Exploring the neuroprotective role of artesunate in mouse models of anti-NMDAR encephalitis: insights from molecular mechanisms and transmission electron microscopy.

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.

The T1-weighted/T2-weighted ratio as a biomarker of anti-NMDA receptor encephalitis.

BACKGROUND: Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis rarely causes visible lesions in conventional MRI, yet advanced imaging detects extensive white matter damage. To improve prognostic capabilities, we evaluate the T1-weighted/T2-weighted (T1w/T2w) ratio, a measure of white matter integrity computable from clinical MRI sequences, in NMDAR encephalitis and examine its associations with cognitive impairment. METHODS: T1-weighted and T2-weighted MRI were acquired cross-sectionally at 3 Tesla in 53 patients with NMDAR encephalitis (81% women, mean age 29 years) and 53 matched healthy controls. Quantitative and voxel-wise group differences in T1w/T2w ratios and associations with clinical and neuropsychological outcomes were assessed. P-values were false discovery rate (FDR) adjusted where multiple tests were conducted. RESULTS: Patients with NMDAR encephalitis had significantly lower T1w/T2w ratios across normal appearing white matter (p=0.009, Hedges' g=-0.51), which was associated with worse verbal episodic memory performance (r=0.39, p=0.005, p(FDR)=0.026). White matter integrity loss was observed in the corticospinal tract, superior longitudinal fascicle, optic radiation and callosal body with medium to large effects (Cohen's d=[0.42-1.17]). In addition, patients showed decreased T1w/T2w ratios in the hippocampus (p=0.002, p(FDR)=0.005, Hedges' g=-0.62), amygdala (p=0.002, p(FDR)=0.005, Hedges' g=-0.63) and thalamus (p=0.010, p(FDR)=0.019, Hedges' g=-0.51). CONCLUSIONS: The T1w/T2w ratio detects microstructural changes in grey and white matter of patients with NMDAR encephalitis that correlate with cognitive performance. Computable from conventional clinical MRI sequences, this measure shows promise in bridging the clinico-radiological dissociation in NMDAR encephalitis and could serve as an imaging outcome measure in clinical trials.

Brain magnetic resonance imaging as predictors in pediatric anti-N-methyl-D-aspartate receptor encephalitis.

OBJECTIVE: To investigate the associations between brain magnetic resonance imaging (MRI) changes and clinical profiles in children with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. METHODS: Clinical data and brain MRI results of children diagnosed with anti-NMDAR encephalitis in Guangzhou Women and Children's Medical Center from October 2014 to June 2022 were retrospectively studied. RESULTS: A total of 143 children (Male: female 54:89) were enrolled, with a mean onset age of 6.8 years (6.8 ± 3.1). 40.6 % (58/143) of patients had abnormal initial brain MRI. Lesions in temporal lobe (34.5 %, 20/58) and frontal lobe (25.9 %, 15/58) were relatively common. Children with abnormal initial brain MRI were prone to have fever (P = 0.023), dystonia (P = 0.037), positive MOG antibodies (P = 0.015), higher cerebrospinal fluid (CSF) white blood cell count (WBC) (P = 0.019) and to receive rituximab treatment (P = 0.037). There were no significant differences in modified Rankin Scale (mRS) scores before immunotherapy, after immunotherapy and at last follow-up between the normal initial brain MRI group and abnormal group. No initial brain MRI changes were found to be associated with relapses. Brain MRI was reviewed in 72 patients at last follow-up with a median follow-up time of 25.5 months and 48.6 % (35/72) of patients had abnormal brain MRI. The mRS score of the group with normal brain MRI at last follow-up was significantly lower than that of the abnormal group. CONCLUSIONS: About 40.0 % of children with anti-NMDAR encephalitis had abnormal initial brain MRI. Initial brain MRI was associated with certain clinical profiles, but not with relapse and prognosis. Around half of patients had abnormal brain MRI at last follow-up and were prone to have higher mRS score.

MRI Features and Their Association With Outcomes in Children With Anti-NMDA Receptor Encephalitis.

