Type 2 herpes simplex virus-induced anti-N-methyl-D-aspartate receptor encephalitis responsive to immunoglobulin monotherapy.

Herpes simplex virus-2 encephalitis (HSV2E) in immunocompetent adults is exceptionally rare, and the subsequent onset of autoimmune encephalitis after HSV2E is even less common. This report presents the inaugural Chinese case of anti-N-methyl-D-aspartate receptor encephalitis (NMDARE) induced by HSV2E, confirmed via metagenomic next-generation sequencing (mNGS). The patient demonstrated a favorable response to intravenous immunoglobulin (IVIG) monotherapy. This case emphasizes the importance of considering autoimmune encephalitis in patients exhibiting new or recurrent neurological symptoms after HSV2E recovery. Comprehensive mNGS and neuronal antibody testing are essential for timely diagnosis. Moreover, IVIG monotherapy can serve as an effective treatment for NMDARE induced by HSV2, providing a viable alternative, particularly when steroid therapy is contraindicated.

Antibody-secreting cells as a source of NR1-IgGs in N-methyl-D-aspartate receptor-antibody encephalitis.

BACKGROUND: The pathogenicity of NR1-IgGs in N-methyl-D-aspartate receptor (NMDAR)-antibody encephalitis is known, but the immunobiological mechanisms underlying their production remain unclear. METHODS: For the first time, we explore the origin of NR1-IgGs and evaluate the contribution of B-cells to serum NR1-IgGs levels. Peripheral blood mononuclear cells (PBMCs) were obtained from patients and healthy controls (HCs). Naïve, unswitched memory (USM), switched memory B cells (SM), antibody-secreting cells (ASCs), and PBMC depleted of ASCs were obtained by fluorescence-activated cell sorting and cultured in vitro. RESULTS: For some patients, PBMCs spontaneously produced NR1-IgGs. Compared to the patients in PBMC negative group, the positive group had higher NR1-IgG titers in cerebrospinal fluid and Modified Rankin scale scores. The proportions of NR1-IgG positive wells in PBMCs cultures were correlated with NR1-IgGs titers in serum and CSF. The purified ASCs, SM, USM B cells produced NR1-IgGs in vitro. Compared to the patients in ASCs negative group, the positive group exhibited a worse response to second-line IT at 3-month follow-up. Naïve B cells also produce NR1-IgGs, implicating that NR1-IgGs originate from naïve B cells and a pre-germinal centres defect in B cell tolerance checkpoint in some patients. For HCs, no NR1-IgG from cultures was observed. PBMC depleted of ASCs almost eliminated the production of NR1-IgGs. CONCLUSIONS: These collective findings suggested that ASCs might mainly contribute to the production of peripheral NR1-IgG in patients with NMDAR-antibody encephalitis in the acute phase. Our study reveals the pathogenesis and helps develop tailored treatments (eg, anti-CD38) for NMDAR-antibody encephalitis.

Development of a short-term prognostic model for anti-N-methyl-D-aspartate receptor encephalitis in Chinese patients.

BACKGROUND: Recognizing the predictors of poor short-term prognosis after first-line immunotherapy in patients with anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is essential for individualized treatment strategy. The objective of this study was to ascertain the factors that forecast short-term prognosis in patients with anti-NMDAR encephalitis, develop a prognostic prediction model, and authenticate its efficacy in an external validation cohort. Further, all patients were followed-up long-term to assess the factors of long-term outcome and relapses. METHODS: A prospective enrollment of patients diagnosed with anti-NMDAR encephalitis was conducted across five clinical centers in China from June 2014 to Mar 2022. The enrolled patients were divided into the derivation and validation sets based on enrollment time. The short-term prognostic model was visualized using a nomogram. Further, all patients were followed-up long-term to assess the factors of long-term outcome. RESULTS: This study found that poor short-term prognosis was a risk factor for poor long-term outcome (6-month prognosis, OR 29.792, 95%CI 6.507-136.398, p < 0.001; 12-month prognosis, OR 15.756, 95%CI 3.384-73.075, p < 0.001; 24-month prognosis, OR 5.500, 95%CI 1.045-28.955, p = 0.044). Abnormal behavior or cognitive dysfunction (OR 8.57, 95%CI 1.48-49.79, p = 0.017), consciousness impairment (OR19.32, 95%CI 3.03-123.09, p = 0.002), autonomic dysfunction or central hypoventilation (OR 5.66, 95%CI 1.25-25.75, p = 0.025), CSF pleocytosis (OR 4.33, 95%CI 1.48-12.65, p = 0.007), abnormal EEG (OR 5.48, 95% CI 1.09-27.54, p = 0.039) were independent predictors for a poor short-term prognosis after first-line immunotherapy. A nomogram that incorporated those factors showed good discrimination and calibration abilities. The area under the curve (AUC) for the prognostic model were 0.866 (95%CI: 0.798-0.934) with a sensitivity of 0.761 and specificity of 0.869. CONCLUSION: We established and validated a prognostic model that can provide individual prediction of short-term prognosis after first-line immunotherapy for patients with anti-NMDAR encephalitis. This practical prognostic model may help neurologists to predict the short-term prognosis early and potentially assist in adjusting appropriate treatment timely.

