Encephalitis in children is a serious inflammatory brain disease caused by infectious or autoimmune-mediated processes. The frequency of autoimmune variants in pediatric populations is not entirely clear.To study the frequency of myelin oligodendrocyte glycoprotein (MOG) antibody (ab)-mediated autoimmune encephalitis (AE) in children included in the Meningitis/Encephalitis register of Lower Saxony (MERIN).Medical records of 1,341 children treated between 2011 and 2020 in two large children's hospitals participating in a prospective study on encephalitis (MERIN) were reviewed. Children meeting diagnostic criteria for possible AE were finally included if serum samples and informed re-consent were available. Children with pathogen-mediated encephalitis were also included as controls. All available serum samples were tested for MOG- and anti-N-methyl-D-aspartate receptor (NMDAR) antibodies (abs) using cell- and tissue-based assay (TBA).We included 55 children of whom 16 had pathogen-associated meningoencephalitis. Thirty-nine out of fifty-five children were classified as possible AE and 3/39 fulfilled the criteria for MOG ab-associated disease (MOGAD). No patients' sera harbored NMDAR abs. However, 5/39 patients fulfilled the criteria for probable, auto-ab-negative AE.In line with recent research our study suggests that ab-mediated AE and probable ab-negative AE are rare in children. The existing criteria seem suitable for identifying patients with AE but should include the testing of serum MOG abs. Further yet unknown abs may play a role in children with AE.

Limbic encephalitis (LE) associated with anti-LGI1 antibodies is an autoimmune disorder characterized by memory decline, behavioral changes, and temporal lobe epilepsy. Faciobrachial dystonic seizures (FBDS) are a hallmark symptom, often preceding cognitive and psychiatric issues. This report presents an 80-year-old male with LGI1 encephalitis, initially manifesting as FBDS. A lung adenocarcinoma was diagnosed two months after the onset of neurological symptoms. Clinical and paraclinical data, including MRI and [18]FDG PET imaging, are described. The patient responded to immunotherapy, including steroids and plasma exchange, along with tumor resection. Following treatment, neurological symptoms resolved, except for mild anxiety and apathy. Further research is needed to determine whether LGI1 encephalitis may occasionally have a paraneoplastic origin, potentially influencing screening and management strategies.

To elucidate current epidemiological, clinical, and immunological profiles, and the treatment of Isaacs syndrome in Japan.

We conducted a nationwide survey using established methods. Questionnaires were sent to neurological facilities throughout Japan to identify Isaacs syndrome patients seen between April 2018 and March 2021.

The estimated total number of Isaacs syndrome patients was 114 (95 % confidence interval [CI]: 89.63-138.91), and the estimated prevalence was 0.091 per 100,000 population. Detailed clinical data were available for 44 patients. The median age at onset was 40 (range, 17-78 years), and 55 % were female. The median time from symptom onset to diagnosis was 24 months (range, 1-372 months). Electrodiagnostic studies showed evidence of nerve hyperexcitability in 90 % (myokymic discharges in 50 % and stimulus-induced repetitive discharges in 32 %). Of the 28 patients examined in the cell-based assay, 22 % tested positive (11 % for both leucine-rich glioma-inactivated 1 [LGI1] and contactin-associated protein-like 2 [CASPR2] antibodies and 11 % for LGI1 antibodies only). The median modified Rankin Scale (mRS) score was 2 at diagnosis and 1.5 at the last visit. A high mRS score (mRS ≥4) at baseline was an independent risk factor for poor outcomes (mRS ≥3) (Odds ratio, 20.7; 95 % CI, 2.90-209.18; p < 0.001).

We elucidated the current epidemiological and clinical characteristics of Isaacs syndrome in Japan. Isaacs syndrome is a rare neuromuscular disorder. Electrophysiologic abnormalities were frequent, and serum antibodies were not detectable in the majority of patients. A high mRS score before treatment was a risk factor for poor outcomes.

Anti-LGI-1 limbic encephalitis, the second most common autoimmune encephalitis, typically presents with psychotic symptoms. However, systematic characterization of psychotic features in this disease remains scarce, with insufficient granularity in existing symptom descriptions. This systematic review aims to characterize the psychotic manifestations in anti-LGI-1 encephalitis through a comprehensive analysis of published cases and institutional data.

Following PRISMA guidelines, we systematically searched PubMed, Embase, and Web of Science for case reports of anti-LGI-1 encephalitis, specifically focusing on cases with confirmed diagnoses and psychotic symptoms. Additionally, clinical data from patients diagnosed with anti-LGI-1 encephalitis and admitted to Shanxi Medical University First Hospital between January 2018 and June 2024 who also exhibited psychotic symptoms were collected. The data were then classified and statistically analyzed to assess patient characteristics.

31articles and 24 clinical cases were found, leading to 74 cases that met the inclusion criteria. Among these, 59.46 % of patients showed initial psychotic symptoms during their illness. Common positive symptoms included hallucinations, delusions, and delirium presenting with disorganized speech, while negative symptoms often involved apathy/indifference, depression, and catatonia-related physical issues. Sleep disturbances were also common.

When a patient presents with an unexplained alteration in mental status, the potential diagnosis of anti-LGI-1 encephalitis must be considered. This consideration facilitates timely and accurate diagnosis for patients suffering from anti-LGI-1 encephalitis, ultimately enhancing their prognosis.

