NMDAR Encephalitis Research Articles

Clinical Analysis of MOG Antibody-Associated Disease Overlapped With Anti-NMDA Receptor Encephalitis: A Long-Term Retrospective Study.

To summarise the clinical characteristics, radiological features, treatments and prognosis of patients with myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD) overlapped with NMDA receptor (NMDAR) encephalitis. We retrospectively analysed patients who exhibited dual positivity for MOG antibodies and NMDAR antibodies in serum/CSF from Jan 2018 to Jun 2023. Ten patients with MOGAD and NMDAR encephalitis were enrolled. The median age of initial attacks was 23 (range: 10-43) years old. Common symptoms were cortical encephalopathies (8/10), focal neurological deficits (4/10), as well as other presentations including headache, fever, optic neuritis and transverse myelitis. CSF pleocytosis was general (9/10, median 63.9 cells/μl). Lesions on brain MRI included brainstem (37.5%), cerebral cortex (33.3%), basal ganglia (25.0%) and hippocampus (20.8%). The average follow-up duration was 25.4 months. 10/10 patients developed more than one relapse attacks, with MOG positivity before (10%), simultaneous (40%) or after anti-NMDAR encephalitis (50%). Most patients (7/10) had good response to first-line therapy but experienced next relapse with an average interval of 6.7 (range: 2-14) months. We conducted initial analysis of lymphocyte subsets in these patients, which revealed that CD3+ and CD4 + T cells increased after immunosuppressants medication (p < 0.01 and p < 0.05, respectively). We concluded that MOGAD overlapping with NMDAR encephalitis presents a distinct clinical phenotype which differs from either MOGAD or NMDAR encephalitis. Brainstem in combination with cortical lesions might be warning signs for this overlapping syndrome. Due to the high recurrent rates, we recommend early diagnosis and timely treatment with efficient immunosuppressants at onset.

Patient-Reported Outcome Measures in NMDA Receptor Encephalitis.

The characteristics of persistent long-term symptoms and their contribution to subjective quality of life remain unclear in patients with NMDAR encephalitis. In this study, we aimed to evaluate postacute neuropsychiatric symptoms, subjective cognitive complaints, and disease coping mechanisms and identify predictors of health-related quality of life (HRQoL) after N-methyl-D-aspartate receptor (NMDAR) encephalitis. This cross-sectional observational study investigated patients with NMDAR encephalitis in the postacute phase. Psychometric scales included assessment of neuropsychiatric symptoms (i.e., fatigue, sleep, anxiety, and depressive symptoms), HRQoL, everyday independence, metamemory (i.e., self-rated ability, satisfaction, and use of strategies), and coping strategies (i.e., self-efficacy, disease-related coping, and stress management). A total of 50 patients (mean age 26.0 ± 10.1 years, 86% female) participated at a median of 4.15 (range 0.3-30.3) years after symptom onset. Patients reported significantly increased levels of anxiety (Beck Anxiety Inventory: 10.5 ± 7.7 [mean ± SD], 95% CI [8.32-12.71], p < 0.001) and depressive (Beck Depression Inventory-II: 11.4 ± 7.7 [9.22-13.62], p = 0.001) symptoms compared with the normative population. Both sleep problems (Pittsburgh Sleep Quality Index: 5.8 ± 3.0 [4.98-6.66], p < 0.001) and motor and cognitive fatigue (Fatigue Scale for Motor and Cognitive Function: 50.5 ± 23.1 [42.5-58.4], p < 0.001) were significantly more prevalent. Moreover, lower self-rated memory ability (Multifactorial Memory Questionnaire score: 54.6 ± 8.5 [52.1-57.1], p = 0.004) was associated with greater reliance on compensatory strategies and memory aids (r = -0.41, p = 0.004). Patients used significantly fewer cognitive coping strategies, such as relativization (11.7 ± 4.7 [10.3-13.1], p = 0.001), while depressive coping prevailed (49.1 ± 15.5 [44.5-53.8], p < 0.001). It is important to note that HRQoL was predicted by self-reported affective symptoms, self-efficacy, and coping behaviors in multivariable regression analyses, but not by acute disease severity or postacute physical disability. Our findings show that persistent neuropsychiatric and subjective cognitive concerns explain a large part of the reduced quality of life in patients with NMDAR encephalitis. These findings have important implications for a patient-centered postacute care and the role of disease coping strategies in the neurorehabilitation of autoimmune encephalitis.

