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An increasing number of epilepsies are being attributed to variants in genes with epigenetic functions. The products of these genes include factors that regulate the structure and function of chromatin and the placing, reading and removal of epigenetic marks, as well as other epigenetic processes. In this Review, we provide an overview of the various epigenetic processes, structuring our discussion around five function-based categories: DNA methylation, histone modifications, histone-DNA crosstalk, non-coding RNAs and chromatin remodelling. We provide background information on each category, describing the general mechanism by which each process leads to altered gene expression. We also highlight key clinical and mechanistic aspects, providing examples of genes that strongly associate with epilepsy within each class. We consider the practical applications of these findings, including tissue-based and biofluid-based diagnostics and precision medicine-based treatments. We conclude that variants in epigenetic genes are increasingly found to be causally involved in the epilepsies, with implications for disease mechanisms, treatments and diagnostics.

BackgroundGliosis only (GO) and hippocampal sclerosis (HS) are distinct histopathological entities in mesial temporal lobe epilepsy. This study explores whether this distinction also exists on a functional level when evaluating pre- and postoperative memory.MethodsUsing a retrospective matched case–control study design, we analysed verbal and visual memory performance in 49 patients with GO and 49 patients with HS before and one year after elective surgery.ResultsClinical differences were evident with a later age at seizure onset (18±12 vs 12±9 years) and fewer postoperative seizure-free patients in the GO group (63% vs 82%). Preoperatively, group and individual-level data demonstrated that memory impairments were less frequent, less severe and relatively non-specific in patients with GO compared with HS. Postoperatively, verbal memory declined in both groups, particularly after left-sided resections, with more significant losses in patients with GO. Factoring in floor effects, GO was also associated with more significant visual memory loss, particularly after left resections.ConclusionsCompared with HS, GO is characterised by (1) a later onset of epilepsy, (2) less pronounced and more non-specific memory impairments before surgery, (3) a less successful surgical outcome and (4) a more significant memory decline after surgery. Overall, our results regarding cognition provide further evidence that GO and HS are distinct clinical entities. Functional integrity of the hippocampus appears higher in GO, as indicated by a better preoperative memory performance and worse memory outcome after surgery. The different risk–benefit ratios should be considered during presurgical patient counselling.

Acta Neuropathol (Berl) 144(1), 107-127 (2022). doi:10.1007/s00401-022-02429-0, Published by Springer, Berlin ; Heidelberg

PDF file - 1616K, Gene expression profile of ATRT like tumors.

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PDF file - 1195K, Additional immunohistopathological features of ATRT like tumor induced by PBCAG-NeuroD1 and PBCAG-HRasV12/AKT.

PDF file - 1491K, Additional immunohistopathological features of ATRT like tumor induced by CAG-Ngn2 and PBCAG-HRasV12/AKT.

PDF file - 2064K, Additional immunohistopathological features of ATRT like tumor induced by PBCAG-NeuroD1 and PBCAG-HRasV12/AKT.

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Brain : a journal of neurology 146(2), 549-560 (2023). doi:10.1093/brain/awac293, Published by Oxford Univ. Press, Oxford

Some patients unexpectedly display an unfavorable cognitive course after epilepsy surgery subsequent to any direct cognitive sequelae of the surgical treatment. Therefore, we conducted in-depth neuropathological examinations of resective specimens from corresponding patients to provide insights as to the underlying disease processes.In this study, cases with significant cognitive deterioration following a previous postoperative assessment were extracted from the neuropsychological database of a longstanding epilepsy surgical program. An extensive reanalysis of available specimens was performed using current, state-of-the-art neuropathological examinations. Patients without cognitive deterioration but matched in regard to basic pathologies served as controls.Among the 355 operated patients who had undergone more than one postoperative neuropsychological examination, 30 (8%) showed significant cognitive decline in the period after surgery. Of the 24 patients with available specimens, 71% displayed further neuropathological changes in addition to the typical spectrum (ie, hippocampal sclerosis, focal cortical dysplasias, vascular lesions, and low-grade tumors), indicating (1) a secondary, putatively epilepsy-independent neurodegenerative disease process; (2) limbic inflammation; or (3) the enigmatic pathology pattern of "hippocampal gliosis" without segmental neurodegeneration. In the controls, the matched individual principal epilepsy-associated pathologies were not found in combination with the secondary pathology patterns of the study group.Our findings indicate that patients who unexpectedly displayed unfavorable cognitive development beyond any direct surgical effects show rare and very particular pathogenetic causes or parallel, presumably independent, neurodegenerative alterations. A multicenter collection of such cases would be appreciated to discern presurgical biomarkers that help with surgical decision-making. ANN NEUROL 2022.