The relevance of anti-N-methyl-D-aspartate receptor encephalitis for psychiatrists.

Psychiatrists are often the first to be consulted in patients with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. While this disease is rare, psychiatrists need to be aware of its relevant fundamental, clinical and therapeutic aspects. We begin by reviewing the connection between anti-NMDAR encephalitis and the glutamate hypothesis of schizophrenia. Next, we focus on the profile of the patient typically afflicted with this disease. Then, we tackle the limited utility of current diagnostic criteria during the early stage of the disease. After reviewing the psychiatric features, we debate the quest for finding specific psychiatric phenotypes that could facilitate early-stage diagnosis. We conclude by discussing the treatment of psychiatric symptoms and disease outcomes. As follows, this paper presents the relevance of anti-NMDAR encephalitis for psychiatrists.

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an essential differential diagnosis in Psychiatry, particularly when dealing with first-episode psychosis.Psychiatrists are often the first to be consulted in patients with NMDAR encephalitis, so they need to be aware of the relevant fundamental, clinical and therapeutic aspects of this disease.

Serum neurofilament light chain is associated with disturbed limbic-based functional connectivity in patients with anti-NMDAR encephalitis.

Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis shows a predilection for affecting the limbic system, but structural MRI in most patients is usually unremarkable. However, the functional connectivity reorganization of limbic nodes remains unknown. Serum neurofilament light chains (sNfL) are clinically linked with the disease severity and neurological disability of anti-NMDAR encephalitis. However, the relationship between sNfL and limbic-based functional architecture has not been explored. We consecutively recruited 20 convalescent patients with anti-NMDAR encephalitis and 24 healthy controls from March 2018 to March 2021. Resting-state functional MRI metrics, including fractional amplitude of low-frequency fluctuation (fALFF), regional homogeneity (ReHo), and atlas-based seed functional connectivity, were analyzed to investigate regional activities and functional connectivity alterations. Correlation analysis among functional connectivity, sNfL, Mini-Mental State Examination (MMSE), and Montreal cognitive assessment outcomes were explored in patients. Compared with those of healthy controls, the fALFF and ReHo were consistently increased in regions of the posterior default mode network (DMN) hub, mainly the bilateral supramarginal gyrus and precuneus, in patients with anti-NMDAR encephalitis (FWE-corrected p < 0.05). Patients demonstrated disturbed functional organization characterized by reduced connectivity of the posterior DMN hub with the sensorimotor cortex and hypoconnectivity of the parahippocampal gyrus (PHG) with the right fusiform gyrus but extensively enhanced thalamocortical connectivity (FWE-corrected p < 0.05). Furthermore, convalescent sNfL showed a positive correlation with enhanced thalamocortical connectivity (r = 0.4659, p = 0.0384). Onset sNfL with an independent linear correlation to convalescent MMSE performance (B coefficient, -0.013, 95% CI, -0.025 ~ -0.002, p = 0.0260) was positively correlated with intra-DMN connectivity (r = 0.8969, p < 0.0001) and limbic-sensory connectivity (r = 0.4866, p = 0.0346 for hippocampus seed and r = 0.5218, p = 0.0220 for PHG seed). Patients with anti-NMDAR encephalitis demonstrated disturbed functional organization with substantial thalamocortical hyperconnectivity, that was positively correlated with convalescent sNfL. Onset sNfL showed a positive correlation with intra-DMN connectivity and limbic-sensory connectivity.