Evidence-based diagnostic prediction score for pediatric NMDA receptor encephalitis.

Early diagnosis and treatment of anti-N-methyl-D-aspartate receptor encephalitis (NMDARE) are crucial for a favorable prognosis. Detecting the causative autoantibodies can be challenging. Probable diagnostic criteria are useful in adults less so in children. We aimed to develop a novel diagnostic score for pediatric NMDARE using cohort data. We retrospectively analyzed pediatric participants (0-18 years) with suspected autoimmune encephalitis who underwent cerebrospinal fluid analysis for antineuronal antibodies (Abs) between January 2015 and March 2023. Clinical data, including symptoms and laboratory findings, were analyzed. Symptoms were selected through univariate analysis and then analyzed with multivariate logistic regression model. Resulting odds ratios were used to calculate scores. Scoring systems were developed and evaluated with five-fold validation and univariate logistic regression. One scoring system was selected to create a diagnostic prediction score for pediatric NMDARE. Of the 504 patients, 264 met the inclusion criteria, and 39 tested positive for NMDAR Abs. Comparing clinical symptoms between cohorts and identified 15 variables significantly different (p<0.05) to create a pediatric NMDARE prediction score. This score showed 82.1% sensitivity and 82.2% specificity, with an 8-point cutoff. The area under the curve was 0.888 (95% confidence interval: 0.838-0.939). A five-fold cross-validation showed a sensitivity of 95.6%, specificity of 71.4%, and kappa coefficient of 0.670. We developed a novel evidence-based diagnostic prediction score for pediatric NMDARE that incorporates specific clinical features and laboratory findings. This score may improve diagnostic accuracy and guide early therapy in children with suspected autoimmune encephalitis.

Association of ovarian teratoma with anti-N-methyl-D-aspartate receptor encephalitis: a case report and narrative review.

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a potentially life-threatening autoimmune disorder which is strongly associated with ovarian teratomas in young female patients. The primary aim is to highlight the importance of considering NMDAR encephalitis in the differential diagnosis of young female patients presenting with acute or subacute neuropsychiatric symptoms, especially when accompanied by ovarian teratomas. This case report and literature review detail the presentation, diagnosis, and treatment of a 35-year-old G4P3 Indigenous woman who initially presented with neuropsychiatric symptoms and fever, having a history of extensive drug and alcohol use. Misdiagnosed initially, the patient's lack of response to standard treatments led to further investigations, revealing paraneoplastic anti-NMDAR encephalitis secondary to a left ovarian teratoma. The report examines the treatment regimen followed, including prednisolone, intravenous immunoglobulin, rituximab injections, and laparoscopic bilateral salpingo-oophorectomy. This case underscores the critical need for increased clinical vigilance for anti-NMDAR encephalitis in patients, particularly young females, presenting with neuropsychiatric symptoms and potential ovarian teratomas. The literature review accompanying the case report provides valuable insights into the presentation, diagnosis, and management of this complex condition. Lastly, this study emphasised the diagnostic challenges inherent in paraneoplastic neuropsychiatric syndromes, advocating for a multidisciplinary approach in similar clinical scenarios.

