Impaired functional connectivity of the hippocampus in murine models of NMDA-receptor antibody associated pathology

Introduction: While decreased hippocampal connectivity and disruption of functional networks are established MRI features in human anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, the underlying pathophysiology for brain network alterations remains poorly understood. Application of patient-derived monoclonal antibodies against the NR1 subunit of the NMDAR allows for the investigation of potential functional connectivity alterations in experimental murine NMDAR antibody disease models. Objective: To explore functional connectivity changes in NR1 antibody mouse models using resting-state functional MRI (rs-fMRI). Methods: Adult C57BL/6J mice (n=10) were intrathecally injected with a recombinant human NR1 antibody over 14 days and then studied using rs-fMRI at 7 Tesla. In addition, a newly established mouse model with in utero exposure to a human recombinant NR1 antibody characterized by a neurodevelopmental disorder (NR1-offspring) was investigated with rs-fMRI at the age of 8 weeks (n=15) and 10 months (n=14). Mice exposed to isotype-matched control antibodies served as controls. Independent component analysis (ICA) and dual regression analysis were performed to compare functional connectivity between NMDAR antibody mouse models and control mice. Results: Adult NR1-antibody injected mice showed significantly impaired functional connectivity within the dentate gyrus of the left hippocampus in comparison to controls, resembling impaired hippocampal functional connectivity patterns observed in human patients with NMDAR encephalitis. Similarly, analyses showed significantly reduced functional connectivity in the dentate gyrus in NR1-offspring compared after 8 weeks, and impaired connectivity in the dentate gyrus and CA3 hippocampal subregion in NR1-offspring at the age of 10 months. Conclusion: Functional connectivity changes within the hippocampus resulting from both direct application and in utero exposure to NMDAR antibodies can be modeled in experimental murine systems. With this translational approach, we successfully reproduced functional MRI alterations previously observed in human NMDAR encephalitis patients. Future experimental studies will identify the detailed mechanisms that cause functional network alterations and may eventually allow for non-invasive monitoring of disease activity and therapeutic effects in autoimmune encephalitis.

Anti-NMDAr Encephalitis and COVID-19 in a Patient With Systemic pANCA-Vasculitis and Recurrent Varicella Zoster Infection

Introduction There is a complex interplay between systemic autoimmunity, immunosuppression, and infections. Any or all of these can result in neurologic manifestations, requiring diligence on the part of neurologists. Case report We herein report a case of a patient on immunosuppressive treatment for a vasculitis that resulted in zoster meningoencephalitis. This was further complicated by the development of anti-NMDAr encephalitis, the etiology of which is undetermined and further discussed in this paper. The patient eventually developed COVID-19 during hospitalization, succumbing to the respiratory infection. Conclusion This case emphasizes that post-infectious autoimmune disorders are becoming increasingly recognized and that they should still be considered in patients who are on immunosuppression. Practitioners should be aware of the complex relationship between autoimmunity and immunosuppression and consider both throughout the disease course.

Clinical Characteristics and Follow-Up of Seizures in Children With Anti-NMDAR Encephalitis

Objective: To analyze the seizure characteristics of children with anti-NMDAR encephalitis.Methods: This was a retrospective analysis of 50 children with anti-NMDAR encephalitis between July 1, 2013, and July 1, 2019.Results: Fifty children with anti-NMDAR encephalitis were included in this study, of which 34 (68.0%) had seizures. During the follow-up, three patients with anti-NMDAR encephalitis secondary to herpes simplex virus encephalitis had persistent seizures. The average duration of seizures in the remaining patients was 14.6 days (range 1–47 days). Compared to patients without seizures, those with seizures were more likely to experience consciousness disturbances (p = 0.008) and epileptic form discharge on electroencephalograms (p = 0.002). The Glasgow coma scale scores (p = 0.014), and Rankin scale scores (p = 0.019) were also different. The cranial MRI findings of children were reviewed, and clinical characteristics were compared between children without cranial lesions and those with lesions in the limbic system and neocortex. Compared to children in the non-lesion group, children with lesions in the limbic system and neocortex had a higher incidence of status epilepticus. Further, children in the limbic system and neocortical lesions groups were more likely to be taking anti-seizure medications (ASMs) and receive second-line drugs.Conclusion: Long-term oral ASMs are not recommended for most children with anti-NMDAR encephalitis. Children with involvement of the limbic system and neocortex are prone to status epilepticus, and sequelae of epilepsy may remain when the neocortex is involved.

Gray Matter Atrophy And Corresponding Impairments In Connectivity In Patients With Anti-N-Methyl-D-Aspartate Receptor Encephalitis

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

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

ObjectiveWe 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.MethodsIn 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.ResultsThere 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).InterpretationThe 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.