Phenotyping the late- and younger-onset neuronal surface antibody-mediated autoimmune encephalitis: a multicenter study.

Neuronal surface antibody-mediated autoimmune encephalitis (NSAE) occurs across a wide age range. However, few studies focused on the onset age and their related characteristics. We aimed to explore the age-dependent profile of NSAE. A total of 134 patients with a definite diagnosis of NSAE were retrospectively enrolled from 3 tertiary hospitals between July 2014 and August 2020. Demographic, clinical, therapeutic, and prognostic data were collected and compared between the late- (≥45) and younger-onset (<45) groups. The results showed that 56 (41.8%) patients were classified as late-onset NSAE, and 78 (58.2%) as younger-onset NSAE. There were more males, especially in the late-onset group (P = 0.036). Prodromal symptoms were more common in the younger-onset group (P = 0.004). Among the onset symptoms, more late-onset patients presented as seizures, while more younger-onset patients presented as psychiatric symptoms. Throughout the disease course, the late-onset patients were more likely to have memory dysfunction (P < 0.001), but less likely to have central hypoventilation (P = 0.045). The late-onset patients also had a significantly lower modified Rankin Scale score on admission (P = 0.042), required intensive care unit (ICU) admission less frequently during hospitalization (P = 0.042) and had a shorter hospital stay (P = 0.014). Our study revealed that the late- and younger-onset NSAE had a distinct spectrum of demographic features, presentations, and prognoses. More attention is needed for the younger-onset patients, given a higher disease severity on admission, more frequent requirement for ICU admission and longer length of stay.

Typical metabolic pattern of 18F-FDG PET in Anti-NMDAR encephalitis in the acute and subacute phases and its correlation with T2 FLAIR-MRI features.

BACKGROUND/AIMS: Early diagnosis of Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis with non-invasive imaging modalities benefiting is crucial to guarantee prompt treatments decision-making and good prognosis for patients. The present study aimed to explore the correlation of MRI features with brain metabolism characteristics of 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) and to describe the metabolic patterns in Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis at acute and subacute phases. Twenty-four patients with anti-NMDAR encephalitis confirmed by serum and/or CSF tests at acute and subacute phases, 9 females and 15 males, with an age range of 6-80 years, were enrolled in this retrospective study as encephalitis group. 18F-FDG PET and MRI findings of all patients were investigated and interpreted with visual analysis. Chi-square test was performed to compare the diagnostic sensitivity between MRI and PET. Independent sample t-test was used to compare the standardized uptake value ratio (SUVR) of each ROI between the encephalitis group and control group, which consisted of 24 healthy volunteers of the same age and gender. RESULTS: There was no statistical difference in the diagnostic sensitivity between FDG PET (23/24, 95.83%) and MRI (18/24, 75.00%) in anti-NMDAR encephalitis patients (P > 0.05). Three categories of abnormalities shown on T2 FLAIR, including shallow of sulci and swelling of brain tissue, increased signal in the sulci, increased signal on brain gray matter or adjacent white matter presented hypermetabolism on PET, excepting increased signal in brain linear structure with hypometabolism of the basal ganglia on PET. We identified 19 brain regions with hypermetabolism and 16 brain regions with hypometabolism that exhibited statistically significant changes in SUVRs between anti-NMDAR encephalitis group and control group (FDR P < 0.05). CONCLUSION: Anteroposterior glucose metabolism gradient (frontal-temporal/parietal-occipital) is proved to be a typical pattern of anti-NMDAR encephalitis at the acute and subacute phases in both visual and statistical testing. Interestingly, the pattern is also commonly found in the anterior and posterior portions of the parietal lobe and cingular cortex, which may be a potential indicator for the diagnosis of this disorder. In addition, MRI is an important and reliable neuroimaging modality to assist in the correct evaluation of activity changes on individual 18F-FDG PET.

