbance of consciousness. Although their condition is relatively serious, most patients with anti-NMDAR encephalitis with disturbance of consciousness will achieve favorable long-term outcomes after long-term treatment.Keywords: anti-NMDAR encephalitis, disturbance of consciousness, severity of disease, prognosis

Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is an antibody-related autoimmune encephalitis. It is characterized by the existence of antibodies against NMDAR, mainly against the GluN1 subunit, in cerebrospinal fluid (CSF). Recent research suggests that anti-NMDAR antibodies may reduce NMDAR levels in this disorder, compromising synaptic activity in the hippocampus. Although anti-NMDAR antibodies are used as diagnostic indicators, the origin of antibodies in the central nervous system (CNS) is unclear. The blood–brain barrier (BBB), which separates the brain from the peripheral circulatory system, is crucial for antibodies and immune cells to enter or exit the CNS. The findings of cytokines in this disorder support the involvement of the BBB. Here, we aim to review the function of NMDARs and the relationship between anti-NMDAR antibodies and anti-NMDAR encephalitis. We summarize the present knowledge of the composition of the BBB, especially by emphasizing the role of BBB components. Finally, we further provide a discussion on the impact of BBB dysfunction in anti-NMDAR encephalitis.

Objective: Anti-N-methyl-D-aspartate receptor encephalitis (anti-NMDARE) is autoimmune encephalitis with a characteristic neuropsychiatric syndrome and persistent cognition deficits even after clinical remission. The objective of this study was to uncover the potential noninvasive and quantified biomarkers related to residual brain distortions in convalescent anti-NMDARE patients. Methods: Based on resting-state electroencephalograms (EEG), both power spectral density (PSD) and brain network analysis were performed to disclose the persistent distortions of brain rhythms in these patients. Potential biomarkers were then established to distinguish convalescent patients from healthy controls. Results: Oppositely configured spatial patterns in PSD and network architecture within specific rhythms were identified, as the hyperactivated PSD spanning the middle and posterior regions obstructs the inter-regional information interactions in patients and thereby leads to attenuated frontoparietal and frontotemporal connectivity. Additionally, the EEG indexes within delta and theta rhythms were further clarified to be objective biomarkers that facilitated the noninvasive recognition of convalescent anti-NMDARE patients from healthy populations. Conclusion: Current findings contributed to understanding the persistent and residual pathological states in convalescent anti-NMDARE patients, as well as informing clinical decisions of prognosis evaluation. [ABSTRACT FROM AUTHOR]

Background: Patients with anti- N -methyl-d-aspartate (NMDA) receptor encephalitis (ANMDARE) show a wide range of behavioral abnormalities and are often mistaken for primary psychiatric presentations. We aimed to determine the behavioral hallmarks of ANMDARE with the use of systematic neuropsychiatric and cognitive assessments. Methods: A prospective study was conducted, with 160 patients admitted to the National Institute of Neurology and Neurosurgery of Mexico, who fulfilled criteria for possible autoimmune encephalitis and/or red flags along a time window of seven years. Cerebrospinal fluid (CSF) antibodies against the NR1 subunit of the NMDAR were processed with rat brain immunohistochemistry and cell-based assays with NMDA expressing cells. Systematic cognitive, neuropsychiatric, and functional assessments were conducted before knowing NMDAR antibodies results. A multivariate analysis was used to compare patients with and without definite ANMDARE according to antibodies in CSF. Results: After obtaining the CSF antibodies results in 160 consecutive cases, 100 patients were positive and classified as having definite ANMDARE. The most frequent neuropsychiatric patterns were psychosis (81%), delirium (75%), catatonia (69%), anxiety-depression (65%), and mania (27%). Cognition was significantly impaired. A total of 34% of the patients had a predominantly neuropsychiatric presentation without seizures. After multivariate analysis, the clinical hallmarks of ANMDARE consisted of a catatonia–delirium comorbidity, tonic-clonic seizures, and orolingual dyskinesia. Conclusions: Our study supports the notion of a neurobehavioral phenotype of ANMDARE characterized by a fluctuating course with psychotic and affective symptoms, catatonic signs, and global cognitive dysfunction, often accompanied by seizures and dyskinesia. The catatonia–delirium comorbidity could be a distinctive neurobehavioral phenotype of ANMDARE. [ABSTRACT FROM AUTHOR]

