Search Results (31)

The autoantibodies against the NR1 subunit are well known in the pathomechanism of NMDAR encephalitis. The dysfunction of the NR2 subunit could be a critical factor in this neurological disorder due to its important role in the postsynaptic pathways that direct synaptic plasticity. We report a case of paraneoplastic anti-NMDAR encephalitis presented alongside very severe illness. Computed tomography (CT) of the brain, as well as FLAIR and T2-weighted MRI, was performed to rule out any other acute brain processes. A semi-quantitative method was applied to detect the presence of anti-NMDAR antibodies in the serum and CSF. A CT chest–abdomen–pelvis scan was performed that detected an ovarian teratoma. A histopathological examination was performed after a laparoscopic right-ovary cystectomy. Subsequent immunofluorescence immunohistochemical staining showed the expression of NMDA receptors of type NR2B. Treatment included first-line immunotherapy, second-line immunotherapy, tumor removal, and intrathecal injections with methotrexate and dexamethasone. The histological finding for our patient after tumor removal was ovarian teratoma. Hematoxylin–eosin (HE) staining revealed a characteristic spectrum of elements, including stratified squamous epithelium and fat tissue accompanied by neuroglial cells. Subsequent immunohistochemical staining showed an expression of NMDA receptors of type NR2B in different structures of the teratoma, including the neuroglial cells. The first-line immunotherapy following the tumor removal was insufficient in our patient. The paraneoplastic anti-NMDAR encephalitis with a coexpressed NR2B subunit on the neural cells of the ovarian teratoma may suggest a different inflammation process and could be the key factor in the pathomechanism and treatment of the refractory anti-NMDAR encephalitis. Full article

Objective: To establish a mouse model of anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis and assess the potential therapeutic benefits of D-serine supplementation in mitigating synaptic plasticity impairments induced by anti-NMDAR antibodies. Methods: Anti-NMDAR antibodies were purified from cerebrospinal fluid (CSF) samples of patients diagnosed with anti-NMDAR encephalitis and verified using a cell-based assay. CSF from patients with non-inflammatory neurological diseases served as the control. These antibodies were then injected intraventricularly into C57BL/6 mice. Forty-eight hours following the injection, mice were administered either D-serine (500 mg/kg) or sterile saline intraperitoneally for three consecutive days. Subsequent analyses included Western blotting, immunofluorescence, electrophysiological studies, and a series of behavioral tests to assess pathological changes caused by anti-NMDAR antibodies. Results: Mice injected with anti-NMDAR antibodies exhibited a significant reduction in hippocampal long-term potentiation compared to controls, which was notably ameliorated by D-serine treatment. Additionally, these mice displayed decreased levels of hippocampal membrane NMDAR1 protein and postsynaptic NMDAR1 density. However, D-serine administration did not significantly alter these conditions. Notably, no significant behavioral differences were observed between mice injected with anti-NMDAR antibodies and controls in open fields, elevated plus maze, novel object recognition, or Morris water maze tests. Conclusions: Our findings indicate that exogenous D-serine can improve hippocampal plasticity impairments caused by anti-NMDAR antibodies but does not reverse the decreased expression of NMDAR. Furthermore, a single intraventricular injection of patients’ antibodies was insufficient to induce anti-NMDAR encephalitis-related behaviors in mice. Full article

Background: Anti-N-Methyl-d-aspartate receptor (NMDAR) autoimmune encephalitis (NMDAR AE) is an autoimmune disease characterized by severe psychiatric and neurological symptoms. While the pathogenic role of antibodies (Abs) directed against the GluN1 subunit of NMDAR is well described in this disease, the immune mechanisms involved in the generation of the autoimmune B cell response, especially the role of T helper cells, are poorly understood. Previously, we developed a B-cell-mediated mouse model of NMDAR AE by immunization with a GluN1_359–378 peptide that drives a series of symptoms that recapitulate AE such as anxiety behaviour and spatial memory impairment. Results: In this mouse model, we identified anti-GluN1-specific CD4⁺ but also CD8⁺ T cells in both spleen and meninges. T helper cells have a polyfunctional profile, arguing for a T and B cell crosstalk to generate anti-GluN1 pathogenic Abs. Interestingly, proteomic analysis of AE meninges showed enrichment of differentially expressed proteins in biological processes associated with B cell activation and cytokine signalling pathways. Conclusions: This study identified, for the first time, a potential contribution of T helper cells in the pathology of NMDAR AE and paved the way for the development of future tolerogenic approaches to treat relapses. Full article

