Intestinal dysbiosis exacerbates susceptibility to the anti-NMDA receptor encephalitis-like phenotype by changing blood brain barrier permeability and immune homeostasis.

Changes in the intestinal microbiota have been observed in patients with anti-N-methyl-D-aspartate receptor encephalitis (NMDARE). However, whether and how the intestinal microbiota is involved in the pathogenesis of NMDARE susceptibility needs to be demonstrated. Here, we first showed that germ-free (GF) mice that underwent fecal microbiota transplantation (FMT) from NMDARE patients, whose fecal microbiota exhibited low short-chain fatty acid content, decreased abundance of Lachnospiraceae, and increased abundance of Verrucomicrobiota, Akkermansia, Parabacteroides, Oscillospirales, showed significant behavioral deficits. Then, these FMT mice were actively immunized with an amino terminal domain peptide from the GluN1 subunit (GluN1356-385) to mimic the pathogenic process of NMDARE. We found that FMT mice showed an increased susceptibility to an encephalitis-like phenotype characterized by more clinical symptoms, greater pentazole (PTZ)-induced susceptibility to seizures, and higher levels of T2 weighted image (T2WI) hyperintensities following immunization. Furthermore, mice with dysbiotic microbiota had impaired blood-brain barrier integrity and a proinflammatory condition. In NMDARE-microbiota recipient mice, the levels of Evan's blue (EB) dye extravasation increased, ZO-1 and claudin-5 expression decreased, and the levels of proinflammatory cytokines (IL-1, IL-6, IL-17, TNF-α and LPS) increased. Finally, significant brain inflammation, mainly in hippocampal and cortical regions, with modest neuroinflammation, immune cell infiltration, and reduced expression of NMDA receptors were observed in NMDARE microbiota recipient mice following immunization. Overall, our findings demonstrated that intestinal dysbiosis increased NMDARE susceptibility, suggesting a new target for limiting the occurrence of the severe phenotype of NMDARE.

Malignant atrophic papulosis (Degos disease) with central nervous system involvement.

A 49-year-old man presented with a 2-year history of weakness and sensory disturbances in the bilateral lower extremities, vesicorectal dysfunction, and progressive gait disturbances. Brain MRI revealed multiple ischemic and hemorrhagic cortical/subcortical lesions with patchy enhancement involving the frontal and parietal lobes, suggesting the possibility of distal perforating arteries injury. Spine MRI revealed lesions of the cervical and thoracic spinal cord with associated enhancement. The diagnosis of malignant atrophic papulosis (Degos disease) with central nervous system involvement was prompted by the characteristic skin lesions.

Limitations on knowledge of autoimmune encephalitis and barriers to its treatment among neurologists: a survey from western China.

BACKGROUND: Autoimmune encephalitis (AE) is a group of severe antibody-mediated brain diseases. The understanding of clinical management of AE has developed rapidly. However, the knowledge level of AE and barriers to effective treatment among neurologists remains unstudied. METHODS: We conducted a questionnaire survey among neurologist in western China on knowledge of AE, treatment practices, and perspectives on barriers to treatment. RESULTS: A total of 1113 neurologists were invited and 690 neurologists from 103 hospitals completed the questionnaire with a response rate of 61.9%. Respondents correctly answered 68.3% of medical questions about AE. Some respondents (12.4%) never assayed for diagnostic antibodies if patients had suspected AE. Half (52.3%) never prescribed immunosuppressants for AE patients, while another 7.6% did not know whether they should do so. Neurologists who never prescribed immunosuppressants were more likely to have less education, a less senior job title, and to practice in a smaller setting. Neurologists who did not know whether to prescribe immunosuppressants were associated with less AE knowledge. The most frequent barrier to treatment, according to respondents, was financial cost. Other barriers to treatment included patient refusal, insufficient AE knowledge, lack of access to AE guidelines, drugs or diagnostic test, etc. CONCLUSION: Neurologists in western China lack AE knowledge. Medical education around AE is urgent needed and should be more targeted to individuals with less educated level or working in non-academic hospitals. Policies should be developed to increase the availability of AE related antibody testing or drugs and reduce the economic burden of disease.