Autoimmune encephalitis (AE) is a form of brain inflammation where pathogenic autoantibodies bind surface proteins. In humans, AE is at least as common as infective encephalitis, and seizures are a prominent manifestation. The most common adult human AE is associated with antibodies to leucine-rich glioma-inactivated 1 (LGI1-Ab-E). AE in non-human mammals is also recognised, notably the polar bear 'Knut', diagnosed with N-methyl D-aspartate receptor antibody encephalitis. LGI1-Ab-E is an emerging cause of spontaneously-arising AE in domestic cats. Our objective was to phenotype the seizure profile of feline LGI1-Ab-E and probe parallels to its human counterpart.

We characterised seizures in naturally-occurring feline LGI1-Ab-E. Three veterinary and two human neurologists independently blind-rated 35 LGI1-antibody positive and negative feline seizure videos from 24 cats (16 LGI1-Ab-E positive, 8 negative). Data analysed included seizure frequency, semiologies and their co-occurrence, localisation, inter-rater agreement, and predictive factors.

The mean number of daily seizures at peak was significantly higher in LGI1-antibody positive compared to LGI1-antibody-negative cats (12.6 vs. 1.9/day, pcorr = 0.011). Semiologies statistically significantly enriched in LGI1-Ab-E observations included orofacial automatisms (88/120, 73 % vs. 26/55, 47 %, pcorr = 0.024), salivation (87/120, 73 % vs. 23/55, 42 %, pcorr = 0.004); and mydriasis (79/120, 66 % vs 19/55, 35 %, pcorr = 0.004), and almost exclusively seen in LGI1-Ab-E were circling (39/120, 33 % vs. 1/55, 2 %, pcorr=<0.001) and aggression (14/120, 12 % vs. 0/55, 0 %, non significant after correction). A temporal lobe onset was proposed in 67 % (80/120) of seropositive ratings, compared to 28 % (15/55) LGI1-Ab-E negative (p < 0.0001). Network analysis depicted complex and overlapping relationships between features, akin to the frequent and multifaceted seizures of human LGI1-Ab-E. Orofacial automatisms, mydriasis and temporal lobe localisation were predictive semiological features of feline LGI1-Ab-E.

Feline LGI1-Ab-E represents a clinically distinctive seizure disorder. Our findings highlight the value of studying naturally-occurring, biologically representative animal models which closely mimic human diseases. This bidirectional translational approach confers benefits across species and unites human and veterinary neurology.

Morvan Syndrome is a rare autoimmune-mediated clinical condition. This retrospective study aims at assessing the effectiveness and safety of intravenous Efgartigimod in 2 cases of the Morvan Syndrome with positive LGI1 and CASPR2 antibodies.

We reviewed the clinical manifestations, autoantibodies detection, electromyography (EMG) characteristics, treatments and follow-up outcomes in 2 patients of Morvan Syndrome with positive LGI1 and CASPR2 antibodies. Especially, we evaluated the therapeutic effectiveness and safety of intravenous Efgartigimod based on the improvement of symptoms, relapse conditions and adverse reactions.

The patient 1 was a 35-year-old female who presented with muscle tremors and pain in lower limbs. The serum VGKC, LGI1 and CASPR2 antibodies were positive. M-wave and muscle tremor discharges were observed in both gastrocnemius muscles with EMG examination. She was treated with efgartigimod (800 mg, once a week for 4 times), and the symptoms were almost alleviated at 6 months follow-up. The patient 2 was a 31 year-old female who presented with muscle soreness and weakness in four limbs. The serum VGKC, LGI1 and CASPR2 antibodies also were positive. M-wave discharges were observed with EMG examination. She was treated with efgartigimod (400 mg, once a week for 4 times), and follow-up at 6 months also showed recovery of muscle strength.

Morvan Syndrome is an antibody-related autoimmune syndrome with complex clinical manifestations. Our findings showed that the treatments of intravenous Efgartigimod could be effective and well tolerant in patients of Morvan Syndrome with LGI1 and CASPR2 antibodies.

Autoimmune encephalitis (AE) is an important cause of neurologic morbidity and mortality. Treatment algorithms are primarily based on observational studies, retrospective series, and expert opinion. Despite clinical improvement with empiric therapy, recovery is often incomplete with a substantial burden of residual neurologic deficits and recurring symptoms. There is a pressing need for higher quality evidence-based therapies. However, designing and conducting clinical trials for patients with rare diseases such as AE has specific challenges, including slow recruitment, suboptimal outcome measures, and inclusivity vs exclusivity of the various disease subtypes. The anticipated knowledge gained from AE clinical trials emphasizes the need to overcome these challenges and support the development of the next generation of clinical trials. Yet, given these challenges, alternative approaches may be required. In this article, we review past and present clinical trials in AE with a focus on studies enrolling patients with neural surface antibodies. We discuss the potential challenges and opportunities inherent to clinical trials in rare diseases and provide an outlook for the field.