The blood–brain barrier (BBB) acts as a structural and functional barrier for brain homeostasis. This review highlights the pathological contribution of BBB dysfunction to neuroimmunological diseases, including multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), autoimmune encephalitis (AE), and paraneoplastic neurological syndrome (PNS). The transmigration of massive lymphocytes across the BBB caused by the activation of cell adhesion molecules is involved in the early phase of MS, and dysfunction of the cortical BBB is associated with the atrophy of gray matter in the late phase of MS. At the onset of NMOSD, increased permeability of the BBB causes the entry of circulating AQP4 autoantibodies into the central nervous system (CNS). Recent reports have shown the importance of glucose-regulated protein (GRP) autoantibodies as BBB-reactive autoantibodies in NMOSD, which induce antibody-mediated BBB dysfunction. BBB breakdown has also been observed in MOGAD, NPSLE, and AE with anti-NMDAR antibodies. Our recent report demonstrated the presence of GRP78 autoantibodies in patients with MOGAD and the molecular mechanism responsible for GRP78 autoantibody-mediated BBB impairment. Disruption of the BBB may explain the symptoms in the brain and cerebellum in the development of PNS, as it induces the entry of pathogenic autoantibodies or lymphocytes into the CNS through autoimmunity against tumors in the periphery. GRP78 autoantibodies were detected in paraneoplastic cerebellar degeneration and Lambert–Eaton myasthenic syndrome, and they were associated with cerebellar ataxia with anti-P/Q type voltage-gated calcium channel antibodies. This review reports that therapies affecting the BBB that are currently available for disease-modifying therapies for neuroimmunological diseases have the potential to prevent BBB damage. Full article

Anti-N-methyl-D-aspartate receptor encephalitis (anti-NMDARE) is a complex neuropsychiatric syndrome known for its diverse neurological manifestations, often involving psychiatric symptoms and seizures that elevate the risk of suicidal ideation and behavior. We present a case illustrating the potentially lethal nature of anti-NMDARE, wherein an unexpected suicide attempt occurred 10 days after the onset of seizures in a 21-year-old man. Upon arrival at the emergency room, immediate interventions addressed hypovolemic shock, followed by subsequent neurosurgical and orthopedic procedures. Six days after cessation of sedation, the patient exhibited atypical focal seizures, behavioral arrest, psychotic responses, and delusions. Despite normal brain magnetic resonance imaging and cerebrospinal fluid (CSF) analysis results, a high CSF immunoglobulin G index and posterior hypometabolism on brain F-fluorodeoxyglucose positron emission tomography raised suspicion of autoimmune encephalitis. Steroids and intravenous immunoglobulins were administered. A comprehensive evaluation ruled out other conditions. Serum and CSF tests confirmed the presence of anti-NMDAR antibodies. This case highlights the potential lethality of the acute stage of anti-NMDARE, emphasizing the absence of apparent psychiatric symptoms before a suicide attempt. Further studies on suicidality associated with anti-NMDARE are crucial, underscoring the importance of vigilance in cases involving newly diagnosed seizures or psychoses. Full article

Rationale: Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis is a form of autoimmune synaptic encephalitis, often mediated by neuronal surface antibodies. Clinically, it manifests through a diverse range of neurological and psychiatric symptoms, primarily affecting young women with ovarian teratoma, which is rare in pregnant women. Patient concerns: We report a case of a 35-year-old multiparous pregnant patient at 38 weeks of gestation presented to the emergency room with seizure, psychiatric symptoms like delirious speech with mystical visual and auditory hallucinations, bradylalia, and retrograde amnesia. Diagnosis: The diagnosis of autoimmune encephalitis with anti-NMDA antibodies was concluded by considering the lumbar puncture results, brain imaging, and the patient’s persistent symptoms. Outcomes: This case is noteworthy for its rarity and the symptoms’ breadth. At 38 weeks of gestation, the patient underwent a cesarean section, resulting in excellent maternal recovery observed during the 6-month follow-up and good neonatal adaptation. Lessons: Our goals include raising awareness about this condition and emphasizing the significance of early diagnosis. This encephalitis is treatable and potentially reversible, underscoring the importance of prompt identification. Full article

