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

Intraoperative electrocorticography using high-frequency oscillations or spikes to tailor epilepsy surgery in the Netherlands (the HFO trial): a randomised, single-blind, adaptive non-inferiority trial

Background Intraoperative electrocorticography is used to tailor epilepsy surgery by analysing interictal spikes or spike patterns that can delineate epileptogenic tissue. High-frequency oscillations (HFOs) on intraoperative electrocorticography have been proposed as a new biomarker of epileptogenic tissue, with higher specificity than spikes. We prospectively tested the non-inferiority of HFO-guided tailoring of epilepsy surgery to spike-guided tailoring on seizure freedom at 1 year.Methods The HFO trial was a randomised, single-blind, adaptive non-inferiority trial at an epilepsy surgery centre (UMC Utrecht) in the Netherlands. We recruited children and adults (no age limits) who had been referred for intraoperative electrocorticography-tailored epilepsy surgery. Participants were randomly allocated (1:1) to either HFO-guided or spike-guided tailoring, using an online randomisation scheme with permuted blocks generated by an independent data manager, stratified by epilepsy type. Treatment allocation was masked to participants and clinicians who documented seizure outcome, but not to the study team or neurosurgeon. Ictiform spike patterns were always considered in surgical decision making. The primary endpoint was seizure outcome after 1 year (dichotomised as seizure freedom [defined as Engel 1A-11 vs seizure recurrence [Engel 1C-4]). We predefined a non-inferiority margin of 10% risk difference. Analysis was by intention to treat, with prespecified subgroup analyses by epilepsy type and for confounders. This completed trial is registered with the Dutch Trial Register, Toetsingonline ABR.NL44527.041.13, and ClinicalTrials.gov, NCT02207673.Findings Between Oct 10, 2014, and Jan 31,2020,78 individuals were enrolled to the study and randomly assigned (39 to HFO-guided tailoring and 39 to spike-guided tailoring). There was no loss to follow-up. Seizure freedom at 1 year occurred in 26 (67%) of 39 participants in the HFO-guided group and 35 (90%) of 39 in the spike-guided group (risk difference -23.5%, 90% CI -39.1 to -7.9; for the 48 patients with temporal lobe epilepsy, the risk difference was -25.5%, -45.1 to -6.0, and for the 30 patients with extratemporal lobe epilepsy it was -20.3%, -46.0 to 5.4). Pathology associated with poor prognosis was identified as a confounding factor, with an adjusted risk difference of-7.9% (90% CI -20.7 to 4.9; adjusted risk difference -12.5%, -31.0 to 5.9, for temporal lobe epilepsy and 5.8%, -7.7 to 19.5, for extratemporal lobe epilepsy). We recorded eight serious adverse events (five in the HFO-guided group and three in the spike-guided group) requiring hospitalisation. No patients died.Interpretation HFO-guided tailoring of epilepsy surgery was not non-inferior to spike-guided tailoring on intraoperative electrocorticography. After adjustment for confounders, HFOs show non-inferiority in extratemporal lobe epilepsy. This trial challenges the clinical value of HFOs as an epilepsy biomarker, especially in temporal lobe epilepsy. Further research is needed to establish whether HFO-guided intraoperative electrocorticography holds promise in extratemporal lobe epilepsy. Copyright (C) 2022 The Author(s). Published by Elsevier Ltd

Identification of Srp9 as a febrile seizure susceptibility gene

Objective: Febrile seizures (FS) are the most common seizure type in young children. Complex FS are a risk factor for mesial temporal lobe epilepsy (mTLE). To identify new FS susceptibility genes we used a forward genetic strategy in mice and subsequently analyzed candidate genes in humans. Methods: We mapped a quantitative trait locus (QTL1) for hyperthermia-induced FS on mouse chromosome 1, containing the signal recognition particle 9 (Srp9) gene. Effects of differential Srp9 expression were assessed in vivo and in vitro. Hippocampal SRP9 expression and genetic association were analyzed in FS and mTLE patients. Results: Srp9 was differentially expressed between parental strains C57BL/6J and A/J. Chromosome substitution strain 1 (CSS1) mice exhibited lower FS susceptibility and Srp9 expression than C57BL/6J mice. In vivo knockdown of brain Srp9 reduced FS susceptibility. Mice with reduced Srp9 expression and FS susceptibility, exhibited reduced hippocampal AMPA and NMDA currents. Downregulation of neuronal Srp9 reduced surface expression of AMPA receptor subunit GluA1. mTLE patients with antecedent FS had higher SRP9 expression than patients without. SRP9 promoter SNP rs12403575(G/A) was genetically associated with FS and mTLE. Interpretation: Our findings identify SRP9 as a novel FS susceptibility gene and indicate that SRP9 conveys its effects through endoplasmic reticulum (ER)-dependent synthesis and trafficking of membrane proteins, such as glutamate receptors. Discovery of this new FS gene and mechanism may provide new leads for early diagnosis and treatment of children with complex FS at risk for mTLE

