Anti-NMDA Receptor Encephalitis, Human Papillomavirus, and microRNA.

BACKGROUND: Anti-N-methyl-d-aspartate (Anti-NMDA) receptor encephalitis is a rare autoimmune disease, which is caused by antibodies attacking NMDA receptors in the brain. Previous studies revealed that this disorder might be induced by vaccination. Vaccination is the most useful strategy to prevent human or animal infectious diseases. MATERIALS AND METHODS: Although vaccines can produce immunity against diseases, at low risk, they may trigger serious adverse events. Anti-NMDA receptor encephalitis has been studied to be related to the H1N1 (influenza A virus subtype H1N1), tetanus/diphtheria/ pertussis and polio vaccine, Japanese encephalitis, yellow fever, and coronavirus disease 2019 (COVID-19) vaccination. Several cases have been reported that anti-NMDA receptor encephalitis could also be triggered by the human papillomavirus (HPV) vaccine. However, there is a lack of studies to investigate the underlying mechanism. RESULT: In this paper, the association between anti-NMDA receptor encephalitis and HPV vaccination is discussed in terms of their microRNA (miRNA) biomarkers. Phylogenetic tree and distance similarity analyses are used to explore the relationship between their miRNA biomarkers. The results show a higher degree of similarity between miRNA biomarkers associated with HPV and anti-NMDA receptor encephalitis or related vaccines when compared to the overall miRNAs. It indicates that while the risk of HPV triggering anti-NMDA receptor encephalitis is low, a connection between anti-NMDA receptor encephalitis and HPV vaccination cannot be ruled out. CONCLUSION: This finding suggests that in cases where individuals receiving HPV vaccination experience psychiatric or neurological symptoms, it should be considered to diagnose anti-NMDA receptor encephalitis, given the exclusion of other possible complications.

Blood and CSF findings of cellular immunity in anti-NMDAR encephalitis.

OBJECTIVES: To investigate the immunopathogenic mechanisms of anti-N-methyl-D-aspartate receptor encephalitis (NMDAR-E) by characterizing the changes of immune cells in both peripheral blood (PB) and cerebrospinal fluid (CSF) of patients with NMDAR-E. METHODS: Cytology and flow cytometry were used to explore and compare different immunological parameters in PB and CSF of patients with NMDAR-E, viral encephalitis (VE) and healthy volunteers. Moreover, different models were established to assess the possibility of identifying NMDAR-E patients based on PB and CSF parameters. RESULTS: The neutrophil counts and monocyte-to-lymphocyte ratios (MLR) in PB are higher in NMDAR-E patients than in both VEs and controls (P < 0.001, respectively), while the percentages of CD3 + T, CD4 + T lymphocytes, and the leukocytes count in CSF were lower in NMDAR-Es than in VEs (P < 0.01, respectively). The higher percentages of CD8 + T cells in blood and CSF were both correlated with more severe NMDAR-E (P < 0.05, respectively). The poor neurological status group had significantly higher PB leukocytes but lower CSF leukocyte count (P < 0.05). Longitudinal observations in patients with NMDAR-E showed a decreasing trend of leukocyte count, neutrophils count, neutrophil-to-monocyte ratios (NMR), and neutrophil-to-lymphocyte ratios (NLR) with the gradual recovery of neurological function. CONCLUSIONS: The expression patterns of T lymphocyte subsets were different in patients with NMDAR-E and viral encephalitis. The changing trends of leukocyte and lymphocyte populations in peripheral blood and cerebrospinal fluid may provide clues for the diagnosis of different types of encephalitides, including NMDARE, and can be used as immunological markers to assess and predict the prognosis.

MyD88-mediated signaling is critical for the generation of seizure responses and cognitive impairment in a model of anti-N-methyl-D-aspartate receptor encephalitis.

