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.

Inhibiting PI3K/Akt-Signaling Pathway Improves Neurobehavior Changes in Anti-NMDAR Encephalitis Mice by Ameliorating Blood-Brain Barrier Disruption and Neuronal Damage.

The disruption of the blood-brain barrier (BBB) is hypothesized to be involved in the progression of anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, but its mechanism is still unclear. Recently, the phosphatidylinositol 3-kinase (PI3K)/threonine kinase (Akt) pathway is involved in the regulation of the BBB in various diseases. This study is aimed to investigate the mechanism of BBB damage and neurobehavior changes in anti-NMDAR encephalitis mice. Female C57BL/6J mice were actively immunized to establish an anti-NMDAR encephalitis mouse model and evaluate the neurobehavior changes of mice. To study its potential mechanism, LY294002 (PI3K inhibitor, 8 mg/kg) and Recilisib (PI3K agonist, 10 mg/kg) were treated by intraperitoneal injection, respectively. Anti-NMDAR encephalitis mice showed neurological deficits, increased BBB permeability, open endothelial tight junctions (TJs), and decreased expression of TJ-related proteins zonula occludens (ZO)-1 and Claudin-5. However, administration of PI3K inhibitor significantly reduced the expression of p-PI3K and p-Akt, improved neurobehavior function, decreased BBB permeability, and upregulated the expressions of ZO-1 and Claudin-5. Furthermore, PI3K inhibition reversed the decline of NMDAR NR1 in the membranes of hippocampal neurons, which reduced the loss of neuron-specific nucleoprotein (NeuN) and microtubule-associated protein 2 (MAP2). In contrast, administration of the PI3K agonist Recilisib showed a tendency to exacerbate BBB breakdown and neurological deficits. Our results showed that the activation of PI3K/Akt, along with the changes in TJ-related proteins ZO-1 and Claudin-5, may be closely related to BBB damage and neurobehavior changes in anti-NMDAR encephalitis mice. PI3K inhibition attenuates BBB disruption and neuronal damage in mice, thereby improving neurobehavior.

NMDAR Antibodies Alter Dopamine Receptors and Cause Psychotic Behavior in Mice.

OBJECTIVE: The aim was to demonstrate that antibodies from patients with anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis alter the levels of dopamine 1 receptor (D1R) and dopamine 2 receptor (D2R) and cause psychotic-like features in mice. METHODS: Cultured rat hippocampal neurons were treated with cerebrospinal fluid (CSF) from patients with anti-NMDAR encephalitis or controls, and the effects on clusters of D1R and D2R were quantified. In vivo studies included 71 C57BL/6J mice that were chronically infused with CSF from patients or controls through ventricular catheters connected to subcutaneous osmotic pumps. Prepulse inhibition of the acoustic startling reflex (PPI; a marker of psychotic-like behavior), memory, locomotor activity, and the density of cell-surface and synaptic D1R, D2R, and NMDAR clusters were examined at different time points using reported techniques. RESULTS: In cultured neurons, CSF from patients, but not from controls, caused a significant decrease of cell-surface D1R and an increase of D2R clusters. In mice, CSF from patients caused a significant decrease of synaptic and total cell-surface D1R clusters and an increase of D2R clusters associated with a decrease of PPI. These effects were accompanied by memory impairment and a reduction of surface NMDARs, as reported in this model. The psychotic-like features, memory impairment, and changes in levels of D1R, D2R, and NMDAR progressively improved several days after the infusion of CSF from patients stopped. INTERPRETATION: In addition to memory deficits and reduction of NMDARs, CSF antibodies from patients with anti-NMDAR encephalitis cause reversible psychotic-like features accompanied by changes (D1R decrease, D2R increase) in cell-surface dopamine receptor clusters. ANN NEUROL 2020 ANN NEUROL 2020;88:603-613.

N-Methyl-D-Aspartate Receptor Antibodies in Autoimmune Encephalopathy Alter Oligodendrocyte Function.

