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Abstract Lifestyle interventions are strategies used to self‐manage medical conditions, such as epilepsy, and often complement traditional pharmacologic and surgical therapies. The need for integrating evidence‐based lifestyle interventions into mainstream medicine for the treatment of epilepsy is evident given that despite the availability of a multitude of treatments with medications and surgical techniques, a significant proportion of patients have refractory seizures, and even those who are seizure‐free report significant adverse effects with current treatments. Although the evidence base for complementary medicine is less robust than it is for traditional forms of medicine, the evidence to date suggests that several forms of complementary medicine including yoga, mindfulness meditation, cognitive behavioral therapy, diet and nutrition, exercise and memory rehabilitation, and music therapy may have important roles as adjuncts in the treatment armamentarium for epilepsy. These topics were discussed by a diverse group of medical providers and scientists at the “Lifestyle Intervention for Epilepsy (LIFE)” symposium hosted by Cleveland Clinic. Plain Language Summary There are many people with epilepsy who continue to have seizures even though they are being treated with medication or brain surgery. Even after seizures stop, some may experience medication side effects. There is research to suggest that certain lifestyle changes, such as yoga, mindfulness, exercise, music therapy, and adjustments to diet, could help people with epilepsy, when used along with routine treatment. Experts discussed the latest research at the “Lifestyle Intervention for Epilepsy (LIFE)” symposium hosted by Cleveland Clinic.

Abstract Introduction Given the prevalence and staggering cost of neurological disorders, there is dire need for effective early detection and intervention tools. Emerging evidence suggests that multidisciplinary lifestyle interventions (MLI) may mitigate the risk and progression of neurological disorders. The objectives of this protocol are (1) to test the impact of MLI on the progression of neurological disorders and (2) to identify multi-omic biomarkers for early stages of neurological disease and the impact of MLIs on these biomarkers. Methods and analysis We present the Multidisciplinary lifestyle Interventions for Neurological Disorders during the Silent phase (MINDS) protocol, a randomized controlled trial of MLI in neurologically healthy older adults (≥ 50 years old) exhibiting elevated risk for common neurological disorders: stroke, epilepsy, Parkinson’s Disease, or Alzheimer’s disease and related dementias. Participants will be randomly assigned to intervention (n = 100) or control (n = 100) groups. The intervention group will receive 3 months of weekly 2-hour sessions on diet education, yoga, music therapy, and cognitive skills training. The participants’ neurological health and engagement in relevant lifestyle practices will be assessed at regular intervals for 12 months. Neuroimaging and samples for multi-omic analyses will be collected at baseline, and at 3 months and 12 months after enrollment. Primary outcomes will be signs of progression of the neurological disorder risk that qualified them for study enrollment or a clinical diagnosis of the disorder. Secondary and exploratory outcomes will be based on self-reported health and multi-omic data. Data analysis will include between-group and longitudinal within-group analyses. Perspectives The MINDS protocol and trial aims to clarify the impact of MLI on the progression of neurological disorder risk or diagnosis in older adults and to identify biomarkers that can be used to confirm MLI efficacy. The ability to validate the impact of MLI on neurological disorder progression based on biomarker data allows the identification of individuals most likely to benefit from such therapies in the early stages of neurological disease. Trial registration The trial is registered on the National Institutes of Health (NIH) ClinicalTrials.gov (NCT05984056) site. It was registered on August 2nd, 2023. The trial has full approval of the Cleveland Clinic Internal Review Board.

ObjectiveSeizure outcomes after brain surgery for drug-resistant epilepsy (DRE) are very heterogeneous and difficult to predict with models utilizing the current clinical, imaging, and electrophysiological variables. In this pilot study, we investigated whether genetic and molecular biomarkers (e.g., genomic, transcriptomic) can provide additional insight into differential response to surgery.MethodsPost-operative seizure-outcomes were collected at last follow-up (>6 months) for 201 adult patients with DRE who underwent surgery between 2004 and 2020. Resected tissue was sent for miRNA sequencing (n = 132) and mRNA sequencing (n = 135). Following the selection of 10 genes (SCN1A, NBEA, PTEN, GABRA1, LGL1, DEPDC5, IL1A, ABCB1, C3, CALHM1), we investigated SNPs in those 10 genes from previously acquired exome sequencing data (n = 106). Logistic regression was performed to test for associations between individual features (mRNAs, miRNAs, and SNPs) and post-operative seizure-outcome with an exploratory FDR P < 0.25 as the threshold for significance. Post-operative time-to-seizure analyses were performed for each SNP using a Cox proportional hazards model.ResultsThe majority of patients (83%) had temporal lobe epilepsy. Mean age at surgery was 38.3 years, and 56% were female. Three SNPs (rs10276036, rs11975994, rs1128503) in multi-drug resistance gene, ABCB1, were associated with post-operative seizure outcomes. Patients with alternate alleles in ABCB1 were more likely to be seizure-free at last follow-up (52–56% reduction in seizure recurrence; FDR P = 0.24). All three SNPs were in linkage disequilibrium and highly correlated with each other. Median post-operative time-to-seizure was 63 months for patients with 2 alternate alleles, 24–33 months with 1 alternate allele, and 10–11 months with 0 alternate alleles. These SNPs improved outcome prediction beyond MRI and sex alone. No independent miRNAs or mRNAs were significantly associated with seizure-outcome (P > 0.05). However, pathway analysis identified “cancer drug resistance by drug efflux” (mir-154 and mir-379) as enriched (P = 0.02), supporting the role of drug response genes in post-operative seizure recurrence.SignificanceABCB1 may have a role in epileptogenesis and surgery outcomes independent of its drug efflux activity necessitating further investigation. SNPs in ABCB1 may serve as independent predictors of post-operative outcome.