Systolic Blood Pressure Differentiates Pediatric NMDA Receptor Encephalitis in Acute-Onset Psychosis

Systolic Blood Pressure Differentiates Pediatric NMDA Receptor Encephalitis in Acute-Onset Psychosis

Anti-NMDAR encephalitis in a paediatric patient: A case report

A rare autoimmune disease called anti-NMDAR encephalitis usually affects young people and frequently manifests as cognitive deterioration, seizures, and psychiatric symptoms. The diagnostic challenge and the importance in recognizing the clinical features and employing appropriate laboratory and imaging techniques for accurate and timely diagnosis will be discussed. We describe the example of an 8-year-old girl who suddenly began exhibiting strange behavioral and speech problems. Anti-NMDAR encephalitis was diagnosed after further investigation. This casee illustrates how different clinical presentations can lead to a delay in the disorder’s diagnosis. Healthcare practitioners continue to have difficulties in diagnosing heterogeneous clinical manifestations of anti- NMDAR encephalitis, particularly in the juvenile age range. Bangladesh Journal of Medical Science Vol. 23 No. 04 October’24 Page : 1233-1237

Management of neuropsychiatric symptoms in anti NMDAR encephalitis: a case report

Anti-N-Methyl-D-Aspartate receptor (NMDAR) encephalitis is recognized as the most commonly diagnosed autoimmune encephalitis and is one of the most common causes of encephalitis. A wide spectrum of symptoms such as psychosis, catatonia, behavioral and memory changes, seizures, abnormal movements and autonomic dysregulation usually requires a multidisciplinary treatment approach.Early recognition and prompt initiation of immunotherapy improves patient outcomes.We present a case of a 16-year-old female who had seizures and later had catatonia and psychotic symptoms.Our patient was treated with Rituxumab when he did not get enough benefit from the first-line treatments. Significant improvement in both neurological and psychiatric symptoms occurred after rituxumab treatment.This case highlights the importance of multidisciplinary approach in patients with NMDAR encephalitis and the importance of early transition to second-line treatments in patients who do not respond adequately to first-line treatments. It is aimed to draw attention to the fact that early diagnosis and treatment can dramatically improve neuropsychiatric symptoms, and therefore clinicians should definitely remember NMDAR encephalitis in the differential diagnosis.

The value of the systemic immune-inflammation index in assessing disease severity in autoimmune encephalitis

Background Autoimmune encephalitis (AE) is a group of autoimmune diseases targeting the central nervous system, characterized by severe clinical symptoms and substantial consumption of medical resources. Neuroinflammation plays a crucial role in disease progression, and detecting inflammatory responses can provide insights into disease status and disease severity. The systemic immune-inflammation index (SII), a novel marker of inflammatory status, has been rarely studied in AE. Methods Retrospective analysis of data from AE patients admitted to the First Affiliated Hospital of Zhengzhou University between January 2019 and September 2023 was conducted. Univariate analysis and logistic regression were used to assess the association between SII and patient severity. Nomograms for predicting AE severity were established, and receiver operating characteristic (ROC) curves, concordance index (C-index), calibration curves, and decision curve analysis were employed to evaluate predictive accuracy. Additionally, the Clinical Assessment Scale in Autoimmune Encephalitis (CASE) score was used to assess patient severity. Results This study enrolled 157 patients, of whom 57 were classified as severe according to the CASE score. SII, cerebrospinal fluid (CSF) cell counts, disturbance of consciousness, and behavioural abnormalities independently associated with the occurrence of severe cases. The C-index of the nomograms was 0.87, indicating strong association with disease severity, as supported by the calibration. Additionally, SII levels were highest within seven days of onset and decreased after one month. In subgroup analyses of different antibodies, SII also associations with severe cases in NMDAR encephalitis. Conclusions Higher SII levels are associated with an increased likelihood of developing severe AE, peaking within 7 days of disease onset and decreasing thereafter, potentially offering a prognostic marker to assess disease progression early in its course.

