Project description:Samples used in the study originated from three UK sites: the Walton Centre for Neurology and Neurosurgery in Liverpool, the Salford Royal Hospital in Salford and the Southern General Hospital in Glasgow. We recruited patients with pharmacoresistant mesial temporal lobe epilepsy for whom a therapeutic temporal lobectomy was being undertaken. After surgery, the hippocampus was divided into two portions: (1) one portion was preserved for RNA isolation, and (2) the other portion underwent histological analysis by an experienced neuropathologist. Frozen post-mortem histologically-normal hippocampal samples from donors with no known brain diseases were obtained from the MRC Edinburgh Brain Bank (Edinburgh, UK) and the Queen Square Brain Bank (London, UK). Brain samples were disrupted and homogenized in an appropriate volume of QIAzol lysis reagent (Qiagen, Crawley, United Kingdom) by using a TissueRuptor handheld rotor-stator homogenizer (Qiagen, Crawley, United Kingdom). Total RNA was extracted from the homogenates using the RNeasy Lipid Tissue Mini Kit (Qiagen, Crawley, United Kingdom), according to the manufacturer’s instructions. RNA quality was examined by capillary electrophoresis on an Agilent Bioanalyzer 2100 (Agilent, Palo Alto, CA) and Agilent 2100 Expert software was used to calculate the RNA Integrity number (RIN) of each sample. Purity of the RNA sample was assessed using a NanoDrop1000 Spectrophotometer. Capillary electrophoresis traces were also examined. Samples with RNA integrity number scores (RIN) below 6, obvious RNA degradation, significant 18S or 28S ribosomal RNA degradation, ratio of absorbance at 260nm and 280nm <1.95, or with noticeable DNA or background contaminants did not pass QC, and were withheld from microarray analysis. The microarrays were processed at the Centre for Genomics Research in the University of Liverpool (http://www.liv.ac.uk/genomic-research/). 50ng of total RNA was amplified and labelled using the Agilent Low Input Quick Amp One-Colour Labeling Kit and labelled RNA was hybridized to Agilent SurePrint G3 Custom Exon 8x60K Microarrays designed to contain probes for each exon of 936 selected genes, including all known SLC genes. Standard Agilent protocols were followed. One array failed on five of the QC criteria and, hence, was excluded. Intensity data were extracted from the remaining arrays using the Feature Extraction Software, in line with the manufacturer’s recommendations. The uploaded files contain data both for a custom exon array designed to contain probes for each exon of 936 selected genes and for a custom gene expression array designed to contain gene expression probes for genes across the whole genome.

Project description:Neuropathology-based studies in neurosurgically resected brain tissue obtained from carefully examined patients with focal epilepsies remain a treasure box for excellent insights into human neuroscience, including avenues to better understand the neurobiology of human brain organization and neuronal hyperexcitability at the cellular level including glio-neuronal interaction. It also allows to translate results from animal models in order to develop personalized treatment strategies in the near future. A nice example of this is the discovery of a new disease entity in 2017, termed mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy or MOGHE, in the frontal lobe of young children with intractable seizures. In 2021, a brain somatic missense mutation of the galactose transporter SLC35A2 leading to altered glycosylation of lipoproteins in the Golgi apparatus was detected in 50 % of MOGHE samples. In 2023, the first clinical trial evaluated galactose supplementation in patients with histopathologically confirmed MOGHE carrying brain somatic SLC35A2 mutations that were not seizure free after surgery. The promising results of this pilot trial are an example of personalized medicine in the arena of epileptology. Besides this, neuropathological studies of epilepsy samples have revealed many other fascinating results for the main disease categories in focal epilepsies, such as the first deep-learning based classifier for Focal Cortical Dysplasia, or the genomic landscape of cortical malformations showing new candidate genes such as PTPN11, which is associated with ganglioglioma and adverse clinical outcome. This update will also ask why common pathogenic variants accumulate in certain brain regions, e.g., MTOR in the frontal lobe, and BRAF in the temporal lobe. Finally, I will highlight the ongoing discussion addressing commonalities between temporal lobe epilepsy and Alzheimer's disease, the impact of adult neurogenesis and gliogenesis for the initiation and progression of temporal lobe seizures in the human brain as well as the immunopathogenesis of glutamic acid decarboxylase antibody associated temporal lobe epilepsy as a meaningful disease entity. This review will update the reader on some of these fascinating publications from 2022 and 2023 which were selected carefully, yet subjectively, by the author.