Isolated Memory Loss in Anti-NMDAR Encephalitis

Background and ObjectivesTo report a case of anti-NMDAR encephalitis presenting with isolated memory dysfunction.MethodsA 29-year-old woman was admitted to the Neurology Department referring memory impairment with a subacute onset. The initial assessment included EEG, neuropsychological tests, and brain MRI. Serum and CSF samples were collected for immunologic studies. The diagnostic evaluation was completed with a total body PET scan.ResultsPatient's neurologic examination was unremarkable apart from an episodic memory deficit, confirmed by neuropsychological examination. The EEG revealed epileptiform discharges in the temporal lobes, whereas brain MRI showed bilateral temporal lobes hyperintense lesions on fluid-attenuated inversion recovery images and T2-weighted images. NMDAR-IgG was detected in the patient's serum and CSF by cell-based assay confirming the diagnosis of definite anti-NMDAR encephalitis. The total body PET showed only a slight hypometabolism in the right temporal cortex and in the cerebellar hemispheres. After a course of IV immunoglobulin and corticosteroid therapy, a marked improvement of the memory deficit was observed.DiscussionThis case shows that anti-NMDAR encephalitis can present with isolated memory loss. Neural antibody testing in these patients could play a pivotal role in early diagnosis and prompt treatment.

Anti-NMDAR Encephalitis in the Netherlands, Focusing on Late-Onset Patients and Antibody Test Accuracy

Background and ObjectivesTo describe the clinical features of anti-NMDAR encephalitis, emphasizing on late-onset patients and antibody test characteristics in serum and CSF.MethodsNationwide observational Dutch cohort study, in patients diagnosed with anti-NMDAR encephalitis between 2007 and 2019.ResultsOne hundred twenty-six patients with anti-NMDAR encephalitis were included with a median age of 24 years (range 1–86 years). The mean annual incidence was 1.00/million (95% CI 0.62–1.59). Patients ≥45 years of age at onset (19%) had fewer seizures (46% vs 71%, p = 0.021), fewer symptoms during disease course (3 vs 6 symptoms, p = 0.020), and more often undetectable serum antibodies compared with younger patients (p = 0.031). In the late-onset group, outcome was worse, and all tumors were carcinomas (both p < 0.0001). CSF was more accurate than serum to detect anti-NMDAR encephalitis (sensitivity 99% vs 68%, p < 0.0001). Using cell-based assay (CBA), CSF provided an unconfirmed positive test result in 11/2,600 patients (0.4%); 6/11 had a neuroinflammatory disease (other than anti-NMDAR encephalitis). Patients with anti-NMDAR encephalitis, who tested positive in CSF only, had lower CSF antibody titers (p = 0.003), but appeared to have an equally severe disease course.DiscussionAnti-NMDAR encephalitis occurs at all ages and is less rare in the elderly patients than initially anticipated. In older patients, the clinical phenotype is less outspoken, has different tumor association, and a less favorable recovery. Detection of antibodies in CSF is the gold standard, and although the CBA has very good validity, it is not perfect. The clinical phenotype should be leading, and confirmation in a research laboratory is recommended, when in doubt.

Clinical Relevance of Cerebrospinal Fluid Antibody Titers in Anti-N-Methyl-d-Aspartate Receptor Encephalitis

Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis is the most common autoimmune encephalitis. To date, there has been no study on the relationship between antibody (Ab) titers and clinical phenotype. This study aims to clarify the relationship between cerebrospinal fluid Ab titers and clinical manifestations of anti-NMDAR encephalitis at onset. Seventy-six consecutive patients with a definite diagnosis were enrolled. The relationship between Ab titers and different onset symptoms including psychiatric symptoms, seizures, and memory deficits were analyzed. We further investigated the correlation between Ab titers and clinical severity as assessed by the modified Rankin scale (mRS) and the clinical assessment scale for autoimmune encephalitis (CASE), respectively. The Ab titers had a median value of 1:10 (range 1:1–1:100). There was no significant difference in titers among various clinical factors including gender and combination of tumor and other diseases (each p > 0.05). Patients presenting with psychiatric symptoms at onset had higher titers than those with seizures (p = 0.008) and memory deficits (p = 0.003). The mRS scores revealed a significant but weak correlation with Ab titers (r = 0.243, p = 0.034), while CASE scores did not correlate with the titers (p = 0.125). Our findings indicated that the Ab titers were associated with the type of onset symptoms, with a higher level of patients with psychiatric symptoms. Regarding the clinical severity, the titers showed a weak correlation with the mRS, but no correlation with the CASE.