A Case Report on Anti-N-methyl-d-aspartate Receptor Encephalitis in a 52-year-old Female with Schizophrenia

Abstract Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis is a complex neurological and psychiatric disorder. It often presents with psychiatric symptoms, leading to misdiagnosis, but can progress to severe neurological manifestations. In this study, we presented a 52-year-old woman with a 30-year history of schizophrenia who suddenly developed mutism, agitation, and incontinence. Electroencephalography showed generalized slowing, and autoimmune testing revealed NMDAR antibody positivity. Treatment with intravenous methylprednisone led to rapid improvement, highlighting the importance of considering autoimmune causes in such cases. NMDAR encephalitis is a condition with both neurological and psychiatric symptoms. It is often initially mistaken for psychiatric issues. Physicians should carefully assess and be vigilant in psychiatric cases. If routine tests show no significant issues, but the neurological state worsens, considers NMDAR encephalitis, and acts promptly. Delayed treatment can be harmful.

Assessment of long-term psychosocial outcomes in N-methyl-D-aspartate receptor encephalitis – the SAPIENCE study protocol

BackgroundN-methyl-D-aspartate-receptor (NMDAR) encephalitis is a rare neurological autoimmune disease with severe neuropsychiatric symptoms during the acute phase. Despite good functional neurological recovery, most patients continue to experience cognitive, psychiatric, psychological, and social impairments years after the acute phase. However, the precise nature and evolving patterns over time of these long-term consequences remain unclear, and their implications for the well-being and quality of life of predominantly young patients have yet to be thoroughly examined.MethodsSAPIENCE is a European multi-center (n = 3) prospective observational cohort study studying the long-term cognitive, psychiatric, psychological, and social outcome in patients with NMDAR encephalitis. The study consists of three interconnected levels. Level 1 comprises a qualitative interview and focus groups with patients and their caregivers. Level 2 consists of a condensed form of the interview, standardized questionnaires, and a detailed neuropsychological examination of patients. Level 3 involves an online survey that will be open to patients world-wide and explores patient-reported outcomes (PROMs), and patient-reported experiences (PREMs) in association with clinical and cognitive outcomes. Levels 1 to 3 will progressively contribute developing of structured interviews, survey questions, and treatment guidelines by informing one another.DiscussionSAPIENCE is an in-depth study of the long-term effects of NMDAR encephalitis and bridges the gap between standardized assessments and individual patient experiences, intending to improve patient care and to increase awareness of the psychosocial long-term consequences of the disease. Through collaboration of experts in clinical neurology and social and health psychology across Europe, SAPIENCE aims to create online assessment tools and formulate guidelines for patient-centered post-acute care that will help enhance the quality of life for patients and caregivers.

Efficacy and Safety of Rituximab Treatment for Anti-N-Methyl-d-Aspartate Receptor Encephalitis Without Tumor in Children

BackgroundTo evaluate the efficacy and safety of rituximab treatment for anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis without tumor in children. MethodsEighteen pediatric patients with NMDAR encephalitis treated with rituximab after failure of intravenous immunoglobulin (IVIG) and methylprednisolone treatment were analyzed retrospectively in terms of their medical history, clinical features, laboratory examination results, and treatments. The modified Rankin scale (mRS) score, peripheral blood CD19+ B cells, recurrence, and adverse events were used to evaluate the efficacy and safety of rituximab. ResultsThe patients were treated with rituximab 3.2 ± 1.0 days after the end of IVIG and methylprednisolone treatment. After initial rituximab treatment for four weeks, the mRS score and number of CD19+ B cells in all patients were significantly lower than those before treatment (P < 0.05). At the last follow-up (44.1 months, 17.7 S.D.), all patients had recovered well (mRS ≤2), 14 patients (77.8%) recovered completely (mRS = 0), three patients had recurrent seizures, and one patient had mental and language impairment. Two patients had transient mild adverse events during infusion, and none of the other patients experienced severe adverse events during hospitalization or follow-up. ConclusionsRituximab appears safe and may be effective for the treatment of anti-NMDAR encephalitis without tumor in children refractory to first-line agents.

Encephalitis lethargica: clinical features and aetiology.

