Anti-N-methyl-d-aspartate receptor encephalitis: insights and future treatment directions.

Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis results in severe neuropsychiatric symptoms and persistent cognitive impairment; however, the underlying mechanism is still not fully understood. The present study utilized the degree centrality (DC), functional connectivity (FC) and multivariate pattern analysis (MVPA) to further explore neurofunctional symptoms in patients with anti-NMDAR encephalitis. A total of 29 patients with anti-NMDAR encephalitis and 26 healthy controls (HCs) were enrolled for neuropsychological assessment and resting-state functional MRI (rs-fMRI) scans. DC, FC and MVPA were examined to investigate cerebral functional activity and distinguish neuroimaging characteristics between the patient and HC groups based on the rs-fMRI data. Compared with the HCs, the patients exhibited cognitive deficits, anxiety and depression. In the DC analysis, the patients exhibited significantly decreased DC strength in the left rectus gyrus, left caudate nucleus (LCN) and bilateral superior medial frontal gyrus, as well as increased DC strength in the cerebellar anterior lobe, compared with the HCs. In the subsequent FC analysis, the LCN showed decreased FC strength in the bilateral middle frontal gyrus and right precuneus. Furthermore, correlation analysis indicated that disrupted cerebral functional activity was significantly correlated with the alerting effect and Hamilton Depression Scale score. Using DC maps and receiver operating characteristic curve analysis, the MVPA classifier exhibited an area under curve of 0.79, and the accuracy classification rate was 76.36%, with a sensitivity of 79.31% and a specificity of 78.18%. The present study revealed that the disrupted functional activity of hub and related networks in the cerebellum, including the default mode network and executive control network, contributed to deficits in cognition and emotion in patients with anti-NMDAR encephalitis. In conclusion, the present study provided imaging evidence and primary diagnostic markers for pathological and compensatory mechanisms of anti-NMDAR encephalitis, with the aim of improving the understanding of this disease.

Evaluation of the Anti-N-Methyl-D-Aspartate Receptor Encephalitis One-Year Functional Status Score in Predicting Functional Outcomes in Pediatric Patients with Anti-N-Methyl-D-Aspartate Receptor Encephalitis

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an autoimmune condition associated with neuropsychiatric and cognitive deficits. Changes in the cingulate cortex may be central to this disorder. This study investigates subregional alterations in the cingulate cortex of patients with anti-NMDAR encephalitis and their relationship to cognitive deficits using functional and perfusion imaging. Thirty-eight patients with anti-NMDAR encephalitis and 30 healthy controls (HC) underwent resting-state MRI and neuropsychological assessments. We measured low-frequency amplitude (fALFF), degree centrality (DC), and cerebral blood flow (CBF) in the cingulate cortex, and performed functional connectivity (FC) and CBF connectivity analyses. We also analyzed the relationship between subregional changes and cognitive impairment. Finally, we applied support vector machines (SVM) to classify patients and controls based on functional and perfusion features. Patients with anti-NMDAR encephalitis showed significant cognitive impairments in memory and executive function, along with anxiety symptoms. Neuroimaging revealed decreased fALFF, DC, and CBF in the left pregenual anterior cingulate cortex (pgACC.L). FC between pgACC.L and several brain regions, including the parahippocampal gyrus and precuneus, was reduced. Additionally, pgACC.L exhibited altered CBF connectivity patterns with other brain regions. Moreover, the changes of fALFF, DC, and FC are related to the impaired cognitive function of patients. SVM classification based on fALFF, DC, and CBF features successfully distinguished patients from controls. Our findings suggest that pgACC abnormalities play a key role in the pathomechanism of anti-NMDAR encephalitis and may serve as biomarkers for disease monitoring.

Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is a recently identified autoimmune disorder with heterogeneous neurological, psychiatric, and cognitive manifestations. The NMDAR is a key signaling node for neurovascular coupling, the mechanism by which cerebral blood perfusion is enhanced to meet local metabolic requirements from increased neuronal activity. Therefore, anti-NMDAR encephalitis may disrupt neurovascular coupling and induce cognitive deficits. This study examined neurovascular coupling and cognitive function in anti-NMDAR encephalitis patients to identify prognostic biomarkers, reveal potential pathogenic mechanisms, and provide clues to possible therapeutic strategies. In this study, twenty-three anti-NMDAR encephalitis patients and thirty healthy controls received neuropsychological testing and multimodal magnetic resonance imaging (MRI). Cerebral blood flow (CBF) was calculated from arterial spin labeling, and regional homogeneity (ReHo) was computed from functional MRI. Pearson's correlation coefficients between CBF and ReHo were calculated to obtain neurovascular coupling. At the whole gray matter level, CBF‒ReHo coupling was reduced in patients compared to healthy controls. At the regional level, CBF‒ReHo was significantly lower among patients in the precentral gyrus, frontal gyrus, insula, cuneus, inferior parietal lobe, supramarginal gyrus, angular gyrus, precuneus, temporal gyrus, and temporal pole. Reduced CBF‒ReHo in the left superior medial frontal gyrus of patients was significantly correlated with a deficit in verbal inhibition control, and the reduced CBF‒ReHo in the left insula was significantly correlated with impaired executive function. In conclusion, anti-NMDAR encephalitis is associated with both global and regional disruptions in neurovascular coupling that may in turn lead to deficits in specific cognitive domains.

