Anti-glutamate Receptor Antibodies Research Articles

Multiple serum anti-glutamate receptor antibody levels in clozapine-treated/naïve patients with treatment-resistant schizophrenia

BackgroundGlutamatergic function abnormalities have been implicated in the etiology of treatment-resistant schizophrenia (TRS), and the efficacy of clozapine may be attributed to its impact on the glutamate system. Recently, evidence has emerged suggesting the involvement of immune processes and increased prevalence of antineuronal antibodies in TRS. This current study aimed to investigate the levels of multiple anti-glutamate receptor antibodies in TRS and explore the effects of clozapine on these antibody levels.MethodsEnzyme linked immunosorbent assay (ELISA) was used to measure and compare the levels of anti-glutamate receptor antibodies (NMDAR, AMPAR, mGlur3, mGluR5) in clozapine-treated TRS patients (TRS-C, n = 37), clozapine-naïve TRS patients (TRS-NC, n = 39), and non-TRS patients (nTRS, n = 35). Clinical symptom severity was assessed using the Positive and Negative Symptom Scale (PANSS), while cognitive function was evaluated using the MATRICS Consensus Cognitive Battery (MCCB).ResultThe levels of all four glutamate receptor antibodies in TRS-NC were significantly higher than those in nTRS (p < 0.001) and in TRS-C (p < 0.001), and the antibody levels in TRS-C were comparable to those in nTRS. However, no significant associations were observed between antibody levels and symptom severity or cognitive function across all three groups after FDR correction.ConclusionOur findings suggest that TRS may related to increased anti-glutamate receptor antibody levels and provide further evidence that glutamatergic dysfunction and immune processes may contribute to the pathogenesis of TRS. The impact of clozapine on anti-glutamate receptor antibody levels may be a pharmacological mechanism underlying its therapeutic effects.

A case of autoimmune encephalitis in a patient with a solitary intracranial plasmacytoma.

A 65-year-old woman presented with fever and abnormal behavior. Magnetic resonance imaging showed swelling of the left medial temporal lobe and an intracranial extra-axial occipital tumor. While her neurological symptoms improved after the administration of corticosteroid therapy under the suspicion of autoimmune encephalitis, the occipital tumor unexpectedly shrank, and the diagnosis of a solitary plasmacytoma was confirmed by biopsy. Additional examinations revealed elevated anti-glutamate receptor antibodies in the cerebrospinal fluid. The patient was diagnosed with autoimmune encephalitis concurrent with an intracranial solitary plasmacytoma. Central nervous system involvement can be considered a neurological complication in patients with a solitary plasmacytoma.

Exercise by Shaking Alleviates the Decline in Memory due to Aging: A Study in Mice

Introduction: Although exercise can prevent cognitive decline due to aging, few elderly individuals are able to exercise for long. Therefore, an exercise method for older adults that is feasible for a long duration without overexertion is necessary. In this study, we focused on exercise by shaking. This study examined the possibility to prevent the decline in memory through regular and long-term shaking exercise using a senescence-accelerated mouse (SAM) model. Behavioral analysis was conducted, and histological changes in the mouse brain were examined to evaluate whether this stimulation method could become a novel exercise method. Materials and Methods: The shaking exercise was applied to SAMP10 mice for 30 min 3 times per week for 25 continuous weeks. Behavioral analysis included a step-through passive avoidance test, whereas the histological analysis involved immunohistochemical staining using the anti-glutamate receptor (α-amino-3-hydroxy-5-methyl-4-isoxazole-propionate receptors [AMPAR]) antibody in the hippocampus. The number and area of nerve cells in the hippocampal regions were measured and compared between groups. Results: Behavioral analysis revealed that the shaking group retained memory longer than the control group, and memory capacity decline was suppressed. Additionally, histological examination showed that the shaking group had a higher number of AMPAR receptor-positive neurons per area in the hippocampal CA1 and CA3 regions than the control group, suggesting that degeneration and shedding of neurons due to aging was suppressed. Discussion/Conclusion: We believe that shaking could become an exercise therapy that can reduce the decline in memory with aging and expect its human application in the future.