Synaptic dysfunction and disrupted communication between neuronal and glial cells play an essential role in the underlying mechanisms of multiple sclerosis (MS). Earlier studies have revealed the importance of glutamate receptors, particularly the N-methyl-D-aspartate (NMDA) receptor, in excitotoxicity, leading to abnormal synaptic transmission and damage of neurons. Our study aimed to determine whether antibodies to the NR2 subunit of NMDAR are detected in MS patients and evaluate the correlation between antibody presence and clinical outcome. Furthermore, our focus extended to examine a possible link between NR2 reactivity and anti-coagulant antibody levels as pro-inflammatory molecules associated with MS. A cross-sectional study was carried out, including 95 patients with MS and 61 age- and gender-matched healthy controls (HCs). The enzyme-linked immunosorbent assay was used to detect anti-NR2 antibodies in serum samples of participants along with IgG antibodies against factor (F)VIIa, thrombin, prothrombin, FXa, and plasmin. According to our results, significantly elevated levels of anti-NR2 antibodies were detected in MS patients compared to HCs (p < 0.05), and this holds true when we compared the Relapsing-Remitting MS course with HCs (p < 0.05). A monotonically increasing correlation was found between NR2 seropositivity and advanced disability (r_s = 0.30; p < 0.01), anti-NR2 antibodies and disease worsening (r_s = 0.24; p < 0.05), as well as between antibody activity against NR2 and thrombin (r_s = 0.33; p < 0.01). The presence of anti-NR2 antibodies in MS patients was less associated with anti-plasmin IgG antibodies [OR:0.96 (95%CI: 0.92–0.99); p < 0.05]; however, such an association was not demonstrated when analyzing only RRMS patients. In view of our findings, NR2-reactive antibodies may play, paving the way for further research into their potential as biomarkers and therapeutic targets in MS. Full article

Encephalitis is a condition with a variety of etiologies, clinical presentations, and degrees of severity. The causes of these disorders include both neuroinfections and autoimmune diseases in which host antibodies are pathologically directed against self-antigens. In autoimmune encephalitis, autoantibodies are expressed in the central nervous system. The incidence of this disease is approximately 4% of all reported cases of encephalitis. Autoimmune encephalitis can be induced by antibodies against neuronal surface antigens such as N-methyl-D-aspartate-activated glutamate receptors (NMDAR), α-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptors (AMPAR) or gangliosides GQ1b, DPPX, CASPR2, LGI1, as well as by antibodies against neuronal intracellular antigens. The paper presents a number of both mental and neurological symptoms of autoimmune encephalitis. Moreover, the coexistence of psychoses, neoplastic diseases, and the methods of diagnosing autoimmune encephalitis are discussed. Attention was also drawn to the fact that early diagnosis, as well as early initiation of targeted treatment, increases the chance of a successful course of the therapeutic process. Strategy and Methodology: The articles on which the following paper was based were searched using search engines such as PubMed and Medline. Considering that anti-NMDAR antibodies were first described in 2007, the articles were from 2007 to 2023. The selection of papers was made by entering the phrases “autoimmune encephalitis and psychosis/paraneplastic syndromes or cancer”. The total number of articles that could be searched was 747, of which 100 items were selected, the most recent reports illustrating the presented topic. Thirty-four of them were rejected in connection with case reports or papers that could not be accessed. Full article

Autoimmune encephalitis (AE) is a neurological emergency. We aimed to analyze the application and effectiveness of the currently available prediction tools for AE patients in Taiwan. We retrospectively collected 27 AE patients between January 2008 and December 2019. Antibody Prevalence in Epilepsy (APE) score, Response to Immunotherapy in Epilepsy (RITE) score, and anti-NMDAR Encephalitis One Year Functional Status (NEOS) score were applied to validate their usability. Based on the defined cutoff values, the sensitivity and specificity of each score were calculated. A receiver operating characteristic (ROC) curve and the area under the curve (AUC) were generated for each scoring system. The AUC value of APE was 0.571. The AUC value of RITE was 0.550. The AUC values for the NEOS score at discharge and long-term follow-up were 0.645 and 0.796, respectively. The performance of APE and RITE scores was suboptimal in the Taiwanese cohort, probably due to the limitations of the small sample size and single ethnicity. On the other hand, the NEOS score performed better on long-term follow-up than at discharge. Full article