Autoantibody-mediated diseases targeting one autoantigen provide a unique opportunity to comprehensively understand the development of disease-causing B cells and autoantibodies. Convention suggests that such autoreactivities are generated during germinal center reactions. Here, we explore earlier immune checkpoints, focusing on patients with contactin-associated protein-like 2 (CASPR2)-autoantibody encephalitis. In both disease and health, high (~0.5%) frequencies of unmutated CASPR2-reactive naïve B cells were identified. By contrast, CASPR2-reactive memory B cells were exclusive to patients, and their B cell receptors demonstrated affinity-enhancing somatic mutations with pathogenic effects in neuronal cultures and mice. The unmutated, precursor memory B cell receptors showed a distinctive balance between strong CASPR2 reactivity and very limited binding across the remaining human proteome. Our results identify permissive central tolerance, defective peripheral tolerance, and autoantigen-specific tolerance thresholds in humans as sequential steps that license CASPR2-directed pathology. By leveraging the basic immunobiology, we rationally direct tolerance-restoring approaches, with an experimental paradigm applicable across autoimmunity.

The immune system and sleep are inextricably linked in both health and pathological conditions. Tightly regulated neuroimmune processes are critical for the physiological maintenance of healthy sleep. Reciprocally, sleep disturbances can detrimentally affect immune homeostasis and predispose to increased risk of autoimmune conditions, which themselves are bidirectionally associated with a higher risk of sleep disturbances. Autoimmune diseases of the central nervous system (CNS), particularly conditions that affect neuroanatomical regions involved in sleep homeostasis and nocturnal respiration, are associated with an increased risk sleep disorders that may impact diagnosis, clinical course, and management. This review summarizes the bidirectional relationship between sleep and immunity and highlights several exemplar autoimmune conditions of the CNS that include sleep disorders as a consequence or diagnostic feature of the disorder.

Neuronal hyperexcitability is a key driver of persistent pain states, including neuropathic pain. Leucine-rich, glioma inactivated 1 (LGI1) is a secreted protein known to regulate excitability within the nervous system and is the target of autoantibodies from neuropathic pain patients. Therapies that block or reduce antibody levels are effective at relieving pain in these patients, suggesting that LGI1 has an important role in clinical pain. Here we have investigated the role of LGI1 in regulating neuronal excitability and pain-related sensitivity by studying the consequences of genetic ablation in specific neuron populations using transgenic mouse models. LGI1 has been well studied at the level of the brain, but its actions in the spinal cord and peripheral nervous system are poorly understood. We show that LGI1 is highly expressed in dorsal root ganglion (DRG) and spinal cord dorsal horn neurons in both mouse and human. Using transgenic mouse models, we genetically ablated LGI1, either specifically in nociceptors (LGI1fl/Nav1.8+) or in both DRG and spinal neurons (LGI1fl/Hoxb8+). On acute pain assays, we found that loss of LGI1 resulted in mild thermal and mechanical pain-related hypersensitivity when compared with littermate controls. In LGI1fl/Hoxb8+ mice, we found loss of Kv1 currents and hyperexcitability of DRG neurons. LGI1fl/Hoxb8+ mice displayed a significant increase in nocifensive behaviours in the second phase of the formalin test (not observed in LGI1fl/Nav1.8+ mice), and extracellular recordings in LGI1fl/Hoxb8+ mice revealed hyperexcitability in spinal dorsal horn neurons, including enhanced wind-up. Using the spared nerve injury model, we found that LGI1 expression was dysregulated in the spinal cord. LGI1fl/Nav1.8+ mice showed no differences in nerve injury-induced mechanical hypersensitivity, brush-evoked allodynia or spontaneous pain behaviour compared with controls. However, LGI1fl/Hoxb8+ mice showed a significant exacerbation of mechanical hypersensitivity and allodynia. Our findings point to effects of LGI1 at the level of both the DRG and the spinal cord, including an important impact of spinal LGI1 on pathological pain. Overall, we find a novel role for LGI1 with relevance to clinical pain.

Encephalitis with antibodies to leucine-rich glioma-inactivated 1 (LGI1-Ab-E) is a common form of autoimmune encephalitis, presenting with seizures and neuropsychiatric changes, predominantly in older males. More than 90% of patients carry the human leukocyte antigen (HLA) class II allele, HLA-DRB1*07:01. However, this is also present in 25% of healthy controls. Therefore, we hypothesized the presence of additional genetic predispositions. In this genome-wide association study and meta-analysis, we studied a discovery cohort of 131 French LGI1-Ab-E and a validation cohort of 126 American, British and Irish LGI1-Ab-E patients, ancestry-matched to 2613 and 2538 European controls, respectively. Outside the known major HLA signal, we found two single nucleotide polymorphisms at genome-wide significance (P < 5 × 10-8), implicating PTPRD, a protein tyrosine phosphatase, and LINC00670, a non-protein coding RNA gene. Meta-analysis defined four additional non-HLA loci, including the protein coding COBL gene. Polygenic risk scores with and without HLA variants proposed a contribution of non-HLA loci. In silico network analyses suggested LGI1 and PTPRD-mediated interactions via the established receptors of LGI1, ADAM22 and ADAM23. Our results identify new genetic loci in LGI1-Ab-E. These findings present opportunities for mechanistic studies and offer potential markers of susceptibility, prognostics and therapeutic responses.

Both anterograde and retrograde amnesia can typically co-occur in limbic autoimmune encephalitis (LAE), including the forms associated with antibodies to CASPR2/LGI1, two protein complexed with the voltage-gated potassium channel (VGKC). However, isolated retrograde amnesia is very rare, and it has never been described in LAE.