Long-term seizure outcomes in patients with autoimmune encephalitis: A prospective observational registry study update.

OBJECTIVE: This study was undertaken to update and evaluate long-term seizure outcomes in patients with autoimmune encephalitis (AE) based on a large cohort study with long follow-up. METHODS: In this prospective observational registry study, we analyzed data from patients with AE mediated by common types of neuronal surface antibodies (anti-N-methyl-d-aspartate receptor [NMDAR], anti-leucine-rich glioma-inactivated 1 [LGI1]/contactin-associated protein-like 2 [Caspr2], anti-γ-aminobutyric acid type B receptor [GABAB R]). All patients were recruited from the Department of Neurology at West China Hospital between October 2011 and June 2019, and data were collected prospectively on their demographic and clinical characteristics, treatment strategy, and seizure outcomes, with a median follow-up of 42 months (range = 6-93 months). Potential risk factors associated with seizure recurrence were also assessed. RESULTS: Of 320 AE patients, 75.9% had acute seizures, among whom >90% of patients had their last seizure within 12 months of disease onset. During our follow-up, 21 (9.3%) patients experienced seizure recurrence. Patients with anti-GABAB R encephalitis had a higher cumulative incidence of seizure recurrence than those with anti-NMDAR (log-rank p = .03) or anti-LGI1/Caspr2 encephalitis (log-rank p = .04). Among patients with anti-NMDAR encephalitis, women had a significantly higher cumulative incidence of seizure recurrence than men (log-rank p = .01). Interictal epileptiform discharges (IEDs) or seizures captured on continuous electroencephalogram (EEG) in the acute phase were identified as potential risk factors for seizure recurrence (p = .04, p = .007). Among 163 patients with ≥24 months of follow-up, five (3.1%) showed persistent seizures and required ongoing antiseizure medications despite aggressive immunotherapy. SIGNIFICANCE: Seizure recurrence occurred in a small number of patients and chronic epilepsy occurred in 3.1% of patients during prolonged follow-up. Across all types of AE, risk factors for seizure recurrence were IEDs or seizures captured on EEG in the acute phase; for anti-NMDAR encephalitis, female sex was also a risk factor.

Efficacy and tolerability of intravenous immunoglobulin versus intravenous methylprednisolone treatment in anti-N-methyl-d-aspartate receptor encephalitis.

BACKGROUND AND PURPOSE: The aim was to compare the effectiveness and safety of intravenous immunoglobulin (IVIg) or intravenous methylprednisolone (IVMP) versus IVIg plus IVMP (IPI) as initial therapy in anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis. METHODS: This was a multicenter study of prospectively identified NMDAR encephalitis individuals who presented from October 2011 to August 2020 to the study hospitals of western China, with a median follow-up of 3.9 years. Prespecified candidate variables were the prescriptions of IVIg, IVMP or IPI. Propensity score matching was also performed to control potential confounders. RESULTS: A total of 347 NMDAR encephalitis patients were finally analyzed in this study. After TriMatch for NMDAR encephalitis, 37 triplets were generated. Compared to IVIg or IVMP, the administration of IPI exhibited a significant benefit of a higher response rate (86.5% vs. 55.6% vs. 68.7%, pcorr < 0.01), improved modified Rankin Scale score at 3, 6 and 12 months (pcorr < 0.05), and reduced further recurrence rate (10 of 37 [27.0%] vs. 9 of 37 [24.3%] vs. 2 of 37 [5.4%]; p log rank = 0.01). There was no association between treatment superiority and patient sex or the presence of tumors (p ≥ 0.05). Patients treated with IVMP had a significantly higher number of adverse events, but 99% of adverse events were mild to moderate and did not lead to a change in treatment. CONCLUSION: In patients with NMDAR encephalitis, adequate response, favorable outcome and less recurrence were each more likely to occur in individuals treated with a combined immunotherapy than in monotherapy individuals.