OBJECTIVE Temporal lobe epilepsy (TLE) is one of the most common forms of epilepsy. In approximately 30% of patients, seizures are refractory to drug treatment. Despite the achievements of modern presurgical evaluation in recent years, the presurgical prediction of seizure outcome remains difficult. The aim of this study was to evaluate the seizure outcome in patients with drug-refractory TLE who underwent resective temporal lobe surgery (rTLS) and to determine features associated with unfavorable postsurgical seizure outcome. METHODS Patients with medically refractory TLE who underwent rTLS between 2012 and 2017 were reviewed from the prospectively collected epilepsy surgery database. A retrospective analysis of clinical, radiological, neuropsychological, histopathological, and perioperative findings of 161 patients was performed. The patients were divided into two groups according to seizure outcome (group I, International League Against Epilepsy [ILAE] class 1; group II, ILAE class ≥ 2). For identification of independent risk factors for unfavorable postoperative seizure outcome (ILAE class ≥ 2), a multivariate logistic regression analysis was performed. RESULTS Seizure freedom (ILAE class 1) was achieved in 121 patients (75.2%). The neuropsychological evaluation demonstrated that losses in cognitive performance were more pronounced in verbal memory after resections in the left temporal lobe and in nonverbal memory after right-sided resections, whereas attention improved after surgery. Overall, postoperative visual field deficits (VFDs) were common and occurred in 51% of patients. There was no statistically significant difference in the incidence of VFD in patients with selective surgical procedures compared to the patients with nonselective procedures. The lack of MRI lesions and placement of depth electrodes were preoperatively identified as predictors for unfavorable seizure outcome. CONCLUSIONS rTLS is an effective treatment method in patients with refractory TLE. However, patients with a lack of MRI lesions and placement of depth electrodes prior to rTLS are at higher risk for an unfavorable postsurgical seizure outcome.

Gangliogliomas (GGs), composed of dysmorphic neurons and neoplastic astroglia, represent the most frequent tumor entity associated with chronic recurrent epileptic seizures. So far, a systematic analysis of potential differences in neurochemical profiles of dysmorphic tumoral neurons as well as neurons of the peritumoral microenvironment (PTME) was hampered by the inability to unequivocally differentiate between the distinct neuronal components in human GG biopsies. Here, we have applied a novel GG mouse model that allows to clearly resolve the neurochemical profiles of GG-intrinsic versus PTME neurons. For this purpose, glioneuronal tumors in mice were induced by intraventricular in utero electroporation (IUE) of piggyBac-based plasmids for BRAFV600E and activated Akt (AktT308D/S473D, further referred to as AktDD) and analyzed neurochemically by immunocytochemistry against specific marker proteins. IUE of BRAFV600E/AktDD in mice resulted in tumors with the morphological features of human GGs. Our immunocytochemical analysis revealed a strong reduction of GABAARα1 immunoreactivity in the tumor compared to the PTME. In contrast, the extent of NMDAR1 immunoreactivity in the tumor appeared comparable to the PTME. Interestingly, tumor cells maintained the potential to express both receptors. Fittingly, the abundance of the presynaptic vesicular neurotransmitter transporters VGLUT1 and VGAT was also decreased in the tumor. Additionally, the fraction of parvalbumin and somatostatin non-neoplastic interneurons was reduced. In conclusion, changes in the levels of key proteins in neurotransmitter signaling suggest a loss of synapses and may thereby lead to neuronal network alterations in mouse GGs.