We report two patients with CASPR2 LAE who showed isolated retrograde amnesia, without other significant cognitive impairments. A systematic literature review was performed in accordance with the PRISMA guidelines on patients with LAE, antibodies to the VGKC complex (including LGI1, CASPR2, or the VGKC), and memory impairment.

We identified 467 patients from 29 studies. Fourteen/467 had retrograde amnesia (2.9%), which co-occurred with anterograde amnesia in 12 with VGKC antibodies (7 with LGI1 LAE-like clinical phenotypes). Our two cases with CASPR2 LAE (2/469, 0.4%) were the only ones with isolated retrograde amnesia, which was actively investigated in only 56/467 patients. Thirteen/14 patients, including the two with isolated retrograde amnesia, had partial or poor cognitive improvement.

Retrograde amnesia is rare but likely under-recognized in VGKC-complex antibodies LAE and associates with poor recovery. When isolated, it adds to the spectrum of CASPR2 LAE. These findings promote insights into retrograde amnesia pathophysiology, deserving investigation across the whole spectrum of AE.

The long-term clinical outcomes and associated prognostic factors in contactin-associated protein-like 2 (CASPR2)-antibody diseases are unknown. A total of 75 participants with CASPR2 antibodies were longitudinally assessed for disability, quality-of-life, and chronic pain. Although most symptoms improved within 6 months of treatment, neuropathic pain and fatigue were the most immunotherapy refractory, and persisted for up to 6 years. Furthermore, these two factors-but not CASPR2 antibody levels or subclasses-independently predicted worse disability and quality-of-life at 24 months. Quality-of-life varied widely for any given modified Rankin Scale score, indicating a divergence between patient and clinician assessed outcomes. Further work should study the relative importance of these measures, and the immunopathogenesis underlying intractable symptoms. ANN NEUROL 2025;97:521-528.

Cognitive deficits represent a major long-term complication of anti-leucine-rich, glioma-inactivated 1 encephalitis (LGI1-E). Although severely affecting patient outcomes, the structural brain changes underlying these deficits remain poorly understood. In this study, we hypothesized a link between white matter (WM) networks and cognitive outcomes in LGI1-E.

In this cross-sectional study, we combined clinical assessments, comprehensive neuropsychological testing, diffusion tensor MRI, probabilistic WM tractography, and computational network analysis in patients with LGI1-E referred to Charité-Universitätsmedizin Berlin. Healthy individuals were recruited as control participants and matched to patients for age and sex with logistic regression propensity scores.

Twenty-five patients with LGI1-E (mean age = 63 ± 12 years, 76% male) and 25 healthy controls were enrolled. Eighty-eight percent of patients presented persistent cognitive symptoms at postacute follow-up (median: 12 months from onset, interquartile range: 6-23 months)-despite treatment with immunotherapy and good overall recovery (modified Rankin Scale [mRS] score at peak illness vs postacute: z = -4.1, p < 0.001, median mRS score at postacute visit: 1). Neuroimaging revealed that WM networks in LGI1-E are characterized by (1) a systematic reduction in whole-brain connectivity (t = -2.16, p = 0.036, d = -0.61), (2) a cortico-subcortical hypoconnectivity cluster affecting both limbic and extralimbic brain systems, and (3) a "topological reorganization" marked by a bidirectional shift in the relative importance of individual brain regions in the WM network. The extent of this WM reorganization was strongly associated with long-term deficits of verbal memory (r = -0.56), attention (r = -0.55), and executive functions (r = -0.60, all pFDR = 0.017).

Although traditionally viewed as a form of limbic encephalitis, our study characterizes LGI1-E as a "network disorder" that affects the whole brain. Structural reorganization of WM networks was linked to long-term and multidomain cognitive impairment, which was not prevented by immunotherapy. These findings highlight the need for closer monitoring and improved treatment strategies to mitigate long-term cognitive impairment in LGI1-E.

The aim of this review is to summarize clinical, radiological and laboratory findings in autoimmune dementia, to help clinicians in promptly identify this elusive condition.

The rapid advances in the field of autoimmune neurology have led to the discovery of novel antibodies and associated disorders, which are more frequent than previously hypothesized. The correct and prompt identification of cognitive decline of autoimmune origin is vital to ensure early treatment and better outcomes. The diagnosis of autoimmune dementia relies on specific clinical and radiological features and on the detection of specific autoantibodies. Autoantibody specificities predict response to treatment and the occurrence of cancer. In recent years, the differential diagnosis of autoimmune dementia has become more relevant, as the overinterpretation of antibody results, clinical and radiological findings may lead to an erroneous diagnosis of autoimmune dementia, with potential harm to patients due to inappropriate exposure to immunosuppressants.

Autoimmune dementia is a potentially treatable condition and should not be missed in clinical practice given the potential for reversibility with immunotherapy. The diagnosis of autoimmune dementia relies on a comprehensive review of clinical, radiological and laboratory data, and exclusion of other causes of dementia.

Language disorder, a prevalent developmental disorder, impedes children's communication skills, with genetic and environmental factors playing pivotal roles in its pathomechanism. This study aims to investigate the involvement of sequence variations in SETBP1 and CNTNAP2 genes, along with environmental variables, in language disorder's etiology.