OBJECTIVE: We previously demonstrated that interleukin-1 receptor-mediated immune activation contributes to seizure severity and memory loss in anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. In the present study, we assessed the role of the myeloid differentiation primary response gene 88 (MyD88), an adaptor protein in Toll-like receptor signaling, in the key phenotypic characteristics of anti-NMDAR encephalitis. METHODS: Monoclonal anti-NMDAR antibodies or control antibodies were infused into the lateral ventricle of MyD88 knockout mice (MyD88-/- ) and control C56BL/6J mice (wild type [WT]) via osmotic minipumps for 2 weeks. Seizure responses were measured by electroencephalography. Upon completion of the infusion, the motor, anxiety, and memory functions of the mice were assessed. Astrocytic (glial fibrillary acidic protein [GFAP]) and microglial (ionized calcium-binding adaptor molecule 1 [Iba-1]) activation and transcriptional activation for the principal inflammatory mediators involved in seizures were determined using immunohistochemistry and quantitative real-time polymerase chain reaction, respectively. RESULTS: As shown before, 80% of WT mice infused with anti-NMDAR antibodies (n = 10) developed seizures (median = 11, interquartile range [IQR] = 3-25 in 2 weeks). In contrast, only three of 14 MyD88-/- mice (21.4%) had seizures (0, IQR = 0-.25, p = .01). The WT mice treated with antibodies also developed memory loss in the novel object recognition test, whereas such memory deficits were not apparent in MyD88-/- mice treated with anti-NMDAR antibodies (p = .03) or control antibodies (p = .04). Furthermore, in contrast to the WT mice exposed to anti-NMDAR antibodies, the MyD88-/- mice had a significantly lower induction of chemokine (C-C motif) ligand 2 (CCL2) in the hippocampus (p = .0001, Sidak tests). There were no significant changes in the expression of GFAP and Iba-1 in the MyD88-/- mice treated with anti-NMDAR or control antibodies. SIGNIFICANCE: These findings suggest that MyD88-mediated signaling contributes to the seizure and memory phenotype in anti-NMDAR encephalitis and that CCL2 activation may participate in the expression of these features. The removal of MyD88 inflammation may be protective and therapeutically relevant.

Cortical atrophy in early-stage patients with anti-NMDA receptor encephalitis: a machine-learning MRI study with various feature extraction.

Conventional brain magnetic resonance imaging (MRI) of anti-N-methyl-D-aspartate-receptor encephalitis (NMDARE) is non-specific, thus showing little differential diagnostic value, especially for MRI-negative patients. To characterize patterns of structural alterations and facilitate the diagnosis of MRI-negative NMDARE patients, we build two support vector machine models (NMDARE versus healthy controls [HC] model and NMDARE versus viral encephalitis [VE] model) based on radiomics features extracted from brain MRI. A total of 109 MRI-negative NMDARE patients in the acute phase, 108 HCs and 84 acute MRI-negative VE cases were included for training. Another 29 NMDARE patients, 28 HCs and 26 VE cases were included for validation. Eighty features discriminated NMDARE patients from HCs, with area under the receiver operating characteristic curve (AUC) of 0.963 in validation set. NMDARE patients presented with significantly lower thickness, area, and volume and higher mean curvature than HCs. Potential atrophy predominately presented in the frontal lobe (cumulative weight = 4.3725, contribution rate of 29.86%), and temporal lobe (cumulative weight = 2.573, contribution rate of 17.57%). The NMDARE versus VE model achieved certain diagnostic power, with AUC of 0.879 in validation set. Our research shows potential atrophy across the entire cerebral cortex in acute NMDARE patients, and MRI machine learning model has a potential to facilitate the diagnosis MRI-negative NMDARE.

Glucocorticoid-dependent multiple sclerosis overlapping anti-NMDA receptor encephalitis: a case report and literature review update.