Immunological parameters for assessing the sports abilities of football players

The creation of diagnostic tests to determine and monitor an athlete’s adaptation resources is a relevant task.Aim. To determine the levels of natural anti-glutamate receptor and anti-GABA antibodies in the dynamics of physical activity during training of football players. To establish the predictive role of these indicators in the objectification of adaptation.Material and methods. The experimental group involved 33 football players aged 18 to 24 years. The control group (n=33) consisted of volunteers of the same age engaged in fitness. Determination of immunological parameters was carried out by solid-phase ELISA.Results. It was found that each subject has an individual immunological profile, the parameters of which change depending on load received. The measured levels of anti-glutamate receptor and anti-GABA antibodies are consistent with the physical activity of a football player. According to the analysis results, the athletes were divided into three groups. The subjects of the first one had reliably high immunological indices and was at the peak of physical activity. Low values of the third group indicated a fatigue. The second group levels were within normal range and demonstrated resource capabilities for the load.Conclusion. The revealed immunological markers are suitable for the diagnostic and prognostic assessment of the athlete’s body functional state.

Anti-NMDA Receptor Encephalitis Presented with Acute Psychotic Symptoms: A Case Report

Introduction: Anti-N-methyl-d-aspartic acid receptor (NMDAR) autoimmune encephalitis is one of the most challenging disorders with both psychiatric and neurologic presentations. Approximately three-fourth of patients with anti-NMDA receptor encephalitis (anti-NMDARE) first referred to psychiatrists. Case Presentation: A 15-year-old female adolescent was admitted to a psychiatric hospital. She presented a history of behavior changes, including aggression, the symptoms mimicking depression, and suicidal ideation, for one year. Then she showed more severe disinhibited behaviors, stupor, and generalized tonic-colonic seizure, so she was hospitalized in a general hospital. After neurological assessments, she was referred to a psychiatric hospital due to her uncontrollable aggressive behaviors in addition to sleep disturbance, rapid mood swings, restlessness, stereotypic behaviors, fluctuating attention and concentration, misidentification delusion, and perceptual changes. All lab tests and brain images were normal. Electroencephalograms showed generalized sharp and slow waves. The autoimmune panel tests were requested. When anti-glutamate receptor antibody was finally reported in her CSF, anti-NMDARE was finally diagnosed. Her symptoms improved by receiving five corticosteroid pulses. Conclusions: In patients with first and acute psychotic symptoms, especially in young individuals with seizures, the possibility of autoimmune disorders should be kept in mind, and complementary tests must be done for autoantibody detection.

Nonparaneoplastic autoimmune cerebellar ataxias.

The current review develops the clinical presentations of nonparaneoplastic autoimmune cerebellar ataxia (ACA) and analyzes the association with autoantibodies. Emerging evidence suggests that autoimmunity is involved in a significant proportion of sporadic ataxia cases. Moreover, numerous autoantibodies have recently been described in association with sporadic cerebellar ataxia, improving diagnosis and patient categorization. Nonparaneoplastic ACA encompasses postinfectious acute cerebellar ataxia, opsoclonus-myoclonus-ataxia syndrome, and pure cerebellar ataxia with or without autoantibodies. There is still confusion about how to diagnose and classify the patients, and retrospective data suggest that these very rare entities are in fact largely underrecognized. Numerous autoantibodies have been found associated with sporadic ataxia, improving diagnosis accuracy, and patient categorization. However, although anti-glutamate decarboxylase isotype 65 (GAD65), anti-contactin-associated protein 2 (CASPR2), and anti metabotropic glutamate receptor (mGluR1) antibodies are well recognized biomarkers, many other autoantibodies have been described in very small numbers of patients and their specificity is unknown. Efficient biomarkers for ACA are still lacking and in many cases the diagnosis has to rely on a body of converging evidence.

Anti-Glutamate Receptor Antibodies: Focusing on Anti-N-methyl-D-aspartate Receptor Encephalitis

The most frequent antibody-mediated autoimmune encephalitis is anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, which presents unique clinical features. Antibodies directly affect the cognitive function of patients with anti-NMDAR encephalitis, and immunotherapy is required to ameliorate their symptoms. The antibody binding is conformational, and antibody detection requires cell surface expression of receptor antigens. There are many unresolved questions surrounding autoimmune encephalitis, such as determination of the triggers of immune reactions against central nervous system antigens, the involved brain lesions responsible for the patients' variable symptoms, the mechanism of neuronal dysfunction, the most effective treatment strategy, and how long the medication should be continued. These questions should be investigated in the future.

Antiglutamate Receptor Antibodies and Cognitive Impairment in Primary Antiphospholipid Syndrome and Systemic Lupus Erythematosus.