Patients with anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis often experience severe symptoms. Resting-state functional MRI (rs-fMRI) has revealed widespread impairment of functional networks in patients. However, the changes in information flow remain unclear. This study aims to investigate the intrinsic functional connectivity (FC) both within and between resting-state networks (RSNs), as well as the alterations in effective connectivity (EC) between these networks. Resting-state functional MRI (rs-fMRI) data were collected from 25 patients with anti-NMDAR encephalitis and 30 healthy controls (HCs) matched for age, sex, and educational level. Changes in the intrinsic functional connectivity (FC) within and between RSNs were analyzed using independent component analysis (ICA). The functional interaction between RSNs was identified by granger causality analysis (GCA). Compared to HCs, patients with anti-NMDAR encephalitis exhibited lower performance on the Wisconsin Card Sorting Test (WCST), both in terms of correct numbers and correct categories. Additionally, these patients demonstrated decreased scores on the Montreal Cognitive Assessment (MoCA). Neuroimaging studies revealed abnormal intra-FC within the default mode network (DMN), increased intra-FC within the visual network (VN) and dorsal attention network (DAN), as well as increased inter-FC between VN and the frontoparietal network (FPN). Furthermore, aberrant effective connectivity (EC) was observed among the DMN, DAN, FPN, VN, and somatomotor network (SMN). Patients with anti-NMDAR encephalitis displayed noticeable deficits in both memory and executive function. Notably, these patients exhibited widespread impairments in intra-FC, inter-FC, and EC. These results may help to explain the pathophysiological mechanism of anti-NMDAR encephalitis.

Allergy in patients with anti-N-methyl-d-aspartate receptor encephalitis

Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is a newly recognized antineuronal antibody-mediated inflammatory brain disease that causes severe psychiatric and neurologic deficits in previously healthy children. The present study was undertaken to describe characteristic clinical features and outcomes in children diagnosed as having anti-NMDAR encephalitis. Consecutive children presenting over a 12-month period with newly acquired psychiatric and/or neurologic deficits consistent with anti-NMDAR encephalitis and evidence of central nervous system (CNS) inflammation were screened. Children were included in the study if they had confirmatory evidence of anti-NMDAR antibodies in the serum and/or cerebrospinal fluid. Features at clinical presentation and results of investigations were recorded. Type and duration of treatment and outcomes at last followup were documented. Seven children were screened, and 3 children with anti-NMDAR encephalitis were identified. All patients presented with neurologic and/or psychiatric abnormalities, seizures, speech disorder, sleep disturbance, and fluctuating level of consciousness. The 2 older patients had more prominent psychiatric features, while the younger child had significant autonomic instability and prominent involuntary movement disorder. None had an underlying tumor. Immunosuppressive therapy resulted in near or complete recovery; however, 2 of the patients had early relapse necessitating re-treatment. Anti-NMDAR encephalitis is an important cause of neuropsychiatric deficits in children, which must be included in the differential diagnosis of CNS vasculitis and other inflammatory brain diseases. Early diagnosis and treatment are essential for neurologic recovery.