Abstract Background Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is one of the most prevalent autoimmune encephalitis and is closely related to catatonia. This study aimed to investigate the clinical features and disease outcomes of adult catatonic anti-NMDAR encephalitis patients. Methods Adult patients diagnosed with anti-NMDAR encephalitis between January 2013 and October 2021 were retrospectively enrolled in this study. According to the Bush Francis Catatonia screening instrument (BFCSI), patients were divided into two groups: those with catatonia and those without catatonia. The modified Rankin scale (mRS), Clinical Assessment Scale for Autoimmune Encephalitis (CASE), Neuropsychiatric Inventory (NPI), Patient Health Questionnaire-9 (PHQ-9) and 7-item Generalized Anxiety Disorder Questionnaire (GAD-7) scores were assessed at follow-up. The Mann–Whitney U test (nonparametric), Student’s t test (parametric), and chi-squared test were used to analyse the differences between the two groups. Results Eighty-four patients were recruited, including twenty-five catatonic patients and fifty-nine noncatatonic patients. Among them, 28 had positive antibody only in cerebrospinal fluid (CSF), 4 had positive antibody only in serum and 52 had positive antibody both in CSF and serum. Catatonic patients experienced more disturbance of consciousness (p = 0.01), aggression (p = 0.046) and affective disorders (p = 0.043) than noncatatonic patients. The mRS scores of the catatonia group assessed at admission (p = 0.045) were worse than those of the non-catatonia group. Catatonic patients were more inclined to develop deep vein thrombosis (p = 0.003), decubitus (p = 0.046), pneumonia (p = 0.025), and to be admitted to the intensive care unit (ICU) (p = 0.011) than noncatatonic patients. All patients in the catatonia group received first-line immunotherapy. At the 24-month follow-up, 2 patients in the catatonia group did not achieve good outcomes. At the last follow-up, the catatonia group had more relapses (p = 0.014) and more neuropsychiatric problems (p = 0.035). Conclusions Adult anti-NMDAR encephalitis patients with catatonia present distinct clinical features in disease course and are prone to experience more relapses and long-term neuropsychiatric problems than those without catatonia.

Linda Nguyen, Cynthia Wang Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX, USACorrespondence: Linda Nguyen, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX, 75390, USA, Tel +1-214-645-0136, Fax +1-214-645-8238, Email linda.nguyen2@utsouthwestern.eduAbstract: Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is the most recognized form of autoimmune encephalitis. It is characterized by a constellation of neurologic and psychiatric features along with positive NMDAR antibody, which is more sensitive and specific in CSF than serum. All patients should be screened at least once for neoplasm, with ovarian teratoma being found in most tumor-related cases. In the acute phase, first-line immunotherapy, often a combination of high-dose steroids, immunoglobulins, and/or plasma exchange, is strongly recommended. When first-line therapy fails, escalation to second-line immunotherapy, particularly rituximab, can further improve outcomes and prevent relapses. In refractory cases, additional complementary immunotherapies, such as cyclophosphamide, bortezomib and/or tocilizumab may be considered. Relapses occur in 10– 30% of cases, mostly within the first two years from onset. Individuals should be followed up to determine if chronic maintenance therapy is required.Keywords: anti-NMDAR encephalitis, clinical features, immunotherapies, treatment options

Abstract Background In recent years, there have been an increasing number of reports on overlapping antibodies in autoimmune encephalitis (AE). There are various types of overlapping antibodies, but the clinical significance of each type is not yet clear. Glial antibodies, such as MOG, AQP4, and especially NMDAR, can be detected in patients with AE. However, little is known about the overlapping antibodies of anti-glial fibrillary acidic protein (GFAP), and only a few case reports have described this overlap. Case presentation The patient was a 7-year-old girl with recurrent intermittent fever and seizures, and viral encephalitis was diagnosed at the beginning of the disease. She was discharged after treatment with acyclovir, high-dose immunoglobulins, and valproic acid as an antiseizure medication. Subsequently, the patient still had occasional seizures and abnormal behavior, and the anti-NMDAR antibody test was positive (1:3.2). She was treated with high-dose methylprednisolone and antiseizure therapy. Approximately half a year later, the patient experienced fever and seizures again, serum GFAP IgG was 1:100, and a head MRI indicated new lesions. Improvement was achieved after repeated high-dose methylprednisolone and continuous prednisone anti-inflammatory therapy. Conclusions Anti-NMDAR encephalitis combined with GFAP-IgG is uncommon, and repeated tests for AE-associated antibodies may be required in patients with recurrent encephalitis. Compared with cerebrospinal fluid antibody-positive children, serum GFAP IgG-positive children should be comprehensively diagnosed according to their clinical manifestations. It is worth considering whether overlapping antibody syndrome can still be an issue for patients with AE who recover and have negative antibodies after a few months if disease recurrence and new antibodies are detected.