Leucine-rich Glioma-inactivated 1 Research Articles

Risk of Seizure Recurrence Due to Autoimmune Encephalitis With NMDAR, LGI1, CASPR2, and GABABR Antibodies: Implications for Return to Driving.

Patients with ongoing seizures are usually not allowed to drive. The prognosis for seizure freedom is favorable in patients with autoimmune encephalitis (AIE) with antibodies against NMDA receptor (NMDAR), leucine-rich glioma-inactivated 1 (LGI1), contactin-associated protein-like 2 (CASPR2), and the gamma-aminobutyric-acid B receptor (GABABR). We hypothesized that after a seizure-free period of 3 months, patients with AIE have a seizure recurrence risk of <20% during the subsequent 12 months. This would render them eligible for noncommercial driving according to driving regulations in several countries. This retrospective multicenter cohort study analyzed follow-up data from patients aged 15 years or older with seizures resulting from NMDAR-, LGI1-, CASPR2-, or GABABR-AIE, who had been seizure-free for ≥3 months. We used Kaplan-Meier (KM) estimates for the seizure recurrence risk at 12 months for each antibody group and tested for the effects of potential covariates with regression models. We included 383 patients with NMDAR-, 440 with LGI1-, 114 with CASPR2-, and 44 with GABABR-AIE from 14 international centers. After being seizure-free for 3 months after an initial seizure period, we calculated the probability of remaining seizure-free for another 12 months (KM estimate) as 0.89 (95% confidence interval [CI] 0.85-0.92) for NMDAR, 0.84 (CI 0.80-0.88) for LGI1, 0.82 (CI 0.75-0.90) for CASPR2, and 0.76 (CI 0.62-0.93) for GABABR. Taking a <20% recurrence risk within 12 months as sufficient, patients with NMDAR-AIE and LGI1-AIE could be considered eligible for noncommercial driving after having been seizure-free for 3 months.

Neuronal autoantibodies in the cerebrospinal fluid of 148 patients with schizophrenia and 151 healthy controls

Schizophrenia is a syndrome with multiple etiologies, one of which is the potential for an autoimmune disease of the brain such as N-methyl-d-aspartate receptor (NMDAR) encephalitis, which can induce psychosis resembling schizophrenia. Here, we examined anti-neuronal autoantibodies related to psychosis using both cell- (CBA) and tissue-based assays (TBA) in the cerebrospinal fluid (CSF) of patients with chronic schizophrenia and control participants. First, we screened for the antibodies against leucine-rich glioma-inactivated 1 (LGI1), γ-aminobutyric acid B receptor (GABABR), dipeptidyl aminopeptidase-like protein 6 (DPPX), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR1/R2), and contactin-associated protein-like 2 (CASPR2) in 148 patients with schizophrenia. No antibodies were detected. Next, we performed CBA for NMDAR antibodies in 148 patients with schizophrenia and 151 age- and sex-matched controls. Although we detected relatively weak immunoreactivity for NMDAR in the CSFs of two patients with schizophrenia and three controls, no samples were positive when strict criteria were applied. For TBA in the rat hippocampus and cerebellum, we detected positive signals in the CSFs of 13 patients with schizophrenia and eight controls. Positive samples were analyzed for paraneoplastic syndrome and antinuclear antibodies using immunoblotting. The CSFs of nine patients and six controls were positive for dense fine speckle 70 (DFS70) antibodies. Additionally, antibodies against centromere protein (CENP)-A and CENP-B were detected in patients with schizophrenia. Our results suggest that autoantibodies against NMDAR, LG1, GABABR, DPPX, AMPAR1/R2, and CASPR2 are not associated with the pathogenesis of chronic schizophrenia. Moreover, we emphasize the importance of considering the effect of anti-DFS70 antibodies when analyzing autoantibodies in CSF samples. Conclusively, we obtained no evidence suggesting that the most frequent neuronal autoantibodies in the CSF play a role in the pathogenesis of schizophrenia, even in our sample.

Peripherally-derived LGI1-reactive monoclonal antibodies cause epileptic seizures in vivo.

