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Paraneoplastic neurological syndromes (PNSs) are a group of neurological disorders triggered by an underlying remote tumor. Ovarian teratoma (OT) is the most common histologic type of germ cell tumor in females. The most common PNSs associated with OT is anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. However, with the increasing number of new antibodies reported over the last decade, the clinical spectrum of OT-related PNSs is also expanding. Our knowledge of OT-related PNSs is still far from complete. Here, we provide a comprehensive review of the most recent findings in the field of OT-related PNSs, with a particular focus on their clinical and pathological characteristics. Overall, the description of neuronal antibodies in PNSs associated with OT strongly suggests that antibodies may be responsible for the clinical symptoms in some cases. OT-related PNSs are associated with various clinical manifestations, including anti-NMDAR encephalitis, limbic encephalitis, encephalomyelitis, progressive cerebellar syndrome and opsoclonus-myoclonus syndrome. The pathological characteristics of the OT suggest that the mechanism of PNSs is probably due to heteromorphic neurons in the tumor tissue, the ectopic expression of the antigens in neural tissue within the teratomas and patients’ unusual immune response. Despite the severity of the neurological syndromes, most patients with OT-related PNSs showed good neurologic response to early tumor resection combined with immunotherapy. To further advance the management of OT-related PNSs, additional studies are needed to explore this complex topic.

BackgroundAnti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is the most common autoimmune encephalitis (AE), and the prognosis may significantly be improved if identified earlier and immune-related treated more effectively. This study evaluated the brain metabolic network using fluorodeoxyglucose positron emission tomography (FDG PET).Material and methodsFDG PET imaging of patients with NMDAR encephalitis was used to investigate the metabolic connectivity network, which was analyzed using the graph theory. The results in patients were compared to those in age- and sex-matched healthy controls.ResultsThe hub nodes were mainly in the right frontal lobe in patients with NMDAR encephalitis. The global and local efficiencies in most brain regions were significantly reduced, and the shortest characteristic path length was significantly longer, especially in the temporal and occipital lobes. Significant network functions of topology properties were enhanced in the right frontal, caudate nucleus, and cingulate gyrus. In addition, the internal connection integration in the left cerebral hemisphere was poor, and the transmission efficiency of Internet information was low.ConclusionThe present findings indicate that those characteristic and connections of metabolic network were changed in the brain by graph theory analysis quantitatively, which is helpful to better understand neuropathological and physiological mechanisms in patients with anti-NMDAR encephalitis.

ObjectiveTo investigate factors that could impact or predict the probability of anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis recurrence in central China.MethodsFrom November 2014 to October 2020, observational data of anti-NMDAR encephalitis inpatients in our institution were collected and analyzed prospectively. The demographics, clinical characteristics, tumor status, lesion locations on MRI and immunotherapies, etc. had entered into a Cox regression model for the identification of the factors associated with relapse-free survival.ResultsWe enrolled 113 patients in a row (median age: 28 years, range: 1–61 years). The gender distribution was not statistically significant (p = 0.158), with 49 people (43.4%) being female. The median follow-up time was 16 (4–77) months. Among them, 16.8% of patients relapsed. The average interval between recurrences was 8 months (range 3–54 mo). The severity of the initial relapse was less severe than it had been at the start. The first relapse had considerably fewer symptoms (median 2, range 1–6) than the first episode (median 4, range 1–8, p = 0.005). The mRS at first relapse (median 3, mean 2.84, range 1–5) had been significantly lower than that at onset (median 4, mean 3.89, range 3–5, p = 0.004). The length of hospitalization at first relapse (median 17 days, range 5–46) was significantly shorter than the first episode (median 35 days, range 14–102, p = 0.002). In the survival analysis, the risk of recurrence was significantly higher for patients with a brainstem lesion (HR: 4.112, 95% CI: 1.205–14.030; p = 0.024) or ≥3 abnormal sites (HR: 2.926, 95% CI: 1.085–7.896; p = 0.034) on brain MRI at the first episode. There was no significant difference in neurological outcomes between the recurrent and monophasic groups at the most recent follow-up (mRS 0–2 in 17/19 vs. 86/94; p = 0.674).ConclusionsAnti-NMDAR encephalitis can recur in around one out of every six cases, and symptoms are generally milder than when it first appears. Recurrence is not related to the severity in the acute phase or the prognosis at follow-up. Patients with ≥3 abnormal sites on MRI or lesions located in the brainstem at onset must be alert to the possibility of recurrence.

