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

Development after epilepsy surgery in children

The aim of this thesis was to explore the development of children who underwent epilepsy surgery, based on a series of questions that arose from the clinical care for these patients. Different aspects of cognitive outcome following epilepsy surgery in children, in particular hemispherectomy, were explored. The study addressing the influence of AED withdrawal on intelligence quotient (IQ) was performed on data from a large European multicenter group of pediatric epilepsy surgery patients (TimeToStop study). The other studies are based on standardized longitudinal assessment performed in a cohort of Dutch children who underwent epilepsy surgery in the UMCU between 1992 and 2009. Chapter 2 provides a critical review of the literature with respect to predictors of cognitive change and eventual cognitive outcome after epilepsy surgery. Early surgical intervention may halt deterioration and open the possibility for appropriate development relative to the pre-surgical situation. It is, however, unlikely that surgery results in major improvement of MDI/DQ/IQ values. True developmental decline, in the sense of permanent deterioration, is rare. Multiple variables, of which many mutually dependent, determine cognitive development after epilepsy surgery. Unraveling their respective impacts requires studies in large cohorts and advanced statistical methodology. Chapter 3 reports on the attempt to detect change in mental development or intelligence over two years following functional hemispherectomy. Measuring mental age as a marker of development allows one to at least unveil and quantify minor change in poor cognitive functioning. Such change may go unnoticed when relying on intelligence quotients. We found that MRI-abnormalities in the ‘healthy’ contralateral hemisphere are significantly associated not only with seizure recurrence but also with severe mental delay and less increase in IQ-scores after functional hemispherectomy. Chapter 5 reports on functioning of patients five to eleven years after childhood hemispherectomy. At least half a decade after hemispherectomy, cognition, behavior and daily functioning vary from profound retardation and almost complete dependence on others to relatively unproblematic functioning. We retrospectively evaluated the impact of post-surgical antiepileptic drug (AED) withdrawal on psychomotor speed (chapter 6) as well as on intelligence (chapter 7), in seizure-free children who had been operated on for pharmacoresistant epilepsy. We concluded that drug reduction after surgery improves psychomotor speed and IQ. Our findings are promising and add to the growing body of knowledge with respect to AED effects on several aspects of functioning. In Chapter 8 we report that Children of higher educated parents had on average a larger increase in IQ after surgery and a higher post-surgical – but not pre-surgical – IQ than children whose parents had completed at most lower secondary education. Environmental variables such as parental education should be considered in the prognosis of cognitive change after childhood epilepsy surgery. In Chapter 9 we report how parents and patients evaluate the decision to agree with epilepsy surgery in their children. With the benefit of hindsight, even epilepsy surgery that does not result in seizure freedom is felt to be beneficial. Most patients and their parents would opt again for epilepsy surgery. Main conclusions are discussed (Chapter 10)

Development after epilepsy surgery in children

The aim of this thesis was to explore the development of children who underwent epilepsy surgery, based on a series of questions that arose from the clinical care for these patients. Different aspects of cognitive outcome following epilepsy surgery in children, in particular hemispherectomy, were explored. The study addressing the influence of AED withdrawal on intelligence quotient (IQ) was performed on data from a large European multicenter group of pediatric epilepsy surgery patients (TimeToStop study). The other studies are based on standardized longitudinal assessment performed in a cohort of Dutch children who underwent epilepsy surgery in the UMCU between 1992 and 2009. Chapter 2 provides a critical review of the literature with respect to predictors of cognitive change and eventual cognitive outcome after epilepsy surgery. Early surgical intervention may halt deterioration and open the possibility for appropriate development relative to the pre-surgical situation. It is, however, unlikely that surgery results in major improvement of MDI/DQ/IQ values. True developmental decline, in the sense of permanent deterioration, is rare. Multiple variables, of which many mutually dependent, determine cognitive development after epilepsy surgery. Unraveling their respective impacts requires studies in large cohorts and advanced statistical methodology. Chapter 3 reports on the attempt to detect change in mental development or intelligence over two years following functional hemispherectomy. Measuring mental age as a marker of development allows one to at least unveil and quantify minor change in poor cognitive functioning. Such change may go unnoticed when relying on intelligence quotients. We found that MRI-abnormalities in the ‘healthy’ contralateral hemisphere are significantly associated not only with seizure recurrence but also with severe mental delay and less increase in IQ-scores after functional hemispherectomy. Chapter 5 reports on functioning of patients five to eleven years after childhood hemispherectomy. At least half a decade after hemispherectomy, cognition, behavior and daily functioning vary from profound retardation and almost complete dependence on others to relatively unproblematic functioning. We retrospectively evaluated the impact of post-surgical antiepileptic drug (AED) withdrawal on psychomotor speed (chapter 6) as well as on intelligence (chapter 7), in seizure-free children who had been operated on for pharmacoresistant epilepsy. We concluded that drug reduction after surgery improves psychomotor speed and IQ. Our findings are promising and add to the growing body of knowledge with respect to AED effects on several aspects of functioning. In Chapter 8 we report that Children of higher educated parents had on average a larger increase in IQ after surgery and a higher post-surgical – but not pre-surgical – IQ than children whose parents had completed at most lower secondary education. Environmental variables such as parental education should be considered in the prognosis of cognitive change after childhood epilepsy surgery. In Chapter 9 we report how parents and patients evaluate the decision to agree with epilepsy surgery in their children. With the benefit of hindsight, even epilepsy surgery that does not result in seizure freedom is felt to be beneficial. Most patients and their parents would opt again for epilepsy surgery. Main conclusions are discussed (Chapter 10)