Systemic lupus erythematosus (SLE) and antiphospholipid syndrome have an increased risk to develop cognitive impairment. A possible role for antiphospholipid antibodies (aPL) and antiglutamate receptor (anti-NMDA) antibodies in the pathogenesis of neurological manifestations of these two conditions, have been suggested. In particular, the role of anti-NMDA antibodies in the pathogenesis of neuropsychiatric SLE is supported by several experimental studies in animal models and by the finding of a correlation between anti-NMDA positivity in cerebrospinal fluid and neurological manifestations of SLE. However, data from the literature are controversial, as several studies have reported a correlation of these antibodies with mild cognitive impairment in SLE, but more recent studies have not confirmed this finding. The synergism between anti-NMDA and other concomitant autoantibodies, such as aPL, can be hypothesized to play a role in inducing the tissue damage and eventually the functional abnormalities. In line with this hypothesis, we have found a high incidence of at least one impaired cognitive domain in a small cohort of patients with primary APS (PAPS) and SLE. Interestingly, aPL were associated with low scoring for language ability and attention while anti-NMDA titers and mini-mental state examination scoring were inversely correlated. However, when patients were stratified according to the presence/absence of aPL, the correlation was confirmed in aPL positive patients only. Should those findings be confirmed, the etiology of the prevalent defects found in PAPS patients as well as the synergism between aPL and anti-NMDA antibodies would need to be explored.

Lack of serum antineuronal antibodies in children with autism.

Autism spectrum disorders (ASDs) are a severe group of neurodevelopmental disorders that are characterized by impairment in social communication, and imagination and social interaction. The aetiology of autism is complex, but some studies suggest autoimmunity to the central nervous system in the pathogenesis. The aim of this study is to investigate the positivity of antineuronal antibodies including anti-glutamic acid decarboxylase antibodies (anti-GAD), anti-glutamate receptor (anti-GluR) antibodies and seven types of anti-ganglioside antibodies, in children with autism. We conducted the study over a period of one year from May 2012 to December 2013. Human anti-GAD in serum were investigated with ELISA; human autoantibodies against the N-methyl-D-aspartate subtype of GluR were investigated with indirect immunofluorescence test; class IgG antibodies against the seven gangliosides were investigated with immunoblot assay. Serum antineuronal antibodies were measured in 42 children (24 male, 18 female) with autism in comparison to 21 (13 male, 8 female) healthy-matched children aged between 2-12 years. There was no seropositivity of antineuronal antibodies in either of the groups. There is no evidence to support an association between autism and antibodies positivity of anti-GAD, anti-GluR and anti-gangliosides (Ref. 26).

Anti-Ganglioside, Anti-Glutamate, and Anti-Gad Antibody Levels in Attention-Deficit Hyperactivity Disorder

Objective: The etiology of Attention-Deficit Hyperactivite Disorder (ADHD) is still unclear. In the present study, we aimed to demonstrate the relationship among anti-ganglioside antibodies, anti-glutamate receptor antibodies, and anti-glutamic acit decarboksilaz (anti-GAD) antibodies, which are believed to be involved in the etiology of ADHD. Materials and Methods: The study included 36 children who were diagnosed with ADHD according to DSM IV diagnostic criteria and 21 healthy children as the control group. In all subjects, anti-ganglioside antibodies, anti-glutamate receptor antibodies, and anti-GAD antibodies were studied in the Microbiology Laboratory of Erciyes University, Medical School. Results: The mean age was 9.34 years in the ADHD group, which consisted of 5 girls and 31 boys. The mean age was 7.8 years in the control group, which consisted of 8 girls and 13 boys. No significant differences were observed in the levels of antiganglioside antibodies, anti-glutamate receptor antibodies, and anti-GAD antibodies between the ADHD and control groups. Conclusion: Although the etiology is unknown in ADHD, it is believed that autoimmune factors may be involved in the etiopathogenesis according to currently available information. However, there is a need for further studies with larger sample size to clarify the linkage between ADHD and anti-neuronal antibody levels.