The presence of human respiratory syncytial virus in the cerebrospinal fluid of a child with Anti-N-methyl-D-aspartate receptor encephalitis of unknown trigger.

BACKGROUND: Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is an important type of brain inflammation caused by autoantibody. As one of the primary agents responsible for respiratory tract infection, the human respiratory syncytial virus (hRSV) has also been reported to be capable of causing extrapulmonary diseases. Here, we first describe a case of anti-NMDAR encephalitis when hRSV was shown to be present in the cerebrospinal fluid. CASE PRESENTATION: The child was noted to have ataxia and positive anti-NMDA receptors in the cerebrospinal fluid, diagnosed as anti-NMDA receptor encephalitis in combination with cranial MRI images. After high-dose hormone pulse therapy and medication, the disease improved, and he was discharged. However, a relapse occurred almost a year later, and the cranial MRI imaging showed progressive cerebellar atrophy. An hRSV strain from group B was detected in his cerebrospinal fluid, and the whole genome sequence was recovered using transcriptome sequencing. CONCLUSIONS: To our knowledge, this is the first report of hRSV being found in the cerebrospinal fluid of a patient with anti-NMDAR encephalitis. Even though more clinical records and experimental evidence are needed for validation, this work expands the types of diseases linked to hRSV and the likely cause of anti-NMDAR encephalitis.

Paraneoplastic or not? Sirtuin 2 in anti-N-methyl-d-aspartate receptor encephalitis.

BACKGROUND AND PURPOSE: N-methyl-d-aspartate receptor (NMDAR) and leucine-rich glioma-inactivated protein 1 (LGI1) encephalitis are important types of autoimmune encephalitis (AE) with significant morbidity. In this study, we used a proteomic approach in search of novel clinically relevant biomarkers in these types of encephalitides. METHODS: Swedish and Czech tertiary neuroimmunology centers collaborated in this retrospective exploratory study. Fifty-eight cerebrospinal fluid (CSF) samples of 28 patients with AE (14 definite NMDAR, 14 with definite LGI1 encephalitis) and 30 controls were included. CSF samples were analyzed using proximity extension assay technology (Olink Target 96 Inflammation panel). For each CSF sample, 92 proteins were measured. Clinical variables were retrospectively collected, and correlations with protein levels were statistically analyzed. RESULTS: Patients and controls differed significantly in the following 18 biomarkers: TNFRSF9, TNFRSF12, TNFRSF14, TNFß, TNFα, IL7, IL10, IL12B, IFNγ, CD5, CD6, CASP8, MMP1, CXCL8, CXCL10, CXCL11, IL20RA, and sirtuin 2 (SIRT2). In LGI1 encephalitis, no clinically useful association was found between biomarkers and clinical variables. In the NMDAR encephalitis group, SIRT2, TNFß, and CD5 were significantly associated with ovarian teratoma. For SIRT2, this was true even for the first patients' CSF sample (SIRT2 without vs. with tumor, mean ± SD = 2.2 ± 0.29 vs. 2.88 ± 0.48; p = 0.007, 95% confidence interval = -1.15 to -0.22; r statistic in point-biserial correlation (rpb) = 0.66, p = 0.011). SIRT2 was positively correlated with age (rpb = 0.39, p = 0.018) and total hospital days (r = 0.55, p = <0.001). CONCLUSIONS: SIRT2 should be investigated as a biomarker of paraneoplastic etiology in NMDAR encephalitis.

Persistent psychosis associated with extreme delta brush in anti-NMDA receptor encephalitis: a case report.

