Introduction Headache disorders are common in patients with epilepsy and functional/dissociative seizures (FDS) and may influence quality of life and clinical outcomes. Migraine has been proposed as a reciprocal risk factor for epileptic and functional seizures. We aimed to determine the prevalence of headache disorders and associated clinical factors in a cohort of patients undergoing video-EEG monitoring at a tertiary epilepsy center.Methods In this retrospective cross-sectional study, clinical data from 164 adult inpatients evaluated in an epilepsy monitoring unit were analyzed. Headache diagnoses were established using a structured interview based on International Classification of Headache Disorders (ICHD-3) criteria. Associations between headache disorders and clinical variables - including epilepsy subtype, seizure localization, antiseizure medication (ASM), and pre-existing illnesses - were assessed using Fisher's exact tests and logistic regression analyses.Results Seventy percent of patients were diagnosed with epilepsy and 13% with FDS. Among epilepsy patients, 48% reported headache (21% migraine, 18% tension-type headache), whereas 77% of patients with FDS reported headache (50% migraine, 14% tension-type headache). Epilepsy overall, particularly lesional focal epilepsy, was negatively associated with headache and migraine compared with no-epilepsy patients. In contrast, FDS was positively associated with headache and migraine. Migraine with aura was not disproportionately represented in epilepsy or FDS. Female sex and younger age were associated with headache. Levetiracetam and valproic acid use were negatively associated with migraine. Frontal seizure onset was negatively associated with migraine, whereas temporal onset showed a non-significant positive trend. Obesity was positively associated with migraine with aura, while depression showed a negative association with migraine.Discussion Headache disorders are frequent in patients undergoing evaluation for paroxysmal neurological disorders, particularly in FDS. Systematic headache screening-especially in young and female patients-may help reduce disease burden. Further studies should clarify shared mechanisms and potential therapeutic implications.

This case study demonstrates the value of combined 7 T structural and functional MRI in the presurgical workup of a 24-year-old male with drug-resistant focal epilepsy who was initially considered MRI-negative on clinical 3 T MRI. The patient underwent extensive presurgical workup with 7 T MRI, magnetoencephalography, stereo-electroencephalography, and resection of the suspected right frontal epileptogenic zone. Histopathology showed focal cortical dysplasia (FCD) type IIb. The patient remained 11 months after surgery seizure-free. Retrospective analysis revealed that both structural and functional 7 T MRI showed abnormalities within the resected area. Morphometric Analysis Program (MAP18) detected abnormalities on both 3 T and 7 T images. However, abnormalities were more conspicuous on 7 T. Resting-state functional MRI metrics, particularly regional homogeneity and fractional amplitude of low-frequency fluctuations, demonstrated significantly increased values in both a MAP18-defined region of interest and the entire resected area compared to a healthy control group (p < 0.05). However, extensive unspecific abnormalities were also observed outside the resected region, highlighting the importance of a multimodal approach. This case study illustrates that advanced image processing of ultra-high field structural and resting-state functional MRI scans may enhance the detection of subtle epileptogenic lesions in presurgical evaluation, potentially improving post-operative seizure outcome and associated quality of life.

OBJECTIVE:Resective epilepsy surgery is an evidence-based treatment option for patients with focal drug-resistant epilepsy (DRE). Seizure outcome after surgery is largely dependent on detection and delineation of an epileptogenic lesion on magnetic resonance imaging (MRI). However, detection fails in 30% of patients at 3 Tesla (T) MRI, thereby limiting surgical options. Diagnostic and therapeutic gain of ultra-high-field MRI in patients with 3T MRI-negative DRE is evaluated in the EpiUltraStudy. Here we report the diagnostic gain of structural 7T MRI. METHODS:Inclusion criteria were age ≥12 years and DRE with a suspected epileptogenic focus and negative conventional 3T MRI during pre-surgical workup. Images were evaluated independently by two neuroradiologists and a neurologist or neurosurgeon in two runs: blinded (Run 1) and with the results of additional clinical investigations (Run 2). RESULTS:Sixty patients underwent 7T MRI. No persistent adverse events were reported. Visual assessment of 7T MRI identified lesions in 9 cases (15%), undetected on prior 3T MRI. Possible positive scan rates increased from 17% (10/60) in the blinded run to 47% (28/60) in the informed run. However, after consensus review, many of these were reclassified as negative. Eight of nine positive 7T MRI scans were initially identified by only one or two assessors. After reassessment, a total of 56% (5/9) of 7T lesions were retrospectively identified on 3T. SIGNIFICANCE:Our data suggest a benefit of 7T MRI for the detection of subtle epileptogenic lesions in patients with DRE and negative 3T MRI. Although the detection rate may appear modest compared to other reports, we present a nuanced discussion of our methodology and patient population, contributing meaningful context to the current literature. The availability of multimodal information and consensus reviews enhanced diagnostic accuracy but with higher rates of false positives, underscoring the importance of multidisciplinary cooperation in the clinical care for patients with DRE. TRIAL REGISTRATION NUMBER:www.trialregister.nl: NTR7536.