OBJECTIVES: How brain MRI lesions associate with outcomes in pediatric anti-NMDA receptor encephalitis (pNMDARE) is unknown. In this study, we correlate T2-hyperintense MRI brain lesions with clinical outcomes in pNMDARE. METHODS: This was a multicenter retrospective cohort study from 11 institutions. Children younger than 18 years with pNMDARE were included. One-year outcomes were assessed by the modified Rankin Score (mRS) with good (mRS ≤2) and poor (mRS ≥3) outcomes. RESULTS: A total of 175 pNMDARE subjects were included, with 1-year mRS available in 142/175 (81%) and 60/175 (34%) had abnormal brain MRIs. The most common T2-hyperintense lesion locations were frontal, temporal, and parietal. MRI features that predicted poor 1-year outcomes included abnormal MRI, particularly T2 lesions in the frontal and occipital lobes. After adjusting for treatment within 4 weeks of onset, improvement within 4 weeks, and intensive care unit admission, MRI features were no longer associated with poor outcomes, but after multiple imputation for missing data, T2 frontal and occipital lesions associated with poor outcomes. DISCUSSION: Abnormal frontal and occipital lesions on MRI may associate with 1-year mRS in pNMDARE. MRI of the brain may be a helpful prognostication tool that should be examined in future studies.

Single-nucleus RNA sequencing unveils critical regulators in various hippocampal neurons for anti-N-methyl-D-aspartate receptor encephalitis.

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a neuropsychiatric disease with variable clinical manifestations caused by NMDAR autoantibody. The underlying molecular underpinnings of this disease are rarely characterized on a genomic scale. Anti-NMDAR encephalitis mainly affects the hippocampus, however, its effect on gene expression in hippocampal neurons is unclear at present. Here, we construct the active and passive immunization mouse models of anti-NMDAR encephalitis, and use single-nucleus RNA sequencing to investigate the diverse expression profile of neuronal populations isolated from different hippocampal regions. Dramatic changes in cell proportions and differentially expressed genes were observed in excitatory neurons of the dentate gyrus (DG) subregion. In addition, we found that ATP metabolism and biosynthetic regulators related genes in excitatory neurons of DG subregion were significantly affected. Kcnq1ot1 in inhibitory neurons and Meg3 in interneurons also changed. Notably, the latter two molecules exhibited opposite changes in different models. Therefore, the above genes were used as potential targets for further research on the pathological process of anti-NMDAR encephalitis. These data involve various hippocampal neurons, which delineate a framework for understanding the hippocampal neuronal circuit and the potential molecular mechanisms of anti-NMDAR encephalitis.

Lymphomatosis cerebri with coexistent anti-N-methyl-D-aspartate receptor antibody: A case report.

Diagnosis of lymphomatosis cerebri (LC) is usually delayed because of its rarity and the need for pathological confirmation. The association of LC with humoral immunity has scarcely been reported. Herein, we present a woman with a 2-week history of dizziness and gait ataxia, followed by diplopia, altered mental status, and spasticity of all limbs. Magnetic resonance imaging (MRI) of the brain showed multifocal lesions involving bilateral subcortical white matter, deep gray structures, and brainstem. Oligoclonal bands and anti-N-methyl-D-aspartate receptor (NMDAR) antibodies were present in cerebrospinal fluid (CSF) twice. She was initially treated with methylprednisolone but still worsening. A stereotactic brain biopsy confirmed the diagnosis of LC. This is a report on the distinctive coexistence of the rare CNS lymphoma variant and the anti-NMDAR antibody.

Reduced resilience of brain state transitions in anti-N-methyl-D-aspartate receptor encephalitis.

Patients with anti-N-methyl-aspartate receptor (NMDA) receptor encephalitis suffer from a severe neuropsychiatric syndrome, yet most patients show no abnormalities in routine magnetic resonance imaging. In contrast, advanced neuroimaging studies have consistently identified disrupted functional connectivity in these patients, with recent work suggesting increased volatility of functional state dynamics. Here, we investigate these network dynamics through the spatiotemporal trajectory of meta-state transitions, yielding a time-resolved account of brain state exploration in anti-NMDA receptor encephalitis. To this end, resting-state functional magnetic resonance imaging data were acquired in 73 patients with anti-NMDA receptor encephalitis and 73 age- and sex-matched healthy controls. Time-resolved functional connectivity was clustered into brain meta-states, giving rise to a time-resolved transition network graph with states as nodes and transitions between brain meta-states as weighted, directed edges. Network topology, robustness and transition cost of these transition networks were compared between groups. Transition networks of patients showed significantly lower local efficiency (t = -2.41, pFDR  = .029), lower robustness (t = -2.01, pFDR  = .048) and higher leap size (t = 2.18, pFDR  = .037) compared with controls. Furthermore, the ratio of within-to-between module transitions and state similarity was significantly lower in patients. Importantly, alterations of brain state transitions correlated with disease severity. Together, these findings reveal systematic alterations of transition networks in patients, suggesting that anti-NMDA receptor encephalitis is characterized by reduced stability of brain state transitions and that this reduced resilience of transition networks plays a clinically relevant role in the manifestation of the disease.

