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Objectives Whether and when to immunologically treat epilepsy patients with suggested autoantibody ( AB)-negative limbic encephalitis ( LE) is clinically challenging. Therefore, we evaluated the clinical outcome and eventual outcome predictors of immunotherapy in a group of AB-negative patients with recent-onset temporal lobe epilepsy ( TLE), magnetic resonance imaging ( MRI) indicators of LE, subjective cognitive decline, and/or psychiatric symptoms. Methods This retrospective, observational, uncontrolled study monitored 28 TLE patients with suggested AB-negative LE along with methylprednisolone immunotherapy. Results All patients had seizures, amygdala and/or -hippocampal enlargement, subjective cognitive decline and/or behavioral problems. Eighty-six percent (24/28) were impaired in executive or memory functions, 39% (10/25) depressed, 81% were on antiepileptic drugs when pulse therapy started. After a median follow-up of 18 months, 46% (13/28) of the patients were seizure free (>2 months), 48% (13/27) showed MRI improvements (amygdala and/or hippocampal volume reduction), cognition improved in 57% (16/28), worsened in 32% (9/28), mood improved in 14% (4/25), and deteriorated in 11% (3/25). Immunotherapy was discontinued in 75% (21/28). Clinical changes did not correlate to each other. Outcomes could not be predicted. Conclusion Immunological treatment of suggested AB-negative LE showed reasonable seizure control, MRI and cognitive improvements. Treatment success was not predictable from clinical features, nor definitely attributable to immunological treatment. Lacking biomarkers for the reliable diagnosis of AB-negative LE, we suggest that in presence of mild manifestations, and after initiating antiepileptic drug therapy, negative dynamics in MRI, seizures, cognition, and behavior should be documented before immunosuppressive treatment is initiated. [ABSTRACT FROM AUTHOR]

Background: Clinical trials have shown that cenobamate (CNB) is an efficacious and safe anti-seizure medication (ASM) for drug-resistant focal epilepsy. Here, we analyzed one of the largest real-world cohorts, covering the entire spectrum of epilepsy syndromes, the efficacy and safety of CNB, and resulting changes in concomitant ASMs., Methods: We conducted a retrospective observational study investigating CNB usage in two German tertiary referral centers between October 2020 and June 2023 with follow-up data up to 27 months of treatment. Our primary outcome was treatment response. Secondary outcomes comprised drug response after 12 and 18 months, seizure freedom rates, CNB dosage and retention, adverse drug reactions (ADRs), and changes in concomitant ASMs., Results: 116 patients received CNB for at least two weeks. At 6 months, 98 patients were eligible for evaluation. Thereof 50% (49/98) were responders with no relevant change at 12 and 18 months. Seizure freedom was achieved in 18.4% (18/98) at 6 months, 16.7% (11/66), and 3.0% (1/33) at 12 and 18 months. The number of previous ASMs did not affect the seizure response rate. Overall, CNB was well-tolerated, however, in 7.7% (9/116), ADRs led to treatment discontinuation. The most frequent changes of concomitant ASMs included the discontinuation or reduction of sodium channel inhibitors, clobazam reduction, and perampanel discontinuation, while brivaracetam doses were usually left unchanged., Conclusions: CNB proved to be a highly effective and generally well-tolerated ASM in patients with severe drug-resistant epilepsy, comprising a broad array of epilepsy syndromes beyond focal epilepsy., (© 2024. The Author(s).)

Background: In the pre-surgical evaluation of people with focal epilepsy and a normal MRI, Morphometric Analysis Program v2018 (MAP18) aids in detecting visually inconspicuous focal cortical dysplasia (FCD). We investigated the impact of MRI scans with reduced signal-to-noise ratio (SNR) and spatial resolution (SR) on FCD detection by MAP18, aiming to improve the chances of achieving seizure freedom through epilepsy surgery., Methods: Thirty MRI scans with the identified lesion using MAP18 radiologically confirmed as FCD by a neuroradiologist, were retrospective analysed. SNR and SR were artificially reduced in ten steps, and their impact on MAP18 outcomes was assessed using multilevel analysis., Results: There was a significant effect after reducing SR and SNR for z-score and volume of the FCD cluster, the total number of detected clusters, and volume of these clusters. After SNR reduction, there was also a significant effect for z-score of the total number of detected clusters. FCD became undetectable by MAP18 after six steps of SR reduction (voxel size 2.8 × 2.8 × 2.8 mm³) and after two steps of SNR reduction., Conclusions: This exploratory study suggests that reduced SR and SNR negatively affect FCD detection with MRI post-processing (MAP18). The MAP18 evaluator should screen MRI quality before post-processing, particularly for scans with significant visual noise or voxel sizes of 2.8 × 2.8 × 2.8 mm³ and upwards, as repeating a low-quality MRI scan is less burdensome than the adverse effects of continued seizures due to failure to detect FCD., Competing Interests: Declaration of competing interest None of the authors has any conflict of interest to disclose., (Copyright © 2024 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