Project description:Focality in electro-clinical or neuroimaging data often motivates epileptologists to consider epilepsy surgery in patients with medically-uncontrolled seizures, while not all focal findings are causally associated with the generation of epileptic seizures. With the help of Hill's criteria, we have discussed how to establish causality in the context of the presurgical evaluation of epilepsy. The strengths of EEG include the ability to determine the temporal relationship between cerebral activities and clinical events; thus, scalp video-EEG is necessary in the evaluation of the majority of surgical candidates. The presence of associated ictal discharges can confirm the epileptic nature of a particular spell and whether an observed neuroimaging abnormality is causally associated with the epileptic seizure. Conversely, one should be aware that scalp EEG has a limited spatial resolution and sometimes exhibits propagated epileptiform discharges more predominantly than in situ discharges generated at the seizure-onset zone. Intraoperative or extraoperative electrocorticography (ECoG) is utilized when noninvasive presurgical evaluation, including anatomical and functional neuroimaging, fails to determine the margin between the presumed epileptogenic zone and eloquent cortex. Retrospective as well as prospective studies have reported that complete resection of the seizure-onset zone on ECoG was associated with a better seizure outcome, but not all patients became seizure-free following such resective surgery. Some retrospective studies suggested that resection of sites showing high-frequency oscillations (HFOs) at >80Hz on interictal or ictal ECoG was associated with a better seizure outcome. Others reported that functionally-important areas may generate HFOs of a physiological nature during rest as well as sensorimotor and cognitive tasks. Resection of sites showing task-related augmentation of HFOs has been reported to indeed result in functional loss following surgery. Thus, some but not all sites showing interictal HFOs are causally associated with seizure generation. Furthermore, evidence suggests that some task-related HFOs can be transiently suppressed by the prior occurrence of interictal spikes. The significance of interictal HFOs should be assessed by taking into account the eloquent cortex, seizure-onset zone, and cortical lesions. Video-EEG and ECoG generally provide useful but still limited information to establish causality in presurgical evaluation. A comprehensive assessment of data derived from multiple modalities is ultimately required for successful management.

Project description:ObjectiveDespite modern anti-epileptic drug treatment, approximately 30% of epilepsies remain medically refractory and for these patients, epilepsy surgery may be a treatment option. There have been numerous studies demonstrating good outcome of epilepsy surgery in the short to median term however, there are a limited number of studies looking at the long-term outcomes. The aim of this study was to ascertain the long-term outcome of resective epilepsy surgery in a large neurosurgery hospital in the U.K.MethodsThis a retrospective analysis of prospectively collected data. We used the 2001 International League Against Epilepsy (ILAE) classification system to classify seizure freedom and Kaplan-Meier survival analysis to estimate the probability of seizure freedom.ResultsWe included 284 patients who underwent epilepsy surgery (178 anterior temporal lobe resections, 37 selective amygdalohippocampectomies, 33 temporal lesionectomies, 36 extratemporal lesionectomies), and had a prospective median follow-up of 5 years (range 1-27). Kaplan-Meier estimates showed that 47% (95% CI 40-58) remained seizure free (apart from simple partial seizures) at 5 years and 38% (95% CI 31-45) at 10 years after surgery. 74% (95% CI 69-80) had a greater than 50% seizure reduction at 5 years and 70% (95% CI 64-77) at 10 years. Patients who had an amygdalohippocampectomy were more likely to have seizure recurrence than patients who had an anterior temporal lobe resection (p = 0.006) and temporal lesionectomy (p = 0.029). There was no significant difference between extra temporal and temporal lesionectomies. Hippocampal sclerosis was associated with a good outcome but declined in relative frequency over the years.ConclusionThe vast majority of patients who were not seizure free experienced at least a substantial and long-lasting reduction in seizure frequency. A positive long-term outcome after epilepsy surgery is possible for many patients and especially those with hippocampal sclerosis or those who had anterior temporal lobe resections.