One striking clinical hallmark in patients with autoantibodies to leucine-rich glioma inactivated 1 (LGI1) is the very frequent focal seizure semiologies, including faciobrachial dystonic seizures (FBDS), in addition to the amnesia. Polyclonal serum IgGs have successfully modelled the cognitive changes in vivo but not seizures. Hence, it remains unclear whether LGI1-autoantibodies are sufficient to cause seizures. We tested this with the molecularly precise monoclonal antibodies directed against LGI1 (LGI1-mAbs), derived from patient circulating B cells. These were directed towards both major domains of LGI1, LRR and EPTP and infused intracerebroventricularly over 7 days into juvenile male Wistar rats using osmotic pumps. Continuous wireless EEG was recorded from a depth electrode placed in hippocampal CA3 plus behavioural tests for memory and hyperexcitability were performed. Following infusion completion (Day 9), post-mortem brain slices were studied for antibody binding and effects on Kv1.1. The LGI1-mAbs bound most strongly in the hippocampal CA3 region and induced a significant reduction in Kv1.1 cluster number in this subfield. By comparison to control-Ab injected rats video-EEG analysis over 9 days revealed convulsive and non-convulsive seizure activity in rats infused with LGI1-mAbs, with a significant number of ictal events. Memory was not impaired in the novel object recognition test. Peripherally-derived human LGI1-mAbs infused into rodent CSF provide strong evidence of direct in vivo epileptogenesis with molecular correlations. These findings fulfill criteria for LGI1-antibodies in seizure causation.

Autoantibodies in epileptic patients indicate the autoimmune epilepsy

Background Epilepsy is a multifaceted neurological condition marked by recurring seizures. Delving into the functions of VGKC (voltage-gated potassium channels), AMPA GluR3 (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor subunit 3), GAD65 (glutamate decarboxylase 65), and LGI1 (leucine-rich glioma-inactivated 1) in epilepsy yields significant perspectives into the fundamental immunological mechanisms of this disorder. Objective The study target was to assess the clinical significance of neural autoantibody biomarkers in patients with epilepsy and determine the types of autoimmune epilepsy. Materials and methods A case–control study that comprised 50 epilepsy patients (33 males and 17 females) and 40 controls (21 males and 19 females), the patients and controls attending Basrah Teaching Hospital between November 2022 and March 2023, Basrah City, Southern Iraq. The control age ranged from 2 to 62 years and patients’ age 2–68 years were considered the control group in this study. The VGKC, AMPA GluR3, GAD65, and LGI1 were measured using the sandwich ELISA technique. Results and conclusion There is no statistically significant difference between the patients and control group for VGKC, GAD65, and LGI1 (P=0.460, P=0.061, and P=0.440, respectively), while there is a statistically significant difference between the patients and the control group for AMPA GluR3 (P=0.012). GAD65 appeared an elevation in epilepsy patients but was not statistically significant. This upregulation may contribute to the hyperexcitability observed in the epileptic brain and potentially play a role in seizure generation and propagation.

Leucine-Rich Glioma-Inactivated 1 (LGI1) Protein Stimulates Proliferation and IL-10 Production in Peripheral Blood Mononuclear Cells of Patients with LGI1 Antibody-Mediated Autoimmune Encephalitis In Vitro.

Limbic encephalitis (LE) due to anti-leucine-rich glioma-inactivated 1 (LGI1) antibodies is an autoimmune disease characterized by distinct clinical features unique to LGI1 LE, such as faciobrachial dystonic seizures. However, it is unclear whether an additional disease-related LGI1 antigen-specific T cell response is involved in the pathogenesis of this disease. To address this question, we studied the effect of recombinant LGI1 on the proliferation and effector-specific cytokine production (IFN-γ, IL-5, IL-10, and IL-17) of peripheral blood mononuclear cells (PBMCs) from patients with LGI1 LE and healthy controls. We observed that recombinant LGI1 stimulated the proliferation of PBMCs from patients with LGI1 LE, but not from healthy controls. Cytokine measurement of cell culture supernatants from PBMCs incubated with recombinant LGI1 revealed a highly significant increase in IL-10 release in PBMCs from patients with LGI1 LE in comparison with healthy controls. These results suggest that LGI1-mediated stimulation of PBMCs from patients with LGI1 LE leads to the establishment of an IL-10-dominated immunosuppressive cytokine milieu, which may inhibit Th1 differentiation and support B cell proliferation, IgG production, and IgG subclass switching.

Leucine-rich Glioma Inactivated 1 (LGI-1) Limbic Encephalitis Presenting with Psychotic Symptoms without Seizures: A Case Report with Five-year Follow-up and Review of Literature

Leucine-rich Glioma Inactivated 1 (LGI-1) Limbic Encephalitis Presenting with Psychotic Symptoms without Seizures: A Case Report with Five-year Follow-up and Review of Literature

Ultrahigh frequencies of peripherally matured LGI1- and CASPR2-reactive B cells characterize the cerebrospinal fluid in autoimmune encephalitis