BACKGROUND: Anti-NMDAR encephalitis is an emerging differential diagnosis of first episode and persistent psychosis in the psychiatric community, as clinical manifestations include psychiatric symptoms, cognitive dysfunction, seizures, decreased consciousness, and dyskinesias. This disease is associated with extreme delta brush (EDB), but the significance and temporal course of this EEG pattern still needs to be determined. Herein, we report a case of anti-NMDAR encephalitis with persistent psychosis associated with EDB occurrence on multiple occasions during a 5-year disease course. CASE PRESENTATION: A 15-year-old girl was diagnosed with anti-NMDAR encephalitis and treated with progressive improvement. Four years after initial manifestations, an EDB pattern was seen on electroencephalogram (EEG) without new neurological symptoms. She had residual symptoms of episodic auditory hallucinations and impulsivity. One year later, the patient had a recurrence of neurological symptoms (seizures, dyskinesias and impaired attention), persisting with EDB on EEG. Clinical symptoms and EDB resolved after second-line treatment with rituximab. CONCLUSION: We describe the first case of persistent psychosis in anti-NMDAR encephalitis associated with extreme delta brush on multiple EEGs on prolonged follow-up. Electroencephalographic patterns such as EDB may serve as markers of residual disease activity, including psychiatric symptoms. Further studies with prolonged EEG monitoring are needed to better understand these findings.

The imbalance between Bregs, Tfh, and Tregs in patients with anti-N-methyl-D-aspartate receptor encephalitis.

OBJECTIVE: To 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. METHODS: We 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. RESULTS: Compared 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. CONCLUSION: We 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.

Non-infectious meningitis and CNS demyelinating diseases: A conceptual review.

Many cases of aseptic meningitis or meningoencephalitis, unresponsive to antimicrobial treatments, have been reported recently in patients with established/new-onset central nervous system (CNS) inflammatory demyelinating diseases (CNSIDDs). Given the higher probability of infectious etiologies, CNSIDDs are rarely considered among the differentials in meningitis or meningoencephalitis cases. We gathered and tabulated cases of non-infectious, steroid-responsive meningitis or meningoencephalitis associated with neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein-associated disease (MOGAD). This conceptual review highlights the need to bolster routine infectious workups with immunological workups in cases of meningoencephalitis or meningitis where potential autoimmune etiologies can be suspected. Although differentiating CNSIDDs with meningeal involvement from infectious meningitis may not substantially affect acute treatment strategies, long-term management and follow-up of the two are entirely different. We also discuss future research directions and hypotheses on how CNSIDDs may be associated with meningitis-like presentations, e.g. overlapping glial fibrillary acidic protein astrocytopathy or autoimmune encephalitis, alterations in regulatory T-helper cells function, and undetected viral agents.

Contribution of diffusion-weighted imaging to distinguish herpetic encephalitis from auto-immune encephalitis at an early stage.

OBJECTIVES: To determine whether diffusion-weighted imaging (DWI) can help to distinguish early stage autoimmune (AI) and herpes simplex virus (HSV) encephalitides. METHODS: This case-control study included patients from a multi-center cohort of AI encephalitides whose initial MRI including DWI was performed within ten days after symptoms onset. They were compared with patients with HSV encephalitis enrolled prospectively in a single-center from June, 2020 to December, 2020. The final diagnosis of AI encephalitis required a positive autoantibody assay, and that of HSV encephalitis required a positive HSV polymerase chain reaction based on cerebrospinal fluid. Brain MRI were evaluated for restricted diffusion, fluid-inversion recovery (FLAIR) abnormalities, lesion topography, hemorrhagic changes, and contrast enhancement. RESULTS: Forty-nine patients were included of which, 19 (38.8%) had AI encephalitis. Twenty-seven patients (55.1%) were males and the median age was 46.0 years (interquartile range (IQR):[22.0; 65.0]). Brain MRI were performed after a median of 4 days (IQR:[2.0; 7.0]) of symptom onset and time between symptom onset and MRI was not significantly different (p = 0.60). Twenty-six patients had restricted diffusion lesions in the medial temporal lobe, including 25/30 in the HSV encephalitis group (p < 0.001). FLAIR abnormalities were observed in 36 patients, including 29/30 in the HSV encephalitis group (p < 0.001). Lesion topography, hemorrhagic changes, and contrast enhancement did not differ significantly between the two groups. CONCLUSION: Our results suggest that restricted diffusion lesions in the medial temporal lobe are a hallmark of HSV encephalitis and may help distinguish it from early-stage AI encephalitis.

[Electroencephalogram Features of Anti-N-Methyl-D-Aspartate Receptor Encephalitis and Their Value for Clinical Assessment].