OBJECTIVE: Antibodies against neuronal N-methyl-D-aspartate receptors (NMDARs) in patients with anti-NMDAR encephalitis alter neuronal synaptic function and plasticity, but the effects on other cells of the nervous system are unknown. METHODS: Cerebrospinal fluid (CSF) of patients with anti-NMDAR encephalitis (preabsorbed or not with GluN1) and a human NMDAR-specific monoclonal antibody (SSM5) derived from plasma cells of a patient, along the corresponding controls, were used in the studies. To evaluate the activity of oligodendrocyte NMDARs and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in vitro after exposure to patients' CSF antibodies or SSM5, we used a functional assay based on cytosolic Ca2+ imaging. Expression of the glucose transporter (GLUT1) in oligodendrocytes was assessed by immunocytochemistry. RESULTS: NMDAR agonist responses were robustly reduced after preincubation of oligodendrocytes with patients' CSF or SSM5 but remained largely unaltered with the corresponding controls. These effects were NMDAR specific, as patients' CSF did not alter responses to AMPA receptor agonists and was abrogated by preabsorption of CSF with HEK cells expressing GluN1 subunit. Patients' CSF also reduced oligodendrocyte expression of glucose transporter GLUT1 induced by NMDAR activity. INTERPRETATION: Antibodies from patients with anti-NMDAR encephalitis specifically alter the function of NMDARs in oligodendrocytes, causing a decrease of expression of GLUT1. Considering that normal GLUT1 expression in oligodendrocytes and myelin is needed to metabolically support axonal function, the findings suggest a link between antibody-mediated dysfunction of NMDARs in oligodendrocytes and the white matter alterations reported in patients with this disorder. ANN NEUROL 2020;87:670-676.

Allosteric modulation of NMDA receptors prevents the antibody effects of patients with anti-NMDAR encephalitis.

Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis is an immune-mediated disease characterized by a complex neuropsychiatric syndrome in association with an antibody-mediated decrease of NMDAR. About 85% of patients respond to immunotherapy (and removal of an associated tumour if it applies), but it often takes several months or more than 1 year for patients to recover. There are no complementary treatments, beyond immunotherapy, to accelerate this recovery. Previous studies showed that SGE-301, a synthetic analogue of 24(S)-hydroxycholesterol, which is a potent and selective positive allosteric modulator of NMDAR, reverted the memory deficit caused by phencyclidine (a non-competitive antagonist of NMDAR), and prevented the NMDAR dysfunction caused by patients' NMDAR antibodies in cultured neurons. An advantage of SGE-301 is that it is optimized for systemic delivery such that plasma and brain exposures are sufficient to modulate NMDAR activity. Here, we used SGE-301 to confirm that in cultured neurons it prevented the antibody-mediated reduction of receptors, and then we applied it to a previously reported mouse model of passive cerebroventricular transfer of patient's CSF antibodies. Four groups were established: mice receiving continuous (14-day) infusion of patients' or controls' CSF, treated with daily subcutaneous administration of SGE-301 or vehicle (no drug). The effects on memory were examined with the novel object location test at different time points, and the effects on synaptic levels of NMDAR (assessed with confocal microscopy) and plasticity (long-term potentiation) were examined in the hippocampus on Day 18, which in this model corresponds to the last day of maximal clinical and synaptic alterations. As expected, mice infused with patient's CSF antibodies, but not those infused with controls' CSF, and treated with vehicle developed severe memory deficit without locomotor alteration, accompanied by a decrease of NMDAR clusters and impairment of long-term potentiation. All antibody-mediated pathogenic effects (memory, synaptic NMDAR, long-term potentiation) were prevented in the animals treated with SGE-301, despite this compound not antagonizing antibody binding. Additional investigations on the potential mechanisms related to these SGE-301 effects showed that (i) in cultured neurons SGE-301 prolonged the decay time of NMDAR-dependent spontaneous excitatory postsynaptic currents suggesting a prolonged open time of the channel; and (ii) it significantly decreased, without fully preventing, the internalization of antibody-bound receptors suggesting that additional, yet unclear mechanisms, contribute in keeping unchanged the surface NMDAR density. Overall, these findings suggest that SGE-301, or similar NMDAR modulators, could potentially serve as complementary treatment for anti-NMDAR encephalitis and deserve future investigations.

The Association of Ovarian Teratoma and Anti-N-Methyl-D-Aspartate Receptor Encephalitis: An Updated Integrative Review.