Anti-N-methyl-D-aspartate receptor encephalitis with concurrent human herpes virus-6A deoxyribonucleic acid detection: An autopsy case.

We report an autopsy case of anti-N-methyl-D-aspartate (NMDA) receptor (NMDAR) encephalitis with concurrent human herpes virus-6 (HHV-6) A deoxyribonucleic acid (DNA) detection in cerebrospinal fluid (CSF). A 38-year-old previously healthy Japanese man presented with a generalized seizure. Brain magnetic resonance imaging (MRI) findings were unremarkable, but CSF revealed pleocytosis. On Day 11, HHV-6 DNA was detected in CSF, and IgG antibodies against the NR1 subunit of the NMDAR (GluN1) were subsequently detected. Since HHV-6 encephalitis was initially suspected, the patient was treated with foscarnet and ganciclovir, but the HHV-6A copy number increased from 200 (Day 22) to 2000 copies/mL (Day 47), and the therapy was ineffective. As typical symptoms of anti-NMDAR encephalitis developed, we changed the patient's treatment to combat anti-NMDAR encephalitis. He was repeatedly treated with first-line immunotherapy, and GluN1 antibody titer decreased. He was not treated with second-line immunotherapy because of recurrent infections; he died on Day 310. Postmortem examinations did not show systemic tumors. Microscopic examination of the brain revealed only severe neuronal rarefaction in the hippocampal cornu ammonis (CA) 3-4 areas with gliosis. Early initiation of aggressive immunotherapy may be required in a refractory case of anti-NMDAR encephalitis, even with HHV-6A DNA detection, because the significance of this concurrent detection in autoimmune encephalitis remains unclear.

Brain MRI features of anti-N-methyl-D-aspartate (anti-NMDA) receptor encephalitis secondary to central nervous system infection in adult patients.

BACKGROUND: Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis secondary to central nervous system (CNS) infection is a unique subtype of the autoimmune-mediated disease, of which the imaging features are unclear. PURPOSE: To compare the brain magnetic resonance imaging (MRI) features between the anti-NMDAR encephalitis secondary to CNS infection and that without initial infection. MATERIAL AND METHODS: A total of 70 adult patients with anti-NMDAR encephalitis were retrospectively enrolled (24 in the post-infection group, 46 in the non-infection-related group). Their clinical and imaging features (lesion distribution, lesion shape, enhancement pattern, brain atrophy) were reviewed and summarized. Lesion distributions were compared between the two groups on lesion probability maps. RESULTS: The patients with normal brain MRI scans in the post-infection group were less than those in the non-infection related group (29% vs. 63%; P = 0.0113). Among the 24 patients in the post-infection group, visible lesions were shown at the anti-NMDAR encephalitis onset in 17 patients; lesion distribution was more diffuse than the non-infection-related group, showing higher lesion peak probabilities in the bilateral hippocampus, frontal lobe, temporal lobe, insula, and cingulate. The lesions with contrast enhancement were also more common in the post-infection group than the non-infection-related group (7/13 vs. 2/10). Brain atrophy was observed in eight patients in the post-infection group and three in the non-infection-related group. CONCLUSION: Anti-NMDAR encephalitis secondary to CNS infection has its imaging features-extensive lesion distribution, leptomeningeal enhancement, early atrophy, and necrosis-that could deepen the understanding of the pathophysiology and manifestation of the autoimmune encephalitis besides the classic type.

Gray matter atrophy and corresponding impairments in connectivity in patients with anti-N-methyl-D-aspartate receptor encephalitis.