BACKGROUND: Previous studies suggest a relationship between central nervous system inflammatory demyelinating diseases and anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis. Also, the overlap between anti-NMDAR encephalitis and multiple sclerosis (MS) has been reported. However, the pathogenesis and clinical characteristics are still obscure. CASE PRESENTATION: A 33-year-old woman presented with diplopia and sensory ataxia at the onset. The cerebrospinal fluid (CSF) anti-NMDAR antibodies were positive (1:3.2), and nuclear magnetic resonance imaging (MRI) showed bilateral centrum ovale and lateral ventricle demyelinating lesions. Therefore, she was diagnosed with anti-NMDAR encephalitis. After administering intravenous immunoglobulin and oral prednisone, her lesions disappeared, and symptoms were relieved. The condition was maintained with a low dose of prednisone, but her lesions reappeared on MRI. Consequently, immunomodulatory therapy of mycophenolate mofetil was initiated. However, she developed dysarthria and right limb ataxia after 10 months with a positive CSF anti-NMDAR antibody (1:1) and positive oligoclonal band. The MRI showed symmetrical multiple demyelinating lesions. Considering the MS diagnosis, her neurological dysfunction again improved significantly after intravenous methylprednisolone. Unfortunately, her symptoms aggravated for the second time when teriflunomide was started. Finally, her condition was controlled again with oral prednisone. CONCLUSIONS: Consistent with previous cases of overlapping anti-NMDAR encephalitis and MS, patients often show atypical symptoms on MRIs and immunological tests. The overlap cannot be arbitrarily treated because of the recurrence of previous diseases. Long-term follow-up, dynamic antibody monitoring, and MRI examination are crucial for these patients. The special dependency of the patient on glucocorticoids in this study has been rarely reported, which may guide the treatment of insensitivity to disease-modifying therapy in recurrent overlapping anti-NMDAR encephalitis and MS.

Single-cell RNA sequencing reveals diverse B cell phenotypes in patients with anti-NMDAR encephalitis.

BACKGROUNDS: Anti-N-methyl-D-aspartate receptor encephalitis (NMDAR-E) is a severe autoimmune disorder characterized by prominent psychiatric symptoms. Although the role of NMDAR antibodies in the disease has been extensively studied, the phenotype of B cell subsets is still not fully understood. METHODS: We utilized single-cell RNA sequencing, single-cell B cell receptor sequencing (scBCR-seq), bulk BCR sequencing, flow cytometry, and enzyme-linked immunosorbent assay to analyze samples from both NMDAR-E patients and control individuals. RESULTS: The cerebrospinal fluid (CSF) of NMDAR-E patients showed significantly increased B cell counts, predominantly memory B (Bm) cells. CSF Bm cells in NMDAR-E patients exhibited upregulated expression of differential expression genes (DEGs) associated with immune regulatory function (TNFRSF13B and ITGB1), whereas peripheral B cells upregulated DEGs related to antigen presentation. Additionally, NMDAR-E patients displayed higher levels of IgD- CD27- double negative (DN) cells and DN3 cells in peripheral blood (PB). In vitro, DN1 cell subsets from NMDAR-E patients differentiated into DN2 and DN3 cells, while CD27+ and/or IgD+ B cells (non-DN) differentiated into antibody-secreting cells (ASCs) and DN cells. NR1-IgG antibodies were found in B cell culture supernatants from patients. Differential expression of B cell IGHV genes in CSF and PB of NMDAR-E patients suggests potential antigen class switching. CONCLUSION: B cell subpopulations in the CSF and PB of NMDAR-E patients exhibit distinct compositions and transcriptomic features. In vitro, non-DN cells from NMDAR-E can differentiate into DN cells and ASCs, potentially producing NR1-IgG antibodies. Further research is necessary to investigate the potential contribution of DN cell subpopulations to NR1-IgG antibody production.

Brazilian autoimmune encephalitis network (BrAIN): antibody profile and clinical characteristics from a multicenter study.

Background: The frequency of antibodies in autoimmune encephalitis (AIE) may vary in different populations, however, data from developing countries are lacking. To describe the clinical profile of AIE in Brazil, and to evaluate seasonality and predictors of AIE in adult and pediatric patients. Methods: We evaluated patients with possible AIE from 17 centers of the Brazilian Autoimmune Encephalitis Network (BrAIN) between 2018 and 2022. CSF and serum were tested with TBAs and CBAs. Data on clinical presentation, complementary investigation, and treatment were compiled. Seasonality and predictors of AIE in adult and pediatric populations were analyzed. Results: Of the 564 patients, 145 (25.7%) were confirmed as seropositive, 69 (12.23%) were seronegative according to Graus, and 58% received immunotherapy. The median delay to diagnosis confirmation was 5.97 ± 10.3 months. No seasonality variation was observed after 55 months of enrolment. The following antibodies were found: anti-NMDAR (n=79, 54%), anti-MOG (n=14, 9%), anti-LGI1(n=12, 8%), anti-GAD (n=11, 7%), anti-GlyR (n=7, 4%), anti-Caspr2 (n=6, 4%), anti-AMPAR (n=4, 2%), anti-GABA-BR (n=4, 2%), anti-GABA-AR (n=2, 1%), anti-IgLON5 (n=1, 1%), and others (n=5, 3%). Predictors of seropositive AIE in the pediatric population (n=42) were decreased level of consciousness (p=0.04), and chorea (p=0.002). Among adults (n=103), predictors of seropositive AIE were movement disorders (p=0.0001), seizures (p=0.0001), autonomic instability (p=0.026), and memory impairment (p=0.001). Conclusion: Most common antibodies in Brazilian patients are anti-NMDAR, followed by anti-MOG and anti-LGI1. Only 26% of the possible AIE patients harbor antibodies, and 12% were seronegative AIE. Patients had a 6-month delay in diagnosis and no seasonality was found. Findings highlight the barriers to treating AIE in developing countries and indicate an opportunity for cost-effect analysis. In this scenario, some clinical manifestations help predict seropositive AIE such as decreased level of consciousness, chorea, and dystonia among children, and movement disorders and memory impairment among adults.