Ovarian teratomas are by far the most common ovarian germ cell tumor. Most teratomas are benign unless a somatic transformation occurs. The designation of teratoma refers to a neoplasm that differentiates toward somatic-type cell populations. Recent research shows a striking association between ovarian teratomas and anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis, a rare and understudied paraneoplastic neurological syndrome (PNS). Among teratomas, mature teratomas are thought to have a greater relevance with those neurological impairments. PNS is described as a neurologic deficit triggered by an underlying remote tumor, whereas anti-NMDAR encephalitis is characterized by a complex neuropsychiatric syndrome and the presence of autoantibodies in cerebral spinal fluid against the GluN1 subunit of the NMDAR. This review aims to summarize recent reports on the association between anti-NMDAR encephalitis and ovarian teratoma. In particular, the molecular pathway of pathogenesis and the updated mechanism and disease models would be discussed. We hope to provide an in-depth review of this issue and, therefore, to better understand its epidemiology, diagnostic approach, and treatment strategies.

A Metabolic Brain Pattern Associated With Anti-N-Methyl-D-Aspartate Receptor Encephalitis.

BACKGROUND: Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis causes substantial neurological disability. Autoantibodies causing encephalitis directed against the neuronal cell surface or synapse are of diagnostic importance giving the possibility of successful immunotherapy. OBJECTIVE: In this study, we aim to provide supporting evidence that brain 18F-FDG-PET may be helpful in identifying likely patterns of regional brain glucose metabolism. METHODS: Thirty-three patients (18 men and 15 women; age range of 17-55 y) with positive NMDA receptor antibody encephalitis that underwent an 18F-FDG-PET imaging examination were prospectively selected and compared with a reference group of 14 brain 18F-FDG-PET scans from healthy volunteers using voxel-based statistical analysis. Clusters of hyper- and hypo-metabolism were reported for the whole sample of patients (FWE-corrected P < 0.05), and uncorrected at P < 0.005 for a group of relapsed patients. RESULTS: Mixed metabolic patterns (focal/bilateral hypermetabolism in the temporal lobe, insula, and cerebellum; associated with severe bilateral hypometabolism in the occipital and parietal lobes) were found. CONCLUSIONS: Our findings suggest that 18F-FDG-PET should be included as an imaging tool when assessing affected patients in the clinical workup to rule out anti-NMDA encephalitis and help determine the most effective treatment.

Hypoglutamatergic state is associated with reduced cerebral glucose metabolism in anti-NMDA receptor encephalitis: a case report.

BACKGROUND: Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis was first described in 2005 in association with ovarian teratoma. The diagnostic workup of this common autoimmune encephalitis includes cerebrospinal fluid analysis, electroencephalography, magnetic resonance imaging (MRI), and fluorodeoxyglucose positron emission tomography (FDG-PET). In addition to standard diagnostics, we performed metabolic investigations using proton magnet resonance spectroscopy ((1)H-MRS). CASE PRESENTATION: We describe the case of a non-limbic anti-NMDAR encephalitis with a long course of disease (21 months). Laboratory diagnostics showed antibodies against NMDAR; an MRI revealed unspecific findings. (1)H-MRS indicated a hypoglutamatergic state in the left prefrontal cortex associated with a left hemispherical hypometabolism on FDG-PET. Despite the long course of disease, immunosuppressive therapy with methylprednisolone and azathioprine led to almost complete remission of clinical symptoms. Clinical improvement developed in parallel with remarkable normalization of cerebral glucose metabolism on FDG-PET. CONCLUSION: This case of long-lasting extra-limbic anti-NMDAR encephalitis is of high clinical relevance. First, it illustrates that a very good outcome is possible even if adequate therapy is started only 21 months after the onset of severe symptoms. Second, it provides valuable insights into the pathophysiology of such anti-NMDAR encephalitis; these insights prove that anti-NMDAR encephalitis is linked not only to hyperglutamatergic signals but also to hypoglutamatergic states. These findings, contradictory at first glance, can be integrated within the model of excitatory/inhibitory imbalance and local area network inhibition.

A 16-year-old girl with anti-NMDA-receptor encephalitis and family history of psychotic disorders.