The encounter of disorders associated with antibodies to neuronal enzymes caused a paradigm shift in understanding the CNS autoimmunity.The autoimmune disorders targeting the 65kDa isoform of glutamic acid decarboxylase (GAD65) not only comprehends type 1 diabetes mellitus (T1DM), but also rather rare neurological disorders, including stiff-person syndrome (SPS), cerebellar ataxia, limbic encephalitis, and epilepsy.The patients with these autoimmune neurological disorders usually present with T1DM and suggests the presence of GAD65 antibodies.This is suggestive of autoimmune mechanisms for the development and worsening of these disorders.For better prognosis, its advanced screening and swift treatment are essential.Mesenchymal stem cells (MSCs) can be a promising salvage to these autoimmune disorders as they have proven hypoimmunogenic and immunomodulatory properties along with excellent regenerative ability.These self-renewing progenitor cells can differentiate into numerous cell types under explicit conditions, which includes neurons and pancreatic beta cells.MSCs annul the proinflammatory response in autoimmune disorders, may be through paracrine secretions, and hence, can help managing the hurricane of disturbed immunity.We present a link between the mechanisms driving autoimmune neurological diseases and T1DM in this review, based on the existence of GAD65 antibodies and an MSC-mediated solution for their treatment.

To report the effects of adjunctive cenobamate and concomitant antiseizure medications (ASMs) on weight from two double-blind, placebo-controlled, phase 2 studies (YKP3089C013 [C013] and YKP3089C017 [C017]) and their open-label extensions (OLEs) and from a long-term, open-label phase 3 safety study, YKP3089C021 (C021). Cenobamate is an ASM approved in the US and EU for treatment of focal seizures in adults. Some ASMs are associated with weight gain (e.g., valproate, gabapentin, pregabalin), which can negatively affect patient health. Patients with uncontrolled focal seizures taking stable doses of 1–3 ASMs were enrolled in each study. In C013, cenobamate was titrated to a target dose of 200 mg/day (max OLE dose 400 mg/day). In C017, patients were randomized to cenobamate 100, 200, or 400 mg/day (max OLE dose 400 mg/day). In C021, cenobamate was titrated to a target dose of 200 mg/day (max dose 400 mg/day). Median weight changes at 1 and 2 years from baseline were analyzed post hoc. Analyses included 39, 206, and 1054 patients from C013, C017 (dose groups combined), and C021, respectively. Median weight changes from baseline ranged from −0.2 to −0.9 kg at 1 year and from −1.0 to +1.0 kg at 2 years. Some numerical reductions in weight were noted in patients who discontinued valproate by 1 (−13.0 kg, C013, n=1) or 2 years (−24.5 kg, C017, n=2) and in patients who discontinued gabapentin by 1 (−7.1 kg, C017, n=2) or 2 years (−7.0 kg, C017, n=2). Otherwise, median weight changes from baseline for patients receiving concomitant valproate, gabapentin, or pregabalin ranged from −3.1 to +2.6 kg at 1 year and from −1.6 to +2.7 kg at 2 years. Adjunctive cenobamate was not associated with clinically significant changes in weight from baseline in patients treated for 1 and 2 years, including those receiving concomitant valproate, gabapentin, or pregabalin.