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a severe autoimmune disease that is commonly accompanied by cognitive impairment and various neurological and psychiatric symptoms, advanced image analyses help explore the pathogenesis of this disease. Therefore, this study aimed to explore specific structural and functional alterations and their relationship with the clinical symptoms of anti-NMDAR encephalitis. In this study, twenty-two patients with anti-NMDAR encephalitis after the acute stage and 29 controls received cognitive assessments and magnetic resonance imaging. Grey matter atrophy was measured using voxel-based morphometry, and functional alterations in abnormal regions were subsequently investigated using resting state functional connectivity (RSFC). Finally, correlation analyses were performed to explore the associations between imaging alterations and cognitive assessments. The patients demonstrated significant gray matter atrophy in the bilateral triangle part of the inferior frontal gyrus (triIFG.L and triIFG.R) and right precuneus, decreased RSFC between triIFG.L and bilateral Heschl gyrus (HES), decreased RSFC between triIFG.R and HES.R, decreased RSFC between right precuneus and left cerebellum, and increased RSFC between triIFG.R and left superior frontal gyrus. Further correlation analyses showed that the gray matter volume in triIFG.R and decreased RSFC between triIFG.L and HES.R were associated with decreased memory scores, whereas decreased RSFC between triIFG.R and HES.R was marginally correlated with the disease course in patients. In conclusion, this study suggests that cognitive impairments in patients with anti-NMDAR encephalitis may be mainly associated with gray matter atrophy and abnormal RSFC in the triIFG. These findings provide new insights into anti-NMDAR encephalitis pathogenesis and help explore potential treatments.

Abnormal Brain Activation During Verbal Memory Encoding in Postacute Anti-N-Methyl-d-Aspartate Receptor Encephalitis.

Background: Patients with postacute anti-N-methyl-D-aspartate (anti-NMDA) receptor encephalitis are often left with permanent memory impairments. Given that NMDA receptors are essential to memory encoding, and encoding processes have been suggested to contribute to the success of memory retrieval, we investigate whether postacute anti-NMDA receptor encephalitis leads to abnormal brain activation during verbal memory encoding and its potential effects on subsequent memory retrieval performance. Methods: To address this issue, this study recruited 21 adult patients with anti-NMDA receptor encephalitis past the acute stage and 22 healthy controls (HCs). Functional magnetic resonance imaging (fMRI) data were collected when they completed an episodic memory task. Results: At the neural level, the patients showed higher brain activation than the HCs in the bilateral hippocampus/parahippocampus (HG/PHG), right superior temporal gyrus (STG), and right thalamus during memory encoding. At the behavioral level, the patients showed worse memory retrieval performance than the HCs. Importantly, greater brain activation in the left HG/PHG during memory encoding was significantly associated with worse memory retrieval performance among the patients. Conclusion: Our findings indicate that postacute anti-NMDA receptor encephalitis is likely related to altered brain activation during memory encoding. Particularly, less memory retrieval performance often observed in patients with postacute anti-NMDA receptor encephalitis may result from abnormal activation in HG during encoding. These observations may enhance our understanding of NMDA receptor dysfunction in the human brain. Impact statement Patients with anti-N-methyl-D-aspartate (anti-NMDA) receptor encephalitis are often left with permanent memory impairments. In this study, brain activation during verbal memory encoding and its potential effects on subsequent memory retrieval performance are addressed using 21 adult patients with postacute anti-NMDA receptor encephalitis and 22 healthy controls. Greater brain activation in the left hippocampus/parahippocampus during memory encoding was significantly associated with worse memory retrieval performance among the patients. These observations enhance our understanding of NMDA receptor dysfunction in the human brain.

Neuropathological Variability within a Spectrum of NMDAR-Encephalitis.

OBJECTIVE: To describe the neuropathological features of N-methyl-D-aspartate receptor (NMDAR)-encephalitis in an archival autopsy cohort. METHODS: We examined four autopsies from patients with NMDAR-encephalitis; two patients were untreated, three had comorbidities: small cell lung cancer, brain post-transplant lymphoproliferative disease (PTLD), and overlapping demyelination. RESULTS: The two untreated patients had inflammatory infiltrates predominantly composed of perivascular and parenchymal CD3+ /CD8- T cells and CD79a+ B cells/plasma cells in basal ganglia, amygdala, and hippocampus with surrounding white matter. The hippocampi showed a significant decrease of NMDAR-immunoreactivity that correlated with disease severity. The patient with NMDAR-encephalitis and immunosuppression for kidney transplantation developed a brain monomorphic PTLD. Inflammatory changes were compatible with NMDAR-encephalitis. Additionally, plasma cells accumulated in the vicinity of the necrotic tumor along with macrophages and activated microglia that strongly expressed pro-inflammatory activation markers HLA-DR, CD68, and IL18. The fourth patient developed demyelinating lesions in the setting of a relapse 4 years after NMDAR-encephalitis. These lesions exhibited the hallmarks of classic multiple sclerosis with radially expanding lesions and remyelinated shadow plaques without complement or immunoglobulin deposition, compatible with a pattern I demyelination. INTERPRETATION: The topographic distribution of inflammation in patients with NMDAR-encephalitis reflects the clinical symptoms of movement disorders, abnormal behavior, and memory dysfunction with inflammation dominantly observed in basal ganglia, amygdala, and hippocampus, and loss of NMDAR-immunoreactivity correlates with disease severity. Co-occurring pathologies influence the spatial distribution, composition, and intensity of inflammation, which may modify patients' clinical presentation and outcome. ANN NEUROL 2021;90:725-737.