Intrathecal synthesis of central nervous system (CNS)-reactive autoantibodies is observed across patients with autoimmune encephalitis (AE), who show multiple residual neurobehavioral deficits and relapses despite immunotherapies. We leveraged two common forms of AE, mediated by leucine-rich glioma inactivated-1 (LGI1) and contactin-associated protein-like 2 (CASPR2) antibodies, as human models to comprehensively reconstruct and profile cerebrospinal fluid (CSF) B cell receptor (BCR) characteristics. We hypothesized that the resultant observations would both inform the observed therapeutic gap and determine the contribution of intrathecal maturation to pathogenic B cell lineages. From the CSF of three patients, 381 cognate-paired IgG BCRs were isolated by cell sorting and scRNA-seq, and 166 expressed as monoclonal antibodies (mAbs). Sixty-two percent of mAbs from singleton BCRs reacted with either LGI1 or CASPR2 and, strikingly, this rose to 100% of cells in clonal groups with ≥4 members. These autoantigen-reactivities were more concentrated within antibody-secreting cells (ASCs) versus B cells (P < 0.0001), and both these cell types were more differentiated than LGI1- and CASPR2-unreactive counterparts. Despite greater differentiation, autoantigen-reactive cells had acquired few mutations intrathecally and showed minimal variation in autoantigen affinities within clonal expansions. Also, limited CSF T cell receptor clonality was observed. In contrast, a comparison of germline-encoded BCRs versus the founder intrathecal clone revealed marked gains in both affinity and mutational distances (P = 0.004 and P < 0.0001, respectively). Taken together, in patients with LGI1 and CASPR2 antibody encephalitis, our results identify CSF as a compartment with a remarkably high frequency of clonally expanded autoantigen-reactive ASCs whose BCR maturity appears dominantly acquired outside the CNS.

Antibody induced seizure susceptibility and impaired cognitive performance in a passive transfer rat model of autoimmune encephalitis.

Autoimmune encephalitis (AE) is a distinct neuro-immunological disorder associated with the production of autoantibodies against neuronal proteins responsible for pharmacoresistant seizures, cognitive decline and behavioral problems. To establish the causal link between leucine-rich glioma inactivated 1 (LGI1) antibody and seizures, we developed an in-vivo antibody-mediated AE rat model in which serum antibodies (IgG) obtained from blood samples of leucine-rich glioma inactivated 1 (LGI1) protein antibody (IgG) positive encephalitis patients were passively transferred into non-epileptic Wistar rats. Serum IgG of N-methyl-d-aspartate receptor (NMDAR) antibody positive patients were used as positive control since the pathogenicity of this antibody has been previously shown in animal models. Total IgG obtained from the pooled sera of NMDAR and LGI1-IgG positive patients with epileptic seizures and healthy subjects was applied chronically every other day for 11 days into the cerebral lateral ventricle. Spontaneous seizure development was followed by electroencephalography. Behavioral tests for memory and locomotor activity were applied before and after the antibody infusions. Then, pentylenetetrazol (PTZ) was administered intraperitoneally to evaluate seizure susceptibility. Immunohistochemistry processed for assessment of hippocampal astrocyte proliferation and expression intensity of target NMDAR and LGI1 antigens. No spontaneous activity was observed during the antibody infusions. PTZ-induced seizure stage was significantly higher in the NMDAR-IgG and LGI1-IgG groups compared to control. Besides, memory deficits were observed in the NMDAR and LGI1-IgG groups. We observed enhanced astrocyte proliferation in NMDAR- and LGI1-IgG groups and reduced hippocampal NMDAR expression in NMDAR-IgG group. These findings suggest that neuronal surface auto-antibody administration induces seizure susceptibility and disturbed cognitive performance in the passive transfer rat model of LGI1 AE, which could be a potential in-vivo model for understanding immune-mediated mechanisms underlying epileptogenesis and highlight the potential targets for immune-mediated seizures in AE patients.

Rescue of Normal Excitability in LGI1-Deficient Epileptic Neurons.

Leucine-rich glioma inactivated 1 (LGI1) is a glycoprotein secreted by neurons, the deletion of which leads to autosomal dominant lateral temporal lobe epilepsy. We previously showed that LGI1 deficiency in a mouse model (i.e., knock-out for LGI1 or KO-Lgi1) decreased Kv1.1 channel density at the axon initial segment (AIS) and at presynaptic terminals, thus enhancing both intrinsic excitability and glutamate release. However, it is not known whether normal excitability can be restored in epileptic neurons. Here, we show that the selective expression of LGI1 in KO-Lgi1 neurons from mice of both sexes, using single-cell electroporation, reduces intrinsic excitability and restores both the Kv1.1-mediated D-type current and Kv1.1 channels at the AIS. In addition, we show that the homeostatic-like shortening of the AIS length observed in KO-Lgi1 neurons is prevented in neurons electroporated with the Lgi1 gene. Furthermore, we reveal a spatial gradient of intrinsic excitability that is centered on the electroporated neuron. We conclude that expression of LGI1 restores normal excitability through functional Kv1 channels at the AIS.SIGNIFICANCE STATEMENT The lack of leucine-rich glioma inactivated 1 (LGI1) protein induces severe epileptic seizures that leads to death. Enhanced intrinsic and synaptic excitation in KO-Lgi1 mice is because of the decrease in Kv1.1 channels in CA3 neurons. However, the conditions to restore normal excitability profile in epileptic neurons remain to be defined. We show here that the expression of LGI1 in KO-Lgi1 neurons in single neurons reduces intrinsic excitability, and restores both the Kv1.1-mediated D-type current and Kv1.1 channels at the axon initial segment (AIS). Furthermore, the homeostatic shortening of the AIS length observed in KO-Lgi1 neurons is prevented in neurons in which the Lgi1 gene has been rescued. We conclude that LGI1 constitutes a critical factor to restore normal excitability in epileptic neurons.

