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Progressive inflammation of one hemisphere characterises Rasmussen's encephalitis (RE), but contralesional epileptiform activity has been repeatedly reported. We aimed to quantify contralesional epileptiform activity in RE and uncover its functional and structural underpinnings. We retrospectively ascertained people with RE treated between 2000 and 2018 at a tertiary centre (Centre 1) and reviewed all available EEG datasets. The temporal occurrence of preoperative contralesional epileptiform activity (interictal/ictal) was evaluated using mixed-effects logistic regression. Cases with/without contralesional epileptiform activity were compared for cognition, inflammation (ipsilesional brain biopsies), and MRI (cortical and fixel-based morphometry). EEG findings were validated in a second cohort treated at another tertiary centre (Centre 2) between 1995 and 2020. We included 127 people with RE and 687 EEG samples. Preoperatively, contralesional epileptiform activity was seen in 30/68 (44%, Centre 1) and 8/59 (14%, Centre 2). In both cohorts, this activity was associated with younger onset age (OR = 0.9; 95% CI 0.83-0.97; P = 0.006). At centre 1, contralesional epileptiform activity was associated with contralesional MRI alterations, lower intelligence (OR = 5.19; 95% CI 1.28-21.08; P = 0.021), and impaired verbal memory (OR = 10.29; 95% CI 1.97-53.85; P = 0.006). After hemispherotomy, 11/17 (65%, Centre 1) and 28/37 (76%, Centre 2) were seizure-free. Contralesional epileptiform activity was persistent postoperatively in 6/12 (50%, Centre 1) and 2/34 (6%, Centre 2). Preoperative contralesional epileptiform activity reduced the chance of postoperative seizure freedom in both cohorts (OR = 0.69; 95% CI 0.50-0.95; P = 0.029). Our findings question the concept of strict unilaterality of RE and provide the evidence of contralesional epileptiform activity as a possible EEG predictor for persisting postoperative seizures., (© 2024. The Author(s).)

Background and Objectives: 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 (GABA B R). 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., Methods: This retrospective multicenter cohort study analyzed follow-up data from patients aged 15 years or older with seizures resulting from NMDAR-, LGI1-, CASPR2-, or GABA B R-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., Results: We included 383 patients with NMDAR-, 440 with LGI1-, 114 with CASPR2-, and 44 with GABA B R-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 GABA B R., Discussion: 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.

Temporal lobe epilepsy (TLE) is one of the syndromes linked to antibodies against glutamic acid decarboxylase (GAD). It has been questioned whether 'limbic encephalitis with GAD antibodies' is a meaningful diagnostic entity. The immunopathogenesis of GAD-TLE has remained enigmatic. Improvement of immunological treatability is an urgent clinical concern. We retrospectively assessed the clinical, MRI and CSF course as well as brain tissue of 15 adult patients with GAD-TLE who underwent temporal lobe surgery. Brain tissue was studied by means of immunohistochemistry, multiplex fluorescent microscopy and transcriptomic analysis for inflammatory mediators and neuronal degeneration. In 10 patients, there was a period of mediotemporal swelling and T2 signal increase; in nine cases this occurred within the first 6 years after symptom onset. This resulted in unilateral or bilateral hippocampal sclerosis; three cases developed hippocampal sclerosis within the first 2 years. All CSF studies done within the first year (n = 6) revealed intrathecal synthesis of immunoglobulin G. Temporal lobe surgeries were done after a median disease duration of 9 years (range 3 weeks to 60 years). Only two patients became seizure-free. Brain parenchyma collected during surgery in the first 6 years revealed high numbers of plasma cells but no signs of antibody-mediated tissue damage. Even more dense was the infiltration by CD8+ cytotoxic T lymphocytes (CTLs) that were seen to locally proliferate. Further, a portion of these cells revealed an antigen-specific resident memory T cell phenotype. Finally, CTLs with cytotoxic granzyme B+ granules were also seen in microglial nodules and attached to neurons, suggesting a CTL-mediated destruction of these cells. With longer disease duration, the density of all lymphocytes decreased. Whole transcriptome analysis in