Partially Reversible FLAIR Hyperintensity Along the Brainstem Surface in Autoimmune Glial Fibrillary Acidic Protein Astrocytopathy.

A 41-year-old woman presented with headache, fever, irritability, and confusion. She developed a coma after admission. MRI of the brain revealed periventricular and deep white matter lesions. Fluid-attenuated inversion recovery (FLAIR) and diffusion-weighted imaging hyperintensity along the brainstem surface was observed (Figure 1), considered a rare but characteristic finding in leptomeningeal carcinomatosis from lung cancer.1,2 However, serum tumor markers, CSF cytopathology, contrast-enhanced high-resolution chest CT, and whole-body PET were negative. Antiglial fibrillary acidic protein antibodies (cell-based assay) were positive in serum and CSF. After receiving intravenous methylprednisolone and immunoglobulin, the symptoms improved significantly. Repeated MRI of the brain showed partial resolution of the lesions (Figure 2). The lesions were possibly induced by immune-mediated intramyelinic edema.

Differentiation between viral and autoimmune limbic encephalitis: a prospective cohort study with development and validation of a diagnostic model.

BACKGROUND: Distinguishing between viral encephalitis (VE) and autoimmune limbic encephalitis (ALE) presents a clinical challenge due to the overlap in symptoms. We aimed to develop and validate a diagnostic prediction model to differentiate VE and ALE. METHODS: A prospective observational multicentre cohort study, which continuously enrolled patients diagnosed with either ALE or VE from October 2011 to April 2023. The demographic data, clinical features, and laboratory test results were collected and subjected to logistic regression analyses. The model was displayed as a web-based nomogram and then modified into a scored prediction tool. Model performance was assessed in both derivation and external validation cohorts. RESULTS: A total of 2423 individuals were recruited, and 1001 (496 VE, 505 ALE) patients were included. Based on the derivation cohort (389 VE, 388 ALE), the model was developed with eight variables including age at onset, acuity, fever, headache, nausea/vomiting, psychiatric or memory complaints, status epilepticus, and CSF white blood cell count. The model showed good discrimination and calibration in both derivation (AUC 0.890; 0.868-0.913) and external validation (107 VE, 117 ALE, AUC 0.872; 0.827-0.917) cohorts. The scored prediction tool had a total point that ranged from - 4 to 10 also showing good discrimination and calibration in both derivation (AUC 0.885, 0.863-0.908) and external validation (AUC 0.868, 0.823-0.913) cohorts. CONCLUSIONS: The prediction model provides a reliable and user-friendly tool for differentiating between the VE and ALE, which would benefit early diagnosis and appropriate treatment and alleviate economic burdens on both patients and society.

Safety of inactivated COVID-19 vaccines in autoimmune encephalitis: A real-world cross-sectional survey.

OBJECTIVE: To assess safety data of the inactivated COVID-19 vaccines in a real-world sample of people with autoimmune encephalitis (pwAE). METHODS: A cross-sectional study was performed between 1 March and 30 April 2022. We invited pwAE from our previous ONE-WC (Outcome of Autoimmune Encephalitis Study in Western China) registration study database, to attend neurological clinics, at West China Hospital to participate in a face-to-face survey using a custom-designed questionnaire for this study. The ONE-WC study began in October 2011 and prospectively enrolled pwAE from four large comprehensive neurological centers in Sichuan province, China. RESULTS: Of the 387 pwAE, 240 (62.0%) completed the questionnaire. Half the 240 participants (121, 50.4%) reported receiving at least one dose of COVID-19 vaccine, which in all but two patients received inactivated COVID-19 vaccine. Among vaccinated pwAE, the median age was 35 years (range 15-69) and 57.8% of them were women. The most frequent reasons that unvaccinated individuals reported for not receiving the COVID-19 vaccine were concern about vaccine-induced relapse of AE (50.4%) and advice from a physician to delay vaccination (21.0%). Small proportions of vaccinated individuals reported adverse events after the first dose (11.5%) or the second dose (10.2%), and none of the adverse events was serious. Across the entire sample, one individual reported relapsing within 30 days after the first dose and three individuals reported relapsing more than 120 days after the first dose. CONCLUSIONS: This real-world survey indicates an overall favorable safety profile of the inactivated COVID-19 vaccine for pwAE.