Abnormal DNA methylation analysis of leucine-rich glioma-inactivated 1 antibody encephalitis reveals novel methylation-driven genes related to prognostic and clinical features

BackgroundAberrant DNA methylation occurs commonly during pathogenesis of neuroimmunological diseases and is of clinical value in various encephalitis subtypes. However, knowledge of the impact of DNA methylation changes on pathogenesis of leucine-rich glioma-inactivated 1 (LGI1) antibody encephalitis remains limited.MethodsA total of 44 cytokines and 10 immune checkpoint moleculars (ICMs) in the serum of patients with LGI1 encephalitis and healthy donors (HDs) were measured to evaluate the association of them with clinical parameters. Genome-wide DNA methylation profiles were performed in peripheral blood mononuclear cell (PBMC) from LGI1 encephalitis patients and HDs using reduced representation bisulfite sequencing (RRBS) and validated for the methylation status by pyrosequencing. MicroRNA profiles were acquired in serum exosome by small RNA sequencing. Targeted cytokines expression was assessed at the presence or absence of miR-2467-5p in PBMCs and the culture media, and the binding of miR-2467-5p and its targeted genes was validated by luciferase assay.ResultsThere existed significant difference in 22 cytokines/chemokines and 6 ICMs between LGI1 encephalitis patients and HDs. Decreased PDCD1 with increased ICAM1 could predict unfavorable prognosis in one-year follow-up for LGI1 encephalitis patients. Fifteen of cytokines/chemokines and ICMs presented DNA-methylated changes in the promoter and gene body using RRBS in which five were verified as methylation status by pyrosequencing, and the methylation level of CSF3, CCL2, and ICAM1 was conversely associated with their expression in PBMCs. By combining RRBS data with exosome-derived microRNA sequencing, we found that hypomethylated-driven hsa-miR-2467-5p presented elevated expression in serum exosomes and PBMCs in LGI1 encephalitis. Mechanically, miR-2467-5p significantly induced reduced expression of CSF3 and PDCD1 by binding with their 3`UTR while enhanced CCL15 expression, but not significantly correlated with peripheral blood CD19 + B cell proportion of LGI1 encephalitis patients.ConclusionsOur results provided convincing evidence for DNA methylation changes, microRNA profiles in serum exosome for LGI1 encephalitis, and we also identified several novel cytokines related to clinical features in which some represented epigenetic modification of methylated-driven pattern and microRNA modulation. Our study contributed to develop treatment for epigenetic pathogenesis in LGI1 encephalitis.

Anti-CASPR2, Anti-LGI1, and Anti-GAD65 Autoantibodies in Patients with Intractable Epilepsy

Abstract Background Autoimmunity is increasingly being recognized as a cause of intractable epilepsy. The autoimmune epilepsies (AE) are immunologically mediated disorders in which recurrent seizures are a primary and persistent clinical feature. When other etiologies have been excluded, an autoimmune etiology of epilepsy is suggested in the presence of resistance to anti-epileptic drugs (AED). In such patients, immunotherapy may be highly effective, depending on the particular autoimmune epilepsy syndrome present. Objective To investigate the presence of Contactin associated protein like 2 (CASPR2), leucine rich Glioma inactivated1 (LGI1) and Glutamic acid decarboxylase 65 (GAD65) autoantibodies in intractable epilepsy, and their association with clinical and imaging findings. Subjects and Methods Seventeen patients with intractable epilepsy were included. LGI1, CASPR2 and GAD65 autoantibodies testing by indirect immunofluorescence cellbased assay in both serum and cerebrospinal fluid (CSF) were assessed in all patients. Results Both serum and CSF samples of the 17 patients were tested negative for the 3 autoantibodies (Anti CASPR2, Anti LGI1 and Anti GAD 65). Regarding CSF examination, only 5 patients had normal CSF, the other 12 showed some changes; 7 had elevated levels of proteins, 3 showed positive oligoclonal bands and elevated IgG index and 2 patients showed both elevated proteins and cells. Conclusion Some cases of AE are associated with specific autoantibodies to neuronal proteins. Clinicians must make a diagnosis based on a combination of clinical phenotypes, CSF results, and neuroimaging. Meanwhile, patients should be followed-up systematically due to the constant discovery of new neuronal auto antibodies.