Glutamate receptor antibodies in neurological diseases: anti-AMPA-GluR3 antibodies, anti-NMDA-NR1 antibodies, anti-NMDA-NR2A/B antibodies, anti-mGluR1 antibodies or anti-mGluR5 antibodies are present in subpopulations of patients with either: epilepsy, encephalitis, cerebellar ataxia, systemic lupus erythematosus (SLE) and neuropsychiatric SLE, Sjogren's syndrome, schizophrenia, mania or stroke. These autoimmune anti-glutamate receptor antibodies can bind neurons in few brain regions, activate glutamate receptors, decrease glutamate receptor's

Glutamate receptor antibodies in neurological diseases: anti-AMPA-GluR3 antibodies, anti-NMDA-NR1 antibodies, anti-NMDA-NR2A/B antibodies, anti-mGluR1 antibodies or anti-mGluR5 antibodies are present in subpopulations of patients with either: epilepsy, encephalitis, cerebellar ataxia, systemic lupus erythematosus (SLE) and neuropsychiatric SLE, Sjogren's syndrome, schizophrenia, mania or stroke. These autoimmune anti-glutamate receptor antibodies can bind neurons in few brain regions, activate glutamate receptors, decrease glutamate receptor's

Glutamatergic autoencephalitides: an emerging field

Autoimmune responses targeting synaptic proteins are associated with a wide range of neurologic symptoms. Among these disorders are those associated with antibodies to ionotropic glutamate receptors, including the NMDAR (N-methyl-D-aspartate receptor) and AMPAR (α-amino-3-hydrozy-5-methyl-4-isoxazolepropionic acid receptor). Patients with anti-NMDAR encephalitis present with psychiatric symptoms, seizures, movement disorders, impaired consciousness, and autonomic derangements; half of patients have an associated ovarian teratoma, and most patients respond to immunosuppressive therapies. Patients' antibodies bind to the amino terminal domain of the NMDAR, and result in loss of NMDARs from synapses with subsequent NMDAR hypofunction. Anti-NMDAR antibodies have now been reported in other neuropsychiatric conditions, including psychosis, dementia, and HSV encephalitis. The pathophysiologic relevance of anti-NMDAR antibodies in these disorders is not yet clear, but their presence may indicate a role for immunotherapy in some patients. Although considerable work remains to be done, our understanding of disorders associated with anti-glutamate receptor antibodies has grown exponentially since they were first described just over 7 years ago, revolutionizing neurology. These antibodies, by interfering with synaptic function, readily link basic science and clinical medicine, and have revealed the impact of sudden but sustained loss of specific neurotransmitter receptors in humans. Improved understanding of their pathophysiology will lead to better treatments for these diseases while providing novel insights regarding the roles of glutamate receptors in learning, memory, and neuropsychiatric disease.

A Mild Form of Adult-Onset Opsoclonus-Myoclonus Syndrome Associated With Antiglutamate Receptor Antibodies—Reply

A Mild Form of Adult-Onset Opsoclonus-Myoclonus Syndrome Associated With Antiglutamate Receptor Antibodies—Reply

A Case of Anti-glutamate Receptor Antibody Positive Limbic Encephalitis with Positive Various Autoantibodies

A Case of Anti-glutamate Receptor Antibody Positive Limbic Encephalitis with Positive Various Autoantibodies

SLEを背景とし，病態に抗グルタミン酸受容体抗体の関与が示唆された自己免疫疾患関連性辺縁系脳炎の1例

A 23-year-old woman was admitted to our hospital because of consciousness disturbance and convulsion, preceded by high fever, headache and erythema multiforme. Her brain magnetic resonance images showed hyperintense lesions in the left medial temporal lobe and the left pulvinar nucleus of the thalamus on fluid attenuated inversion recovery images. Analysis of cerebrospinal fluid showed mild pleocytosis, but DNA of herpes simplex or herpes type 6 viruses was negative on PCR. Laboratory investigations showed the presence of anti-nuclear antibodies, anti-RNP antibodies and lupus anticoagulant. The clinical diagnosis was made as acute limbic encephalitis associated with SLE, and subsequent administration of prednisolone improved her conditions. In her serum and cerebrospinal fluid, anti-glutamate receptor (ε2, δ2, ζ1) antibodies were detected, and the titers of the antibodies decreased as the symptoms improved. Although the mechanism underlying limbic encephalitis associated with SLE remains unclear, at least in some cases, the anti-glutamate antibodies may play an important role in the pathogenesis of limbic encephalitis with SLE.