Autoimmune encephalitis with mGluR5 antibodies: A case series from China and review of the literature.

Background: Only 15 patients of autoimmune encephalitis with metabotropic glutamate receptor 5 (mGluR5) antibodies have been reported worldwide since 2011, mostly from western countries. Patients with different genetic backgrounds are necessary to further clarify the clinical phenotype and prognosis of this rare disease. Objective: We initially describe a case series from China to confirm the previous findings, expand the clinical phenotype, and identify the prognostic factors of autoimmune encephalitis with mGluR5 antibodies. Methods: Observational data with follow-up were prospectively collected from autoimmune encephalitis patients with mGluR5 antibodies. Clinical information and outcomes on current and previously reported cases were combined and analyzed. Results: We identified five patients (median age 35 years); two were female. The main clinical manifestations were behavioral/personality changes (five of five, 100%) and cognitive disorders (four of five, 80%), accompanied with other neurologic symptoms. Hypoventilation occurred in two (40%) patients, which was life-threatening. One patient had meningoencephalitis, suggesting a new phenotype in anti-mGluR5 encephalitis. All patients received immunotherapy. At the last follow-up (median 18 months), two (40%) patients showed complete recovery, two (40%) patients showed partial recovery, and one (20%) patient died. One (20%) patient had multiple relapses. Together with the 15 previously reported cases, associated tumors occurred in seven of 12 (58%) Western patients vs. one of eight (13%) Chinese patients. Modified Rankin Scale (mRS) scores at the last follow-up (median 31 months) were available in 16 patients. Patients with bad outcomes (mRS > 2, n = 4) were more likely to have hypoventilation at onset and higher mRS scores at peak of the disease. Conclusions: In patients with different genetic background, as Chinese, the clinical phenotype of anti-mGluR5 encephalitis is similar. Fewer paraneoplastic cases were observed in Chinese patients. Most patients showed good responses to immunotherapy and cancer treatment. The clinical outcomes were favorable in most patients.

Clinical characteristics, long-term functional outcomes and relapse of anti-LGI1/Caspr2 encephalitis: a prospective cohort study in Western China.

OBJECTIVE: To study the clinical characteristics of anti-leucine-rich glioma-inactivated 1 (LGI1) encephalitis and anti-contactin-associated protein-like 2 (Caspr2) encephalitis and to investigate factors associated with poor long-term neurological functional outcomes and relapse among patients in western China. METHODS: In this single-center prospective cohort study, we consecutively enrolled patients with anti-LGI1 encephalitis and anti-Caspr2 encephalitis from April 2014 to February 2021. Patient outcomes were assessed using the modified Rankin scale. Predictors of long-term functional outcomes and relapse were analyzed. RESULTS: Forty-four anti-LGI1 encephalitis patients [median age: 44 years, range: 18-82 years; females: 25 (56.8%)], 35 anti-Caspr2 encephalitis patients [median age: 43 years, range: 14-80 years; females: 19 (54.3%)], and 5 dual-positive patients [median age: 44 years, range: 36-58 years; females: 5 (100%)] were enrolled. Overall, 86.4% anti-LGI1 encephalitis patients and 80% anti-Caspr2 encephalitis had a favorable neurological functional outcome (mRS 0-2). Tumor occurrence and weight loss were associated with poor long-term functional outcomes in anti-LGI1 encephalitis, whereas in anti-Caspr2 encephalitis, predictors included behavioral disorder at acute phase, abnormalities in brain magnetic resonance imaging, higher modified Rankin scale scores at onset, poor response to the initial immunotherapy at 4 weeks, age at onset<30 years, and relapse (p<0.05). Overall, 13.6% of anti-LGI1 encephalitis patients and 20% of anti-Caspr2 encephalitis patients had at least one relapse. Sleep disorder at the acute phase was the risk factor of relapse in anti-LGI1 encephalitis, while female, age at onset <30 years, and behavioral disorder at acute phase were the risk factors of relapse in anti-Caspr2 encephalitis (log rank p<0.05). CONCLUSION: The clinical characteristics such as age, gender, and tumor occurrence rates of anti-LGI1 encephalitis and anti-Caspr2 encephalitis in western China are different from those in the Western countries. Most patients in our study had favorable long-term functional outcomes. The relapse rates are still high in both types of encephalitis, which warrants caution.