Discrimination between leucine-rich glioma-inactivated 1 antibody encephalitis and gamma-aminobutyric acid B receptor antibody encephalitis based on ResNet18.

This study aims to discriminate between leucine-rich glioma-inactivated 1 (LGI1) antibody encephalitis and gamma-aminobutyric acid B (GABAB) receptor antibody encephalitis using a convolutional neural network (CNN) model. A total of 81 patients were recruited for this study. ResNet18, VGG16, and ResNet50 were trained and tested separately using 3828 positron emission tomography image slices that contained the medial temporal lobe (MTL) or basal ganglia (BG). Leave-one-out cross-validation at the patient level was used to evaluate the CNN models. The receiver operating characteristic (ROC) curve and the area under the ROC curve (AUC) were generated to evaluate the CNN models. Based on the prediction results at slice level, a decision strategy was employed to evaluate the CNN models' performance at patient level. The ResNet18 model achieved the best performance at the slice (AUC = 0.86, accuracy = 80.28%) and patient levels (AUC = 0.98, accuracy = 96.30%). Specifically, at the slice level, 73.28% (1445/1972) of image slices with GABAB receptor antibody encephalitis and 87.72% (1628/1856) of image slices with LGI1 antibody encephalitis were accurately detected. At the patient level, 94.12% (16/17) of patients with GABAB receptor antibody encephalitis and 96.88% (62/64) of patients with LGI1 antibody encephalitis were accurately detected. Heatmaps of the image slices extracted using gradient-weighted class activation mapping indicated that the model focused on the MTL and BG for classification. In general, the ResNet18 model is a potential approach for discriminating between LGI1 and GABAB receptor antibody encephalitis. Metabolism in the MTL and BG is important for discriminating between these two encephalitis subtypes.

Imbalance of glutamatergic and GABAergic neurotransmission in audiogenic seizure-susceptible Leucine-rich glioma-inactivated 1 (Lgi1)-mutant rats

Leucine-rich glioma-inactivated 1 (LGI1) was identified as a causative gene of autosomal dominant lateral temporal lobe epilepsy. We previously reported that Lgi1-mutant rats carrying a missense mutation (L385R) showed audiogenic seizure-susceptibility. To explore the pathophysiological mechanisms underlying Lgi1-related epilepsy, we evaluated changes in glutamate and GABA release in Lgi1-mutant rats. Acoustic priming (AP) for audiogenic seizure-susceptibility was performed by applying intense sound stimulation (130 dB, 10 kHz, 5 min) on postnatal day 16. Extracellular glutamate and GABA levels in the hippocampus CA1 region were evaluated at 8 weeks of age, using in vivo microdialysis techniques. Under naïve conditions without AP, glutamate and GABA release evoked by high-K+ depolarization was more prominent in Lgi1-mutant than in wild-type (WT) rats. The AP treatment on day 16 significantly increased basal glutamate levels and depolarization-induced glutamate release both in Lgi1-mutant and WT rats, yielding greater depolarization-induced glutamate release in Lgi1-mutant rats. On the other hand, the AP treatment enhanced depolarization-induced GABA release only in WT rats, and not in Lgi1-mutant rats, illustrating reduced GABAergic neurotransmission in primed Lgi1-mutant rats. The present results suggest that enhanced glutamatergic and reduced GABAergic neurotransmission are involved in the audiogenic seizure-susceptibility associated with Lgi1-mutation.

MORVAN'S SYNDROME : A RARE CASE REPORT

Morvan's syndrome is an autoimmune disorder characterized by central, autonomic, and peripheral hyperactivity with associated thymoma in majority. The clinical features include insomnia, hyperhidrosis, myokymia, dysautonomia and hallucinations. Voltage gated potassium channel (VGKC) namely, leucine-rich glioma inactivated 1 (LGI-1) antibody and contactin-associated protein-like 2 (CASPR-2) antibody are thought to play a pathogenic role in peripheral and central nervous system symptoms in Morvan's syndrome. Electromyography (EMG) is useful in diagnosis of Morvan's syndrome characterized by spontaneous myober activity with various denervation potentials. Computed tomography (CT) scan and Magnetic resonance imaging (MRI) brain is usually normal. Immunosuppressive therapies, encompassing corticosteroids, azathioprine, methotrexate and recently, rituximab, are the mainstay of therapy. Other treatments include PE, IVIG, and thymectomy. We report a rare case of morvan syndrome with typical clinical features along with leucine-rich glioma inactivated 1 (LGI-1) antibody and contactin-associated proteinlike 2 (CASPR-2) antibody positivity successfully treated with intravenous immunoglobulin (IVIG) therapy.