Background: Our goal is to investigate the autoantibodies’ presence and immune cells in the bioprobes of autoimmune encephalitis (AE) patients with distinct phenotypes as a promising target in AE. Methods: We retrospectively analyzed immune cells via flow cytometry, serum and cerebrospinal fluid (CSF) autoantibodies, electroencephalography, magnetic resonance imaging in 94 AE patients with suspected temporal lobe epilepsy and classified neuropsychological phenotypes according to their occurrence. Results: We detected different phenotypes in 94 AE patients [10.6% with isolated memory dysfunction (MEM), 11.7% with mood-dysfunction, 12.7% with mood and memory dysfunction, 13.8% with memory and attention dysfunction, 18.1% with memory, mood and attention disturbances and 20.2% with no mood, memory or attention dysfunction]. We did discern a relevant association of phenotypes and CSF antibody-positivity on CSF CD4+ T-cells, CD8+T-cells and HLADR + CD8+T-cells in our patients with MEM presenting elevated CD8+T-cells and HLADR + CD8+T-cells. Furthermore, CSF CD19+B-cells differed significantly between phenotypes in patients with MEM. Discussion: Taken together, the phenotypes in combination with CSF antibody-positivity are biomarkers for stratifying patients. Furthermore, our results confirm the role of CD4+ T-cells, CD8+T-cells and CD19+B-cells in AE patients with a memory dysfunction, providing insights into AE pathogenesis. Our preliminary results should be confirmed by larger-scale investigations.

Abstract Autoimmune neurological syndromes (AINS) with autoantibodies against the 65 kDa isoform of the glutamic acid decarboxylase (GAD65) present with limbic encephalitis, including temporal lobe seizures or epilepsy, cerebellitis with ataxia, and stiff-person-syndrome or overlap forms. Anti-GAD65 autoantibodies are also detected in autoimmune diabetes mellitus, which has a strong genetic susceptibility conferred by human leukocyte antigen (HLA) and non-HLA genomic regions. We investigated the genetic predisposition in patients with anti-GAD65 AINS. We performed a genome-wide association study (GWAS) and an association analysis of the HLA region in a large German cohort of 1214 individuals. These included 167 patients with anti-GAD65 AINS, recruited by the German Network for Research on Autoimmune Encephalitis (GENERATE), and 1047 individuals without neurological or endocrine disease as population-based controls. Predictions of protein expression changes based on GWAS findings were further explored and validated in the CSF proteome of a virtually independent cohort of 10 patients with GAD65-AINS and 10 controls. Our GWAS identified 16 genome-wide significant (P < 5 × 10−8) loci for the susceptibility to anti-GAD65 AINS. The top variant, rs2535288 [P = 4.42 × 10−16, odds ratio (OR) = 0.26, 95% confidence interval (CI) = 0.187–0.358], localized to an intergenic segment in the middle of the HLA class I region. The great majority of variants in these loci (>90%) mapped to non-coding regions of the genome. Over 40% of the variants have known regulatory functions on the expression of 48 genes in disease relevant cells and tissues, mainly CD4+ T cells and the cerebral cortex. The annotation of epigenomic marks suggested specificity for neural and immune cells. A network analysis of the implicated protein-coding genes highlighted the role of protein kinase C beta (PRKCB) and identified an enrichment of numerous biological pathways participating in immunity and neural function. Analysis of the classical HLA alleles and haplotypes showed no genome-wide significant associations. The strongest associations were found for the DQA1*03:01-DQB1*03:02-DRB1*04:01HLA haplotype (P = 4.39 × 10−4, OR = 2.5, 95%CI = 1.499–4.157) and DRB1*04:01 allele (P = 8.3 × 10−5, OR = 2.4, 95%CI = 1.548–3.682) identified in our cohort. As predicted, the CSF proteome showed differential levels of five proteins (HLA-A/B, C4A, ATG4D and NEO1) of expression quantitative trait loci genes from our GWAS in the CSF proteome of anti-GAD65 AINS. These findings suggest a strong genetic predisposition with direct functional implications for immunity and neural function in anti-GAD65 AINS, mainly conferred by genomic regions outside the classical HLA alleles.