early/active cases (but not in late/inactive stages) revealed 'T cell immunity' and 'Regulation of immune processes' as the largest overrepresented clusters. To a lesser extent, pathways associated with B cells and neuronal degeneration also showed increased representation. Surgically treated patients with GAD-TLE go through an early active inflammatory, 'encephalitic' stage (≤6 years) with CTL-mediated, antigen-driven neuronal loss and antibody-producing plasma cells but without signs of complement-mediated cell death. Subsequently, patients enter an apparently immunologically inactive or low-active stage with ongoing seizures, probably caused by the structural damage to the temporal lobe. 'Limbic encephalitis' with GAD antibodies should be subsumed under GAD-TLE. The early tissue damage explains why immunotherapy does not usually lead to freedom from seizures., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background and Objectives: To assess seizure characteristics in antibody (ab)-associated autoimmune encephalitis (ab + AE) with the 3 most prevalent abs against N-methyl-d-aspartate receptor (NMDAR), leucine-rich glioma-inactivated protein 1 (LGI1), and glutamic acid decarboxylase (GAD)., Methods: Multicenter nationwide prospective cohort study of the German Network for Research in Autoimmune Encephalitis., Results: Three hundred twenty patients with ab + AE were eligible for analysis: 190 NMDAR+, 89 LGI1+, and 41 GAD+. Seizures were present in 113 (60%) NMDAR+, 69 (78%) LGI1+, and 26 (65%) GAD+ patients and as leading symptoms for diagnosis in 53 (28%) NMDAR+, 47 (53%) LGI+, and 20 (49%) GAD+ patients. Bilateral tonic-clonic seizures occurred with almost equal frequency in NMDAR+ (38/51, 75%) and GAD+ (14/20, 70%) patients, while being less common in LGI1+ patients (27/59, 46%). Focal seizures occurred less frequently in NMDAR+ (67/113; 59%) than in LGI1+ (54/69, 78%) or in GAD+ patients (23/26; 88%). An aura with déjà-vu phenomenon was nearly specific in GAD+ patients (16/20, 80%). Faciobrachial dystonic seizures (FBDS) were uniquely observed in LGI1+ patients (17/59, 29%). Status epilepticus was reported in one-third of NMDAR+ patients, but only rarely in the 2 other groups. The occurrence of seizures was associated with higher disease severity only in NMDAR+ patients., Discussion: Seizures are a frequent and diagnostically relevant symptom of ab + AE. Whereas NMDAR+ patients had few localizing semiological features, semiology in LGI1+ and GAD+ patients pointed toward a predominant temporal seizure onset. FBDS are pathognomonic for LGI1 + AE. Status epilepticus seems to be more frequent in NMDAR + AE., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Patients with anti-leucine-rich glioma-inactivated 1 protein (LGI1) or anti-contactin-associated protein 2 (CASPR2) antibody encephalitis typically present with frequent epileptic seizures. The seizures generally respond well to immunosuppressive therapy, and the long-term seizure outcome seems to be favorable. Consequentially, diagnosing acute symptomatic seizures secondary to autoimmune encephalitis instead of autoimmune epilepsy was proposed. However, published data on long-term seizure outcomes in CASPR2 and LGI1 antibody encephalitis are mostly based on patient reports, and seizure underreporting is a recognized issue. Clinical records from our tertiary epilepsy center were screened retrospectively for patients with LGI1 and CASPR2 antibody encephalitis who reported seizure freedom for at least 3 months and received video-electroencephalography (EEG) for >24 h at follow-up visits. Twenty (LGI1, n = 15; CASPR2, n = 5) of 32 patients with LGI1 (n = 24) and CASPR2 (n = 8) antibody encephalitis fulfilled these criteria. We recorded focal aware and impaired awareness seizures in four of these patients (20%) with reported seizure-free intervals ranging from 3 to 27 months. Our results question the favorable seizure outcome in patients with CASPR2 and LGI1 antibody encephalitis and suggest that the proportion of patients who have persistent seizures may be greater. Our findings underline the importance of prolonged video-EEG telemetry in this population., (© 2022 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Background and Objective: Rasmussen encephalitis (RE) is characterized by its unilateral cerebral involvement. However, both ipsi- and contralesional cerebellar atrophy have been anecdotally reported raising questions about the nature and extent of