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis (NMDARe) is the most common cause of nonviral encephalitis, mostly affecting young women and adolescents with a strong female predominance (F/M ratio of around 4:1). NMDARe is characterized by the presence of cerebrospinal fluid (CSF) antibodies against NMDARs, even though its pathophysiological mechanisms have not totally been clarified. The clinical phenotype of NMDARe is composed of both severe neurological and neuropsychiatric symptoms, including generalized seizures with desaturations, behavioral abnormalities, and movement disorders. NMDARe is often a paraneoplastic illness, mainly due to the common presence of concomitant ovarian teratomas in young women. Abdominal ultrasonography (US) is a key imaging technique that should always be performed in suspected patients. The timely use of abdominal US and the peculiar radiological features observed in NMDARe may allow for a quick diagnosis and a good prognosis, with rapid improvement after the resection of the tumor and the correct drug therapy. Full article

Various primarily non-autoimmune neurological disorders occur synchronously with autoantibodies against tissues in the nervous system. We aimed to assess serum and cerebrospinal fluid (CSF) autoantibodies in children with neurologic disorders. To find new diagnostic tools, we compared the laboratory and clinical findings between the distinguished groups. Retrospectively, 508 patients were divided into six subgroups: neuroinfections, pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections, neurologic autoimmune and demyelinating diseases, epilepsy, pervasive developmental disorders and other patients. We analysed serum anti-aquaporin-4, antiganglioside, neuronal antinuclear and cytoplasmic antibodies, as well as antibodies against surface neuronal and synaptic antigens in the CSF and serum. We involved available demographic and clinical data. Autoantibodies appeared in 165 (32.3%) children, with 24 showing multiple types of them. The most common were anti-neuroendothelium (anti-NET), anti-N-Methyl-D-Aspartate receptor (anti-NMDAr), anti-glial fibrillary acidic protein and anti-myelin antibodies bothering 46/463 (9.9%), 32/343 (9.4%), 27/463 (5.8%) and 27/463 (5.8%), respectively. Anti-NET and anti-NMDAr antibodies appeared more frequently in children with autoimmunity (p = 0.017; p < 0.001, respectively), increasing the autoimmune disease risk (OR = 2.18, 95% CI 1.13–13.97; OR = 3.91, 95% CI 1.86–8.22, respectively). Similar pathomechanisms appeared in diseases of different aetiology with clinical spectrums mimicking each other, so we proposed the model helping to diagnose autoimmune disease. We proved the influence of age, living place and medical history on the final diagnosis. Full article

Autoimmune encephalitis and neurodegenerative disorders share several clinical features, including behavioural and psychiatric manifestations, cognitive impairment, sleep and movement disorders. Therefore, it is not surprising that autoimmune encephalitis is one of the main differential diagnoses of rapidly progressive dementia. However, more chronic presentations of autoimmune disorders have been reported and can lead to the misdiagnosis of a neurodegenerative disease. On the other hand, antibodies against neuronal proteins, such as those directed against NMDAR, can occur during established neurogenerative disorders, and their role in this context is still unclear. They might be simple bystanders or modify the disease course and phenotype. Indeed, autoimmune encephalitis can leave long-term cognitive sequelae and specific antibodies to neuronal surface antigens are associated with clinical and pathological neurodegenerative features. Here we review the link between these antibodies and neurodegeneration. In particular we discuss: (a) the possibility that autoimmune encephalitis presents as a neurodegenerative disease, identifying the red flags that can help in the differential diagnosis between antibody-mediated and neurodegenerative disorders; (b) the occurrence of antibodies against neuronal surface antigens in patients with neurodegenerative disorders and their possible role in the disease course; and (c) the long-term cognitive and neuroradiological changes associated with autoimmune encephalitis, as well as the biomarkers that can help to predict the cognitive outcome. Finally, we review the clinical and pathological features of IgLON5 antibodies-related encephalitis, a unique model of the relationship between antibodies and neurodegeneration. Full article