Objective: To analyze the electroencephalogram (EEG) features of anti-N-methyl-D-aspartate receptor encephalitis (anti-NMDARE) and to study the clinical assessment value of the degree of EEG background slowing and the presence of δ brush. Methods: We enrolled 52 patients with anti-NMDARE and collected their clinical data, including age, sex, form of disease onset, status of tumor comorbidity, auxiliary examination findings (cerebrospinal fluid [CSF] anti-methyl-D-aspartate receptor antibody titers, magnetic resonance imaging [MRI] reports, and EEG results), treatment status, and follow-up after discharge. The degree of EEG background abnormality and the presence of δ brush in the EEG of patients with different clinical features were analyzed. Results: Among the 52 patients, 7 (14%) had normal EEG, and 45 (87%), abnormal EEG, including 25 (48%) with mild abnormalities, 11 (21%) with moderate abnormalities, and 9 (17%) with severe abnormalities. δ brush was seen in 6 (12%) patients. At the time of EEG, 32 (62%) patients were in the mild condition group and 20 (38%) patients were in the severe condition group. After 1 year of follow-up, there were 45 (86%) patients in the good prognosis group and 7 (14%) patients in the poor prognosis group. The exacerbation of EEG background abnormalities and the presence of δ brush were indications for an increase in the proportion of patients who were in severe condition, who needed ICU admission, and who had poor prognosis ( P<0.01). The worse the EEG background abnormalities, the higher the proportion of CSF antibody titers>1∶10 ( P=0.035), and the higher the proportion of patients initiating second-line immunotherapy ( P=0.008). The δ brush was seen a higher proportion in patients with comorbid tumors ( P=0.012). The probability of δ brush presence was higher in the first-time diagnosis cases than that in recurrent cases ( P=0.023). Conclusions: The degree of EEG slowing and the presence of δ brush have shown consistent performance in assessing patients' condition and predicting prognosis. The slower the EEG, the more severe the disease, and the worse the prognosis. The presence of δ brush indicates severe disease and poor prognosis. EEG slowing is correlated with the immune status of patients with anti-NMDARE. The slower the EEG, the more severe the immune abnormalities. In clinical practice, patient EEG should be under dynamic monitoring in order to evaluate the effect of immunotherapy. If EEG slowing is not improved, enhanced immunotherapy should be considered as early as possible. The δ brush is seen at a higher proportion in patients with comorbid tumors. Therefore, active efforts should be made to screen for tumors when δ brush is present.

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Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an autoimmune inflammatory disease of the central nervous system, and little is known about its immune mechanism at present. There is a lack of disease-related biomarkers in cerebrospinal fluid except anti-NMDAR antibody, which leads to delayed diagnosis and treatment in some patients. Therefore, there has been an increasing number of studies on related cytokines in recent years to assess whether they can be used as new biomarkers for evaluating disease conditions and assisting diagnosis and treatment. Current studies have shown that some cytokines may be associated with the progression of anti-NMDAR encephalitis, and this article reviews the research advances in such cytokines associated with anti-NMDAR encephalitis.

Second-line immunotherapy and functional outcomes in autoimmune encephalitis: A systematic review and individual patient data meta-analysis.