Between September 2022 and March 2023, thirty children aged 2-7 diagnosed with language disorders according to DSM-5 criteria, and evaluated using the Ankara Developmental Screening Inventory, were studied to identify genetic and environmental factors contributing to etiology.Thirty healthy children with similar age were included as a control group. DNA samples isolated from peripheral blood of both groups were analyzed for SETBP1 and CNTNAP2 genes using next-generation sequencing (custom design panel). The frequencies and clinical significance of the identified variants was evaluated, and variant verification and segregation analyses were performed by Sanger sequencing. The obtained data were compared using appropriate statistical methods.

Language disorder showed a male-dominant distribution. The SETBP1 rs11082414-CC genotype frequency was significantly higher in patients (p = 0.024), and two rare variants (CNTNAP2: c.973C>G:p.P325A; CNTNAP2: c.2236 G>A:p.D746N) were exclusive to cases. In silico analyses yielded conflicting results for rare variants, inherited paternally from unaffected parents. Among non-genetic factors, patients had higher birth weights (p = 0.043) and shorter lactation durations (p = 0.044).

Homozygosity for SETBP1 rs11082414 polymorphic variant increases language disorder susceptibility. This study underscores the genetic dimension of language disorder, urging physicians' awareness and early intervention strategies to mitigate its impact.

Immunoglobulin (Ig) G4 auto-antibodies (Abs) against contactin-associated protein-like 2 (Caspr2), a transmembrane cell adhesion protein expressed in the central and peripheral nervous system, are found in patients with a broad spectrum of neurological symptoms. While the adoptive transfer of Caspr2-specific IgG induces brain pathology in susceptible rodents, the mechanisms by which Caspr2-Abs mediate neuronal dysfunction and translate into clinical syndromes are incompletely understood.

We use a systems-level approach combined with high-dimensional characterization of Ab-associated immune features to deeply profile humoral biosignatures in patients with Caspr2-Ab-associated neurological syndromes.

We identify two signatures strongly associated with two major clinical phenotypes, limbic encephalitis (LE) and predominant peripheral nerve hyperexcitability without LE (non-LE). Caspr2-IgG Fc-driven pro-inflammatory features, characterized by increased binding affinities for activating Fcγ receptors (FcγRs) and C1q, along with a higher prevalence of IgG1-class Abs, in addition to IgG4, are strongly associated with LE. Both the occurrence of Caspr2-specific IgG1 and higher serum levels of interleukin (IL)-6 and IL-15, along with increased concentrations of biomarkers reflecting neuronal damage and glial cell activation, are associated with poorer clinical outcomes at 1-year follow-up.

The presence of IgG1 isotypes and Fc-mediated effector functions control the pathogenicity of Caspr2-specific Abs to induce LE. Biologics targeting FcR function might potentially restrain Caspr2-Ab-induced pathology and improve clinical outcomes.

This study was funded by a German-French joint research program supported by the German Research Foundation (DFG) and the Agence Nationale de la Recherche (ANR) and by the Interdisciplinary Centre for Clinical Research (IZKF) Münster.

Autoimmune encephalitis (AE) is a rare and recently described neuroinflammatory disease associated with specific autoantibodies. Anti-leucine-rich glioma inactivated 1 (anti-LGI1) encephalitis is a rare but treatable type of AE discovered in recent years. Alzheimer's disease (AD) is a degenerative brain disease and the most common cause of dementia. AD may undergo a series of pathological physiological changes in brain tissue 20 years before the onset of typical symptoms. The stage of mild cognitive impairment (MCI) that occurs during this process, known as MCI due to AD, is the earliest stage with clinical symptoms. MCI is typically categorized into two subtypes: Amnestic MCI (aMCI) and non-aMCI.

This report describes a patient with rapid cognitive impairment, diagnosed with anti-LGI1 antibody-mediated AE and aMCI, and treated at Peking University Shenzhen Hospital in March 2023. The patient was hospitalized with acute memory decline for more than 3 months. Both the cerebrospinal fluid and serum were positive for anti-LGI1 antibodies, biomarkers of AD coexisting in the patient's cerebrospinal fluid. Following combination treatment with immunoglobulin therapy and glucocorticoid, plus inhibition of acetylcholinesterase, the patient's cognitive function significantly improved. Throughout the 3-month follow-up period, a sustained improvement in cognitive function was observed. The results of serum anti-LGI1 antibody were negative.

This case has raised awareness of the possible interaction between AE and early AD (including MCI due to AD), and alerted clinicians to the possibility of concurrent rare and common diseases in patients presenting with cognitive impairment.

The objective was to utilize nine machine learning (ML) methods to predict the prognosis of antibody positive autoimmune encephalitis (AE) patients.

The encephalitis data from the Global Burden of Disease (GBD) study is analyzed to reflect the disease burden of encephalitis. This study included 187 patients with AE. 121 patients as training set and 67 patients as validation set. Decision trees (DT), random forest (RF), extreme gradient boosting (XGBoost), k-nearest neighbor (KNN), support vector machine (SVM), naive bayes (NB), neural network (NN), light gradient boosting machine (LGBM), and logistic regression (LR) are ML methods used to construct predictive models. The constructed models were validated for discrimination, calibration and clinical applicability using validation set data. Shapley additive explanation (SHAP) analysis was used to explain the model.