Anti-NMDA receptor encephalitis and brain atrophy in children and adults: A quantitative study.

PURPOSE: To determine whether brain atrophy was present in patients with anti-N-methyl-d-aspartate receptor encephalitis (anti-NMDARE) using qualitative and quantitative analyses of brain magnetic resonance imaging (MRI) and to explore clinical differences in patients with anti-NMDARE with or without brain atrophy. METHODS: A retrospective observational study encompassing the serologic, cerebrospinal fluid, and brain MRI data of 23 patients with anti-NMDARE was conducted. Median patient age was 14 years (interquartile range [IQR], 12 years). The cohort included 15 children (<18 years old) and 8 adults (≥18 years old). There were 6 male and 17 female patients. Imaging analysis involved 2 expert readers' observations of MRIs and automated volumetric quantification using NeuroQuant (CorTechs Labs, Inc.) software. RESULTS: Of 23 pediatric and adult patients, 11 patients had 14 brain MRIs that were quantitatively analyzed. Quantitative NeuroQuant volumetric analysis showed atrophy in 9 of 14 MRIs for 7 of 11 patients compared to age-controlled normative data. In these 9 MRIs, atrophy was present in the temporal lobes (n = 9), cerebral cortex (n = 3), and cerebellum (n = 3). Qualitative analysis of 59 MRIs (23 patients) revealed volume loss in 6 patients: 5 with global cerebral and temporal lobe volume loss and 1 with temporal lobe volume loss. No patient showed cerebellar volume loss on qualitative analysis. Mean length of stay in the intensive care unit was not significantly different for patients with or without quantitative volume loss (3.5 [5.2] vs 27.4 [23.4] days; p = 0.08). CONCLUSIONS: In this cohort of patients with anti-NMDARE, quantitative volumetric analysis showed brain atrophy, particularly affecting the temporal lobes, in 64% (7/11) of the patients. Qualitative analysis showed brain atrophy in 26% (6/23). These findings highlight the increased sensitivity of quantitative methods for volume loss detection. Larger studies are needed.

Aberrant multimodal brain networks in patients with anti-NMDA receptor encephalitis.

AIMS: To explore large-scale brain network alterations and examine their clinical and neuropsychological relevance in patients with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. METHODS: Twenty-four patients with anti-NMDAR encephalitis and 26 matched healthy controls (HCs) were enrolled in our study. Based on the multimodal MRI dataset, individual morphological, structural, and functional brain networks were constructed and compared between the two groups at multiple levels. The associations with clinical/neuropsychological variables and the discriminant ability of significant alterations were further studied. RESULTS: Multimodal network analysis revealed that anti-NMDAR encephalitis mainly affected morphological and structural networks, but subtle alterations were observed in functional networks. Intriguingly, decreased network local efficiency was observed for both morphological and structural networks and increased nodal centrality in the lateral orbital gyrus was convergently observed among the three types of networks in the patients. Moreover, the alterations, particularly those from structural networks, accounted largely for cognitive deficits of the patients and could distinguish the diseased individuals from the HCs with excellent performance (area under the curve =0.933). CONCLUSIONS: The current study provides a comprehensive view of characteristic multimodal network dysfunction in anti-NMDAR encephalitis, which is crucial to establish new diagnostic biomarkers and promising therapeutic targets for the disease.

Ovarian teratoma-associated anti-NMDAR encephalitis: a single-institute series of six patients from China.