A Pediatric Case of LGI1 Autoimmune Encephalitis Presenting with Faciobrachial Dystonic Seizures (P5-5.014)

<h3>Objective:</h3> NA <h3>Background:</h3> 15-year-old male presented with acute behavioral changes (agitation, confusion, declining grades), frequent falls, and abnormal movements involving the right corner of the mouth, cheek, arm and hand. His lower face appeared to be pulling to the right with concomitant flexion of the ipsilateral elbow and wrist in a motion that brought his hand close to his face <h3>Design/Methods:</h3> NA <h3>Results:</h3> Continuous EEG demonstrated approximately 70 seizures with either right or left rhythmic delta activity and superimposed spikes with associated twitching or dystonia in the contralateral arm or hand. MRI imaging showed T2 hyperintensity of the left hippocampus and amygdala. His seizures were controlled after loading 3 ASM’s (lacosamide, levetiracetam, valproate) followed by IVIG and methyl prednisolone administration. The diagnosis was confirmed by Mayo autoimmune encephalitis panel that was positive in the CSF and serum for LGI1 (leucine-rich glioma-inactivated 1) antibody. <h3>Conclusions:</h3> LGI1 autoimmune encephalitis is the second most common autoimmune encephalitis after NMDA(N-Methyl-D-aspartate). It is most commonly seen in middle aged men and estimated to occur in 0.83 per million. LGI1 autoimmune encephalitis is associated with multiple seizure types including focal seizures and tonic clonic seizures. The most distinctive feature of LGI1 autoimmune encephalitis is faciobrachial dystonic seizures that have been reported extensively in adult patients. LGI1 autoimmune encephalitis with seizures is exceedingly rare in the pediatric population. We found only 6 reported cases. Our case is the first reported faciobrachial dystonic seizures at presentation in a pediatric patient. <b>Disclosure:</b> Dr. Fields has nothing to disclose. Dr. Dalvi has nothing to disclose. Dr. Duberstein Coad has nothing to disclose. Dr. Eizadkhah has nothing to disclose. Dr. Moshe has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Elsevier/Neurobiology Of Disease. Dr. Moshe has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for MedLink. Dr. Moshe has received publishing royalties from a publication relating to health care. Dr. Moshe has received personal compensation in the range of $500-$4,999 for serving as a Reviewer of study sections with NINDS.

Monitoring Faciobrachial Dystonic Seizures with Wearable Devices (P5-5.015)

<h3>Objective:</h3> This study sought to assess whether faciobrachial dystonic seizures (FBDS) can be reliably identified and differentiated from normal nocturnal arousals using a wrist-worn device. <h3>Background:</h3> Detection of FBDS in patients with Leucine-rich glioma inactivated-1 (LGI1-IgG) associated autoimmune encephalitis is challenging due to high event frequency and lack of a robust EEG correlate. Wearable devices may provide a convenient, noninvasive means to measure these events and provide an objective seizure diary. <h3>Design/Methods:</h3> Two LGI1-IgG seropositive patients (P1 and P2) and four control subjects, wearing Empatica E4 devices, were recruited for this study. Two eight-hour sleep periods of each patient: pre- and post-treatment, were analyzed. An algorithm was developed based on accelerometry (ACC) signals to detect events of interest. After event identification, we calculated the ACC magnitude, duration, and electrodermal activity (EDA) characteristics of detected events. Presently, we are actively expanding the patient cohort and are investigating machine learning methods to improve the accuracy of event detection. <h3>Results:</h3> Statistically significant differences were found in device signals pre- and post-treatment, and between FBDS events in LGI1-IgG and nocturnal arousals in control subjects. The frequency of actigraphy events was higher in both patients (P1: pre-treatment 13.93±3.82 ev/h, post-treatment 9.66±3.37 ev/h; P2: pre-treatment 26.21±13.16 ev/h, post-treatment 29.06±9.79 ev/h), than controls (3.47±2.77 ev/h). For ACC magnitude and event duration, the medians were lower post-treatment and significantly lower for ACC magnitude in P2. Post-treatment, significant differences were only observed between controls and P1. For EDA activity, tonic and phasic components for controls were significantly lower than for patients pre-treatment. Additionally, means and medians decreased post-treatment in both patients. <h3>Conclusions:</h3> Robust characteristics were identified in actigraphy and EDA signals from a wrist-worn device during FBDS events. This evidence suggests an accurate monitor can be developed to automatically detect FBDS, providing objective measurements for treatment guidance and clinical decisions. <b>Disclosure:</b> Dr. Cui has nothing to disclose. Dr. Faust has nothing to disclose. Boney Joseph has nothing to disclose. The institution of Dr. Dubey has received personal compensation in the range of $500-$4,999 for serving as a Consultant for UCB. The institution of Dr. Dubey has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Astellas. The institution of Dr. Dubey has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Argenx. Dr. Dubey has received personal compensation in the range of $0-$499 for serving on a Speakers Bureau for AGRIMS. Dr. Dubey has received personal compensation in the range of $0-$499 for serving on a Speakers Bureau for Advances in Neurology . Dr. Dubey has received personal compensation in the range of $0-$499 for serving on a Speakers Bureau for Moffit Cancer Center . Dr. Dubey has received research support from Department of Defense . Dr. Dubey has received intellectual property interests from a discovery or technology relating to health care. Dr. Dubey has received intellectual property interests from a discovery or technology relating to health care. Dr. Dubey has received intellectual property interests from a discovery or technology relating to health care. Dr. Brinkmann has received personal compensation in the range of $0-$499 for serving as a Consultant for Otsuka Pharmaceuticals. Dr. Brinkmann has stock in Cadence Neuroscience. The institution of Dr. Brinkmann has received research support from Epilepsy Foundation of America. The institution of Dr. Brinkmann has received research support from National Institutes of Health. The institution of Dr. Brinkmann has received research support from National Institutes of Health. The institution of Dr. Brinkmann has received research support from UNEEG A/S. The institution of Dr. Brinkmann has received research support from Seer Medical Pty. Dr. Brinkmann has received intellectual property interests from a discovery or technology relating to health care. Dr. Brinkmann has a non-compensated relationship as a Co-Investigator with Medtronic Inc. that is relevant to AAN interests or activities.