BACKGROUND: Autoimmune NMDA-R encephalitis (ANRE) shares clinical features with schizophrenia. Recent research also indicates that both disorders are associated with dysfunction of the N-Methyl-D-Aspartate glutamate receptors (NMDA-R) subunit 1. METHODS: We present the case of Ms A, 16 years old. Ms A presented with acute personality change, bizarre behaviour, delusional ideas and atypical seizures. She had a family history of psychotic disorders, and autistic traits diagnosed in childhood. She was initially diagnosed with a psychotic disorder. Delayed testing of CSF indicated ANRE. As the patient was a Jehovah's witness the treating team was unable to use gammaglobulin therapy; they instead relied on combined plasmapheresis and rituximab. To exclude the possibility that the affected members of this family shared a gene coding for an abnormal configuration of the NMDA receptor subunit 1 we sequenced the region of the GRIN1 gene in DNA extracted from blood in both Ms A and her grandmother. RESULTS: Ms A's condition improved dramatically, though her long-term memory is still demonstrably impaired. No genetic abnormality was detected. CONCLUSIONS: This case emphasizes how important it is, for a first episode psychosis, to exclude ANRE and other autoimmune synaptic encephalitides, even in the face of significant family history, and if seronegative, the importance of testing for CSF autoantibodies.

Functional and structural brain changes in anti-N-methyl-D-aspartate receptor encephalitis.

OBJECTIVE: Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an autoimmune encephalitis with a characteristic neuropsychiatric syndrome and severe and prolonged clinical courses. In contrast, standard clinical magnetic resonance imaging (MRI) remains normal in the majority of patients. Here, we investigated structural and functional brain changes in a cohort of patients with anti-NMDAR encephalitis. METHODS: Twenty-four patients with established diagnosis of anti-NMDAR encephalitis and age- and gender-matched controls underwent neuropsychological testing and multimodal MRI, including T1w/T2w structural imaging, analysis of resting state functional connectivity, analysis of white matter using diffusion tensor imaging, and analysis of gray matter using voxel-based morphometry. RESULTS: Patients showed significantly reduced functional connectivity of the left and right hippocampus with the anterior default mode network. Connectivity of both hippocampi predicted memory performance in patients. Diffusion tensor imaging revealed extensive white matter changes, which were most prominent in the cingulum and which correlated with disease severity. In contrast, no differences in T1w/T2w structural imaging and gray matter morphology were observed between patients and controls. INTERPRETATION: Anti-NMDAR encephalitis is associated with characteristic alterations of functional connectivity and widespread changes of white matter integrity despite normal findings in routine clinical MRI. These results may help to explain the clinicoradiological paradox in anti-NMDAR encephalitis and advance the pathophysiological understanding of the disease. Correlation of imaging abnormalities with disease symptoms and severity suggests that these changes play an important role in the symptomatology of anti-NMDAR encephalitis.

The N-methyl-D-aspartate receptor, a precursor to N-methyl-D-aspartate receptor encephalitis, is found in the squamous tissue of ovarian teratomas.

Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is the most common antibody-mediated limbic encephalitis and is associated with underlying ovarian teratoma. Previous studies suggest that expression of NMDAR on teratoma neural tissue initiates an autoimmune response to NMDAR in the brain. As some teratomas of patients with anti-NMDAR encephalitis lack neuronal tissue, we questioned if there could be an alternate mechanism of the disease. We performed immunohistochemical analyses for NMDAR and correlated its expression with histology on 10 control teratomas and 5 teratomas associated with anti-NMDAR encephalitis. Both control and case teratomas expressed NMDAR-bearing neural tissue. All 15 teratomas contained large amounts of NMDAR bearing squamous epithelium; in 2 cases this was the only tissue expressing NMDAR. NMDAR-bearing neural tissue is not the sole source of encephalitis in all patients. Furthermore, we speculate that NMDAR expression by squamous epithelium may contribute to the disease development in some patients.

Anti-leucine rich glioma inactivated 1 protein and anti-N-methyl-D-aspartate receptor encephalitis show distinct patterns of brain glucose metabolism in 18F-fluoro-2-deoxy-d-glucose positron emission tomography.