Encephalitis lethargica, an epidemic neurological illness, typically involved a severe sleep disorder and progressive parkinsonism. A century later, our understanding relies on seminal descriptions, more recent historical research and the study of small numbers of possible sporadic cases. Theories around infection, environmental toxins, catatonia and autoimmune encephalitis have been proposed. We aimed to describe the presentation of encephalitis lethargica and test these diagnostic and aetiological theories. Subjects with encephalitis lethargica were identified in the archives of the National Hospital for Neurology and Neurosurgery, UK between 1918 and 1946. Case notes were examined to establish illness temporality, clinical features and cerebrospinal fluid results. Controls from the archives were identified for 10% of cases, matching on discharge year, sex and neurologist. Clinical presentation was compared to modern diagnostic criteria for encephalitis lethargica, catatonia and autoimmune encephalitis. In a case-control design, a multilevel logistic regression was conducted to ascertain whether cases of encephalitis lethargica were associated with febrile illnesses and with environmental exposures. Six hundred and fourteen cases of encephalitis lethargica and 65 controls were identified. Cases had a median age of 29 years (interquartile range 18) and a median time since symptomatic onset of 3.00 years (interquartile range 3.52). Motor features were present in 97.6%, cranial nerve findings in 91.0%, ophthalmological features in 77.4%, sleep disorders in 66.1%, gastrointestinal or nutritional features in 62.1%, speech disorders in 60.8% and psychiatric features in 53.9%. Of the 167 cases who underwent lumbar puncture, 20 (12.0%) had a pleocytosis. The Howard and Lees criteria for encephalitis lethargica had a sensitivity of 28.5% and specificity of 96.9%. Among the cases, 195 (31.8%, 95% confidence interval 28.1-35.6%) had a history of febrile illness within one calendar year prior to illness onset, which was more common than among the controls (odds ratio 2.70, 95% confidence interval 1.02-7.20, P = 0.05), but there was substantial reporting bias. There was no evidence that occupational exposure to solvents or heavy metals was associated with encephalitis lethargica. Two hundred and seventy-six (45.0%) of the cases might meet criteria for possible autoimmune encephalitis, but only 3 (0.5%) might meet criteria for probable NMDA receptor encephalitis. Only 11 cases (1.8%) met criteria for catatonia. Encephalitis lethargica has a distinct identity as a neuropsychiatric condition with a wide range of clinical features. Evidence for a relationship with infectious or occupational exposures was weak. Autoimmune encephalitis may be an explanation, but typical cases were inconsistent with NMDA receptor encephalitis.

Prognostic factors and treatment outcomes in pediatric autoimmune encephalitis: a multicenter study.

The last few decades have increased our understanding of autoimmune encephalitis (AE). In both the pediatric and adult populations, it proves to be a disease of dramatic acute onset of heterogeneous clinical manifestations, notably encephalopathy with neuropsychiatric symptoms, seizures, and extrapyramidal symptoms. More often, it is triggered by a viral infection in the pediatric age groups, as suggested by the preceding febrile symptoms in over half of cases, and more ostensibly, NMDAR encephalitis post herpes encephalitis. An underlying neoplasm may be present in certain types (i.e., NMDAR encephalitis). The rising rate of antibody detection and subsequent confirmation has been boosted by improved live cellular assay detection methods. The corresponding clinical phenotypes, common underlying malignancies, and histopathological findings have helped improve our management regarding intervention and choice of immunotherapy. New assessment tools such as the Clinical Assessment Scale in Autoimmune Encephalitis (CASE score) have helped improve the objective assessment of impact on cognitive functions (1). Early intervention with immunotherapy (and tumor removal in proven underlying neoplasms) has improved overall outcomes in most presenting patients. But nearly 40% of cases fail to respond to the first tier of treatment (2). The complex interplay between pathogenic autoantibodies, T-cells, B-cells, and cytokines has led to the emergence of additional immunotherapy agents (i.e., tocilizumab and bortezomib). In this retrospective observational study of pediatric AE conducted at two tertiary care centers, we observed the clinical characteristics, autoantibody yield, treatment modalities used, and disability scores during presentation and follow-up. Our secondary aim was to delineate prognostic factors for poor outcomes. Neuropsychiatric symptoms, encephalopathy, and seizures were the predominant manifestations in most of our patients. Younger age groups, refractory seizures, profound encephalopathy, and refractory disease harbored higher disability scores. The group that received combined immunotherapy has shown mitigation of disability score from severe to mild during long-term follow-up, signifying the role of multifaceted immunotherapy in pediatric refractory AE. Early implementation of combined immunotherapy in refractory cases significantly improved longterm disability scores, in spite of lingering residual effects on neurologic functions, notably cognition, behavior, and speech.