Temporal transformer-spatial graph convolutional network: an intelligent classification model for anti N-methyl-D-aspartate receptor encephalitis based on electroencephalogram signal.

Encephalitis is a disease typically caused by viral infections or autoimmunity. The most common type of autoimmune encephalitis is anti-N-methyl-D-aspartate receptor (NMDAR) antibody-mediated, known as anti-NMDA receptor encephalitis, which is a rare disease. Specific EEG patterns, including "extreme delta brush" (EDB), have been reported in patients with anti-NMDA receptor encephalitis. The aim of this study was to develop an intelligent diagnostic model for encephalitis based on EEG signals. A total of 131 Participants were selected based on reasonable inclusion criteria and divided into three groups: health control (35 participants), viral encephalitis (58 participants), and anti NMDAR receptor encephalitis (55 participants). Due to the low prevalence of anti-NMDAR receptor encephalitis, it took several years to collect participants' EEG signals while they were in an awake state. EEG signals were collected and analyzed following the international 10-20 system layout. We proposed a model called Temporal Transformer-Spatial Graph Convolutional Network (TT-SGCN), which consists of a Preprocess Module, a Temporal Transformer Module (TTM), and a Spatial Graph Convolutional Module (SGCM). The raw EEG signal was preprocessed according to traditional procedures, including filtering, averaging, and Independent Component Analysis (ICA) method. The EEG signal was then segmented and transformed using short-time Fourier transform (STFT) to produce concatenated power density (CPD) maps, which served as inputs for the proposed model. TTM extracted the time-frequency features of each channel, and SGCM fused these features using graph convolutional methods based on the location of electrodes. The model was evaluated in two experiments: classification of the three groups and pairwise classification among the three groups. The model was trained using two stages and achieved the performance, with an accuracy of 82.23%, recall of 80.75%, precision of 82.51%, and F1 score of 81.23% in the classification of the three groups. The proposed model has the potential to become an intelligent auxiliary diagnostic tool for encephalitis.

Elevated blood and cerebrospinal fluid biomarkers of microglial activation and blood‒brain barrier disruption in anti-NMDA receptor encephalitis.

BACKGROUND: Anti-NMDA receptor (NMDAR) encephalitis is an autoimmune disease characterized by complex neuropsychiatric syndrome and cerebrospinal fluid (CSF) NMDAR antibodies. Triggering receptor expressed on myeloid cells 2 (TREM2) has been reported to be associated with inflammation of the central nervous system (CNS). Matrix metalloproteinase-9 (MMP9) and cluster of differentiation (CD44) were measured to evaluate blood‒brain barrier (BBB) permeability in anti-NMDAR encephalitis. The roles of microglial activation and BBB disruption in anti-NMDAR encephalitis are not well known. FINDINGS: In this work, we detected increased expression levels of CSF sTREM2, CSF and serum CD44, and serum MMP9 in anti-NMDAR encephalitis patients compared with controls. CSF sTREM2 levels were positively related to both CSF CD44 levels (r = 0.702, p < 0.0001) and serum MMP9 levels (r = 0.428, p = 0.021). In addition, CSF sTREM2 levels were related to clinical parameters (modified Rankin Scale scores, r = 0.422, p = 0.023, and Glasgow Coma Scale scores, r = - 0.401, p = 0.031). CONCLUSION: Increased sTREM2 levels in CSF as well as increased CD44 and MMP9 in serum and CSF reflected activation of microglia and disruption of the BBB in anti-NMDAR encephalitis, expanding the understanding of neuroinflammation in this disease. The factors mentioned above may have potential as novel targets for intervention or novel diagnostic biomarkers.