BACKGROUND: Pathogenic autoantibodies targeting the recently identified leucine rich glioma inactivated 1 protein and the subunit 1 of the N-methyl-D-aspartate receptor induce autoimmune encephalitis. A comparison of brain metabolic patterns in 18F-fluoro-2-deoxy-d-glucose positron emission tomography of anti-leucine rich glioma inactivated 1 protein and anti-N-methyl-D-aspartate receptor encephalitis patients has not been performed yet and shall be helpful in differentiating these two most common forms of autoimmune encephalitis. METHODS: The brain 18F-fluoro-2-deoxy-d-glucose uptake from whole-body positron emission tomography of six anti-N-methyl-D-aspartate receptor encephalitis patients and four patients with anti-leucine rich glioma inactivated 1 protein encephalitis admitted to Hannover Medical School between 2008 and 2012 was retrospectively analyzed and compared to matched controls. RESULTS: Group analysis of anti-N-methyl-D-aspartate encephalitis patients demonstrated regionally limited hypermetabolism in frontotemporal areas contrasting an extensive hypometabolism in parietal lobes, whereas the anti-leucine rich glioma inactivated 1 protein syndrome was characterized by hypermetabolism in cerebellar, basal ganglia, occipital and precentral areas and minor frontomesial hypometabolism. CONCLUSIONS: This retrospective 18F-fluoro-2-deoxy-d-glucose positron emission tomography study provides novel evidence for distinct brain metabolic patterns in patients with anti-leucine rich glioma inactivated 1 protein and anti-N-methyl-D-aspartate receptor encephalitis.

Immunopathological significance of ovarian teratoma in patients with anti-N-methyl-d-aspartate receptor encephalitis.

BACKGROUND: The clinical importance of ovarian teratoma in anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis has been established, however investigations of ovarian teratoma in patients with anti-NMDAR encephalitis remain limited. OBJECTIVE: To clarify differences in NMDAR distribution and lymphocyte infiltration in ovarian teratoma between patients with and without anti-NMDAR encephalitis. METHODS: Participants initially comprised 26 patients with ovarian teratomas. NMDAR distribution and lymphocyte infiltration in ovarian teratomas were examined using immunopathological techniques. Clinical, laboratory, and radiological data were compared between patients showing the features of encephalitis. Anti-NMDAR antibodies in the serum and cerebrospinal fluid were also measured in encephalitis patients. RESULTS: Neuronal tissues were obtained from ovarian teratomas in 22 patients (after excluding 4 patients who did not satisfy the inclusion criteria), and the presence of NMDA receptor subunits was revealed in all patients. Lymphocyte infiltration was more frequent in the encephalitis group (n = 3) than in the non-encephalitis group. In particular, dense B-lymphocyte infiltration near neural tissues was observed in the encephalitis group. CONCLUSIONS: Differences in lymphocyte infiltration in ovarian teratomas between anti-NMDAR encephalitis and non-encephalitis patients suggest the immunological importance of the ovarian teratoma as the site of antigen presentation in anti-NMDAR encephalitis.

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

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

Pseudopseudoseizures: conditions that may mimic psychogenic non-epileptic seizures.

BACKGROUND: Video electroencephalography (vEEG) has proven to be a valuable tool in the differentiation of pseudoseizures or psychogenic non-epileptic seizures (PNES) from epileptic seizures. Clinicians should, however, be aware of a number of conditions that may be misdiagnosed as pseudoseizures. OBJECTIVE: To review a number of somatic conditions that can present with disturbances of consciousness and unusual motor activity without epileptiform findings on vEEG. METHOD: We report a case of a young woman who presented with a number of neuropsychiatric symptoms, including episodic posturing and rhythmic movements. The absence of epileptiform findings on vEEG resulted in a diagnosis of conversion disorder with pseudoseizures. She was ultimately diagnosed with N-methyl-D-aspartate (NMDA) receptor autoimmune encephalitis (AIE) secondary to an ovarian tumor. AIE and other potential mimics of pseudoseizures are discussed. RESULTS: A number of somatic conditions can present with symptoms that may be misinterpreted as pseudoseizure.

The diverse and complex modes of action of anti-NMDA receptor autoantibodies.

NMDA receptors are ligand-gated ion channels that are found throughout the brain and are required for both brain development and many higher order functions. A variety of human patients with diverse clinical phenotypes have been identified that carry autoantibodies directed against NMDA receptor subunits. Here we focus on two general classes of autoantibodies, anti-GluN1 antibodies associated with anti-NMDA receptor encephalitis and anti-GluN2 antibodies associated with systemic lupus erythematosus (SLE). These two general classes of anti-NMDA receptor autoantibodies display a wide range of pathophysiological mechanisms from altering synaptic composition to gating of NMDARs. While we have made progress in understanding how these autoantibodies work at the molecular and cellular level, many unanswered questions remain including their long-term actions on brain function, the significance of clonal variations, and their effects on different NMDA receptor-expressing cell types in local circuits. This information will be needed to define fully the transition from anti-NMDA receptor autoantibodies to a clinical phenotype.

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.