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., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background: 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., Objective: To evaluate a rapid TPM titration scheme for the early detection of adverse cognitive side effects., Methods: 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)., Results: 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% at follow-up, and 55.1% experienced a statistically significant intraindividual decline. When using the standard titration scheme, impairments increased from 52.2 to 65.2%, with an intraindividual deterioration found in 52.2% of the patients., Conclusion: Physicians might be able to detect adverse cognitive side effects sooner in epilepsy patients if TPM is administered using a faster titration rate while applying repeated cognitive assessments within days. This approach might help prevent any unnoticed intolerance and eventual negative consequences for the patient. Therefore, we recommend monitoring early on for adverse changes instead of withholding a potentially effective treatment option because of anticipated side effects., (© 2022. The Author(s).)

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., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

Objective: Direct 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., Methods: We 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., Results: Compared 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 GAD65 114-123 peptide in humans., Interpretation: Our data suggest a pathogenic effect of CD8 + T cells and a regulatory effect of CD4 + T cells in patients with long-standing GAD65-LE., (© 2021 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

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 antibody-negative 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., Competing Interests: Declaration of competing interest NH, DÖ, GW, KS, JAW, PL, IP, and AJB have no potential conflict of interest to declare. CEE has received speaker and consultant fees from ESAI, Cyberonics, Desitin, Novartis, Union Chimique Belge, and Medtronic. RS reports speaker or consultant fees from Bial, Desitin, Eisai, Liva Nova, Novartis, and UCB, Pharma. CH has received fees as a speaker and consultant from Desitin, Esai, UCB, GW, and Precisis., (Copyright © 2020 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., (Copyright © 2019 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., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: Paraneoplastic limbic encephalitis (LE) occurs frequently with considerable variability according to literature reports. We thus determined the cancer frequency in mixed LE subtypes sharing the diagnosis of temporal lobe epilepsy (TLE)., Methods: All patients underwent magnetic resonance imaging (MRI) of the brain, electroencephalography (EEG) recordings, neuropsychological testing, immunohistochemistry, and clinical examination together with whole body 2-fluor-2-desoxy-d-glucose (FDG)-positron emission tomography (PET)/computed tomography (CT) to detect cancer in this observatory study., Results: Ninety-three patients (median: 52 years) with TLE due to autoimmune LE were investigated. Cancer was detected in the FDG-PET/CTs of 3 out of 93 (3.2%) patients with LE. Cancer was diagnosed upon, 5 years earlier and 5 years after FDG-PET/CT in 7 of 93 (7.5%) of all patients with LE. The cancer frequency in those patients was significantly lower than that reported in the largest series of patients with LE associated with and without different antibodies (7.5% vs. 23.5%, Bootstrap test, p < 0.05), but was indistinguishable from the estimated age-dependent cancer frequency in the German regional North-Rhine-Westfalian population without LE in 2014 (Chi-square test: p = 0.2)., Conclusions: Our findings reveal that the cancer frequency in patients with TLE with LE detected by FDG-PET/CT is low and not different from the age-dependent natural cancer occurrence in a regional population., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: Limbic encephalitis (LE) is defined by mesiotemporal lobe structure abnormalities, seizures, memory, and psychiatric disturbances. This study aimed to identify the long-term clinical and neuropsychological outcome of selective amygdalohippocampectomy (sAH) in drug-resistant patients with temporal lobe epilepsy due to known or later diagnosed subacute LE not responding to immunotherapy associated with neuronal autoantibodies., Methods: In seven patients with temporal lobe epilepsy due to antibody positive LE (glutamic acid decarboxylase (GAD65): n=5; voltage-gated potassium channel complex (VGKC), N-methyl d-aspartate receptor (NMDAR): n=1; Ma-2/Ta: n=1) sAH (6 left, 1 right) was performed. Those patients underwent repeated electroencephalography (EEG) recordings, magnetic resonance imaging (MRI) volumetry of the amygdala and hippocampus, and neuropsychological examinations and were followed up for 6-7years on average., Results: Verbal memory and figural memory were affected in 57% of patients at baseline and 71% at the last follow-up. At the last follow-up, 14% of the patients had declined in verbal memory and figural memory. We observed improved memory in 43% of patients regarding figural memory, but not in a single patient regarding verbal memory. Repeated evaluations across the individual courses reveal cognitive and MRI dynamics that appear to be unrelated to surgery and drug treatment. Three of the seven patients with LE with different antibodies (NMDAR: n=1, Ma-2/Ta: n=1 and GAD65: n=1) achieved persistent seizure freedom along with no accelerated memory decline after surgery. Two of the five GAD65-antibody patients positive with LE showed progressive memory decline and a long-term tendency to contralateral hippocampus atrophy., Conclusions: While memory demonstrated some decline in the long run, what is most important is that a progressive decline in memory is seldom found after sAH in patients with LE. Moreover, the dynamics in performance and MRI before and after surgery reveal disease dynamics independent of surgery. Selective amygdalohippocampectomy can lead to seizure freedom, but should be considered as a last resort treatment option for drug-resistant patients with temporal lobe epilepsy due to LE. Particular caution is recommended in patients with GAD65-LE., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Detailed neuropathological information on the structural brain lesions underlying seizures is valuable for understanding drug-resistant focal epilepsy., Methods: We report the diagnoses made on the basis of resected brain specimens from 9523 patients who underwent epilepsy surgery for drug-resistant seizures in 36 centers from 12 European countries over 25 years. Histopathological diagnoses were determined through examination of the specimens in local hospitals (41%) or at the German Neuropathology Reference Center for Epilepsy Surgery (59%)., Results: The onset of seizures occurred before 18 years of age in 75.9% of patients overall, and 72.5% of the patients underwent surgery as adults. The mean duration of epilepsy before surgical resection was 20.1 years among adults and 5.3 years among children. The temporal lobe was involved in 71.9% of operations. There were 36 histopathological diagnoses in seven major disease categories. The most common categories were hippocampal sclerosis, found in 36.4% of the patients (88.7% of cases were in adults), tumors (mainly ganglioglioma) in 23.6%, and malformations of cortical development in 19.8% (focal cortical dysplasia was the most common type, 52.7% of cases of which were in children). No histopathological diagnosis could be established for 7.7% of the patients., Conclusions: In patients with drug-resistant focal epilepsy requiring surgery, hippocampal sclerosis was the most common histopathological diagnosis among adults, and focal cortical dysplasia was the most common diagnosis among children. Tumors were the second most common lesion in both groups. (Funded by the European Union and others.).