Disturbance of Gut Bacteria and Metabolites Are Associated with Disease Severity and Predict Outcome of NMDAR Encephalitis: A Prospective Case-Control Study.

Objective: We aimed to investigate the associations between the intestinal microbiota, metabolites, cytokines, and clinical severity in anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis and to further determine the predictive value of the intestinal microbiota or metabolites in clinical prognosis. Methods: In this prospective observational cohort study of 58 NMDAR encephalitis patients and 49 healthy controls, fecal microbiota, metabolites, and cytokines were quantified and characterized by16S rRNA gene sequencing, liquid chromatography-mass spectrometry, and the Luminex assay, respectively. Results: There were marked variations in the gut microbiota composition and metabolites in critically ill patients. We identified 8 metabolite modules (mainly characterized by fatty acid, glycerophosphoethanolamines, and glycerophosphocholines) that were distinctly classified as negatively or positively associated with bacterial co-abundance groups (CAGs). These CAGs were mainly composed of Bacteroides, Eubacterium_hallii_group, Anaerostipes, Ruminococcus, Butyricicoccus, and Faecalibacterium, which were substantially altered in patients. In addition, these fecal and serum metabolic modules were further correlated with the serum cytokines. Additionally, the combination of clinical features, microbial marker (Granulicatella), and a panel of metabolic markers could further enhance the performance of prognosis discrimination significantly, which yielded an area under the receiver operating characteristic curve of (AUC) of 0.94 (95%CI = 0.7-0.9). Patients with low bacterial diversity are more likely to develop relapse than those with higher bacterial diversity (log-rank p = 0.04, HR = 2.7, 95%CI = 1.0-7.0). Interpretation: The associations between the multi-omics data suggested that certain bacteria might affect the pathogenesis of NMDAR encephalitis by modulating the metabolic pathways of the host and affecting the production of pro-inflammatory cytokines. Furthermore, the disturbance of fecal bacteria may predict the long-term outcome and relapse in NMDAR encephalitis.

Long-term Functional Outcomes and Relapse of Anti-NMDA Receptor Encephalitis: A Cohort Study in Western China.

OBJECTIVE: To study the factors associated with relapse and functional outcomes in patients with anti-NMDA receptor encephalitis in Western China. METHODS: The Outcome of the anti-NMDA receptor Encephalitis Study in Western China was initiated in October 2011 to collect prospective observational data from consecutively enrolled patients with anti-NMDA receptor encephalitis. RESULTS: We consecutively enrolled 244 patients (median age: 26 years, range: 9-78 years; females: 128 [52.45%]) between October 2011 and September 2019. Fatality occurred in 17 (6.96%) patients, and tumors were found in 38 (15.57%) patients. The median follow-up duration was 40 (6-96) months. Of these patients, 84.8% showed clinical improvements within 4 weeks after immunotherapy, with a median modified Rankin Scale of 2 (interquartile range [IQR]: 2-3), and 80.7% (median: 1, IQR: 0-2) and 85.7% (median: 0, IQR: 0-1) had substantial recovery (i.e., mild or no residual symptoms) at 12 and 24 months, respectively. The overall prognosis was still improving at 42 months after onset. Disturbance of consciousness during the first month was the only independent predictor (OR: 2.91, 95% CI: 1.27-6.65; p = 0.01) of a poor functional neurologic outcome. Overall, 15.9% of the patients had one or multiple relapses, with 82.0% experiencing the first relapse within 24 months and 76.9% experiencing relapses that were less severe than the initial episodes. Relapse-related risk factors included the female sex and delayed treatment (p < 0.05). CONCLUSIONS: Most patients achieved favorable long-term functional outcomes. Some patients experienced one or multiple relapses, especially female patients. Timely immunotherapy at onset may reduce the risk of relapse.