Fatigue is a widespread and complex symptom with motor and cognitive components; it is diagnosed predominantly by questionnaire. We recently published a correlation between anti-N-methyl-D-aspartate receptor (NMDAR) antibodies and fatigue in patients with SLE (systemic lupus erythematosus). In the present study, we examined whether this association also applies to patients with other rheumatic diseases. Serum samples of 88 patients with different rheumatic diseases were analyzed for the presence of anti-NR2 antibodies and Neurofilament light chain (NfL) protein. The severity of fatigue was determined according to the FSMC questionnaire (Fatigue Scale for Motor and Cognitive Functions) and correlated with the circulating antibody titer and NfL level accordingly. Positive titers of anti-NR2 antibodies were detected in patients with both autoimmune and non-autoimmune rheumatic diseases. These patients suffer predominantly from severe fatigue. The circulating NfL level did not correlate with the anti-NR2 titer and the fatigue severity in all patient groups. The association of severe fatigue with circulating anti-NR2 antibodies in patients with rheumatic diseases, independently from the main disease, suggests an individual role of these autoantibodies in fatigue pathophysiology. Thus, the detection of these autoantibodies might be a helpful diagnostic tool in rheumatic patients with fatigue. Full article

Introduction: Autoimmune encephalitis (AE) diagnosis and follow-up remain challenging. Brain ¹⁸F-fluoro-deoxy-glucose positron emission tomography (FDG PET) has shown promising results in AE. Our aim was to investigate FDG PET alterations in AE, according to antibody subtype. Methods: We retrospectively included patients with available FDG PET and seropositive AE diagnosed in our center between 2015 and 2020. Brain PET Z-score maps (relative to age matched controls) were analyzed, considering metabolic changes significant if |Z-score| ≥ 2. Results: Forty-six patients were included (49.4 yrs [18; 81]): 13 with GAD autoantibodies, 11 with anti-LGI1, 9 with NMDAR, 5 with CASPR2, and 8 with other antibodies. Brain PET was abnormal in 98% of patients versus 53% for MRI. The most frequent abnormalities were medial temporal lobe (MTL) and/or striatum hypermetabolism (52% and 43% respectively), cortical hypometabolism (78%), and cerebellum abnormalities (70%). LGI1 AE tended to have more frequent MTL hypermetabolism. NMDAR AE was prone to widespread cortical hypometabolism. Fewer abnormalities were observed in GAD AE. Striatum hypermetabolism was more frequent in patients treated for less than 1 month (p = 0.014), suggesting a relation to disease activity. Conclusion: FDG PET could serve as an imaging biomarker for early diagnosis and follow-up in AE. Full article

The main causes of anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis are ovarian teratoma and herpes simplex virus (HSV) encephalitis. We present a rare case of suspected anti-NMDAR encephalitis caused by corpus callosotomy (CC). An 18-year-old woman with Lennox-Gastaut syndrome underwent CC. Although left hemiplegic due to cerebral hemorrhage and impaired consciousness due to cerebral venous sinus thrombosis (CVST) appeared postoperatively, anticoagulant therapy quickly improved CVST and impaired consciousness. However, various unexplained symptoms such as insomnia, hallucination, impulsivity, impaired consciousness, and a new type of drug-resistant cluster seizures gradually developed over a 2-month period. Magnetic resonance imaging revealed the gradual extension of a hyperintense area from the right frontal lobe on fluid-attenuated inversion recovery images. Intravenous methylprednisolone pulse was initiated from postoperative day (POD) 74, followed by intravenous immunoglobulin (IVIg) therapy, although white blood cell counts were normal in all three cerebrospinal fluid (CSF) examinations. After IVIg therapy, the above unexplained symptoms promptly improved. On POD 103, antibodies against NMDAR were revealed in both the serum and CSF collected before these immunotherapies. The patient was transferred to a rehabilitation hospital due to residual left hemiplegia. Psychiatric symptoms and a new onset of drug-resistant seizures may be suggestive of postoperative anti-NMDAR encephalitis, even if CSF findings are mild. Full article