The number of encephalitis worldwide deaths, incidence and prevalence is increasing every year from 2010 to 2021. The training set included 121 patients with AE. Univariate analysis and LASSO screening identified six variables. The results of constructing models using 9 ML methods showed RF had the highest accuracy (0.860), followed by XGBoost (0.826), with F1 scores of 0.844 and 0.807, respectively. Validation set data showed good discrimination, calibration and clinical applicability of the model. The SHAP values of infection, CSF monocyte percentage, and prealbumin were 0.906, 0.790, and 0.644, respectively.

As a rare disease, the sample size of this study is relatively small.

The model constructed using RF and XGBoost has good performance, good discrimination, calibration, clinical applicability, and interpretability.

Autoimmunity affects 10% of the population. Within this umbrella, autoantibody-mediated diseases targeting one autoantigen provide a unique opportunity to comprehensively understand the developmental pathway of disease-causing B cells and autoantibodies. While such autoreactivities are believed to be generated during germinal centre reactions, the roles of earlier immune checkpoints in autoantigen-specific B cell tolerance are poorly understood. We address this concept in patients with CASPR2-autoantibody encephalitis and healthy controls. In both groups, comparable and high (~0.5%) frequencies of unmutated CASPR2-reactive naïve B cells were identified. By contrast, CASPR2-reactive memory B cells were exclusive to patients, and their B cell receptors demonstrated affinity-enhancing somatic mutations with heterogenous binding kinetics. These effector molecules possessed epitope-dependent pathogenic effects in vitro neuronal cultures and in vivo. The unmutated common ancestors of these memory B cells showed a distinctive balance between strong CASPR2 reactivity and very limited binding across the remaining human proteome. Our results are the first to propose mechanisms underlying autoantigen-specific tolerance in humans. We identify permissive central tolerance, defective peripheral tolerance and heterogenous autoantibody binding properties as sequential pathogenic steps which licence CASPR2-directed pathology. By leveraging the basic immunobiology, we rationally direct tolerance-restoring approaches in CASPR2-antibody diseases. This paradigm is applicable across autoimmune conditions.

An 81-year-old man was brought to our hospital with tonic-clonic seizures and a gradual progression of cognitive dysfunction. Four months prior, he experienced transient episodes of stiffness and unresponsiveness. One month later, the patient began to exhibit disorientation to time and place. Upon admission, fluid-attenuated inversion recovery (FLAIR) brain magnetic resonance imaging (MRI) revealed hyperintense lesions in the right limbic cortex. Electroencephalography (EEG) revealed lateralized periodic discharges in the right temporal lobe. Serum anti-LGI1 antibody was detected. Based on these findings, anti-LGI1 limbic encephalitis (LE) was diagnosed. His symptoms improved with corticosteroid treatment; however, six months of hospitalization were necessary for him to regain independence in daily living. Although the prognosis of anti-LGI1 LE is generally favorable, older age at onset, non-convulsive status epilepticus, diffuse limbic lesions, and delayed treatment may have influenced the clinical course in this case.

Neuromyotonia, also known as Isaac syndrome, is a rare neurological disorder characterized by continuous muscle activity, stiffness, and spontaneous muscle contractions, it is very rare in children. We report a 16-year-old female patient with neuromyotonia. She presented with pain, stiffness, autonomic symptoms and muscle myokymia in both lower limbs. The patient was treated with a short course of methylprednisolone, IVIG over the course of 4 weeks, and symptomatic management which resulted in a dramatic improvement and relief of symptoms. A literature review for pediatric patients with neuromyotonia was conducted revealing 10 reported cases so far. All pediatric patients with neuromyotonia showed favorable prognosis despite using different treatment modalities. Although the association between neuromyotonia and malignancy is known in adult population, this has not been seen in the reported pediatric cases. Indeed, given the scarcity of data, we still do recommend screening for malignancy in pediatric patients with neuromyotonia.

Autoimmune encephalitis (AE) is a neuroimmune disorder that presents significant diagnostic challenges. The FDA Adverse Event Reporting System (FAERS) database can help explore the relationship between drugs and AE, but comprehensive studies are lacking. This study aims to analyze the association between drugs and AE using the FAERS database, providing insights for clinical practice and pharmacovigilance.

Adverse event reports in the FAERS database were analyzed, focusing on the incidence of drug-induced AE, as well as characteristics such as gender and age. Multiple statistical methods were employed to assess the association between drugs and adverse reactions.

The study revealed that drug-induced AE predominantly occurred in individuals aged 41 and above, with a higher prevalence among female patients. Nivolumab and pembrolizumab were among the drugs most frequently reported for adverse drug reactions. However, only a minority of drug labels mentioned these adverse reactions.

This study underscores the potential risk of drug-induced AE, advocating for close monitoring in clinical practice. Further epidemiological investigations are warranted to elucidate the exact relationship between drugs and these disorders. While the FAERS database provides crucial leads for such research, additional studies and validation are necessary.