Effects of sodium bicarbonate on VO2 kinetics during heavy exercise

Objective: To know whether change in the intelligence quotient (IQ) of children who undergo epilepsy surgery is associated with the educational level of their parents. Methods: Retrospective analysis of data obtained from a cohort of children who underwent epilepsy surgery between January 1996 and September 2010. We performed simple and multiple regression analyses to identify predictors associated with IQ change after surgery. In addition to parental education, six variables previously demonstrated to be associated with IQ change after surgery were included as predictors: age at surgery, duration of epilepsy, etiology, presurgical IQ, reduction of antiepileptic drugs, and seizure freedom. We used delta IQ (IQ 2 years after surgery minus IQ shortly before surgery) as the primary outcome variable, but also performed analyses with pre- and postsurgical IQ as outcome variables to support our findings. To validate the results we performed simple regression analysis with parental education as the predictor in specific subgroups. Results: The sample for regression analysis included 118 children (60 male; median age at surgery 9.73 years). Parental education was significantly associated with delta IQ in simple regression analysis (p = 0.004), and also contributed significantly to postsurgical IQ in multiple regression analysis (p = 0.008). Additional analyses demonstrated that parental education made a unique contribution to prediction of delta IQ, that is, it could not be replaced by the illness-related variables. Subgroup analyses confirmed the association of parental education with IQ change after surgery for most groups. Significance: Children whose parents had higher education demonstrate on average a greater increase in IQ after surgery and a higher postsurgical - but not presurgical - IQ than children whose parents completed at most lower secondary education. Parental education - and perhaps other environmental variables - should be considered in the prognosis of cognitive function after childhood epilepsy surgery

Cognitive Functions in Children and Adults with Moyamoya Vasculopathy: A Systematic Review and Meta-Analysis

Contains fulltext : 199999.pdf (publisher's version ) (Open Access)BACKGROUND AND PURPOSE: Patients with moyamoya vasculopathy (MMV) may experience cognitive impairment, but its reported frequency, severity, and nature vary. In a systematic review and metaanalysis, we aimed to assess the presence, severity, and nature of cognitive impairments in children and adults with MMV. METHODS: We followed the MOOSE guidelines for meta-analysis and systematic reviews of observational studies. We searched Ovid Medline and Embase for studies published between January 1, 1969 and October 4, 2016. Independent reviewers extracted data for mean intelligence quotient (IQ) and standardized z-scores for cognitive tests, and determined percentages of children and adults with cognitive deficits, before and after conservative or surgical treatment. We explored associations between summary measures of study characteristics and cognitive impairments by linear regression analysis. RESULTS: We included 17 studies (11 studies reporting on 281 children, six on 153 adults). In children, the median percentage with impaired cognition was 30% (range, 13% to 67%); median IQ was 98 (range, 71 to 107). Median z-score was -0.39 for memory, and -0.43 for processing speed. In adults, the median percentage with impaired cognition was 31% (range, 0% to 69%); median IQ was 95 (range, 94 to 99). Median z-scores of cognitive domains were between -0.9 and -0.4, with multiple domains being affected. We could not identify determinants of cognitive impairment. CONCLUSION: s A large proportion of children and adults with MMV have cognitive impairment, with modest to large deficits across various cognitive domains. Further studies should investigate determinants of cognitive deficits and deterioration, and the influence of revascularization treatment on cognitive functioning