Cognitive Impairment is Associated with Longitudinal Disability in LGI-1-IgG Encephalitis (S22.007)

<h3>Objective:</h3> To determine predictors of longitudinal clinical outcomes in leucine-rich glioma inactivated-1 immunoglobulin G (LGI-1)-IgG autoimmune encephalitis (AE). <h3>Background:</h3> Longitudinal studies prognosticating outcomes in LGI-1-IgG AE are needed to identify key drivers of disability. We examine disability utilizing modified Rankin Scale (mRS) and an AE specific scale, the clinical assessment scale in AE (CASE). <h3>Design/Methods:</h3> A retrospective observational study of seropositive LGI-1-IgG AE patients was conducted between 2013–2022. Clinical predictors included demographics, clinical and paraclinical data, magnetic resonance imaging (MRI), and Montreal Cognitive Assessment (MoCA). Clinical outcomes included mRS and CASE scores. Logistic and linear regressions were used for modeling mRS and CASE, respectively. Baseline clinical characteristics were included as independent variables in the regression models. <h3>Results:</h3> Thirty patients (60% male, median age=69.5; IQR=63.0–76.0) were included, with a median follow-up time of 8.7 months (IQR=4.3–24.1). Seizures (29, [96.7%]), and cognitive impairment (CI) (30, [100%]) were present in the majority. Median initial MoCA was 23/30 (IQR=21.0–25.0). The majority received acute immunotherapy (27, [90%]), and maintenance immunotherapy, (26 [86.7%]). Baseline mRS (median=2.0, IQR=2.0–3.0) and CASE (mean=4.3, SD=3.7) correlated with each other (<i>r</i>=0.58, <i>P</i>&lt;.001) and with initial MoCA score (mRS <i>r</i>=−0.60, <i>P</i>=.009, CASE <i>r</i>=−0.51, <i>P</i>=.031). After 12 months from symptom onset, mRS (OR=0.88, [CI=0.82–0.94], <i>P</i>&lt;.001) and CASE (β=−0.03, [SE=0.01], <i>P</i>&lt;.001) decreased significantly. Temporal lobe(s) Fluid Attenuation Inversion Recovery (FLAIR) hyperintensity correlated with higher mRS longitudinally (OR=17.49, [CI=2.37, 129.05], <i>P</i>=.005). Higher initial MOCA was associated with lower mRS (OR=0.66, [CI=0.45–0.98], <i>P</i>=.04) and CASE (β=−0.24, [SE=0.13], <i>P</i>=.061) longitudinally. At last follow-up, most patients had ongoing cognitive symptoms (25, [83.3%]), while few had ongoing seizure activity (3, [10%]). <h3>Conclusions:</h3> CI is associated with disability at baseline and long-term follow up, underscoring cognition as an important determinant of disability outcomes in LGI-1-IgG AE. Severity of CI on baseline MoCA may offer prognostic information on long-term disability. <b>Disclosure:</b> Dr. Aboseif has a non-compensated relationship as a AAN Autoimmune Neurology Section -- Education Workgroup with AAN that is relevant to AAN interests or activities. Ms. Li has nothing to disclose. Dr. Amin has nothing to disclose. Brittany Lapin has received personal compensation for serving as an employee of Cleveland Clinic. Brittany Lapin has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Quality of Life Research. Brittany Lapin has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Anesthesia and Analgeisa. Dr. Abbatemarco has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for EMD Serono. Dr. Abbatemarco has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Horizon. Dr. Abbatemarco has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Genentech . The institution of Dr. Abbatemarco has received research support from Horizon. Dr. Rae-Grant has received publishing royalties from a publication relating to health care. Dr. Rae-Grant has received publishing royalties from a publication relating to health care. Dr. Punia has nothing to disclose. Rachel Galioto has nothing to disclose. Dr. Kunchok has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Genentech. Dr. Kunchok has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Horizon therapeutics . Dr. Kunchok has received personal compensation in the range of $10,000-$49,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Neurology.