Finger snapping during seizures

We describe two patients who showed snapping of the right hand fingers during invasive intracranial EEG evaluation for epilepsy surgery. We correlated the EEG changes with the finger-snapping movements in both patients to determine the underlying pathophysiology of this phenomenon. At the time of finger snapping, EEG spread from the supplementary motor area towards the temporal region was seen, suggesting involvement of these sites

High frequency oscillations and high frequency functional network characteristics in the intraoperative electrocorticogram in epilepsy

Objective: High frequency oscillations (HFOs; >80 Hz), especially fast ripples (FRs, 250–500 Hz), are novel biomarkers for epileptogenic tissue. The pathophysiology suggests enhanced functional connectivity within FR generating tissue. Our aim was to determine the relation between brain areas showing FRs and ‘baseline’ functional connectivity within EEG networks, especially in the high frequency bands. Methods: We marked FRs, ripples (80–250 Hz) and spikes in the electrocorticogram of 14 patients with refractory temporal lobe epilepsy. We assessed ‘baseline’ functional connectivity in epochs free of epileptiform events within these recordings, using the phase lag index. We computed the Eigenvector Centrality (EC) per channel in the FR and gamma band network. We compared EC between channels that did or did not show events at other moments in time. Results: FR-band EC was higher in channels with than without spikes. Gamma-band EC was lower in channels with ripples and FRs. Conclusions: We confirmed previous findings of functional isolation in the gamma-band and found a first proof of functional integration in the FR-band network of channels covering presumed epileptogenic tissue. Significance: ‘Baseline’ high-frequency network parameters might help intra-operative recognition of epileptogenic tissue without the need for waiting for events. These findings can increase our understanding of the ‘architecture’ of epileptogenic networks and help unravel the pathophysiology of HFOs

Visual Outcomes after Endoscopic Endonasal Transsphenoidal Resection of Pituitary Adenomas: Our Institutional Experience

Objectives Visual dysfunction in patients with pituitary adenomas is a clear indication for endoscopic endonasal transsphenoidal surgery (EETS). However, the visual outcomes vary greatly among patients and it remains unclear what tumor, patient, and surgical characteristics contribute to postoperative visual outcomes.Methods One hundred patients with pituitary adenomas who underwent EETS between January 2011 and June 2015 in a single institution were retrospectively reviewed. General patient characteristics, pre- and postoperative visual status, clinical presentation, tumor characteristics, hormone production, radiological features, and procedural characteristics were evaluated for association with presenting visual signs and visual outcomes postoperatively. Suprasellar tumor extension (SSE) was graded 0 to 4 following a grading system as formulated by Fujimoto et al.Results Sixty-six (66/100) of all patients showed visual field defects (VFD) at the time of surgery, of whom 18% (12/66) were asymptomatic. VFD improved in 35 (35%) patients and worsened in 4 (4%) patients postoperatively. Mean visual acuity (VA) improved from 0.67 preoperatively to 0.84 postoperatively ( p =0.04). Nonfunctioning pituitary adenomas (NFPAs) and Fujimoto grade were independent predictors of preoperative VFD in the entire cohort ( p =0.02 and p <0.01 respectively). A higher grade of SSE was the only factor independently associated with postoperative improvement of VFD ( p =0.03). NFPA and Fujimoto grade 3 were independent predictors of VA improvement (both p =0.04).Conclusion EETS significantly improved both VA and VFD for most patients, although a few patients showed deterioration of visual deficits postoperatively. Higher degrees of SSE and NFPA were independent predictors of favorable visual outcomes.Scientific Assessment and Innovation in Neurosurgical Treatment Strategie