BackgroundAnti-N-methyl-D-aspartate (anti-NMDA) receptor encephalitis is a condition that was only identified relatively recently. It often presents in psychiatric settings, with clinical presentations that may overlap with those of other psychiatric disorders such as psychoses secondary to schizophrenia, substance use, or brief delusional disorder. It often presents in women of child bearing age and has a relatively high mortality rate. The treatment approach for anti- NMDA receptor encephalitis is considerably different from that used for other psychiatric and neurological conditions. Early recognition, correct diagnosis, and appropriate management of the condition are of vital importance to the prognosis, including reducing mortality rate, admissions to intensive care units, recurrence, complications of the disease and in some cases, irreversible hippocampal damage.Case report, discussion and management: We present a case that highlights the typical presentation of anti-NMDA receptor encephalitis in a young woman and discuss management and outcome.The N-methyl-Daspartate (NMDA) receptor, which is involved in memory, has also been implicated in the etiology of schizophrenia. While previously not wellknown, there is increasing awareness of anti- NMDA receptor encephalitis as a presentation of otherwise unexplained psychosis in emergency settings. Anti-NMDA receptor encephalitis is an autoimmune disease where the body attacks the receptors. It can present with an array of symptoms, but commonly patients experience psychosis (delusions, disorganization, hallucinations), catatonia, cognitive deficits, movement disorders, altered sensorium, and speech deficits It is 4 times more common in women, and, in over half of the cases, patients present with an ovarian teratoma. The diagnosis can be confirmed with antibodies in the cerebrospinal fluid, as well as changes on magnetic resonance imaging (MRI) and electroencephalogram (EEG). Given the nature of the symptoms and how the disease can mimic a primary psychotic episode, and the high morbidity and mortality associated with this condition, it is important to notice the atypical symptoms of anti-NMDA receptor encephalitis and test appropriately (imaging, EEG, antibody testing) to ensure patients get rapid treatment

Cystatin C (CysC) is associated with many neurodegenerative disorders and autoimmune diseases, but its relationship with anti-N-Methyl-D-aspartate receptor (anti-NMDAR) encephalitis is unknown. Serum levels of CysC were determined in 66 patients with anti-NMDAR encephalitis and 115 healthy controls. Of the 66 patients, 30 had a follow-up evaluation at 3months after admission. Association of CysC with anti-NMDAR encephalitis and its clinical parameters were evaluated in the patients. The serum levels of CysC were significantly lower in patients with anti-NMDAR encephalitis than in controls (0.70±0.13 vs 0.83±0.17mg/mL, P<.001). Disease severity and disease duration were significantly associated with CysC levels. Furthermore, a follow-up evaluation revealed that after treatment anti-NMDAR encephalitis patients had significantly increased serum CysC levels (P<.001) and significantly decreased modified Rankin Scale (mRS) scores (P<.001) compared with before treatment. In addition, a significant negative correlation was observed between the change in CysC levels and the change in mRS scores (r=-.700, P<.001). Our results show that the serum levels of CysC are associated with anti-NMDAR encephalitis and its clinical parameters and that the changes in CysC levels correlate with therapeutic effect. Therefore, our findings provide new insights into the association between serum CysC and anti-NMDAR encephalitis.

Seizure Characteristics, Outcome, and Risk of Epilepsy in Pediatric Anti-N-Methyl-d-Aspartate Receptor Encephalitis

Objective To describe the clinical features, ancillary tests, treatments and outcomes of adult male patients with anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis. Methods Observational study of clinical data, ancillary tests, treatments and outcomes of 5 adult male patients, admitted to our hospital from August 2014 to May 2016 and diagnosed as having anti- NMDAR encephalitis, was carried out. And the pathologic mechanism was discussed combining with literature review. Results All of the 5 adult male patients were not associated with treatoma, 4 patients had significant relevant past medical histories, including purulent meningitis, drug abuse, colon descendens adenocarcinoma after radical resection and idiopathic inflammatory demyelinating disease (IIDD). For ancillary tests, positive virus antibodies were detected in two patients, and one of them presented positive EBV-DNA in CSF sample; one patient presented elevated thyroid autoantibodies in sera sample; four patients presented atypical abnormal brain contrast enhancement MRI, and three of them exhibited punctiform and/or patchy enhancement in brain parenchyma; one of them showed gliacyte proliferation after necrosis and another one presented demyelination. All patients had favorable outcomes after timely immune therapies. Conclusion Adult male patients who are rarely associated with teratomas may trigger by virus infection, other autoimmune or demyelinating diseases; the earlier application of immune therapies, the better the prognosis. Key words: Anti-NMDAR encephalitis; Adult male; Blood brain barrier; Virus infection; Demyelination