Comprehensive B-Cell Immune Repertoire Analysis of Anti-NMDAR Encephalitis and Anti-LGI1 Encephalitis.

Anti-N-methyl-D-aspartate receptor encephalitis (anti-NMDARE) and anti-leucine-rich glioma-inactivated 1 encephalitis (anti-LGI1E) are the two most common types of antibody-mediated autoimmune encephalitis. We performed a comprehensive analysis of the B-cell immune repertoire in patients with anti-NMDARE (n = 7) and anti-LGI1E (n = 10) and healthy controls (n = 4). The results revealed the presence of many common clones between patients with these two types of autoimmune encephalitis, which were mostly class-switched. Additionally, many differences were found among the anti-NMDARE, anti-LGI1E, and healthy control groups, including the diversity of the B-cell immune repertoire and gene usage preference. These findings suggest that the same adaptive immune responses occur in patients with anti-NMDARE and anti-LGI1E, which deserves further exploration.

Study of B Cell Repertoire in Patients With Anti-N-Methyl-D-Aspartate Receptor Encephalitis.

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is the most common antibody-mediated encephalitis. There are several studies on B cell repertoire of anti-NMDAR encephalitis in Caucasians. Here, the cerebrospinal fluid (CSF) samples of 12 Chinese patients with first-episode anti-NMDAR encephalitis were collected to investigate the B cell receptor (BCR) binding to NMDAR by single cell amplification of BCR and Sanger sequencing. BCR data of healthy persons, and of patients with anti-leucine-rich glioma inactivated 1 (anti-LGI1) encephalitis, multiple sclerosis (MS), and neuromyelitis optica spectrum disorder (NMOSD) from the public databases were used as control. A heavy chain common clone IGHV1-18*04,IGHD1-26*01/ IGHD2-2*03/IGHD2-8*01, IGHJ3*02_(CDR3) ARVGSKYGFETFDI was found in 11 of 12 enrolled patients but not in the comparison data set. In addition, 4 shared clonotypes were found among these patients, and three of them contained the common clone. This study also revealed that the antibody gene family usage preference between patients and healthy controls were different, while they had similar antibody mutation rate. Our findings may have potential clinical implications for the diagnosis of anti-NMDAR encephalitis.

Different FDG-PET metabolic patterns of anti-AMPAR and anti-NMDAR encephalitis: Case report and literature review.

INTRODUCTION: 18 F-fluorodeoxyglucose (FDG)-PET metabolic patterns of brain differ among autoimmune encephalitis with different neuronal surface antigens. In this case report, we compared the topographical relationship of cerebral glucose metabolism and antigen distribution in the patients with anti-NMDAR and anti-AMPAR encephalitis. Literature review summarized the common features of brain metabolism of autoimmune encephalitis. METHODS: The cerebral glucose metabolism was evaluated by FDG-PET/CT during acute-to-subacute stage of autoimmune encephalitis and after treatment. The stereo and quantitative analysis of cerebral metabolism used standardized z-score and visualized on three-dimensional stereotactic surface projection. To map NMDAR and AMPAR in human brain, we adopted genetic atlases from the Allen Institute and protein atlases from Zilles's receptor densities. RESULTS: The three-dimensional stereotactic surface projection displayed frontal-dominant hypometabolism in a 66-year-old female patient with anti-AMPAR encephalitis and occipital-dominant hypometabolism in a 29-year-old female patient with anti-NMDAR encephalitis. Receptor density maps revealed opposite frontal-occipital gradients of AMPAR and NMDAR, which reflect reduced metabolism in the correspondent encephalitis. FDG-PET hypometabolic areas possibly represent receptor hypofunction with spatial correspondence to receptor distributions of the autoimmune encephalitis. The reversibility of hypometabolism was in line with patients' cognitive improvement. The literature review summarized six features of metabolic anomalies of autoimmune encephalitis: (a) temporal hypermetabolism, (b) frontal hypermetabolism and (c) occipital hypometabolism in anti-NMDAR encephalitis, (d) hypometabolism in association cortices, (e) sparing of unimodal primary motor cortex, and (e) reversibility in recovery. CONCLUSIONS: The distinct cerebral hypometabolic patterns of autoimmune encephalitis were representative for receptor hypofunction and topographical distribution of antigenic receptors. The reversibility of hypometabolism marked the clinical recovery of autoimmune encephalitis and made FDG-PET of brain a valuable diagnostic tool.