Nonparaneoplastic anti-NMDA receptor encephalitis in an adolescent girl: a case report.

Anti-N-methyl D-aspartate (NMDA) receptor encephalitis is an autoimmune neurologic disorder that classically presents with psychiatric, neurologic, and autonomic symptoms, often with a viral prodrome. Case presentation: A 17-year-old female presented to the hospital with an 11-day history of fever, altered behavior, abnormal body movements, and altered sensorium. Upon examination, she was found to be febrile, tachycardic, and tachypneic, with a Glasgow Coma Scale score of 8. Discussion: The diagnosis of anti-NMDA receptor encephalitis is usually confirmed by the presence of anti-NMDA receptor antibodies in the cerebrospinal fluid. The first-line treatment options include steroids, intravenous immunoglobulin, and plasmapheresis, while second-line therapies such as rituximab and cyclophosphamide may be necessary for some patients. While most patients respond well to treatment, complications can arise, and as in this case, death can occur. Conclusion: New onset symptoms like alteration in behavior, abnormal body movement, altered sensorium, and psychiatric symptoms in a young female should raise suspicion of this disease. Immunotherapy is promising; however, anticipation and management of complication are essential in reducing mortality.

Sleep Characteristics in Pediatric Anti-N-methyl-d-aspartate (NMDA) Receptor Encephalitis: A Retrospective Cohort Study.

Background: Rates of sleep problems in children with anti-N-methyl-d-aspartate (NMDA) receptor encephalitis are unknown. Methods: We used a retrospective observational cohort database of children with a diagnosis of NMDA receptor encephalitis at a single freestanding institution. One-year outcomes were assessed with the pediatric modified Rankin Score (mRS), with 0 to 2 as good and 3 or greater as poor outcome. Results: Ninety-five percent (39/41) of children with NMDA receptor encephalitis had sleep dysfunction at onset; 34% (11/32) reported sleep problems at 1 year. Sleep problems at onset and propofol use were not associated with poor outcomes at 1 year. Poor sleep at 1 year correlated with mRS scores (range 2-5) at 1 year. Discussion: High rates of sleep dysfunction occur in children with NMDA receptor encephalitis. Persistent sleep problems at 1 year may correlate with outcomes as assessed by mRS at 1 year. Further studies comparing the relationship of poor sleep with outcomes in NMDA receptor encephalitis are needed.

Encephalitis in adults in the Auckland and Northland regions of New Zealand, 2009 to 2018.

We conducted a retrospective study to determine the incidence and frequency of different subtypes of encephalitis in patients aged 15 and older in the Auckland and Northland regions of New Zealand between 2009 and 2018. Residents in Auckland and Northland presenting with encephalitis between 2009 and 2018 were identified from three overlapping databases: positive cerebrospinal fluid (CSF) viral polymerase chain reaction (PCR) tests, CSF neuronal antibody requests, and CSF neuronal antibody tests sent overseas. A diagnosis of autoimmune encephalitis required fulfilment of diagnostic criteria published by Graus and colleagues (2016). One hundred and thirty-six (69, 50.7% female) patients met study inclusion criteria. The median age was 59 (range 15-92). The annual incidence was 1.10 cases per 100,000 person-years. Of these 136 patients, 56 (41.2%) had an infectious aetiology, with varicella zoster (26, 46.4%) and herpes simplex (23, 41.1%) being the most common agents. Autoimmune encephalitis was diagnosed in 32 patients (23.5%). LGI-1 antibody was the most commonly identified neuronal autoantibody (10 patients, 13.2%). Forty-eight patients (35.3%) had encephalitis of unknown cause. In-hospital mortality for infectious encephalitis was 12.5%, autoimmune encephalitis 6.3%, and encephalitis of unknown cause 10.4%. Compared to a previous analysis of encephalitis in adults in Auckland, the incidence of encephalitis and autoimmune encephalitis had increased. The proportion of patients with an unknown cause for encephalitis had decreased.