Extensive evidence suggests a dysfunction of the glutamate NMDA receptor (NMDAR) in schizophrenia, a severe psychiatric disorder with putative early neurodevelopmental origins, but clinical onset mainly during late adolescence. On the other hand, pharmacological models using NMDAR antagonists and the clinical manifestation of anti-NMDAR encephalitis indicate that NMDAR blockade/hypofunction can trigger psychosis also at adult stages, without any early developmental dysfunction. Previous genetic models of NMDAR hypofunction restricted to parvalbumin-positive interneurons indicate the necessity of an early postnatal impairment to trigger schizophrenia-like abnormalities, whereas the cellular substrates of NMDAR-mediated psychosis at adolescent/adult stages are unknown. Neuregulin 1 (NRG1) and its receptor ErbB4 represent schizophrenia-associated susceptibility factors that closely interact with NMDAR. To determine the neuronal populations implicated in “late” NMDAR-driven psychosis, we analyzed the effect of the inducible ablation of NMDARs in ErbB4-expressing cells in mice during late adolescence using a pharmacogenetic approach. Interestingly, the tamoxifen-inducible NMDAR deletion during this late developmental stage did not induce behavioral alterations resembling depression, schizophrenia or anxiety. Our data indicate that post-adolescent NMDAR deletion, even in a wider cell population than parvalbumin-positive interneurons, is also not sufficient to generate behavioral abnormalities resembling psychiatric disorders. Other neuronal substrates that have to be revealed by future studies, may underlie post-adolescent NMDAR-driven psychosis.

Treatments for negative symptoms and cognitive dysfunction in schizophrenia remain issues that psychiatrists around the world are trying to solve. Their mechanisms may be associated with N-methyl-D-aspartate receptors (NMDARs). The NMDAR hypofunction hypothesis for schizophrenia was brought to the fore mainly based on the clinical effects of NMDAR antagonists and anti-NMDAR encephalitis pathology. Drugs targeted at augmenting NMDAR function in the brain seem to be promising in improving negative symptoms and cognitive dysfunction in patients with schizophrenia. In this review, we list NMDAR-targeted drugs and report on related clinical studies. We then summarize their effects on negative symptoms and cognitive dysfunction and analyze the unsatisfactory outcomes of these clinical studies according to the improved glutamate hypothesis that has been revealed in animal models. We aimed to provide perspectives for scientists who sought therapeutic strategies for negative symptoms and cognitive dysfunction in schizophrenia based on the NMDAR hypofunction hypothesis.

Background: Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a cause of autoimmune encephalitis and is characterized by epileptic seizures, psychosis, and consciousness impairments. It mostly affects young adults with ovarian cancers. We herein reported a case of anti-NMDAR encephalitis associated with clear cell renal carcinoma.Case Presentation: A 54-year-old male with headache for 1 week and mood and behavioral changes for 3 days was presented, but his clinical presentation and poor response to antiviral treatment did not support a diagnosis of viral encephalitis. Positive anti-NMDAR antibodies in serum and cerebrospinal fluid confirmed autoimmune encephalitis. A subsequent evaluation revealed a paraneoplastic etiology of a renal mass, and this was then resected and pathologically confirmed as clear cell renal carcinoma. The patient's symptoms showed improvement after resection of the mass. The patient relapsed 6 months after discharge, and the symptoms completely disappeared after treatment with corticosteroids and intravenous immunoglobulin.Conclusion: Our findings suggested that NMDAR encephalitis might be associated with clear cell renal carcinoma. When patients present with unexplained seizures, neuropsychiatric disorder, or other brain symptoms, clinicians should be careful with paraneoplastic neurological disorders. Early diagnosis and treatment of primary tumors might show improvement.