Astragalus polysaccharides (APS), a group of bioactive compounds obtained from the natural source Astragalus membranaceus (AM), exhibits numerous pharmacological actions in the central nervous system, such as anti-inflammatory, antioxidant, and immunomodulatory properties. Despite the remarkable benefits, the effectiveness of APS in treating anti- N-methyl-D-aspartate receptor (NMDAR) encephalitis and the corresponding mechanism have yet to be fully understood. As such, this study aims to investigate the impact of APS on anti-NMDAR encephalitis and explore the potential molecular network mechanism. The impact of APS intervention on mice with anti-NMDAR encephalitis was assessed, and the possible molecular network mechanism was investigated utilizing network pharmacology and bioinformatics techniques such as Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG),protein-protein interaction (PPI) network, and molecular docking. Enzymelinked immunosorbent assay (ELISA) was applied to detect the expression of core target proteins. APS significantly ameliorated cognitive impairment and reduced susceptibility to PTZinduced seizures in mice with anti-NMDAR encephalitis, confirming the beneficial effect of APS on anti-NMDAR encephalitis. Seventeen intersecting genes were identified between APS and anti- NMDAR encephalitis. GO and KEGG analyses revealed the characteristics of the intersecting gene networks. STRING interaction in the PPI network was applied to find crucial molecules. The results of molecular docking suggested that APS may regulate interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) as potential targets in anti-NMDAR encephalitis. Furthermore, the levels of IL-1β, IL-6, and TNF-α detected by ELISA in anti-NMDAR encephalitis mice were significantly downregulated in response to the administration of APS. The findings of this study demonstrate the significant role of APS in the treatment of anti-NMDAR encephalitis, as it effectively suppresses inflammatory cytokines. These results suggest that APS has the potential to be considered as a viable herbal medication for the treatment of anti-NMDAR encephalitis.

Objective: Lipid metabolism has been implicated in autoimmune disorders, but its relationship with anti-N-methyl-<smlcap>D</smlcap>-aspartate receptor (anti-NMDAR) encephalitis is unclear. This study examined the association of serum lipids with anti-NMDAR encephalitis. Methods: Serum lipid profiles and C-reactive protein (CRP) were evaluated in 68 patients with anti-NMDAR encephalitis, and 68 age- and sex-matched healthy controls (CTLs). Follow-up evaluations were conducted 3 months after admission in 32 of the 68 patients. Modified Rankin scale (mRS) scores and clinical and cerebrospinal fluid parameters were evaluated in all patients. Results: Compared with CTLs, patients with anti-NMDAR encephalitis had significantly lower serum high-density lipoprotein cholesterol (HDL-C) and apolipoprotein A-I (apoA-I) levels but significantly higher serum apoB levels and apoB/apoA-I ratios. Serum HDL and apoA-I were significantly and negatively associated with serum CRP levels, whereas serum aopB levels and apoB/apoA-I ratios were positively associated with age, CRP levels, and mRS scores. Follow-up evaluations revealed that serum total cholesterol, apoA-I, and HDL-C levels were significantly higher but mRS scores were significantly lower than those before treatment, and that the increased HDL-C levels were significantly and negatively correlated with decreased mRS scores. Conclusion: Serum HDL-C and apoA-I levels are reduced in the initial phase of anti-NMDAR encephalitis and recover after treatment. Further studies about the role of serum lipid in anti-NMDAR encephalitis are needed.

ObjectiveTo detect the alteration of regulatory B cells (Bregs), follicular helper T cells (Tfh), and regulatory T cells (Tregs) frequencies in patients with anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis. Analyze their association with clinical severity and activity, and explore the effects of different immunotherapies on those immune cell subsets.MethodsWe enrolled 21 patients with anti-NMDAR encephalitis, 22 patients with neuromyelitis optica spectrum disorder (NMOSD), 14 patients with idiopathic intracranial hypertension (IIH), and 20 healthy controls (HC) in our study. The frequencies of various immune cell subsets were determined using flow cytometry.ResultsCompared to patients with IIH and HC, the frequencies of CD24hiCD38hi transitional B cells as well as Tregs were significantly lower while the frequency of Tfh was significantly higher in patients with anti-NMDAR encephalitis. The frequency of CD24hiCD38hi transitional B cells was significantly lower in the acute stage than in the recovery stage, and was negatively correlated with the modified Rankin scale (mRS) and the clinical assessment scale for autoimmune encephalitis (CASE). The frequency of CD24hiCD38hi transitional B cells at the last follow-up after rituximab (RTX) treatment was significantly higher than those treated with oral immunosuppressants or untreated. There was no clear difference between anti-NMDAR encephalitis and NMOSD in the above immune cell subsets.ConclusionWe suggested that the frequencies of CD24hiCD38hi transitional B cells and Tregs were decreased while the frequency of Tfh was increased in patients with anti-NMDAR encephalitis. CD24hiCD38hi transitional B cells frequency may be a potential indicator to estimate the disease activity and severity.

Anti-N-methyl-d-aspartate receptor encephalitis in children of Central South China: Clinical features, treatment, influencing factors, and outcomes