Intrathecal Rituximab as a Rescue Therapy in Refractory Pure CSF Positive, Non-Teratomatous Type Anti-NMDAR Encephalitis.

NMDAR antibody encephalitis is the most common autoimmune encephalitis characterized by a myriad of neuropsychiatric symptoms. It predominantly affects females and is associated with ovarian teratoma (58%). Nineteen percent do not respond to treatment and are left with serious neurological deficits. A subset of NMDAR encephalitis with antibody positivity in CSF alone without ovarian teratoma is often found to be refractory to treatment. We name them Pure CSF positive, non-teratomatous type anti-NMDAR encephalitis . We report two such cases who responded to intrathecal rituximab, to highlight a novel treatment as a rescue therapy to prevent long-term disability and improve clinical outcomes.

A Mysterious Case of Encephalitis: Diagnostic Challenge and Our Clinical Reasoning.

Acute psychotic symptoms in young patients are frequently attributed to toxic or infectious causes. After ruling out the most common causes, obtaining a firm diagnosis becomes challenging. In this case report, we present the case of a young woman who presented with acute psychosis after returning from a five-day vacation in Mexico. We treated this as a case of cerebral spinal fluid (CSF)-negative anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, as testing for CSF-NMDA receptor IgG antibodies was negative, and the absence of anti-NMDAR IgG antibodies does not rule out this autoimmune encephalitis. Moreover, IV methylprednisolone remarkably improved our patient's mental status and behavior. Anti-NMDAR encephalitis manifests itself in a variety of ways. As a result, providers must maintain a high level of suspicion based on their clinical assessment, as delays in labs or failure to diagnose early based on the clinical presentation can lead to delays in treatment with which this severe immune-mediated paraneoplastic condition can quickly escalate and have worse consequences. We describe our thought process behind our clinical judgment toward this atypical scenario to contribute to identifying this condition early on in the complex clinical presentation.

Isolated Leptomeningeal Enhancement in Anti-N-Methyl D-Aspartate Receptor Encephalitis: The Diagnostic Value of Contrast-Enhanced Fluid-Attenuated Inversion Recovery Imaging.

Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is a common autoimmune encephalitis that is noted to be a severe but treatable disease entity. Patients with anti-NMDAR encephalitis often develop psychotic symptoms, including delusions, hallucinations, and paranoia, as well as memory impairment and persistent loss of attention. However, MRI findings in such patients show no abnormalities in most cases. Although typical brain abnormality features, known as T2 hyperintensities, involve the brain parenchyma and contrast enhancement at the cerebral cortex or overlying meninges, isolated leptomeningeal enhancement has been rarely reported in anti-NMDAR encephalitis. Herein, we report a patient with anti-NMDAR encephalitis who presented with isolated leptomeningeal enhancement, additionally showing the diagnostic value of contrast-enhanced fluid-attenuated inversion recovery imaging.

Teenager with acute psychosis due to non-paraneoplastic anti-N-methyl-d-aspartate receptor encephalitis with a successful recovery: A case report.

Introduction: Anti NMDAR encephalitis is a neuropsychiatric syndromic disease caused by an immunological response. Acute behavioral changes, psychosis, and catatonia are common clinical manifestations, are seizures, amnesia, speech difficulties, dyskinesia, and autonomic dysregulation. Case presentation: We discuss the case of a 14-year-old girl who had psychotic symptoms and tested positive for anti-NMDAR antibodies. Discussion: Patients present with psychiatric symptoms such as delusions, hallucinations, agitation, changes in speech mania, disorganized thinking, catatonia, insomnia, and often seizures. Anti-NMDAR encephalitis should be suspected in teenage patient with acute psychotic symptoms and seizure episodes. A multidisciplinary treatment strategy is required. Conclusion: The delayed treatment can lead to complications and delayed recovery complicating the disease process so multidisciplinary approach of treatment is necessary.

White matter abnormalities and multivariate pattern analysis in anti-NMDA receptor encephalitis.