Project description:BACKGROUND: In British Columbia, Canada, all necessary medical services are funded publicly. Concerned with growing wait lists in the mid-1990s, the provincial government started providing extra funding for coronary artery bypass grafting (CABG) operations annually. Although aimed at improving access, it is not known whether supplementary funding changed the time that patients spent on wait lists for CABG. We sought to determine whether the period of registration on wait lists had an effect on time to isolated CABG and whether the period effect was similar across priority groups. METHODS: Using records from a population-based registry, we studied the wait-list time before and after supplementary funding became available. We compared the number of weeks from registration to surgery for equal proportions of patients in synthetic cohorts defined by five registration periods in the 1990s. RESULTS: Overall, 9,231 patients spent a total of 137,126 person-weeks on the wait lists. The time to surgery increased by the middle of the decade, and decreased toward the end of the decade. Relative to the 1991-92 registration period, the conditional weekly probabilities of undergoing surgery were 30% lower among patients registered on the wait lists in 1995-96, hazard ratio (HR) = 0.70 (0.65-0.76), and 23% lower in 1997-98 patients, HR = 0.77 (0.71-0.83), while there were no differences with 1999-2000 patients, HR = 0.94 (0.88-1.02), after adjusting for priority group at registration, comorbidity, age and sex. We found that the effect of registration period was different across priority groups. CONCLUSION: Our results provide evidence that time to CABG shortened after supplementary funding was provided on an annual basis to tertiary care hospitals within a single publicly funded health system. One plausible explanation is that these hospitals had capacity to increase the number of operations. At the same time, the effect was not uniform across priority groups indicating that changes in clinical practice should be considered when adding extra funding to reduce wait lists.

Project description:Importance:Although wait times for hip fracture surgery have been linked to mortality and are being used as quality-of-care indicators worldwide, controversy exists about the duration of the wait that leads to complications. Objective:To use population-based wait-time data to identify the optimal time window in which to conduct hip fracture surgery before the risk of complications increases. Design, Setting, and Participants:Population-based, retrospective cohort study of adults undergoing hip fracture surgery between April 1, 2009, and March 31, 2014, at 72 hospitals in Ontario, Canada. Risk-adjusted restricted cubic splines modeled the probability of each complication according to wait time. The inflection point (in hours) when complications began to increase was used to define early and delayed surgery. To evaluate the robustness of this definition, outcomes among propensity-score matched early and delayed surgical patients were compared using percent absolute risk differences (RDs, with 95% CIs). Exposure:Time elapsed from hospital arrival to surgery (in hours). Main Outcomes and Measures:Mortality within 30 days. Secondary outcomes included a composite of mortality or other medical complications (myocardial infarction, deep vein thrombosis, pulmonary embolism, and pneumonia). Results:Among 42 230 patients with hip fracture (mean [SD] age, 80.1 years [10.7], 70.5% women) who met study entry criteria, overall mortality at 30 days was 7.0%. The risk of complications increased when wait times were greater than 24 hours, irrespective of the complication considered. Compared with 13 731 propensity-score matched patients who received surgery earlier, 13 731 patients who received surgery after 24 hours had a significantly higher risk of 30-day mortality (898 [6.5%] vs 790 [5.8%]; % absolute RD, 0.79; 95% CI, 0.23-1.35) and the composite outcome (1680 [12.2%]) vs 1383 [10.1%]; % absolute RD, 2.16; 95% CI, 1.43-2.89). Conclusions and Relevance:Among adults undergoing hip fracture surgery, increased wait time was associated with a greater risk of 30-day mortality and other complications. A wait time of 24 hours may represent a threshold defining higher risk.

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Epilepsy Surgery Works - So Why the Wait?

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