Small fiber neuropathy (SFN) is a peripheral nerve condition affecting thin myelinated Aδ and unmyelinated C-fibers, characterized by severe neuropathic pain and other sensory and autonomic symptoms. A variety of medical disorders can cause SFN; however, more than 50% of cases are idiopathic (iSFN). Some investigations suggest an autoimmune etiology, backed by evidence of the efficacy of IVIG and plasma exchange. Several studies suggest that autoantibodies directed against nervous system antigens may play a role in the development of neuropathic pain. For instance, patients with CASPR2 and LGI1 antibodies often complain of pain, and in vitro and in vivo studies support their pathogenicity. Other antibodies have been associated with SFN, including those against TS-HDS, FGFR3, and Plexin-D1, and new potential targets have been proposed. Finally, a few studies reported the onset of SFN after COVID-19 infection and vaccination, investigating the presence of potential antibody targets. Despite these overall findings, the pathogenic role has been demonstrated only for some autoantibodies, and the association with specific clinical phenotypes or response to immunotherapy remains to be clarified. The purpose of this review is to summarise known autoantibody targets involved in neuropathic pain, putative attractive autoantibody targets in iSFN patients, their potential as biomarkers of response to immunotherapy and their role in the development of iSFN.

Paraneoplastic neurologic syndrome (PNS) diagnostic criteria were first proposed in 2004 and updated in 2021. The PNS-CARE score, derived from the updated criteria, is a composite model for assigning likelihood for patients with suspected PNS. In this study, we evaluated the utility and applicability of the 2021 PNS-CARE score and present our PNS cohort.

This is a retrospective study. We identified Mayo Clinic patients suspected to have PNS (1/2005-12/2020) and collected relevant information including demographics, PNS presentation, and clinical outcomes. Inclusion criteria were the following: (1) patients with a syndrome consistent with PNS and (2) patients with sufficient information available in charts. Exclusion criteria were the following: (1) evaluation only before 2005, (2) patients not evaluated by neurology, (3) presentation after immune checkpoint inhibitors, and (4) syndromes not included in 2021 criteria. All patients were evaluated for the 2021 and 2004 PNS criteria.

We identified 484 patients suspected to have PNS at initial presentation, of whom 212 (44%) were considered to have PNS after completion of evaluation. Among these 212 patients, the most common autoantibodies were PCA1 (Yo)-IgG (17%), KLHL11-IgG (16%), and CRMP5-IgG (14%) and the most common phenotypes were rapidly progressive cerebellar syndrome (29%), brainstem encephalitis (14%), and limbic encephalitis (8%). The 2021 PNS criteria definite/probable categorization (PNS-CARE score ≥ 6) had a sensitivity and specificity of 93% and 100%, respectively, while the 2004 PNS criteria definite categorization had a sensitivity and specificity of 67% and 99%, respectively. We found 15 patients with a PNS-CARE score ≤5 who likely had PNS on our review. The most common presentation among these patients was KLHL11-IgG brainstem encephalitis (7/15, 47%) with likely burned-out testicular tumor.

Our study validates the PNS-CARE score. A clearer understanding of typical PNS presentation and common underlying malignancies and autoantibodies can aid in earlier and more accurate diagnosis, which is crucial for downstream clinical decisions. Some patients with an intermediate-risk phenotype do not meet probable/definite criteria despite the presence of high-risk antibodies and/or underlying malignancy.

Sleep disturbances are a hallmark feature of various autoimmune neurological diseases (AINDs). However, limited awareness of these sleep manifestations exists among clinicians. We provide a comprehensive overview of assessment methods, characteristic sleep disturbances, the impact of specific antibodies on sleep patterns, and treatment strategies for sleep disturbances in AINDs.

Research advancements in sleep disturbances in autoimmune neurological disease focus primarily on four areas: mechanisms, clinical characteristics, assessment, and treatment. Regarding mechanisms, animal models for AINDs, particularly those involving specific antibodies like anti-NMDAR, anti-LGI1, and anti-IgLON5, have become more comprehensive. Recent advancements in animal models have led to the establishment of numerous models for AINDs; these models include a wide range of antibodies, including anti-NMDAR, anti-LGI1, and anti-IgLON5. Several studies using these models have revealed common mechanisms underlying sleep disturbances in these diseases. In terms of clinical characteristics, the identification of antibodies associated with recently discovered AINDs has expanded the spectrum of sleep disturbance symptoms observed compared to prior findings. A comprehensive evaluation system for the assessment of sleep disturbances has been established, including questionnaires, polysomnography, functional magnetic resonance imaging, and 18F-FDG PET/CT. Additionally, cardiopulmonary coupling shows promise as a novel assessment tool. Currently, no universally effective treatment exists for sleep disturbances in autoimmune neurological diseases, either through symptomatic treatment or immunosuppressive therapy. Further studies are needed to confirm the efficacy of new therapies and validate the benefits of existing treatments. Sleep disturbances are a hallmark feature of AINDs. Recent advancements have significantly expanded our understanding of their assessment and treatment. However, further studies are needed to address the remaining uncertainties in sleep disturbance management.