Objectives: Whether and when to immunologically treat epilepsy patients with suggested autoantibody (AB)-negative limbic encephalitis (LE) is clinically challenging. Therefore, we evaluated the clinical outcome and eventual outcome predictors of immunotherapy in a group of AB-negative patients with recent-onset temporal lobe epilepsy (TLE), magnetic resonance imaging (MRI) indicators of LE, subjective cognitive decline, and/or psychiatric symptoms., Methods: This retrospective, observational, uncontrolled study monitored 28 TLE patients with suggested AB-negative LE along with methylprednisolone immunotherapy., Results: All patients had seizures, amygdala and/or -hippocampal enlargement, subjective cognitive decline and/or behavioral problems. Eighty-six percent (24/28) were impaired in executive or memory functions, 39% (10/25) depressed, 81% were on antiepileptic drugs when pulse therapy started. After a median follow-up of 18 months, 46% (13/28) of the patients were seizure free (>2 months), 48% (13/27) showed MRI improvements (amygdala and/or hippocampal volume reduction), cognition improved in 57% (16/28), worsened in 32% (9/28), mood improved in 14% (4/25), and deteriorated in 11% (3/25). Immunotherapy was discontinued in 75% (21/28). Clinical changes did not correlate to each other. Outcomes could not be predicted., Conclusion: Immunological treatment of suggested AB-negative LE showed reasonable seizure control, MRI and cognitive improvements. Treatment success was not predictable from clinical features, nor definitely attributable to immunological treatment. Lacking biomarkers for the reliable diagnosis of AB-negative LE, we suggest that in presence of mild manifestations, and after initiating antiepileptic drug therapy, negative dynamics in MRI, seizures, cognition, and behavior should be documented before immunosuppressive treatment is initiated., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: Recent reports define temporal lobe epilepsy with amygdala enlargement (TLE-AE) as a distinct electroclinical syndrome comparable to TLE with hippocampal sclerosis. In this retrospective observational study, we present the largest consecutive series of patients with new-onset TLE-AE to date and describe clinical characteristics and seizure outcome, and we aim to explore underlying autoimmune mechanisms within this syndrome., Methods: We reviewed all consecutive patients between 2004 and 2014 at our tertiary epilepsy center at the University of Bonn, Germany, with new-onset (<5 years) TLE-AE, negative serum antibody (ab) test results, and with available follow-up data for at least 12 months., Results: We identified 40 patients (23 male) with TLE-AE with a median age at epilepsy onset of 51 years (range 10-73) and a median disease duration of 11 months (range 0.5-55) at first presentation. At follow-up, 50% of the entire cohort achieved seizure freedom. Of interest, patients with remittent features of AE at follow-up (N = 24) had a superior outcome compared to those with stable magnetic resonance imaging (MRI) features of AE (N = 16): 17 (71%) of 24 were seizure-free for at least 6 months compared to 3 (19%) of 16, respectively (p = 0.003). MRI volumetry confirmed significantly enlarged amygdalae in TLE-AE in relation to healthy controls, and additionally showed significantly greater volume reductions in patients with remittent AE compared to those with stable AE., Significance: TLE-AE is a clinical syndrome beginning mostly in middle age, and in addition to its known association with ab-positive limbic encephalitis, it occurs in an ab-negative condition. Remission of AE in the course of the disease could be identified as a predictor for a favorable clinical outcome and is suspicious of an autoimmune etiology, although we could not confirm this hypothesis unequivocally with currently available noninvasive diagnostic tools., (Wiley Periodicals, Inc. © 2016 International League Against Epilepsy.)

Objectives: To characterize the cellular autoimmune response in patients with γ-aminobutyric acid (GABA)B receptor antibody-associated limbic encephalitis (GABAB-R LE)., Methods: Patients underwent MRI, extensive neuropsychological assessment, and multiparameter flow cytometry of peripheral blood and CSF., Results: We identified a series of 3 cases of nonparaneoplastic GABAB-R LE and one case of paraneoplastic GABAB-R LE associated with small cell lung cancer. All patients exhibited temporal lobe epilepsy, neuropsychological deficits, and MRI findings typical of LE. Absolute numbers of CD19(+) B cells, CD138(+) CD19(+) plasma cells, CD4(+) T cells, activated HLADR(+) CD4(+) T cells, as well as CD8(+) T cells and HLADR(+) CD8(+) T cells did not differ in peripheral blood but were elevated in CSF of patients with GABAB-R LE compared to controls. Augmented absolute numbers of CD138(+) CD19(+) plasma cells and activated HLADR(+) CD8(+) T cells in CSF corresponded to higher overall neuropsychological and memory deficits in patients with GABAB-R LE. A histologic specimen of one patient following selective amygdalohippocampectomy revealed perivascular infiltrates of CD138(+) plasma cells and CD4(+) T cells, whereas cytotoxic CD8(+) T cells were detected within the brain parenchyma in close contact to neurons., Conclusion: Our data suggest a pathogenic role for CD8(+) T cells in addition to the established role of plasma cell-derived autoantibodies in GABAB-R LE.

Rasmussen encephalitis (RE) is a rare paediatric epilepsy with uni-hemispheric inflammation and progressive neurological deficits. To elucidate RE immunopathology, we applied T-cell receptor (TCR) sequencing to blood (n=23), cerebrospinal fluid (n=2) and brain biopsies (n=5) of RE patients, and paediatric controls. RE patients present with peripheral CD8(+) T-cell expansion and its strength correlates with disease severity. In addition, RE is the only paediatric epilepsy with prominent T-cell expansions in the CNS. Consistently, common clones are shared between RE patients, who also share MHC-I alleles. Public RE clones share Vβ genes and length of the CDR3. Rituximab/natalizumab/basiliximab treatment does not change TCR diversity, stem cell transplantation replaces the TCR repertoire with minimal overlap between donor and recipient, as observed in individual cases. Our study supports the hypothesis of an antigen-specific attack of peripherally expanded CD8(+) lymphocytes against CNS structures in RE, which might be ameliorated by restricting access to the CNS.