Topiramate (TPM) is effective for treating epilepsy, but executive dysfunction is a common side effect that could significantly affect everyday life. Additionally, previous studies have suggested that patients might be unaware of these changes. To evaluate a rapid TPM titration scheme for the early detection of adverse cognitive side effects. In this retrospective study, we assessed changes in objective cognitive performance (EpiTrack®) after rapidly titrating TPM (50 mg per day during an inpatient stay) in 49 epilepsy patients and compared those results with an outpatient control group that underwent the recommended standard titration (n = 23 with 25–50 mg per week). Using Bayesian statistics, analyses revealed decisive evidence of a negative effect on cognitive performance when TPM was introduced (BF 31480000000) independent of the titration speed (BF 0.739). When using a fast titration rate, deficits in executive function increased from a baseline of 53.1 to 73.5

Smartphone videos can be an important diagnostic tool in the differential diagnosis of seizure-like events. The aim of this review is to present the relevance and hurdles of smartphone videos in the differential diagnosis of ictal events based on a literature review and expert opinions. Challenges arise primarily in ensuring sufficient quality of the recordings and presentation display of seizures and legal aspects of the creation, storage and transmission of the seizure video. Optimized seizure recording can improve the diagnostic value of videos. This can most likely be achieved by educating and instructing relatives. Secure data transfer can be organized by providing a secure web platform which patients can directly access to upload videos from their smartphone, and which can be accessed by physicians and clinicians to review recordings. A GDPR-compliant video platform developed in Scotland has demonstrated that routine use of smartphone video in the differential diagnosis of seizure-like events is very helpful for physicians and reduces costs by avoiding further diagnostic procedures.

AbstractObjectiveDirect pathogenic effects of autoantibodies to the 65 kDa isoform of glutamic acid decarboxylase (GAD65) in autoimmune limbic encephalitis (LE) have been questioned due to its intracellular localization. We therefore hypothesized a pathogenic role for T cells.MethodsWe assessed magnet resonance imaging, neuropsychological and peripheral blood, and CSF flow cytometry data of 10 patients with long‐standing GAD65‐LE compared to controls in a cross‐sectional manner. These data were related to each other within the GAD65‐LE group and linked to neuropathological findings in selective hippocampectomy specimen from another two patients. In addition, full‐resolution human leukocyte antigen (HLA) genotyping of all patients was performed.ResultsCompared to controls, no alteration in hippocampal volume but impaired memory function and elevated fractions of activated HLADR+ CD4+ and CD8+ T cells in peripheral blood and cerebrospinal fluid were found. Intrathecal fractions of CD8+ T cells negatively correlated with hippocampal volume and memory function, whereas the opposite was true for CD4+ T cells. Consistently, antigen‐experienced CD8+ T cells expressed increased levels of the cytotoxic effector molecule perforin in peripheral blood, and perforin‐expressing CD8+ T cells were found attached mainly to small interneurons but also to large principal neurons together with wide‐spread hippocampal neurodegeneration. 6/10 LE patients harbored the HLA‐A*02:01 allele known to present the immunodominant GAD65114–123 peptide in humans.InterpretationOur data suggest a pathogenic effect of CD8+ T cells and a regulatory effect of CD4+ T cells in patients with long‐standing GAD65‐LE.

In der Differenzialdiagnostik anfallsartig auftretender Ereignisse können Handyvideos ein wichtiger diagnostischer Baustein sein. Ziel dieser Übersichtsarbeit ist es, anhand einer Literaturrecherche und Expertenmeinungen darzulegen, welchen Nutzen und welche Herausforderungen Handyvideos in der Diagnostik anfallsartig auftretender Ereignisse haben. Herausforderungen ergeben sich in der Sicherstellung einer ausreichenden Qualität zur Erfassung und Darstellung der Anfälle und in juristischen Aspekten der Erstellung, Speicherung und Übermittlung des Videos. Eine Verbesserung der diagnostischen Aussagekraft von Videos durch optimierte Anfallsaufzeichnung kann am ehesten durch Aufklärung und Anleitung von Angehörigen erfolgen. Für die sichere Datenübermittlung eignen sich gesicherte Webplattformen, die sowohl das direkte Hochladen des Videos vom Handy des Patienten als auch Ärzten und Kliniken den Zugriff hierauf erlauben. Eine in Schottland entwickelte DSGVO-konforme Videoplattform konnte zeigen, dass ein routinemäßiger Einsatz von Handvideos in der Differenzialdiagnostik von anfallsartig auftretenden Ereignissen für Ärzte sehr hilfreich ist und durch Vermeidung weiterer diagnostischer Prozeduren Kosten reduziert.