A feline model of spontaneously occurring autoimmune limbic encephalitis

Autoimmune encephalitis (AE) is an important cause of encephalitis in humans and occurs at a similar rate to infectious encephalitis. It is frequently associated with antibodies against the extracellular domain of neuronal proteins. Among human AE, that with antibodies against leucine-rich glioma-inactivated 1 (LGI1) is one of the most prevalent forms, and was recently described in cats with limbic encephalitis (LE). In this study, we describe a large cohort (n = 32) of cats with AE, tested positive for voltage gated potassium channel (VGKC)-antibodies, of which 26 (81%) harboured LGI1-antibodies. We delineate their clinical and paraclinical features as well as long-term outcomes up to 5 years.Similar to human cases, most cats with LGI1-antibodies had a history of focal seizures (83%), clustering in the majority (88%), with interictal behavioural changes (73%). Among feline AE patients, there was no seizure type or other clinical characteristic that could distinguish LGI1-antibody positive from negative cats, unlike the pathognomic faciobrachial dystonic seizures seen in humans. Although six cats were euthanased in the first year for epilepsy-associated reasons, those attaining at least 1-year survival had good seizure control and quality of life with appropriate veterinary care and medication. Acute-phase immunotherapy (prednisolone) was given to the most severely unwell cases and its effect is retrospectively evaluated in 10 cats. Our data show LGI1-antibodies are an important cause of feline encephalitis, sharing many features with human AE. Further research should examine optimal therapeutic management strategies and the cause of LE in seronegative cats, building on paradigms established in the counterpart human disease.

In Vivo Injection of Anti-LGI1 Antibodies into the Rodent M1 Cortex and Hippocampus Is Ineffective in Inducing Seizures.

Autoimmune encephalitis (AIE) associated with antibodies directed against the leucine-rich glioma inactivated 1 (LGI1) protein is the second most common AIE and is responsible for deleterious neocortical and limbic epileptic seizures. Previous studies demonstrated a pathogenic role of anti-LGI1 antibodies via alterations in the expression and function of Kv1 channels and AMPA receptors. However, the causal link between antibodies and epileptic seizures has never been demonstrated. Here, we attempted to determine the role of human anti-LGI1 autoantibodies in the genesis of seizures by analyzing the impact of their intracerebral injection in rodents. Acute and chronic injections were performed in rats and mice in the hippocampus and primary motor cortex, the two main brain regions affected by the disease. Acute infusion of CSF or serum IgG of anti-LGI1 AIE patients did not lead to the emergence of epileptic activities, as assessed by multisite electrophysiological recordings over a 10 h period after injection. A chronic 14 d injection, coupled with continuous video-EEG monitoring, was not more effective. Overall, these results demonstrate that acute and chronic injections of CSF or purified IgG from LGI1 patients are not able to generate epileptic activity by themselves in the different animal models tested.

A patient-derived mutation of epilepsy-linked LGI1 increases seizure susceptibility through regulating Kv1.1

BackgroundAutosomal dominant lateral temporal epilepsy (ADLTE) is an inherited syndrome caused by mutations in the leucine-rich glioma inactivated 1 (LGI1) gene. It is known that functional LGI1 is secreted by excitatory neurons, GABAergic interneurons, and astrocytes, and regulates AMPA-type glutamate receptor-mediated synaptic transmission by binding ADAM22 and ADAM23. However, > 40 LGI1 mutations have been reported in familial ADLTE patients, more than half of which are secretion-defective. How these secretion-defective LGI1 mutations lead to epilepsy is unknown.ResultsWe identified a novel secretion-defective LGI1 mutation from a Chinese ADLTE family, LGI1-W183R. We specifically expressed mutant LGI1W183R in excitatory neurons lacking natural LGI1, and found that this mutation downregulated Kv1.1 activity, led to neuronal hyperexcitability and irregular spiking, and increased epilepsy susceptibility in mice. Further analysis revealed that restoring Kv1.1 in excitatory neurons rescued the defect of spiking capacity, improved epilepsy susceptibility, and prolonged the life-span of mice.ConclusionsThese results describe a role of secretion-defective LGI1 in maintaining neuronal excitability and reveal a new mechanism in the pathology of LGI1 mutation-related epilepsy.