OBJECTIVE: Focal cortical dysplasias (FCDs) are a common cause of drug-resistant focal epilepsy but frequently remain undetected by conventional magnetic resonance imaging (MRI) assessment. The visual detection can be facilitated by morphometric analysis of T1-weighted images, for example, using the Morphometric Analysis Program (v2018; MAP18), which was introduced in 2005, independently validated for its clinical benefits, and successfully integrated in standard presurgical workflows of numerous epilepsy centers worldwide. Here we aimed to develop an artificial neural network (ANN) classifier for robust automated detection of FCDs based on these morphometric maps and probe its generalization performance in a large, independent data set. METHODS: In this retrospective study, we created a feed-forward ANN for FCD detection based on the morphometric output maps of MAP18. The ANN was trained and cross-validated on 113 patients (62 female, mean age ± SD =29.5 ± 13.6 years) with manually segmented FCDs and 362 healthy controls (161 female, mean age ± SD =30.2 ± 9.6 years) acquired on 13 different scanners. In addition, we validated the performance of the trained ANN on an independent, unseen data set of 60 FCD patients (28 female, mean age ± SD =30 ± 15.26 years) and 70 healthy controls (42 females, mean age ± SD = 40.0 ± 12.54 years). RESULTS: In the cross-validation, the ANN achieved a sensitivity of 87.4% at a specificity of 85.4% on the training data set. On the independent validation data set, our method still reached a sensitivity of 81.0% at a comparably high specificity of 84.3%. SIGNIFICANCE: Our method shows a robust automated detection of FCDs and performance generalizability, largely independent of scanning site or MR-sequence parameters. Taken together with the minimal input requirements of a standard T1 image, our approach constitutes a clinically viable and useful tool in the presurgical diagnostic routine for drug-resistant focal epilepsy. ispartof: EPILEPSIA vol:62 issue:4 pages:1005-1021 ispartof: location:United States status: published

OBJECTIVE Limbic encephalitis (LE) comprises a spectrum of inflammatory changes in affected brain structures including the presence of autoantibodies and lymphoid cells. However, the potential of distinct lymphocyte subsets alone to elicit key clinicopathological sequelae of LE potentially inducing temporal lobe epilepsy (TLE) with chronic spontaneous seizures and hippocampal sclerosis (HS) is unresolved. METHODS Here, we scrutinized pathogenic consequences emerging from CD8+ T cells targeting hippocampal neurons by recombinant adeno-associated virus-mediated expression of the model-autoantigen ovalbumin (OVA) in CA1 neurons of OT-I/RAG1-/- mice (termed "OVA-CD8+ LE model"). RESULTS Viral-mediated antigen transfer caused dense CD8+ T cell infiltrates confined to the hippocampal formation starting on day 5 after virus transduction. Flow cytometry indicated priming of CD8+ T cells in brain-draining lymph nodes preceding hippocampal invasion. At the acute model stage, the inflammatory process was accompanied by frequent seizure activity and impairment of hippocampal memory skills. Magnetic resonance imaging scans at day 7 of the OVA-CD8+ LE model revealed hippocampal edema and blood-brain barrier disruption that converted into atrophy until day 40. CD8+ T cells specifically targeted OVA-expressing, SIINFEKL-H-2Kb -positive CA1 neurons and caused segmental apoptotic neurodegeneration, astrogliosis, and microglial activation. At the chronic model stage, mice exhibited spontaneous recurrent seizures and persisting memory deficits, and the sclerotic hippocampus was populated with CD8+ T cells escorted by NK cells. INTERPRETATION These data indicate that a CD8+ T-cell-initiated attack of distinct hippocampal neurons is sufficient to induce LE converting into TLE-HS. Intriguingly, the role of CD8+ T cells exceeds neurotoxic effects and points to their major pathogenic role in TLE following LE. ANN NEUROL 2021;89:666-685.

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.

Epigenetics refers broadly to processes that influence medium to long-term gene expression by changing the readability and accessibility of the genetic code. The Neurobiology Commission of the International League Against Epilepsy (ILAE) recently convened a Task Force to explore and disseminate advances in epigenetics to better understand their role and intersection with genetics and the neurobiology of epilepsies and their co-morbidities, and to accelerate translation of these findings into the development of better therapies. Here, we provide a topic primer on epigenetics, explaining the key processes and findings to date in experimental and human epilepsy. We review the growing list of genes with epigenetic functions that have been linked with epilepsy in humans. We consider potential practical applications, including using epigenetic signals as biomarkers for tissue- and biofluid-based diagnostics and the prospects for developing epigenetic-based treatments for epilepsy. We include a glossary of terms, FAQs and other supports to facilitate a broad understanding of the topic for the non-expert. Last, we review the limitations, research gaps and the next challenges. In summary, epigenetic processes represent important mechanisms controlling the activity of genes, providing opportunities for insight into disease mechanisms, biomarkers and novel therapies for epilepsy.

More than 50% of atypical meningiomas regrow within 5 years after surgery. FORGE score is a newly created tool to estimate the MIB-1 index in cranial meningiomas. In this investigation, we aimed to assess the predictive value of the FORGE score in combination with major diagnostic criteria of atypical meningioma (brain invasion, mitotic count ≥ 4) regarding recurrence in atypical meningiomas. We included patients operated on primary atypical meningiomas in our center from 2011 to 2019. The study included 71 patients (58% women, median age 63 years). ROC curves revealed a superiority of FORGE score combined with histopathological diagnostic criteria of atypical meningioma (AT-FORGE) in the prediction of tumor progression compared to FORGE score only (AUC: 0.72, 95% CI: 0.54–0.91, cut-off: ≥5/&lt, 5, sensitivity: 75%, specificity: 78%). Patients with an AT-FORGE score ≥ 5 had a shorter time to tumor progression (32.8 vs. 71.4 months, p &lt, 0.001) in the univariable analysis. Multivariable cox regression analysis revealed significant predictive value of Simpson grade &gt, II, presence of multiple meningiomas and AT-FORGE score ≥ 5 for tumor progression. The combination of histopathological diagnostic criteria for atypical meningioma with FORGE score might facilitate an effective identification of patients with an atypical meningioma who have an increased risk of tumor progression.

Stable function of networks requires that synapses adapt their strength to levels of neuronal activity, and failure to do so results in cognitive disorders. How such homeostatic regulation may be implemented in mammalian synapses remains poorly understood. Here we show that the phosphorylation status of several positions of the active-zone (AZ) protein RIM1 are relevant for synaptic glutamate release. Position RIMS1045 is necessary and sufficient for expression of silencing-induced homeostatic plasticity and is kept phosphorylated by serine arginine protein kinase 2 (SRPK2). SRPK2-induced upscaling of synaptic release leads to additional RIM1 nanoclusters and docked vesicles at the AZ and is not observed in the absence of RIM1 and occluded by RIMS1045E. Our data suggest that SRPK2 and RIM1 represent a presynaptic phosphosignaling hub that is involved in the homeostatic balance of synaptic coupling of neuronal networks.

Background and ObjectivesLimbic encephalitis (LE) is an autoimmune disease often associated with temporal lobe epilepsy and subacute memory deficits. It is categorized into serologic subgroups, which differ in clinical progress, therapy response, and prognosis. Using longitudinal MRI analysis, we hypothesized that mesiotemporal and cortical atrophy rates would reveal serotype-specific patterns and reflect disease severity.MethodsIn this longitudinal case-control study, all individuals with antibody-positive (glutamic acid decarboxylase 65 [GAD], leucine-rich glioma-inactivated protein 1 [LGI1], contactin-associated protein 2 [CASPR2], andN-methyl-d-aspartate receptor [NMDAR]) nonparaneoplastic LE according to Graus' diagnostic criteria treated between 2005 and 2019 at the University Hospital Bonn were enrolled. A longitudinal healthy cohort was included as the control group. Subcortical segmentation and cortical reconstruction of T1-weighted MRI were performed using the longitudinal framework in FreeSurfer. We applied linear mixed models to examine mesiotemporal volumes and cortical thickness longitudinally.ResultsTwo hundred fifty-seven MRI scans from 59 individuals with LE (34 female, age at disease onset [mean ± SD] 42.5 ± 20.4 years; GAD: n = 30, 135 scans; LGI1: n = 15, 55 scans; CASPR2: n = 9, 37 scans; and NMDAR: n = 5, 30 scans) were included. The healthy control group consisted of 128 scans from 41 individuals (22 female, age at first scan [mean ± SD] 37.7 ± 14.6 years). The amygdalar volume at disease onset was significantly higher in individuals with LE (p≤0.048 for all antibody subgroups) compared with that in healthy controls and decreased over time in all antibody subgroups, except in the GAD subgroup. We observed a significantly higher hippocampal atrophy rate in all antibody subgroups compared with that in healthy controls (allp≤0.002), except in the GAD subgroup. Cortical atrophy rates exceeded normal aging in individuals with impaired verbal memory, while those who were not impaired did not differ significantly from healthy controls.DiscussionOur data depict higher mesiotemporal volumes in the early disease stage, most likely due to edematous swelling, followed by volume regression and atrophy/hippocampal sclerosis in the late disease stage. Our study reveals a continuous and pathophysiologically meaningful trajectory of mesiotemporal volumetry across all serogroups and provides evidence that LE should be considered a network disorder in which extratemporal involvement is an important determinant of disease severity.

Neuro-Oncology 24(5), 741-754 (2022). doi:10.1093/neuonc/noab268, Published by Oxford Univ. Press, Oxford

Objective Inflammation of brain structures, in particular the hippocampal formation, can induce neuronal degeneration and be associated with increased excitability manifesting as propensity for repetitive seizures. An increase in the abundance of individual proinflammatory molecules including interleukin 1 beta has been observed in brain tissue samples of patients with pharmacoresistant temporal lobe epilepsy (TLE) and corresponding animal models. The NLRP3-inflammasome, a cytosolic protein complex, acts as a key regulator in proinflammatory innate immune signalling. Upon activation, it leads to the release of interleukin 1 beta and inflammation-mediated neurodegeneration. Transient brain insults, like status epilepticus (SE), can render hippocampi chronically hyperexcitable and induce segmental neurodegeneration. The underlying mechanisms are referred to as epileptogenesis. Here, we have tested the hypothesis that distinct NLRP3-dependent transcript and protein signalling dynamics are induced by SE and whether they differ between two classical SE models. We further correlated the association of NLRP3-related transcript abundance with convulsive activity in human TLE hippocampi of patients with and without associated neurodegenerative damage. Methods Hippocampal mRNA- and protein-expression of NLRP3 and associated signalling molecules were analysed longitudinally in pilocarpine- and kainic acid-induced SE TLE mouse models. Complementarily, we studied NLRP3 inflammasome-associated transcript patterns in epileptogenic hippocampi with different damage patterns of pharmacoresistant TLE patients that had undergone epilepsy surgery for seizure relief. Results Pilocarpine- and kainic acid-induced SE elicit distinct hippocampal Nlrp3-associated molecular signalling. Transcriptional activation of NLRP3 pathway elements is associated with seizure activity but independent of the particular neuronal damage phenotype in KA-induced and in human TLE hippocampi. Significance These data suggest highly dynamic inflammasome signalling in SE-induced TLE and highlight a vicious cycle associated with seizure activity. Our results provide promising perspectives for the inflammasome signalling pathway as a target for anti-epileptogenic and -convulsive therapeutic strategies. The latter may even applicable to a particularly broad spectrum of TLE patients with currently pharmacoresistant disease.

Background and ObjectiveRasmussen 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.MethodsVoxel-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.ResultsPatients 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).DiscussionWe 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.

Brain : a journal of neurology (2022). doi:10.1093/brain/awac119, Published by Oxford Univ. Press, Oxford

ZUSAMMENFASSUNGDie Schläfenlappenepilepsie stellt die häufigste fokale Epilepsieform dar. Trotz etablierter Pathologiemuster ergaben sich zuletzt grundlegende Innovationen im Hinblick sowohl auf erworbene Epilepsien mit hippocampalem Ursprung als auch bei fokalen kortikalen Dysplasien und epilepsieassoziierten, oft glioneuronalen Tumoren. Besondere Erwähnung finden Verbesserungen des molekulargenetischen Verständnisses der Erkrankungen.

Epilepsien sind haufige und stark beeintrachtigende Hirnerkrankungen mit einer erheblichen Belastung fur Betroffene und Angehorige weltweit. Die Epileptogenese wird gemeinhin als der plastische Prozess verstanden, der nach einer Schadigung (also bei erworbenen Epilepsien) mit einer Latenz zu epileptischen Anfallen fuhrt. Er ist in einzelnen Fallen bereits bis auf die molekulare Ebene hin verstanden. Die Entdeckung genetischer Defekte hat parallel entscheidend dazu beigetragen, epileptische Krankheitsmechanismen zu entschlusseln. Beide Forschungsrichtungen haben erste personalisierte Therapieansatze ermoglicht. Zudem konnen mit Epilepsie assoziierte genetische Varianten wahrscheinlich nicht nur selbst direkt Anfalle verursachen, sondern – wie bei den erworbenen Epilepsien – auch einen epileptogenen Prozess auslosen und mit der altersabhangigen Hirnentwicklung interagieren, sodass sich schlieslich genetische Epilepsiesyndrome mit der typischen Altersabhangigkeit manifestieren. Diese Zusammenhange und daraus erwachsende personalisierte Therapiemoglichkeiten werden in diesem Artikel dargestellt.

Transient brain insults, including status epilepticus (SE), can trigger a period of epileptogenesis during which functional and structural reorganization of neuronal networks occurs resulting in the onset of focal epileptic seizures. In recent years, mechanisms that regulate the dynamic transcription of individual genes during epileptogenesis and thereby contribute to the development of a hyperexcitable neuronal network have been elucidated. Our own results have shown early growth response 1 (Egr1) to transiently increase expression of the T-type voltage-dependent Ca2+channel (VDCC) subunit CaV3.2, a key proepileptogenic protein. However, epileptogenesis involves complex and dynamic transcriptomic alterations; and so far, our understanding of the transcriptional control mechanism of gene regulatory networks that act in the same processes is limited. Here, we have analyzed whether Egr1 acts as a key transcriptional regulator for genes contributing to the development of hyperexcitability during epileptogenesis. We found Egr1 to drive the expression of the VDCC subunit α2δ4, which was augmented early and persistently after pilocarpine-induced SE. Furthermore, we show that increasing levels of α2δ4 in the CA1 region of the hippocampus elevate seizure susceptibility of mice by slightly decreasing local network activity. Interestingly, we also detected increased expression levels of Egr1 and α2δ4 in human hippocampal biopsies obtained from epilepsy surgery. In conclusion, Egr1 controls the abundance of the VDCC subunits CaV3.2 and α2δ4, which act synergistically in epileptogenesis, and thereby contributes to a seizure-induced “transcriptional Ca2+channelopathy.”SIGNIFICANCE STATEMENTThe onset of focal recurrent seizures often occurs after an epileptogenic process induced by transient insults to the brain. Recently, transcriptional control mechanisms for individual genes involved in converting neurons hyperexcitable have been identified, including early growth response 1 (Egr1), which activates transcription of the T-type Ca2+channel subunit CaV3.2. Here, we find Egr1 to regulate also the expression of the voltage-dependent Ca2+channel subunit α2δ4, which was augmented after pilocarpine- and kainic acid-induced status epilepticus. In addition, we observed that α2δ4 affected spontaneous network activity and the susceptibility for seizure induction. Furthermore, we detected corresponding dynamics in human biopsies from epilepsy patients. In conclusion, Egr1 orchestrates a seizure-induced “transcriptional Ca2+channelopathy” consisting of CaV3.2 and α2δ4, which act synergistically in epileptogenesis.

Purpose: Focal cortical dysplasias (FCDs) are a frequent cause of drug-resistant focal epilepsies. These lesions are in many cases amenable to epilepsy surgery. We examined 12-month and long-term post-surgical outcomes and its predictors including positive family history of epilepsy.Methods: Twelve-month and long-term outcomes regarding seizure control after epilepsy surgery in patients operated on with FCD type II between 2002 and 2019 in the Epilepsy Center of Bonn were evaluated based on patient records and telephone interviews.Results: Overall, 102 patients fulfilled the inclusion criteria. Seventy-one percent of patients at 12 months of follow-up (FU) and 54% of patients at the last available FU (63 ± 5.00 months, median 46.5 months) achieved complete seizure freedom (Engel class IA), and 84 and 69% of patients, respectively, displayed Engel class I outcome. From the examined variables [histopathology: FCD IIA vs. IIB, lobar lesion location: frontal vs. non-frontal, family history for epilepsy, focal to bilateral tonic–clonic seizures (FTBTCS) in case history, completeness of resection, age at epilepsy onset, age at surgery, duration of epilepsy], outcomes at 12 months were determined by interactions of age at onset, duration of epilepsy, age at surgery, extent of resection, and lesion location. Long-term post-surgical outcome was primarily influenced by the extent of resection and history of FTBTCS. Positive family history for epilepsy had a marginal influence on long-term outcomes only.Conclusion: Resective epilepsy surgery in patients with FCD II yields very good outcomes both at 12-month and long-term follow-ups. Complete lesion resection and the absence of FTBTCS prior to surgery are associated with a better outcome.

The MIB-1 index is an essential predictor of progression-free-survival (PFS) in meningioma. To date, the MIB-1 index is not available in preoperative treatment planning. A preoperative score estimating the MIB-1 index in patients with intracranial meningiomas has not been investigated so far. Between 2013 and 2019, 208 patients with tumor morphology data, MIB-1 index data, and plasma fibrinogen and serum C-reactive protein (CRP) data underwent surgery for intracranial WHO grade I and II meningioma. An optimal MIB-1 index cut-off value (≥6/&lt, 6) in the prediction of recurrence was determined by ROC curve analysis (AUC: 0.71, 95% CI: 0.55–0.87). A high MIB-1 index (≥6%) was present in 50 cases (24.0%) and was significantly associated with male sex, peritumoral edema, low baseline CRP, and low fibrinogen level in the multivariate analysis. A scoring system (“FORGE”) based on sex, peritumoral edema, preoperative CRP value, and plasma fibrinogen level supports prediction of the MIB-1 index (sensitivity 62%, specificity 79%). The MIB-1 labeling index and the FORGE score are significantly associated with an increased risk of poor PFS time. We suggest a novel score (“FORGE”) to preoperatively estimate the risk of an increased MIB-1 index (≥6%), which might help in surgical decision making and follow-up interval determination and inform future trials investigating inflammatory burden and proliferative activity.

OBJECTIVE Focal cortical dysplasia (FCD) is a common cause of early-onset intractable epilepsy, and resection is a highly sufficient treatment option. In this study, the authors aimed to provide a retrospective analysis of pre- and postoperative factors and their impact on postoperative long-term seizure outcome. METHODS The postoperative seizure outcomes of 50 patients with a mean age of 8 ± 4.49 years and histologically proven FCD type II were retrospectively analyzed. Furthermore, pre- and postoperative predictors of long-term seizure freedom were assessed. The seizure outcome was evaluated based on the International League Against Epilepsy (ILAE) classification. RESULTS Complete resection of FCD according to MRI criteria was achieved in 74% (n = 37) of patients. ILAE class 1 at the last follow-up was achieved in 76% (n = 38) of patients. A reduction of antiepileptic drugs (AEDs) to monotherapy or complete withdrawal was achieved in 60% (n = 30) of patients. Twelve patients (24%) had a late seizure recurrence, 50% (n = 6) of which occurred after reduction of AEDs. A lower number of AEDs prior to surgery significantly predicted a favorable seizure outcome (p = 0.013, HR 7.63). Furthermore, younger age at the time of surgery, shorter duration of epilepsy prior to surgery, and complete resection were positive predictors for long-term seizure freedom. CONCLUSIONS The duration of epilepsy, completeness of resection, number of AEDs prior to surgery, and younger age at the time of surgery served as predictors of postoperative long-term seizure outcome, and, as such, may improve clinical practice when selecting and counseling appropriate candidates for resective epilepsy surgery. The study results also underscored that epilepsy surgery should be considered early in the disease course of pediatric patients with FCD type II.

OBJECTIVE: Medial temporal lobe epilepsy (MTLE) is a drug-resistant focal epilepsy that can be caused by a broad spectrum of different inciting events, including tumors, febrile seizures, and viral infections. In human epilepsy surgical resections as well as in animal models, an involvement of the adaptive immune system was observed. We here analyzed the presence of T cells in various subgroups of MTLE. We aimed to answer the question of how much inflammation was present and whether the presence of T cells was associated with seizures or associated with hippocampal neurodegeneration.; METHODS: We quantified the numbers of CD3+ T cells and CD8+ cytotoxic T cells in the hippocampus of patients with gangliogliomas (GGs; intrahippocampal and extrahippocampal, with and without sclerosis), febrile seizures, and postinfectious encephalitic epilepsy and compared this with Rasmussen encephalitis, Alzheimer disease, and normal controls.; RESULTS: We could show that T cell numbers were significantly elevated in MTLE compared to healthy controls. CD3+ as well as CD8+ T cell numbers, however, varied highly among MTLE subgroups. By comparing GG patients with and without hippocampal sclerosis (HS), we were able to show that T-cell numbers were increased in extrahippocampal GG patients with hippocampal neuronal loss and HS, whereas extrahippocampal GG cases without hippocampal neuronal loss (i.e., absence of HS) did not differ from healthy controls. Importantly, T cell numbers in MTLE correlated with the degree of neuronal loss, whereas no correlation with seizure frequency or disease duration was found. Finally, we found that in nearly all MTLE groups, T cell numbers remained elevated even years after the inciting event.; SIGNIFICANCE: We here provide a detailed histopathological investigation of the involvement of T cells in various subgroups of MTLE, which suggests that T cell influx correlates to neuronal loss rather than seizure activity. © 2021 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.