Epilepsy surgery still lacks an operational method for finding the epileptogenic zone (EZ) or the minimal amount of tissue that has to be resected in order to leave the patient seizure-free. Here we propose a method for predicting the result of a resection from data collected before the eventual resection, therefore allowing an optimal surgical planning. Our major hypothesis is that focal generalized epilepsies are caused by sub-systems with excessive afferent connectivity to and from the rest of the neuronal tissue. To address the issue of delineating the EZ before the actual resection, we propose a paradigm performing "virtual surgery" on the matrix of connectivity between local EEG measurements. The virtual resection removes not only the nodes covered by the suspected EZ and their connections but also subtracts the influence of these nodes on the rest of connectivity. The residual connectivity is then compared to the original one and a significant decrease indicate that the resection contains the EZ or at least large part of it. We tested this approach on a computational model of spatially distributed bi-stable units that provides a generic model of focal epileptic neuronal system. In the modelled cases of epileptic system with spreading seizures, we found that the removal of the EZ can be predicted by significant decrease of the residual connectivity after performing virtual resection. This decrease commensurate with the increase of the epileptic threshold (the ground truth) . The method also predicts the actual change of connectivity after removing the nodes from the model dynamics. In addition we tested our techniques against the "naïve" virtual resection which is based on simply removing the corresponding nodes from the connectivity measure. The findings in this work can be exploited to increase the efficiency and accuracy of pre-surgical epileptogenic zone localization in cases of focal epileptic seizure onsets.

Objective Neuropsychological impairments are major symptoms of autoimmune limbic encephalitis (LE) epilepsy patients. In LE epilepsy patients with an autoimmune response against intracellular antigens as well as in antibody-negative patients, the antibody findings and magnetic resonance imaging pathology correspond poorly to the clinical features. Here, we evaluated whether T- and B-cells are linked to cognitive impairment in these groups. Methods In this cross-sectional, observational, case–controlled study, we evaluated 106 patients with adult-onset epilepsies with a suspected autoimmune etiology. We assessed verbal and visual memory, executive function, and mood in relation to the presence or absence of known auto-antibodies, and regarding T- and B-cell activity as indicated by flow cytometry (fluorescence-activated cell sorting = FACS, peripheral blood = PB and cerebrospinal fluid = CSF). Results 56% of the patients were antibody-negative. In the other patients, auto-antibodies were directed against intracellular antigens (GAD65, paraneoplastic: 38%), or cellular surface antigens (LGI1/CASPR2/NMDA-R: 6%). Excluding LGI1/CASPR2/NMDA-R, the groups with and without antibodies did not differ in disease features, cognition, or mood. CD4+ T-cells and CD8+ T-cells in blood and CD4+ T-cells in CSF were prominent in the auto-antibody positive group. Regression analyses indicated the role education, drug load, amygdala and/or hippocampal pathology, and CD4+ T-cells play in verbal memory and executive function. Depressed mood revealed no relation to flow cytometry results. Conclusion Our results indicate a link between T- and B-cell activity and cognition in epilepsy patients with suspected limbic encephalitis, thus suggesting that flow cytometry results can provide an understanding of cognitive impairment in LE patients with autoantibodies against intracellular antigens.

Purpose: Flow cytometry helps to elucidate the cellular immune repertoire's mechanisms in patients with temporal lobe epilepsy (TLE) due to limbic encephalitis (LE) subcategories and carries potential significance for subtype-specific treatment. Methods: We enrolled 62 patients with TLE due to LE associated with no autoantibodies (n= 40), neural autoantibodies (n= 22), as well as autoantibodies against intracellular antigens (n= 15/22). All patients underwent neuropsychological testing, brain magnetic resonance imaging (MRI), electroencephalography (EEG) recordings, and peripheral blood (PB) and cerebrospinal fluid (CSF) investigations including flow cytometry. Results: CD19+ B-cells were increased in the PB and CSF of patients with antibody-negative LE compared with those associated with antibodies against intracellular antigens (Kruskal-Wallis one way analysis of variance (ANOVA) on ranks with Dunn's test, p < 0.05). There were no differences in CD138+ B-cells, CD4+ T-cells, human leukocyte antigen - DR isotype (HLA-DR+) CD4+ T-cells, CD8+ T-cells, and HLA-DR+ CD8+ T-cells in the CSF between groups with LE. The blood-brain barrier is more often impaired in patients with antibodynegative LE than in LE with antibodies against intracellular antigens (chi-square test, p < 0.05). In addition, we detected no correlations between immune cell subsets and clinical or paraclinical parameters in patients with antibody-negative and intracellular antibody-positive LE. Conclusions: The increase of CD19+ B-cells in the CSF and frequent signs of dysfunctional blood-brain barrier in patients with antibody-negative rather than intracellular antibody-positive LE suggest that CD19+ B-cells play a role in antibody-negative encephalitis although their pathogenic role in the central nervous system(CNS) immunity because of missing correlations between immune cells and clinical and paraclinical parameters remains unknown. Further studies are required to evaluate the usefulness of these B-cells as a biomarker for the stratification of treatment strategies. (C) 2020 Elsevier Inc. All rights reserved.