Post-Herpetic Anti-NMDAR Encephalitis in Denmark: Current Status and Future Challenges.

It is well known that N-methyl-D-aspartate receptor encephalitis (NMDARE) can be triggered by infectious encephalitis such as herpes simplex virus 1 encephalitis (HSE). However, the incidence of post-HSE NMDARE in Denmark is unknown. We reviewed literature cases and compared these to retrospectively identified cases of post-HSE NMDARE in Denmark, using a national cohort database of autoimmune encephalitis (AE) and two regional databases of infectious encephalitis patients. We identified 80 post-HSE NMDARE cases in the literature, 66% being children, who more often presented movement disorders, decreased consciousness, and sleep disturbances compared to adults. Eight patients with post-HSE NMDARE were identified from the national cohort database of AE, none being children. Forty-four HSE patients were identified from the regional infectious encephalitis databases. Of these, 16 (36%) fulfilled the Graus criteria for probable/definite NMDARE, and eight (18%) presented a prolonged/relapsing disease course. Ten (23%) were tested for AE during hospitalization. Six (14%) had leftover cerebrospinal fluid available for retrospective autoantibody testing. One out of these six patients (17%) harbored NMDARE antibodies. Thus, in total, nine post-HSE NMDARE patients have been identified in Denmark from 2009 to 2021. Comparing the adult Danish patients to the literature, Danish patients were older, but the clinical phenotype and paraclinical findings were similar. Overall, the incidence of adult post-HSE NMDARE in the Region of Southern Denmark was 0.17 per million people per year and only 7% of adult HSE patients in the region were diagnosed with post-HSE NMDARE. Our findings suggest that adult patients are still underdiagnosed and the absence of pediatric cases diagnosed with post-HSE NMDARE in Denmark is highly concerning.

Hippocampal hub failure is linked to long-term memory impairment in anti-NMDA-receptor encephalitis: insights from structural connectome graph theoretical network analysis

BackgroundAnti-N-methyl-d-aspartate receptor (NMDAR) encephalitis is characterized by distinct structural and functional brain alterations, predominantly affecting the medial temporal lobes and the hippocampus. Structural connectome analysis with graph-based investigations of network properties allows for an in-depth characterization of global and local network changes and their relationship with clinical deficits in NMDAR encephalitis.MethodsStructural networks from 61 NMDAR encephalitis patients in the post-acute stage (median time from acute hospital discharge: 18 months) and 61 age- and sex-matched healthy controls (HC) were analyzed using diffusion-weighted imaging (DWI)-based probabilistic anatomically constrained tractography and volumetry of a selection of subcortical and white matter brain volumes was performed. We calculated global, modular, and nodal graph measures with special focus on default-mode network, medial temporal lobe, and hippocampus. Pathologically altered metrics were investigated regarding their potential association with clinical course, disease severity, and cognitive outcome.ResultsPatients with NMDAR encephalitis showed regular global graph metrics, but bilateral reductions of hippocampal node strength (left: p = 0.049; right: p = 0.013) and increased node strength of right precuneus (p = 0.013) compared to HC. Betweenness centrality was decreased for left-sided entorhinal cortex (p = 0.042) and left caudal middle frontal gyrus (p = 0.037). Correlation analyses showed a significant association between reduced left hippocampal node strength and verbal long-term memory impairment (p = 0.021). We found decreased left (p = 0.013) and right (p = 0.001) hippocampal volumes that were associated with hippocampal node strength (left p = 0.009; right p < 0.001).ConclusionsFocal network property changes of the medial temporal lobes indicate hippocampal hub failure that is associated with memory impairment in NMDAR encephalitis at the post-acute stage, while global structural network properties remain unaltered. Graph theory analysis provides new pathophysiological insight into structural network changes and their association with persistent cognitive deficits in NMDAR encephalitis.