Purpose: The eradication of epileptogenic lesions (e.g. focal cortical dysplasia) can be used for treatment of drug-resistant focal epilepsy, but in highly eloquent cortex areas it can also lead to a permanent neurological deficit. In such cases the neuromodulation effect of low-dose high-precision irradiation of circumscribed lesions may represent an alternative therapy., Method: A total of 10 patients with eloquent localized lesions causing pharmacoresistant focal epilepsy were prospectively identified. After informed consent, six patients agreed and were treated with risk adapted low-dose radiosurgery (SRS) or hypofractionated stereotactic radiotherapy (hfSRT). Comprehensive data concerning treatment modalities and outcome after short-term follow up (mean=16.3 months) were prospectively collected and evaluated., Results: From the six patients, two patients were treated with hfSRT (marginal dose 36 Gy) and four with SRS (marginal dose 13 Gy). Clinical target volume (CTV) ranged from 0.70 ccm to 4.32 ccm. The short-term follow-up ranged from 6 to 27 months. There were no side effects or neurological deficits after treatment. At last available follow-up two patients were seizure-free, one of them being off antiepileptic drugs. The seizure frequency improved in one and remained unchanged in three patients., Conclusion: Treatment of eloquent localized epileptogenic lesions by SRS and hfSRT showed no adverse events and an acceptable seizure outcome in this small prospective patient series. The relatively short-term follow-up comprises one of the study's drawbacks and therefore a longer follow-up should be awaited in order to evaluate the neuromodulation effect of the treatment. These preliminary results may however justify the initiation of a larger prospective trial investigating whether focused low-dose stereotactic irradiation could be an option for lesions in eloquent brain areas., (Copyright © 2016 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Background: Glutamate decarboxylase is an intracellular enzyme converting glutamate into GABA. Antibodies (abs) to its isoform GAD65 were described in limbic encephalitis and other neurological conditions. The significance of GAD65 abs for epilepsy is unclear, but alterations of inhibitory GABAergic neurotransmission may be involved. Here, we investigated the effects of the serum of a female patient suffering from GAD65 ab-associated LE on GABAA currents in cultured hippocampal networks., Methods: Spontaneous or evoked post-synaptic GABAA currents were measured in cultured hippocampal neurons prepared from embryonic mice after 11-21 days in vitro using the patch-clamp technique in the whole-cell mode after incubation with serum of a healthy control or the LE-patient at a final concentration of 1% for 5-8 h., Results: Properties of miniature inhibitory post-synaptic currents were not different in cultures treated with control and LE-serum. Likewise, paired-pulse ratio of evoked GABAA currents as a measure of release probability was not different in both conditions. Evoked GABAA currents were significantly depressed during 10 Hz stimulation without significant differences between control and LE-serum treated cultures., Conclusion: In our experimental paradigms, serum of a patient with confirmed GAD65 ab-associated LE had no apparent effect on GABAergic neurotransmission in murine-cultured hippocampal networks. These results challenge the view that the presence of GAD65 abs invariably compromise inhibitory network function.

Background: Antibodies (ABs) against the 65-kDa isoform of the intracellular enzyme glutamate decarboxylase (GAD65) have been found in limbic encephalitis (LE) and other neurological conditions. The direct significance of anti-GAD65-ABs for epilepsy is unclear. However, in histological preparations from biopsies of resective epilepsy surgeries, predominantly cytotoxic T-lymphocytes were detected making close contacts to neurons. Activated T-lymphocytes can, in turn, be selectively controlled by therapeutic interleukin-2 receptor Abs, such as basiliximab., Case Presentation: We report of a 25-year-old male patient with epilepsy since the age of 18 and displaying clinical signs of LE and a high titer of GAD65 ABs in cerebrospinal fluid (CSF) and serum. Monthly, repetitive, intravenous cortisone pulse therapies that were initially administered for 6 months failed to improve his condition. Subsequent flow-cytometry analysis of CSF showed especially an increased fraction of activated HLA-DR(+) CD8(+) T-lymphocytes (fCD8(+)TL) when compared to controls. Thus, a second, intravenous cortisone pulse therapy with an additional basiliximab dose of 20 mg/month was started. After 3 months, the fCD8(+)TL in the CSF normalized; after 6 months, the psychological impulse-control deficits normalized; and after 11 months the patient was seizure free. However, 7 weeks later, seizures and, later on, psychological deficits recurred and fCD8(+)TL was once again present in the CSF. Flumazenil PET, magnetic resonance imaging-volumetry, and neuropsychological changes during therapy are described., Conclusion: The correlation of the fCD8(+)TL in the CSF with clinical and paraclinical measures of disease activity combined with the unambiguous response to basiliximab strongly argues in favor of the putative pathogenic role fCD8(+)TL in anti-GAD65 LE. The clinical relapse at the end of the observation period might be due to the formation of human anti-drug ABs, a well-known complication of therapy with chimeric ABs.