PURPOSE: Ovarian teratoma-associated anti-N-methyl-D-aspartate receptor encephalitis is a rare disease with uncertain etiology and pathogenesis. The disorder is severe and rare with a great impact on young adults. This study aimed to improve the awareness of the disease from experience in our single center. METHODS: Between July 2012 and December 2019, six patients with ovarian teratoma-associated anti-N-methyl-D-aspartate receptor encephalitis were enrolled in Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University. All patients' data like manifestations, laboratory and radiological data, treatment, and follow-up were reviewed. RESULTS: Typical psychotic symptoms, memory, and consciousness disorders accompanied by seizures were observed in all patients from this study. All six patients showed positive signals in serum and cerebrospinal fluid samples for N-methyl-D-aspartate receptor and received immunotherapy. Three patients underwent unilateral oophorocystectomy and the other three underwent unilateral oophorectomy through minimally invasive surgeries, including laparoscopic and single-port laparoscopic surgeries. The median follow-up time 24.5 months (range from 6 to 93 months). No death occurred. Two patients had recurrent psychotic symptoms while the left four patients had no mental symptoms or tumor recurrence during postoperative follow-up. CONCLUSIONS: For patients with clinical manifestations of unexplained acute psychiatric symptoms accompanied by seizures, memory, and consciousness disorders, the possibility of anti-N-methyl-D-aspartate receptor encephalitis should be considered. To confirm the diagnosis, examinations of anti-N-methyl-D-aspartate receptor antibodies need to be completed as early as possible. Immunotherapy and tumor location should be given in time once the diagnosis is defined. We recommended removing the tumor as soon as possible without concerning whether the patient is in the acute phase or not. The surgical procedure should be decided based on pathology, age, fertility desire, and patients' requirements and it should be ensured that tumors are completely removed during operation. Postoperative follow-up is particularly important.

Solitary juxtacortical lesion associated with anti-N-methyl-D-aspartate receptor encephalitis: a case report.

BACKGROUND: Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis is a severe autoimmune encephalitis mediated by anti-NMDA receptor antibodies. Brain MRI manifestations vary and are non-specific. If there are any lesions, they tend to be diffusely or multifocally distributed. Solitary lesion is relatively rare. CASE PRESENTATION: We report a 16-year-old girl who initially presented with focal seizures but developed severe psychiatric and extrapyramidal symptoms later on. Brain MRI revealed a solitary juxtacortical demyelinating lesion in the left frontal lobe. No enhancement was noted. Electroencephalogram captured epileptiform discharges in the same region. NMDAR IgGs were tested positive in the serum and cerebrospinal fluid. Corticosteroid and intravenous IgG were administered and the patient completely recovered. Brain MRI revealed a fainter lesion in the left frontal lobe. CONCLUSION: In very rare instances, anti-NMDA receptor encephalitis can present with a solitary brain lesion. A full panel of antibodies for autoimmune encephalitis is the key leading to the diagnosis.

Anti-N-methyl-D-aspartate Receptor Encephalitis: a Rare Complication of Ovarian Teratoma.

Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is a potentially life-threatening but reversible autoimmune disorder characterized by psychiatric symptoms, cognitive dysfunction, speech dysfunction, seizures, movement disorder, decreased level of consciousness, and autonomic dysfunction or central hypoventilation. It occurs predominantly in young women and approximately half of them have underlying tumors, mainly ovarian teratoma. A 24-year old woman was admitted because of fever, headache, abnormal movement and decreased mental status. Five cycles of plasmapheresis improved her neurological and mental status. Anti-NMDAR antibodies in her CSF and serum were positive, and computed tomography revealed a 1-cm sized mass suggestive of mature cystic teratoma arising from the right ovary. We promptly performed laparoscopic right ovarian cystectomy. She was discharged after 2 weeks with mild memory deficit. Prompt removal of ovarian teratoma and multidisciplinary care are particularly important for good outcome.

Cryptococcus Meningitis Can Co-occur with Anti-NMDA Receptor Encephalitis.

We herein report a 50-year-old man with alcoholic cirrhosis who developed loss of consciousness and tremor of the upper limbs. Magnetic resonance imaging findings were suggestive of limbic encephalitis with bilateral hippocampal damage, and a cerebrospinal fluid (CSF) examination confirmed anti-N-methyl-D-aspartate (NMDA) and anti-glutamate receptor antibodies. Despite initial corticosteroid therapy, meningeal irritation symptoms appeared, owing to the development of cryptococcal meningitis (CM), diagnosed by the detection of cryptococcal capsular polysaccharide antigen in the follow-up CSF analysis. Cerebral infarction with reversible stenosis of major cerebral arteries during the clinical course was also observed. Following administration of antifungals and corticosteroids, the number of cells in the CSF gradually declined, and NMDA receptor antibodies disappeared. Our study demonstrates the unique coexistence of CM with anti-NMDA receptor encephalitis in adults.