Autoimmune encephalitis (AE) is a neurological disorder caused by autoimmune attack on cerebral proteins. Experts currently recommend staged immunotherapeutic management, with first-line immunotherapy followed by second-line immunotherapy if response to first-line therapy is inadequate. Meta-analysis of the evidence base may provide higher quality evidence to support this recommendation. We undertook a systematic review of observational cohort studies reporting AE patients treated with either second-line immunotherapy or first-line immunotherapy alone, and outcomes reported using the modified Rankin Scale (mRS; search date: April 22, 2020). We performed several one-stage multilevel individual patient data (IPD) meta-analyses to examine the association between second-line immunotherapy and final mRS scores (PROSPERO ID CRD42020181805). IPD were obtained for 356 patients from 25 studies. Most studies were rated as moderate to high risk of bias. Seventy-one patients (71/356, 19%) were treated with second-line immunotherapy. We did not find a statistically significant association between treatment with second-line immunotherapy and final mRS score for the cohort overall (odds ratio [OR] = 1.74, 95% confidence interval [CI] = .98-3.08, p = .057), or subgroups with anti-N-methyl-D-aspartate receptor encephalitis (OR = 1.03, 95% CI = .45-2.38, p = .944) or severe AE (maximum mRS score > 2; OR = 1.673, 95% CI = .93-3.00, p = .085). Treatment with second-line immunotherapy was associated with higher final mRS scores in subgroups with anti-leucine-rich glioma-inactivated 1 AE (OR = 6.70, 95% CI = 1.28-35.1, p = .024) and long-term (at least 12 months) follow-up (OR = 3.94, 95% CI = 1.67-9.27, p = .002). We did not observe an association between treatment with second-line immunotherapy and lower final mRS scores in patients with AE. This result should be interpreted with caution, given the risk of bias, limited adjustment for disease severity, and insensitivity of the mRS in estimating psychiatric and cognitive disability.

Anti-NMDAR encephalitis with bilateral basal ganglia MRI lesions at a distance of time: a case report.

BACKGROUND: Approximately half (55%) of anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is known to show abnormal brain images, including high signal intensity in T2 or fluid attenuated inversion recovery (FLAIR) images. In a minority of anti-NMDAR encephalitis cases, high signal intensity on diffusion-weighted imaging (DWI) has been reported, a finding that is highly suggestive of a stroke. CASE PRESENTATION: We present the case of a 66-year-old man who experienced two separate focal seizure events, which involved first the right and then the left upper extremity in a short period of time. The patient showed focal clonic seizures involving right arm and hand, which sometimes evolved to bilateral tonic-clonic seizures on his first admission. Brain magnetic resonance imaging (MRI) showed high signal intensity on DWI and low signal intensity on the apparent diffusion coefficient (ADC) map of the left caudate nucleus and putamen. The patient was discharged symptom-free with anti-epileptic drugs for 2 weeks. The second admission occurred 4 days after the discharge. He exhibited a new symptom of focal clonic seizures involving left arm and hand while showing a brain lesion on the opposite side which is hyperintense on DWI image and hypointense on ADC map. The patient was eventually diagnosed with anti-NMDAR encephalitis according to the cerebrospinal fluid (CSF) antibody test. CONCLUSIONS: This is the case of anti-NMDAR encephalitis patient whose DWI/ADC images revealed sequential involvement on the left and right basal ganglia with a short time interval. When stroke-like brain lesions on DWI are found in a patient with a focal seizure, a CSF study could help rule out autoimmune encephalitis. We also suggest that DWI/ADC map images may be useful for the early detection of anti-NMDAR encephalitis.

Gut microbiome changes in anti-N-methyl-D-aspartate receptor encephalitis patients.

BACKGROUND: Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a type of autoimmune encephalitis. The underlying mechanism(s) remain largely unknown. Recent evidence has indicated that the gut microbiome may be involved in neurological immune diseases via the "gut-brain axis". This study aimed to explore the possible relationship between anti-NMDAR encephalitis and the gut microbiome. METHODS: Fecal specimens were collected from 10 patients with anti-NMDAR encephalitis and 10 healthy volunteers. The microbiome analysis was based on Illumina sequencing of the V3-V4 hypervariable region of the 16S rRNA gene. The alpha, beta, and taxonomic diversity analyses were mainly based on the QIIME2 pipeline. RESULTS: There were no statistical differences in epidemiology, medication, and clinical characteristics (except for those related to anti-NMDAR encephalitis) between the two groups. ASV analysis showed that Prevotella was significantly increased, while Bacteroides was reduced in the gut microbiota of the patients, compared with the controls. Alpha diversity results showed a decrease in diversity in the patients compared with the healthy controls, analyzed by the Shannon diversity, Simpson diversity, and Pielou_E uniformity based on the Kruskal-Wallis test (P = 0.0342, 0.0040, and 0.0002, respectively). Beta diversity analysis showed that the abundance and composition of the gut microbiota was significantly different between the two groups, analyzed by weighted and unweighted UniFrac distance (P = 0.005 and 0.001, respectively). CONCLUSIONS: The abundance and evenness of bacterial distribution were significantly lower and jeopardized in patients with anti-NMDAR encephalitis than in healthy controls. Thus, our findings suggest that gut microbiome composition changes might be associated with the anti-NMDAR encephalitis. It could be a causal agent, or a consequence.