Objective: This study aimed to investigate white matter (WM) microstructural alterations and their relationship correlation with disease severity in anti-NMDA receptor (NMDAR) encephalitis. Multivariate pattern analysis (MVPA) was applied to discriminate between patients and healthy controls and explore potential imaging biomarkers. Methods: Thirty-two patients with anti-NMDAR encephalitis and 26 matched healthy controls underwent diffusion tensor imaging. Tract-based spatial statistics and atlas-based analysis were used to determine WM microstructural alterations between the two groups. MVPA, based on a machine-learning algorithm, was applied to classify patients and healthy controls. Results: Patients exhibited significantly reduced fractional anisotropy in the corpus callosum, fornix, cingulum, anterior limb of the internal capsule, and corona radiata. Moreover, mean diffusivity was increased in the anterior corona radiata and body of the corpus callosum. On the other hand, radial diffusivity was increased in the anterior limb of the internal capsule, cingulum, corpus callosum, corona radiata, and fornix. WM changes in the cingulum, fornix, and retrolenticular part of the internal capsule were correlated with disease severity. The accuracy, sensitivity, and specificity of fractional anisotropy-based classification were each 78.33%, while they were 67.71, 65.83, and 70% for radial diffusivity. Conclusion: Widespread WM lesions were detected in anti-NMDAR encephalitis. The correlation between WM abnormalities and disease severity suggests that these alterations may serve a key role in the pathophysiological mechanisms of anti-NMDAR encephalitis. The combination of tract-based spatial statistics and MVPA may provide more specific and complementary information at the group and individual levels.

Case report: Anti-NMDA receptor encephalitis manifesting as rapid weight loss and abnormal movement disorders with alternating unilateral ptosis and contralateral limb tremor.

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, associated with immunoglobulin G (IgG) autoantibodies against the GluN1 subunit of the NMDAR, is one of the most common types of autoimmune encephalitis. In patients with anti-NMDAR encephalitis, movement disorders (MDs) are often frequent, mainly presenting as facial dyskinesias and stereotyped movements. The alternating clinical manifestation of limb tremor with unilateral ptosis is rare. Here, we report an interesting case of a 22-year-old woman with rapid weight loss presenting with staged dyskinesia. Interestingly, she typically showed persistent tremor of the right upper limb, which would stop when her left upper eyelid drooped uncontrollably, a phenomenon that lasted for a few seconds, followed by automatic upper eyelid lift and continued persistent tremor of the upper limb. Moreover, it was fortunate to find anti-NMDAR antibodies in her cerebrospinal fluid (CSF), which indicated the patient had anti-NMDAR encephalitis. And abnormal apparent diffusion coefficient (ADC) hyperintense signals on the left midbrain interpeduncular fossa explained this manifestation of focal neurological deficit. After the systematic administration of immunotherapy (intravenous immunoglobulin, IVIG), steroid pulse therapy, and symptomatic treatment, the initial symptoms were significantly relieved except for limb tremor. The MDs were becoming less visible for the next six months under topiramate prescriptions. Noteworthy, there are no specific MD phenotypes in anti-NMDAR encephalitis. We describe the young women with unique MDs and rapid weight loss to help us get a more comprehensive understanding of anti-NMDAR encephalitis.

Overlapping Autoimmune Neurological Syndrome: A Case Report of Triple-Positive Antibody.

The presentation of several autoimmune neurological disorders in a single patient is rare and often debilitating. However, early diagnosis and efficacious treatment can lead to a significant recovery. Here, we present an interesting case of a triple antibody-positive autoimmune neurological syndrome patient who manifested the clinical features of neuromyelitis optica (NMO) spectrum disorder (NMOSD), N-methyl-D-aspartate (NMDA) receptor (NMDAR) encephalitis, and myasthenia gravis (MG). Hence, the patient manifested both central and peripheral nervous system immune-mediated neurological syndromes. A middle-aged female with a history of seropositive aquaporin-4 (AQP4) NMOSD on mycophenolate 1 g twice daily presented with severe fatigue and right eye ptosis (three months since NMOSD diagnosis) and tested positive for acetylcholine receptor (AchR) binding antibody, consistent with MG. Six months after the patient's NMOSD diagnosis, she began to experience subacute progressive cognitive decline, behavioral changes, imbalance, anxiety/panic attacks, and paranoid delusions. NMDAR encephalitis was suspected, and she tested positive for cerebrospinal fluid NMDAR antibodies. After treatment with steroids failed, she was given two doses of rituximab 1 g, two weeks apart, and reported improvement in her symptoms shortly after the second dose.