Direct economic burden of patients with autoimmune encephalitis in western China.

OBJECTIVE: To analyze the cost of autoimmune encephalitis (AE) in China for the first time. METHODS: Patients who were newly diagnosed with antibody-positive AE (anti-NMDA receptor [NMDAR], anti-γ aminobutyric acid type B receptor [GABABR], antileucine-rich glioma-inactivated 1 [LGI1], and anticontactin-associated protein-2 [CASPR2]) at West China Medical Center between June 2012 and December 2018 were enrolled, and a cost-of-illness study was performed retrospectively. Data on clinical characteristics, costs, and utilization of sources were collected from questionnaires and the hospital information system. RESULTS: Of the 208 patients reviewed, the mean direct cost per patient was renminbi (RMB) 94,129 (United States dollars [USD] 14,219), with an average direct medical cost of RMB 88,373 (USD 13,349). The average inpatient cost per patients with AE was RMB 86,810 (USD 13,113). The direct nonmedical cost was much lower than the direct medical cost, averaging RMB 5,756 (USD 869). The direct cost of anti-LGI1/CASPR2 encephalitis was significantly lower than that of anti-NMDAR encephalitis and anti-GABABR encephalitis. The length of stay in the hospital was significantly associated with the direct cost. CONCLUSIONS: The financial burden of AE is heavy for Chinese patients, and there are significant differences between different types of AE.

Alteration of Gut Microbiota in Patients With Epilepsy and the Potential Index as a Biomarker.

OBJECTIVE: To explore the structure and composition of the fecal microbiota of patients with epilepsy. METHODS: Variations in the fecal microbiota between patients with epilepsy and healthy controls (HCs) from the same household were investigated and validated by utilizing 16S ribosomal RNA sequencing in two independent cohorts [exploration cohort (N = 55 patients and N = 46 HCs) and validation cohort (N = 13 patients and N = 10 HCs)]. RESULTS: The alpha diversity indexes of the specimens from patients with epilepsy were much lower than those from the HCs (p < 0.05). The structure and composition of the fecal microbiota differed between patients with different clinical prognoses and between patients and HCs (Adonis: p < 0.05). Microbiome alterations in patients with epilepsy included increases in Actinobacteria and Verrucomicrobia and decreases in Proteobacteria at the phylum level and increases in Prevotella_9, Blautia, Bifidobacterium, and others at the genus level [linear discriminant analysis (LDA): 3.5] Patients with drug-resistant epilepsy showed enrichment of bacterial taxa in Actinobacteria, Verrucomicrobia, and Nitrospirae and the genera Blautia, Bifidobacterium, Subdoligranulum, Dialister, and Anaerostipes (Kruskal-Wallis test: p < 0.05). Analysis of gut microbiome indicated predictive ability for disease diagnosis, with an area under the receiver operating characteristic (ROC) curve (AUC) of 0.97 (95% CI, 0.84-0.98). Applying the model to our validation cohort resulted in an AUC of 0.96 (95% CI, 0.75-0.97). Notably, the model could distinguish drug-resistant from drug-sensitive epilepsy (AUC = 0.85, 95% CI: 0.69-0.94). CONCLUSION: Patients with epilepsy exhibit substantial alterations of fecal microbiota composition, and specific gut commensal strains are altered depending on different clinical phenotypes and thus could serve as potential biomarkers for disease diagnosis.