A case of clinically mild encephalitis/encephalopathy with a reversible splenial lesion associated with anti-glutamate receptor antibody

We report the case of an 18-year-old boy who presented with disturbance of consciousness and generalized seizures following flu-like symptoms such as high fever and arthralgia. T2 and diffusion weighted brain magnetic resonance images showed a hyperintense ovoid lesion in the splenium of the corpus callosum and T, weighted images showed a hypointense lesion; the lesion completely disappeared on repeat imaging after 3 days. Antiglutamate epsilon2 receptor antibodies were detected in his cerebrospinal fluid. Although the patient had several episodes of generalized seizures, he completely recovered within 3 months. Our patient had a clinically mild encephalitis/encephalopathy with a reversible splenial lesion following flu-like symptoms, which indicated viral infection. As compared to previously reported cases, our case was characteristic because of the protracted recovery shown by the patient. Anti-glutamate epsilon2 receptor antibodies may be associated with prolonged generalized seizures in the case of our patient. Our results also suggest that anti-glutamate epsilon2 receptor antibodies may play a role in the pathogenesis of this condition.

A Boy with Non-Herpes Simplex Acute Limbic Encephalitis and Antiglutamate Receptor Antibodies

This report concerns a 12-year-old male with intractable seizures over a long period. The case fulfilled the diagnostic criteria for nonherpetic acute limbic encephalitis. He had frequent convulsions starting with a partial seizure at the left angle of the mouth and progressing to secondary generalized seizures. He was treated with several anticonvulsants, combined with methylprednisolone and γ-globulin under mechanical ventilation. However, his convulsions reappeared after tapering of the barbiturate. His magnetic resonance imaging showed a high intensity area in the hippocampus by FLAIR and diffusion. After five months he recovered without serious sequelae. Virological studies, including for herpes simplex virus, were all negative. He was transiently positive for antiglutamate receptor antibodies in cerebrospinal fluid and serum.

Encephalitis associated with positive anti-GluR antibodies showing abnormal appearance in basal ganglia, pulvinar and gray matter on MRI -Case report

We treated a 25-year-old woman with encephalitis. Following delivery, the patient developed fever, consciousness disturbance, cognitive dysfunction, and progressive motor dysfunction. In addition, mycobacterium tuberculosis was found in the lung, though there was no evidence of such infection in the central nervous system. Cerebrospinal fluid analysis revealed a slight elevation of mononuclear cells with a normal protein level indicating a possible viral infection. We could not find the origin of the infection, though the serum anti-glutamate epsilon2 receptor antibody was positive. Intravenous administration of methylprednisolone (1000 mg/day for 3 days) was temporarily effective for improvement of the clinical signs and symptoms. However, she finally demonstrated rapid deterioration resulting in death. Diffusion-weighted brain magnetic resonance imaging demonstrated abnormal high intensity lesions in the bilateral pulvinar and gray matter, with an abnormal appearance mimicking pulvinar sign.

Anti-Glutamate Receptor Antibodies in Pediatric Enteroviral Encephalitis

ABSTRACTIn order to better understand enteroviral encephalitis we investigated the clinical symptoms and several disease markers. Between 2000 and 2005 eight patients aged between 9 months and 5 years were admitted to our hospital with one case having sequela. Glutamic oxaloacetic transaminase (GOT), serum IL-6, and ferritin were elevated in most of the cases. Their IL-6 and diacron-reactive oxygen metabolites (d-ROM) in cerebral spinal fluid (CSF) were also high (86%%). However, pleocytosis and high protein levels in CSF were rarely found. In viral loads of the first CSF, there were no differences between the patient with sequela and the ones without sequela. However, anti-glutamate receptor IgMδ2 was only detected in the CSF of the patient with sequela. These findings suggest that the immunological phenomenon is more closely related to the development of sequela related to enteroviral encephalitis than other disease markers, such as inflammatory cytokine, free radicals, and viral loads. Therefore, a specific therapy against immunological status might decrease the sequela; however, further research is necessary to confirm this.

A Case of Anti-aquaporin-4 and Anti-glutamate Receptor Antibodies Positive Myelitis Presented with Modest Clinical Signs

We present a case of anti-aquaporin-4 antibody-positive myelitis, which suggests the high-risk syndrome of neuromyelitis optica, whose modest clinical signs were in conspicuous contrast to the extensive spinal cord lesions demonstrated on magnetic resonance (MR) imaging. Follow-up MR imaging showed marked improvement of lesions. Interestingly, an anti-glutamate receptor antibody, which has been suggested to cause dysfunction of N-methy-D-aspartate receptor on neuron, was detected in the cerebrospinal fluid of the patient. We discuss the case and related literature.