Purpose: Investigating immune cells in autoimmune limbic encephalitis (LE) will contribute to our understanding of its pathophysiology and may help to develop appropriate therapies. The aim of the present study was to analyze immune cells to reveal underlying immune signatures in patients with temporal lobe epilepsy (TLE) with LE. Methods: We investigated 68 patients with TLE with LE compared with 7 control patients with TLE with no signs of LE screened from 154 patients with suspected LE. From the patients with TLE-LE, we differentiated early seizure onset (<20 years, n = 9) and late seizure onset group (>= 20 years. n = 59) of patients. Patients underwent neuropsychological assessment, electroencephalography (EEG), brain magnetic resonance imaging (MRI), and peripheral blood (PB) and cerebrospinal fluid (CSF) analysis including flow cytometry. Results: We identified a higher CD4/8+ T-cell ratio in the PB in all patients with TLE-LE and in patients with late-onset TLE-LE each compared with controls (Kruskal-Wallis one-way ANOVA (analysis of variance) with Dunn's test, p < 0.05). Moreover, a lower CD4/CD8+ T-cell ratio is detected in all patients with TLE-LE with blood-CSF barrier dysfunction, unlike in those with none (Kruskal-Wallis one-way ANOVA with Dunn's test, p <0.05). Conclusions: These findings suggest that the proportion of CD4 + and CD8 +T-cells in the CSF of patients with LE associated with blood-CSF barrier dysfunction plays a potential role in CNS (central nervous system) inflammation in these patients. Thus, flow cytometry as a methodology reveals novel insights into LE's genesis and symptomatology. The CD4/8 + T-cell ratio in PB as a biomarker for LE requires further investigation. (C) 2019 Elsevier Inc. All rights reserved.

Objective: No international guideline is available for minimum safety measures at epilepsy monitoring units (EMUs), although recommendations for preferred practices exist. These are mostly based on expert opinion, without evidence of effectiveness. We do not apply all of these preferred practices at our EMU setting. We audited adverse events and diagnostic utility at our EMU over one year. Methods: From May 2018 to May 2019, we prospectively collected data concerning adverse events and diagnostic utility of all EMU admissions (noninvasive video-electroencephalogram (EEG) recordings); during these admissions, individuals can be ambulant within their EMU room. Results: There were 1062 admissions comprising 1518 EMU days. In 2% of the admissions, a complication occurred, mostly a fall without injury (n = 6). In almost half of the falls, this was from the bed. Complications occurred most often during admissions for presurgical evaluation. Antiseizure medication (ASM) was tapered in 86% of presurgical cases, but no serious injury occurred, and occurring seizures were effectively treated with intranasal midazolam if needed. Conclusions: The overall adverse event rate was low. Falls are the most common adverse event comparable with previously published fall rates at other EMUs where people are restricted to their bed. We showed that restricted ambulation at a well-monitored EMU is not necessary and possibly unwanted. No serious injury due to tapering of ASM occurred, and intranasal midazolam was shown to be effective as acute seizure treatment. (C) 2019 Elsevier Inc. All rights reserved.

We read with much interest the recently published article by Jeppesen and colleagues on seizure detection based on heart rate variability.1 We are concerned because it presents an algebraic quandary in its basic formula, which challenges the interpretations of the results of the “HR-diff” parameter. This quandary was also present in an earlier publication from this group2 but was not previously challenged. The authors claim to average or sum up the so-called “heart rate differential method” over 50 or 100 (in the formula k) R-R intervals using the following equation: