Epilepsy surgery in tuberous sclerosis: The Dutch experience

SummaryIntroductionEpilepsy associated with tuberous sclerosis complex (TSC) is drug resistant in more than half of the patients. Epilepsy surgery may be an alternative treatment option, if the epileptogenic tuber can be identified reliably and if seizure reduction is not at the expense of cognitive or other functions. We report the pre-surgical identification of the epileptogenic tuber and post-surgical outcome of patients with TSC in The Netherlands.MethodsTwenty-five patients underwent the pre-surgical evaluation of the Dutch Comprehensive Epilepsy Surgery Programme, including a detailed seizure history, interictal and ictal video EEG registrations, 3D FLAIR MRI scans and neuropsychological testing. Suitability of the candidates was decided in consensus. Seizure outcome, scored with the Engel classification, and cognition were reassessed at fixed post-surgery intervals.ResultsEpilepsy surgery was performed in six patients. At follow-up, four patients had Engel classification 1, two had classification 4. Improved development and behaviour was perceived by the parents of two patients. Epilepsy surgery was not performed in 19 patients because seizures were not captured, ictal onset zones could not be localised or were multiple, interictal EEG, video EEG and MEG results were not concordant, or seizure burden had diminished during decision making. A higher cognition index was found in the surgical patients compared to the non-surgical candidates.ConclusionsEpilepsy surgery can be performed safely and successfully in patients in whom semiology, interictal EEG, ictal EEG, MEG and the location of tubers are concordant. In other cases the risk of surgery should be weighed against the chance of seizure relief and in case of children subsequent impact on neurodevelopment

Balloon cells promote immune system activation in focal cortical dysplasia type 2b

AIMS: Focal cortical dysplasia (FCD) type 2 is an epileptogenic malformation of the neocortex associated with somatic mutations in the mammalian target of rapamycin (mTOR) pathway. Histopathologically, FCD 2 is subdivided into FCD 2a and FCD 2b, the only discriminator being the presence of balloon cells (BCs) in FCD 2b. While pro‐epileptogenic immune system activation and inflammatory responses are commonly detected in both subtypes, it is unknown what contextual role BCs play. METHODS: The present study employed RNA sequencing of surgically resected brain tissue from FCD 2a (n = 11) and FCD 2b (n = 20) patients compared to autopsy control (n = 9) focusing on three immune system processes: adaptive immunity, innate immunity and cytokine production. This analysis was followed by immunohistochemistry on a clinically well‐characterised FCD 2 cohort. RESULTS: Differential expression analysis revealed stronger expression of components of innate immunity, adaptive immunity and cytokine production in FCD 2b than in FCD 2a, particularly complement activation and antigen presentation. Immunohistochemical analysis confirmed these findings, with strong expression of leukocyte antigen I and II in FCD 2b as compared to FCD 2a. Moreover, T‐lymphocyte tissue infiltration was elevated in FCD 2b. Expression of markers of immune system activation in FCD 2b was concentrated in subcortical white matter. Lastly, antigen presentation was strongly correlated with BC load in FCD 2b lesions. CONCLUSION: We conclude that, next to mutation‐driven mTOR activation and seizure activity, BCs are crucial drivers of inflammation in FCD 2b. Our findings indicate that therapies targeting inflammation may be beneficial in FCD 2b

Expression of circ_Satb1 is decreased in mesial temporal lobe epilepsy and regulates dendritic spine morphology

Mesial temporal lobe epilepsy (mTLE) is a chronic disease characterized by recurrent seizures that originate in the temporal lobes of the brain. Anti-epileptic drugs (AEDs) are the standard treatment for managing seizures in mTLE patients, but are frequently ineffective. Resective surgery is an option for some patients, but does not guarantee a postoperative seizure-free period. Therefore, further insight is needed into the pathogenesis of mTLE to enable the design of new therapeutic strategies. Circular RNAs (circRNAs) have been identified as important regulators of neuronal function and have been implicated in epilepsy. However, the mechanisms through which circRNAs contribute to epileptogenesis remain unknown. Here, we determine the circRNA transcriptome of the hippocampus and cortex of mTLE patients by using RNA-seq. We report 333 differentially expressed (DE) circRNAs between healthy individuals and mTLE patients, of which 23 circRNAs displayed significant adjusted p-values following multiple testing correction. Interestingly, hippocampal expression of circ_Satb1, a circRNA derived from special AT-rich sequence binding protein 1 (SATB1), is decreased in both mTLE patients and in experimental epilepsy. Our work shows that circ_Satb1 displays dynamic patterns of neuronal expression in vitro and in vivo. Further, circ_Satb1-specific knockdown using CRISPR/CasRx approaches in hippocampal cultures leads to defects in dendritic spine morphology, a cellular hallmark of mTLE. Overall, our results identify a novel epilepsy-associated circRNA with disease-specific expression and previously unidentified cellular effects that are relevant for epileptogenesis