Anti-contactin associated protein receptor 2 (CASPR2) encephalitis is a severe autoimmune encephalitis with a variable clinical phenotype including behavioral abnormalities, cognitive decline, epileptic seizures, peripheral nerve hyperexcitability and neuropathic pain. The detailed mechanisms of how CASPR2 autoantibodies lead to synaptic dysfunction and clinical symptoms are largely unknown. Aiming for analyses from the molecular to the clinical level, we isolated antibody-secreting cells from the cerebrospinal fluid of two patients with CASPR2 encephalitis. From these we cloned four anti-CASPR2 human monoclonal autoantibodies (mAbs) with strong binding to brain and peripheral nerves. All were highly hypermutated and mainly of the IgG4 subclass. Mutagenesis studies determined selective binding to the discoidin domain of CASPR2. Surface plasmon resonance revealed affinities with dissociation constants KD in the pico- to nanomolar range. CASPR2 mAbs interrupted the interaction of CASPR2 with its binding partner contactin 2 in vitro and were internalized after binding to CASPR2-expressing cells. Electrophysiological recordings of rat hippocampal slices after stereotactic injection of CASPR2 mAbs showed characteristic afterpotentials following electrical stimulation. In vivo experiments with intracerebroventricular administration of human CASPR2 mAbs into mice and rats showed EEG-recorded brain hyperexcitability but no spontaneous recurrent seizures. Behavioral assessment of infused mice showed a subtle clinical phenotype, mainly affecting sociability. Mouse brain MRI exhibited markedly reduced resting-state functional connectivity without short-term structural changes. Together, the experimental data support the direct pathogenicity of CASPR2 autoantibodies. The minimally invasive EEG and MRI techniques applied here may serve as novel objective, quantifiable tools for improved animal models, in particular for subtle neuropsychiatric phenotypes or repeated measurements.

Autoimmune encephalitis encompasses a spectrum of conditions characterized by distinct clinical features and magnetic resonance imaging (MRI) findings. Here, we review the literature on acute MRI changes in the most common autoimmune encephalitis variants. In N-methyl-D-aspartate (NMDA) receptor encephalitis, most patients have a normal MRI in the acute stage. When lesions are present in the acute stage, they are typically subtle and non-specific white matter lesions that do not correspond with the clinical syndrome. In some NMDA receptor encephalitis cases, these T2-hyperintense lesions may be indicative of an NMDA receptor encephalitis overlap syndrome with simultaneous co-existence of multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD) or myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). Encephalitis with leucine-rich glioma-inactivated 1 (LGI1)-, contactin-associated protein-like 2 (CASPR2)- or glutamic acid decarboxylase (GAD)- antibodies typically presents as limbic encephalitis (LE) with unilateral or bilateral T2/fluid attenuated inversion recovery (FLAIR) hyperintensities in the medial temporal lobe that can progress to hippocampal atrophy. Gamma aminobutyric acid-B (GABA-B) receptor encephalitis also often shows such medial temporal hyperintensities but may additionally involve cerebellar lesions and atrophy. Gamma aminobutyric acid-A (GABA-A) receptor encephalitis features multifocal, confluent lesions in cortical and subcortical areas, sometimes leading to generalized atrophy. MRI is unremarkable in most patients with immunoglobulin-like cell adhesion molecule 5 (IgLON5)-disease, while individual case reports identified T2/FLAIR hyperintense lesions, diffusion restriction and atrophy in the brainstem, hippocampus and cerebellum. These findings highlight the need for MRI studies in patients with suspected autoimmune encephalitis to capture disease-specific changes and to exclude alternative diagnoses. Ideally, MRI investigations should be performed using dedicated autoimmune encephalitis imaging protocols. Longitudinal MRI studies play an important role to evaluate potential relapses and to manage long-term complications. Advanced MRI techniques and current research into imaging biomarkers will help to enhance the diagnostic accuracy of MRI investigations and individual patient outcome prediction. This will eventually enable better treatment decisions with improved clinical outcomes.

CASPR2-associated neurological disorders encompass a wide clinical spectrum broadly divided into overlapping three autoimmune syndromes: CASPR2 limbic encephalitis, Morvan syndrome, and Isaacs syndrome. CASPR2 is a neuronal protein expressed at different sites in the central and peripheral nervous system and has a variety of roles and functions regarding neuronal excitability, synaptic plasticity, and homeostasis of inhibitory networks, most of which are only partially understood. CASPR2 antibodies have various pathogenic effects including internalization of CASPR2, disruption of protein-protein interactions, and, possibly, complement activation. Their pathogenic effect is well demonstrated in the limbic encephalitis phenotype, but the role of pathogenic antibodies in the development of other clinical manifestations is less clear. CASPR2 limbic encephalitis also differ from the other CASPR2-associated disorders in regard to HLA allele and paraneoplastic associations, suggesting it has immunological mechanisms distinct from the other clinical forms. Future studies are needed to better understand how the immunological alterations lead to the different phenotypes associated with CASPR2 antibodies.

The past two decades have seen a considerable paradigm shift in the way autoimmune CNS disorders are considered, diagnosed, and treated; largely due to the discovery of novel autoantibodies directed at neuroglial surface or intracellular targets. This approach has enabled multiple bona fide CNS autoantibody-associated diseases to thoroughly infiltrate the sphere of clinical neurology, facilitating advances in patient outcomes. This review focusses on the fundamental immunological concepts behind CNS autoantibody-associated diseases. First, we briefly review the broad phenotypic profiles of these conditions. Next, we explore concepts around immune checkpoints and the related B cell lineage. Thirdly, the sources of autoantibody production are discussed alongside triggers of tolerance failure, including neoplasms, infections and iatrogenic therapies. Penultimately, the role of T cells and leucocyte trafficking into the CNS are reviewed. Finally, biological insights from responses to targeted immunotherapies in different CNS autoantibody-associated diseases are summarised. The continued and rapid expansion of the CNS autoantibody-associated field holds promise for further improved diagnostic and therapeutic paradigms, ultimately leading to further improvements in patient outcomes.