Associations between seizures and MRI in patients with anti-NMDAR encephalitis.

OBJECTIVES: Seizures are a prominent feature of anti-N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis. Nearly half of brain magnetic resonance image (MRI) results are abnormal. The aim of our study was to evaluate the associations between seizures and brain MRI results in patients with anti-NMDAR encephalitis. METHODS: Patients with anti-NMDAR encephalitis were enrolled between January 2015 and December 2018. The patients included were divided into normal and abnormal MRI groups. Seizure outcomes and modified Rankin Scale scores at the 1-year follow-up were assessed. Seizure characteristics and outcomes were compared between groups. RESULTS: Of 35 patients with anti-NMDAR encephalitis, 28 patients (80%) had reported seizures in the acute phase. Patients with abnormal MRI findings more frequently had focal seizures than patients with normal MRI findings (72.7% vs 17.6%, P < .01). The incidence of patients treated with 2 or more antiepileptic drugs was higher in the normal MRI group than in the abnormal MRI group (100% vs 45.4%, P < .01). The onset-immunotherapy time was shorter in the abnormal MRI group than in the normal MRI group (P < .05). There were no statistically significant differences in seizure outcomes between the normal and abnormal MRI groups (P > .05). CONCLUSIONS: Focal seizures were most common in patients with abnormal MRI lesions. In the acute stage of the disease, the abnormal MRI group was more likely than the normal MRI group to achieve seizure control. Abnormal MRI findings did not affect the overall good prognosis of patients with anti-NMDAR encephalitis with seizures.

Clinical analysis of anti-NMDAR encephalitis combined with MOG antibody in children.

OBJECTIVE: To analyze the clinical features in children with anti-NMDAR encephalitis combined with myelin oligodendrocyte glycoprotein antibody (MOG ab). METHODS: Clinical data of 7 children with anti-NMDAR encephalitis combined with MOG ab(+) were collected in Guangzhou Women and Children's Medical Center from January, 2016 to June, 2019. Children with NMDAR ab(+)/MOG ab(-) and MOG ab(+)/NMDAR ab(-) were randomly selected as controls. RESULTS: Onset age was 6.0 (IQR 5.0-7.0) years old, male to female was 2:5. Prominent symptoms include abnormal mental behavior (7/7), sleep disorder (6/7), speech disorder (6/7), involuntary movement (4/7) and paralysis (4/7). There were significant differences between NMDAR ab(+)/MOG ab(+) group versus MOG ab(+)/NMDAR ab(-) and NMDAR ab(+)/MOG ab(-) group versus MOG ab(+)/NMDAR ab(-) group (P< 0.0167, Fisher exact tests) in abnormal mental behavior, sleep disorder, speech disorder and involuntary movement. 1 case developed anti-NMDAR encephalitis 1 year after recovery from MOG ab related acute disseminated encephalomyelitis (ADEM). 4 cases developed anti-NMDAR encephalitis and MOG ab related ADEM simultaneously, with 2 cases relapsed. 2 cases were anti-NMDAR encephalitis with only MOG ab positive. In terms of MRI, there were differences in subcortical white matter, basal ganglia and brainstem (P < 0.0167, Fisher exact tests) between NMDAR ab(+)/MOG ab(+) group versus NMDAR ab(+)/MOG ab(-) (P < 0.0001) and NMDAR ab(+)/MOG ab(-) group versus MOG ab(+)/NMDAR ab(-) group(P<0.0001). There were significant differences in MOG antibody titer (Z = -=2.03, P = 0.042) and duration (Z = -1.97, P = 0.049) between relapsed and non-relapsed patients. 3 cases had neurological sequelae. The differences of NMDAR antibody titer (Z = -2.22, P = 0.026) and duration (Z = -2.18, P = 0.029) were significant between patients with and without neurological sequelae. CONCLUSION: NMDAR and MOG antibodies can coexist in children with autoimmune encephalitis. Double antibody positive subjects had more overlaps in clinical manifestations with NMDAR encephalitis, and more overlaps in MRI changes with MOG ab related disease. Higher persistent MOG antibody titer may indicate recurrence, while higher persistent NMDAR antibodies titer may cause neurological sequelae.