We describe a 35-year-old male patient presenting with depressed mood and emotional instability, who complained about severe anterograde and retrograde memory deficits characterized by accelerated long-term forgetting and loss of autonoetic awareness regarding autobiographical memories of the last 3 years. Months before he had experienced two breakdowns of unknown etiology giving rise to the differential diagnosis of epileptic seizures after various practitioners and clinics had suggested different etiologies such as a psychosomatic condition, burnout, depression, or dissociative amnesia. Neuropsychological assessment indicated selectively impaired figural memory performance. Extended diagnostics confirmed accelerated forgetting of previously learned and retrievable verbal material. Structural imaging showed bilateral swelling and signal alterations of temporomesial structures (left >right). Video-EEG monitoring revealed a left temporal epileptic focus and subclincal seizure, but no overt seizures. Antibody tests in serum and liquor were positive for glutamic acid decarboxylase antibodies. These findings led to the diagnosis of glutamic acid decarboxylase antibody related limbic encephalitis. Monthly steroid pulses over 6 months led to recovery of subjective memory and to intermediate improvement but subsequent worsening of objective memory performance. During the course of treatment, the patient reported de novo paroxysmal non-responsive states. Thus, antiepileptic treatment was started and the patient finally became seizure free. At the last visit, vocational reintegration was successfully in progress. In conclusion, amygdala swelling, retrograde biographic memory impairment, accelerated long-term forgetting, and emotional instability may serve as indicators of limbic encephalitis, even in the absence of overt epileptic seizures. The monitoring of such patients calls for a standardized and concerted multilevel diagnostic approach with repeated assessments.

Objective: Chronic inflammatory processes are important promotors of temporal lobe epilepsy (TLE) development. Based on human herpesvirus 6 (HHV-6) DNA detection in brain tissue from patients with TLE, an association of persistent viral infection with TLE has been discussed. Individual studies reported increased HHV-6 DNA in patients with clinical signs of previous inflammatory brain reaction, that is, febrile seizures or meningoencephalitis. However, detection rates vary considerably between different studies. Here we performed a large-scale analysis of viral DNA/RNA spectrum in high-quality TLE biopsies. In addition to all Herpesviridae, we addressed potentially relevant neurotropic RNA viruses., Methods: DNA and RNA were extracted from 346 fresh-frozen tissue samples removed by epilepsy surgery. Real-time polymerase chain reaction (PCR) and nested PCR were performed for Herpesviridae and RNA viruses, respectively. Clinical data were analyzed for earlier signs of inflammatory brain reactions. Fresh-frozen hippocampal tissue samples from patients without chronic central nervous system (CNS) disease served as controls (n = 62). Seven previous PCR studies with overall 178 TLE patients were additionally analyzed regarding a correlation of clinical parameters and HHV-6 detection., Results: PCR revealed HHV-6B DNA in 34 specimens (9.8%) from TLE patients. HHV-6B DNA was also present in eight control samples (12.9%; p > 0.05), but showed a lower virus concentration (p < 0.001). Other herpesviruses and RNA viruses were virtually absent. In patients with clinical signs of previous brain inflammation, HHV-6B DNA was observed in 15.0%, whereas only 6.3% of the samples from patients without febrile seizures or meningoencephalitis were positive for HHV-6B DNA (p < 0.05). A meta-analysis of the eight HHV-6 PCR studies revealed similar results., Significance: This biopsy-based study shows no differences in frequency of HHV-6B DNA detection between TLE patients and controls. These results do not support the hypothesis of a persistent HHV-6B infection as a major pathogenetic factor in TLE. However, the higher virus load in TLE patients and the increased detection rate of HHV-6B DNA in patients with previous inflammatory brain reactions require further investigations., (Wiley Periodicals, Inc. © 2014 International League Against Epilepsy.)