Simple and effective serum biomarkers potential for predicting status epilepticus in anti-N-methyl-D-aspartate receptor encephalitis.

BACKGROUND: Patients with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis who also present with status epilepticus (SE) often have a poor prognosis. The aim of this study is to explore simple and effective predictors for anti-NMDAR encephalitis accompanied with SE. METHODS: We retrospectively analyzed 65 anti-NMDAR encephalitis patients from January 2015 to December 2018 who admitted to the Third Affiliated Hospital of Sun Yat-sen University. Patients were divided into SE group and non-SE groups. Their pre-treatment data and 3-month follow-up data were retrospectively analyzed. RESULTS: The results showed that compared with the non-SE group, the levels of serum uric acid (UA) and high-density lipoprotein cholesterol (HDL-C) in anti-NMDAR encephalitis patients with SE decreased significantly before treatment. Additionally, the levels of serum UA and HDL-C increased while the level of C-reactive protein (CRP) decreased 3 months after treatment in the SE group. Compared with the non-SE group, the SE patients had higher modified Rankin scale (mRS) scores before (mRS1) and after treatment (mRS2). Serum UA concentrations before treatment showed significantly negative correlations with mRS1 (r = - 0.407, p < 0.01) and mRS2 (r = - 0.458, p < 0.001), while the level of serum CRP before treatment had strong positive correlations with mRS1 (r = 0.304, p < 0.05) and mRS2 (r = 0.301, p < 0.05) in anti-NMDAR encephalitis patients. The receiver operating characteristic curve demonstrated that the combined detection of UA, HDL-C and CRP before treatment had a significantly higher value (the area under the curve = 0.848; 95% confidence interval [CI], 0.74-0.957; p < 0.001) to predict anti-NMDAR encephalitis accompanied with SE than that of single detection. CONCLUSIONS: Hence, the combined detection of serum UA, HDL-C and CRP before treatment may be simple and effective indicators for predicting SE in anti-NMDAR encephalitis, which may be helpful in early stages to remind clinicians to be alert to the emergence of SE.

Anti-N-methyl-D-aspartate receptor encephalitis: characteristics and rapid diagnostic approach in the emergency department.

BACKGROUND: Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is a common type of autoimmune encephalitis. Patients with this condition are frequently very ill but are often misdiagnosed in the Emergency Department (ED). The objective of this study was to analyze the clinical characteristics of anti-NMDAR patients in the ED and to identify any associations with a diagnosis of anti-NMDAR encephalitis. METHODS: We performed a retrospective analysis of a prospectively obtained cohort of ED patients from May 2011 to December 2017. We identified patients diagnosed with anti-NMDAR encephalitis in this cohort and extracted key patient characteristics and clinical data, including patient gender, age, presentation, modified Rank Score (m-RS), laboratory test results, significant treatments, and mortality. RESULTS: Eighty-seven patients with anti-NMDAR encephalitis were identified. 54 (62.1%) were female, 23 (26.4%) were < 18 years old, 14 (16.1%) had teratoma, and 45 (51.7%) had an m-RS ≥ 4. Fever, altered mental status, and seizures were the most common symptoms, with a > 50% incidence of each symptom in the cohort. The sensitivity of CSF oligoclonal band (OB) testing was 78.9%. 22 (25.3%) were admitted to the ICU, 20 (23.0%) patients were intubated, but only one patient died (1.1%). 47 (54.0%) were misdiagnosed prior to ED arrival. All patients underwent immunotherapy as first-line treatment for anti-NMDAR encephalitis. CONCLUSIONS: A majority of anti-NMDAR encephalitis patients presenting to the ED were female and were likely to be misdiagnosed prior to arrival. Patients with symptoms of fever, altered mental status, and seizures need a lumbar puncture, including CSF OB testing, for definitive diagnosis.