Molecularly targeted immunotherapy used to treat a novel overlap syndrome of pediatric N‐methyl‐d‐aspartate receptor encephalitis (NMDARE) and possible neurosarcoidosis

AbstractObjectiveOverlap syndromes have been described between N‐methyl‐ d‐aspartate receptor encephalitis (NMDARE) and other neuroinflammatory conditions, although rarely involving neurosarcoidosis. Molecularly targeted immunotherapy may be helpful in the empiric treatment of these conditions.MethodsWe describe a 9‐year‐old boy with new‐onset seizures and worsening encephalopathy.ResultsInitial evaluation was concerning for neurosarcoidosis, including elevated cerebrospinal fluid (CSF) and serum angiotensin‐converting enzyme and leptomeningeal with multiple cranial nerve enhancement on magnetic resonance imaging. CSF and serum cytokine profiles were used to choose targeted empiric immunotherapy, and the boy's seizure burden and encephalopathy improved after treatment with tocilizumab. The NMDA receptor antibody titer was later found to be elevated, raising suspicion for a novel overlap syndrome.InterpretationOur patient met the criteria for definite NMDARE and possible neurosarcoidosis. Given the mixed radiographic and serologic markers in this child, cytokine levels were used to direct the choice of empiric treatment, resulting in excellent clinical response. This case suggests that targeted immunotherapy informed by cytokine testing may be helpful in cases of high‐acuity pediatric neuroinflammatory disease with limited diagnostic clarity.

Autoimmune-associated seizure disorders.

With the discovery of an expanding number of neural autoantibodies, autoimmune etiologies of seizures have been increasingly recognized. Clinical phenotypes have been identified in association with specific underlying antibodies, allowing an earlier diagnosis. These phenotypes include faciobrachial dystonic seizures with LGI1 encephalitis, neuropsychiatric presentations associated with movement disorders and seizures in NMDA-receptor encephalitis, and chronic temporal lobe epilepsy in GAD65 neurologic autoimmunity. Prompt recognition of these disorders is important, as some of them are highly responsive to immunotherapy. The response to immunotherapy is highest in patients with encephalitis secondary to antibodies targeting cell surface synaptic antigens. However, the response is less effective in conditions involving antibodies binding intracellular antigens or in Rasmussen syndrome, which are predominantly mediated by cytotoxic T-cell processes that are associated with irreversible cellular destruction. Autoimmune encephalitides also may have a paraneoplastic etiology, further emphasizing the importance of recognizing these disorders. Finally, autoimmune processes and responses to novel immunotherapies have been reported in new-onset refractory status epilepticus (NORSE) and febrile infection-related epilepsy syndrome (FIRES), warranting their inclusion in any current review of autoimmune-associated seizure disorders.

NMDA receptor autoantibodies primarily impair the extrasynaptic compartment.