infratentorial findings. Using MRI, we morphometrically investigated the cerebellum and hypothesized abnormalities beyond the effects of secondary atrophy, implicating a primary involvement of the cerebellum by RE., Methods: Voxel-based morphometry of the cerebellum and brainstem was conducted in 57 patients with RE and in 57 matched controls. Furthermore, patient-specific asymmetry indices (AIs) of cerebellar morphometry and fluid-attenuated inversion recovery (FLAIR) intensity were calculated. Using diffusion tensor imaging, the integrity of the cortico-ponto-cerebellar (CPC) tract was assessed. Finally, a spatial independent component analysis (ICA) was used to compare atrophy patterns between groups., Results: Patients with RE showed bilateral cerebellar and predominantly ipsilesional mesencephalic atrophy ( p < 0.01). Morphometric AIs revealed ipsilesional < contralesional asymmetry in 27 and ipsilesional > contralesional asymmetry in 30 patients. In patients with predominant ipsilesional atrophy, morphometric AIs strongly correlated with FLAIR intensity AIs ( r = 0.86, p < 0.0001). Fractional anisotropy was lower for ipsilesional-to-contralesional CPC tracts than opposite tracts ( T = 2.30, p < 0.05). ICA revealed bilateral and strictly ipsi- and contralesional atrophy components in patients with RE ( p < 0.05)., Discussion: We demonstrated atrophy of the ipsilesional-to-contralesional CPC pathway and, consequently, interpret the loss of contralesional gray matter as secondary crossed cerebellar atrophy. The ipsilesional cerebellar atrophy, however, defies this explanation. Based on FLAIR hyperintensities, we interpret ipsilesional atrophy to be due to inflammation in the scope of a primary involvement of the cerebellum by RE., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Objective: Clinical care of rare and complex epilepsies is challenging, because evidence-based treatment guidelines are scarce, the experience of many physicians is limited, and interdisciplinary treatment of comorbidities is required. The pathomechanisms of rare epilepsies are, however, increasingly understood, which potentially fosters novel targeted therapies. The objectives of our survey were to obtain an overview of the clinical practice in European tertiary epilepsy centers treating patients with 5 arbitrarily selected rare epilepsies and to get an estimate of potentially available patients for future studies., Methods: Members of the European Reference Network for rare and complex epilepsies ( EpiCARE) were invited to participate in a web-based survey on clinical practice of patients with Dravet syndrome, tuberous sclerosis complex (TSC), autoimmune encephalitis, and progressive myoclonic epilepsies including Unverricht Lundborg and Unverricht-like diseases. A consensus-based questionnaire was generated for each disease., Results: Twenty-six of 30 invited epilepsy centers participated. Cohorts were present in most responding centers for TSC (87%), Dravet syndrome (85%), and autoimmune encephalitis (71%). Patients with TSC and Dravet syndrome represented the largest cohorts in these centers. The antiseizure drug treatments were rather consistent across the centers especially with regard to Dravet syndrome, infantile spasms in TSC, and Unverricht Lundborg / Unverricht-like disease. Available, widely used targeted therapies included everolimus in TSC and immunosuppressive therapies in autoimmune encephalitis. Screening for comorbidities was routinely done, but specific treatment protocols were lacking in most centers., Significance: The survey summarizes the current clinical practice for selected rare epilepsies in tertiary European epilepsy centers and demonstrates consistency as well as heterogeneity in the treatment, underscoring the need for controlled trials and recommendations. The survey also provides estimates for potential participants of clinical trials recruited via EpiCARE, emphasizing the great potential of Reference Networks for future studies to evaluate new targeted therapies and to identify novel biomarkers., Competing Interests: Sameer M Zuberi has conducted randomized controlled trials for GW Pharma and Zogenix Ltd in patients with Dravet syndrome. He has participated in advisory boards for Zogenix, GW Pharma, Biocodex, and Encoded Genomics. Katarzyna Kotulska was supported by the 7th Framework Programme of European Commission within the Large‐scale Integrating Project EPISTOP (Proposal No: 602 391‐2; Proposal title: “Long term, prospective study evaluating clinical and molecular biomarkers of epileptogenesis in a genetic model of epilepsy – tuberous sclerosis complex”; www.EPISTOP.eu) and the Polish Ministerial funds for science (years 2014‐2018) for the implementation of international co‐financed project and the grant EPIMARKER of the Polish National Center for Research and Development No STRATEGMED3/306306/4/2016. All other authors have no conflict of interest related to this survey to disclose. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines., (© 2020 The Authors. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Objective: Assess occurrence of the dendritic spine scaffolding protein Drebrin as a pathophysiologically relevant autoantibody target in patients with recurrent seizures and suspected encephalitis as leading symptoms., Methods: Sera of 4 patients with adult onset epilepsy and suspected encephalitis of unresolved etiology and equivalent results in autoantibody screening were subjected to epitope identification. We combined a wide array of approaches, ranging from immunoblotting, immunoprecipitation, mass spectrometry, subcellular binding pattern analyses in primary neuronal cultures, and immunohistochemistry in brains of wild-type and Drebrin knockout mice to in vitro analyses of impaired synapse formation, morphology, and aberrant neuronal excitability by antibody exposure., Results: In the serum of a patient with adult onset epilepsy and suspected encephalitis, a strong signal at ∼70kDa was detected by immunoblotting, for which mass spectrometry revealed Drebrin as the putative antigen. Three other patients whose sera also showed strong immunoreactivity around 70kDa on Western blotting were also anti-Drebrin-positive. Seizures, memory impairment, and increased protein content in cerebrospinal fluid occurred in anti-Drebrin-seropositive patients. Alterations in cerebral magnetic resonance imaging comprised amygdalohippocampal T2-signal increase and hippocampal sclerosis. Diagnostic biopsy revealed T-lymphocytic encephalitis in an anti-Drebrin-seropositive patient. Exposure of primary hippocampal neurons to anti-Drebrin autoantibodies resulted in aberrant synapse composition and Drebrin distribution as well as increased spike rates and the emergence of burst discharges reflecting network hyperexcitability., Interpretation: Anti-Drebrin autoantibodies define a chronic syndrome of recurrent seizures and neuropsychiatric impairment as well as inflammation of limbic and occasionally cortical structures. Immunosuppressant therapies should be considered in this disorder. ANN NEUROL 2020;87:869-884., (© 2020 The Authors. Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association.)

In limbic encephalitis (LE) with antibodies (Abs) to the voltage-gated potassium channel complex (VGKC), the Abs are mainly directed to the VGKC-complex proteins, leucine-rich, glioma inactivated 1 protein (LGI1) or contactin-associated protein-like 2 (CASPR-2) or neither. Here, we relate the outcomes of VGKC-LE patients to the presence of Abs to LGI1, CASPR-2 or neither antigen (LGI1/CASPR-2-Ab). Clinical, neuropsychology and MRI data were obtained from patient records for all LE patients from the Bonn Epilepsy Centre positive for VGKC-Abs by radioimmunoprecipitation assay between 2002 and 2011. Eighteen VGKC-LE patients were identified: nine patients (50 %) had LGI1-Abs, three (16 %) had CASPR-2-Abs; and six (33 %) were negative for both LGI1- and CASPR-2-Abs. At first assessment, the groups did not differ clinically or radiologically, but faciobrachial dystonic seizures were only observed in two LGI1-Ab patients. All patients received monthly intravenous methylprednisolone (MP) pulses. At the most recent follow up (median 26 months), thirteen (72 %) were seizure-free, and seizure-freedom rates did not differ between the Ab groups. Hippocampal atrophy had developed in 7/9 LGI1-Ab patients, but in none of the CASPR-2-Ab or LGI/CASPR-2-Ab patients ( p = 0.003). While all subgroups improved, memory scores only normalized in six patients (33 %) and LGI1-Ab patients were left with significantly poorer memory than the other two subgroups. Most VGKC-LE patients become seizure-free with pulsed monthly MP, but memory outcome is less favourable. Hippocampal atrophy and poor memory recovery is common in patients with LGI1-Abs and suggests permanent functional damage. More intense immunotherapies could improve outcomes in LGI1-Ab-LE. [ABSTRACT FROM AUTHOR]