Background: In recent years, the phenomenon of coexisting systemic autoimmune diseases (ADs) in patients with autoimmune encephalitis (AE) has been increasingly found, while its clinical significance remains unexplored. This study aimed to investigate the types and potential clinical associations of autoimmune comorbidities in patients with antibody-positive AE.Methods: A retrospective cohort study of patients with antibody-positive AE was conducted from 2011 to 2018. The demographics, clinical characteristics, and follow-up data were reviewed.Results: We enrolled 517 patients, among whom 45 were affected by one or more types of ADs, including Hashimoto's thyroiditis (HT) (n = 28), systemic lupus erythematosus (SLE) (n = 3), anaphylactoid purpura (n = 3), vitiligo (n = 3), Sjögren's syndrome (SS) (n = 2), chronic urticaria (n = 2), bullous pemphigoid (n = 1), uveitis (n = 1), myasthenia gravis (MG) (n = 1), and the coexistence of SLE and anaphylactoid purpura (n = 1). The proportion of patients with coexisting ADs was higher in those with anti–leucine-rich glioma-inactivated 1 (LGI1) encephalitis than in those with anti–N-methyl-d-aspartate receptor (NMDAR) encephalitis (13/111 vs. 16/307) (P = 0.021). In anti-NMDAR and anti-LGI1 encephalitis patients, there were no significant differences in the age at onset, sex ratio, proportion of patients with tumors, disease severity, or recurrence between the groups with and without ADs.Conclusions: One or more types of ADs developed in AE patients, and patients with anti-LGI1 encephalitis had a higher frequency of autoimmune comorbidities than those with anti-NMDAR encephalitis. And we found that autoimmune comorbidities did not affect the clinical course of AE.

N-Methyl-D-aspartate (NMDA) receptors (NMDARs) are among the most important excitatory neurotransmitter receptors in the human brain. Autoantibodies to the human NMDAR cause the most frequent form of autoimmune encephalitis involving autoantibody-mediated receptor cross-linking and subsequent internalization of the antibody-receptor complex. This has been deemed to represent the predominant antibody effector mechanism depleting the NMDAR from the synaptic and extra-synaptic neuronal cell membrane. To assess in detail the molecular mechanisms of autoantibody-induced NMDAR endocytosis, vesicular trafficking, and exocytosis we transiently co-expressed rat GluN1-1a-EGFP and GluN2B-ECFP alone or together with scaffolding postsynaptic density protein 95 (PSD-95), wild-type (WT), or dominant-negative (DN) mutant Ras-related in brain (RAB) proteins (RAB5WT, RAB5DN, RAB11WT, RAB11DN) in HEK 293T cells. The cells were incubated with a pH-rhodamine-labeled human recombinant monoclonal GluN1 IgG1 autoantibody (GluN1-aAbpH−rhod) genetically engineered from clonally expanded intrathecal plasma cells from a patient with anti-NMDAR encephalitis, and the pH-rhodamine fluorescence was tracked over time. We show that due to the acidic luminal pH, internalization of the NMDAR-autoantibody complex into endosomes and lysosomes increases the pH-rhodamine fluorescence. The increase in fluorescence allows for mechanistic assessment of endocytosis, vesicular trafficking in these vesicular compartments, and exocytosis of the NMDAR-autoantibody complex under steady state conditions. Using this method, we demonstrate a role for PSD-95 in stabilization of NMDARs in the cell membrane in the presence of GluN1-aAbpH−rhod, while RAB proteins did not exert a significant effect on vertical trafficking of the internalized NMDAR autoantibody complex in this heterologous expression system. This novel assay allows to unravel molecular mechanisms of autoantibody-induced receptor internalization and to study novel small-scale specific molecular-based therapies for autoimmune encephalitis syndromes.