Autoantibodies directed against the N-methyl-D-aspartate receptor (NMDAR-Ab) are pathogenic immunoglobulins detected in patients suffering from NMDAR encephalitis. NMDAR-Ab alter the receptor membrane trafficking, synaptic transmission and neuronal network properties, leading to neurological and psychiatric symptoms in patients. Patients often have very little neuronal damage but rapid and massive (treatment-responsive) brain dysfunctions related to an unknown early mechanism of NMDAR-Ab. Our understanding of this early molecular cascade remains surprisingly fragmented. Here, we used a combination of single molecule-based imaging of membrane proteins to unveil the spatiotemporal action of NMDAR-Ab on live hippocampal neurons. We first demonstrate that different clones of NMDAR-Ab primarily affect extrasynaptic (and not synaptic) NMDARs. In the first minutes, NMDAR-Ab increase extrasynaptic NMDAR membrane dynamics, declustering its surface interactome. NMDAR-Ab also rapidly reshuffle all membrane proteins located in the extrasynaptic compartment. Consistent with this alteration of multiple proteins, effects of NMDAR-Ab were not mediated through the sole interaction between the NMDAR and EphB2 receptor. In the long term, NMDAR-Ab reduce the NMDAR synaptic pool by slowing down receptor membrane dynamics in a cross-linking-independent manner. Remarkably, exposing only extrasynaptic NMDARs to NMDAR-Ab was sufficient to produce their full-blown effect on synaptic receptors. Collectively, we demonstrate that NMDAR-Ab initially impair extrasynaptic proteins, then the synaptic ones. These data thus shed new and unsuspected light on the mode of action of NMDAR-Ab and, probably, our understanding of (extra)synaptopathies.

Mechanisms of autoimmune encephalitis.

To provide an overview of the pathogenic mechanisms involved in autoimmune encephalitides mediated by antibodies against neuronal surface antigens, with a focus on NMDAR and LGI1 encephalitis. In antibody-mediated encephalitides, binding of IgG antibodies to neuronal surface antigens results in different pathogenic effects depending on the type of antibody, IgG subclass and epitope specificity. NMDAR IgG1 antibodies cause crosslinking and internalization of the target, synaptic and brain circuitry alterations, as well as alterations of NMDAR expressing oligodendrocytes, suggesting a link with white matter lesions observed in MRI studies. LGI1 IgG4 antibodies, instead, induce neuronal dysfunction by disrupting the interaction with cognate proteins and altering AMPAR-mediated signaling. In-vitro findings have been corroborated by memory and behavioral changes in animal models obtained by passive transfer of patients' antibodies or active immunization. These models have been fundamental to identify targets for innovative therapeutic strategies, aimed at counteracting or preventing antibody effects, such as the use of soluble ephrin-B2, NMDAR modulators (e.g., pregnenolone, SGE-301) or chimeric autoantibody receptor T cells (CAART) in models of NMDAR encephalitis. A deep understanding of the pathogenic mechanisms underlying antibody-mediated encephalitides is crucial for the development of new therapeutic approaches targeting brain autoimmunity.

A case of NMDAR Encephalitis with muscular pain as the main presentation

BackgroundPersistent somatoform pain disorder (PSPD) is often the initial diagnosis in patients seeking treatment in psychiatric departments, making it challenging to consider organic nervous system diseases. However, autoimmune encephalitis can present with atypical initial symptoms, leading to misdiagnosis or missed diagnosis. Lumbar puncture, with antibody support, plays a crucial role in diagnosing autoimmune encephalitis.Case presentationThis report describes a 40-year-old male adult patient who was initially diagnosed with persistent somatoform pain disorder in 2022. The patient reported a reduction in pain while resting on his back. There were no fever or relevant medical history. Despite 8 months of symptomatic treatment, the symptoms did not improve. Moreover, the patient developed confusion, gibberish speech, non-cooperation during questioning, and increased frequency and amplitude of upper limb convulsions. Lumbar puncture revealed elevated protein levels and protein-cell dissociation. The autoimmune encephalitis antibody NMDAR (+) was detected, leading to a diagnosis of autoimmune encephalitis (NMDAR).ConclusionAutoimmune encephalitis (NMDAR), starting with persistent somatoform pain (PSPD), often presents with atypical symptoms and can be easily misdiagnosed. Therefore, it is important to consider the possibility of organic nervous system disease in time, and to test serum or cerebrospinal fluid antibodies to rule out organic nervous system disease after symptomatic treatment of mental disorders is ineffective. This approach facilitates the early diagnosis of autoimmune encephalitis and other underlying organic neurological disorders.