Epilepsy surgery is an effective treatment option for drug-resistant focal epilepsy patients with associated structural brain lesions. However, little epidemiological data are available regarding the number of patients with these lesions. We reviewed data regarding (1) the prevalence and incidence of epilepsy; (2) the proportion of epilepsy patients with focal epilepsy, drug-resistant epilepsy, and drug-resistant focal epilepsies; and (3) the number of epilepsy presurgical evaluations and surgical resections. We also assessed the relative proportion of brain lesions using post-surgical histopathological findings from 541 surgical patients from the Cleveland Clinic and 9,523 patients from a European multi-center cohort. Data were combined to generate surgical candidate incidence and prevalence estimates and the first lesion-specific estimates for hippocampal sclerosis (HS), low-grade epilepsy-associated brain tumors (LEAT), malformations of cortical development (MCD), glial scars, vascular malformations, and encephalitis. The most frequently diagnosed brain lesions were HS (incidence = 2.32 ± 0.26 in 100,000, prevalence = 19.40 ± 2.16 in 100,000) for adults and MCD (incidence = 1.15 ± 0.34 in 100,000, prevalence = 6.52 ± 1.89 in 100,000) for children. Our estimates can guide patient advocacy groups, clinicians, researchers, policymakers in education, development of health care strategy, resource allocation, and reimbursement schedules.

Multimodal image integration (MMII) is a promising tool to help delineate the epileptogenic zone (EZ) in patients with medically intractable focal epilepsies undergoing presurgical evaluation. We report here the detailed methodology of MMII and an overview of the utility of MMII at the Cleveland Clinic Epilepsy Center from 2014 to 2018, exemplified by illustrative cases. The image integration was performed using the Curry platform (Compumedics Neuroscan™, Charlotte, NC, USA), including all available diagnostic modalities such as Magnetic resonance imaging (MRI), Positron Emission Tomography (PET), single-photon emission computed tomography (SPECT) and Magnetoencephalography (MEG), with additional capability of trajectory planning for intracranial EEG (ICEEG), particularly stereo-EEG (SEEG), as well as surgical resection planning. In the 5-year time span, 467 patients underwent MMII; of them, 98 patients (21%) had a history of prior neurosurgery and recurring seizures. Of the 467 patients, 425 patients underwent ICEEG implantation with further CT co-registration to identify the electrode locations. A total of 351 patients eventually underwent surgery after MMII, including 197 patients (56%) with non-lesional MRI and 223 patients (64%) with extra-temporal lobe epilepsy. Among 269 patients with 1-year post-operative follow up, 134 patients (50%) had remained completely seizure-free. The most common histopathological finding is focal cortical dysplasia. Our study illustrates the usefulness of MMII to enhance SEEG electrode trajectory planning, assist non-invasive/invasive data interpretation, plan resection strategy, and re-evaluate surgical failures. Information presented by MMII is essential to the understanding of the anatomo-functional-electro-clinical correlations in individual cases, which leads to the ultimate success of presurgical evaluation of patients with medically intractable focal epilepsies.

Summary Patients 60 years or older are one of the highest risk age groups for development of epilepsy. Clinical and neuroimaging analysis has typically accounted for etiology in two‐thirds of these patients, while the data on histopathology are lacking. We provide the first analysis of the histopathological substrates underlying drug‐resistant epilepsy (DRE) in older adults/elderly patients who underwent resective epilepsy surgery (RES) at Cleveland Clinic. A total of 78 patients (mean age ± standard deviation: 64.7 ± 3.7 years; 59% female) were included in the study. The most common pathologies included hippocampal sclerosis (HS; 35.9%; all visible on magnetic resonance imaging [MRI]), focal cortical dysplasia (FCD; 25.6%) and remote infarct/ischemic changes (12.8%). Underlying pathology did not differ significantly between the patients achieving a good seizure outcome (Engel class I; 77% [47 of 61 patients]) and the rest of the cohort. With one exception, all MRI‐negative cases had FCD type Ib. A receiver‐operating characteristic (ROC) curve analysis found a significant association (P = 0.002) between seizure‐onset age and HS, whereby the odds of its presence were reduced by 4% for every 1 year increase in the age at seizure onset. The model showed that the age cutoff for seizure onset predicting HS was 43 years, with a negative predictive value of 81.6%. None of the 14 patients with late‐onset epilepsy (≥60 years of age) were found to have HS; they mostly had acquired lesions. Our study provides histopathologic evidence for the diminished role of late‐onset HS in DRE in older adults/elderly who undergo RES.

Perfusion patterns observed in Subtraction Ictal SPECT Co-registered to MRI (SISCOM) assist in focus localization and surgical planning for patients with medically intractable focal epilepsy. While the localizing value of SISCOM has been widely investigated, its relationship to the underlying electrophysiology has not been extensively studied and is therefore not well understood. In the present study, we set to investigate this relationship in a cohort of 70 consecutive patients who underwent ictal and interictal SPECT studies and subsequent stereo-electroencephalography (SEEG) monitoring for localization of the epileptogenic focus and surgical intervention. Seizures recorded during SEEG evaluation (SEEG seizures) were matched to semiologically-similar seizures during the preoperative ictal SPECT evaluation (SPECT seizures) by comparing the semiological changes in the course of each seizure. The spectral changes of the ictal SEEG with respect to interictal ones over 7 traditional frequency bands (0.1 to 150Hz) were analyzed at each SEEG site. Neurovascular (SEEG/SPECT) relations were assessed by comparing the estimated spectral power density changes of the SEEG at each site with the perfusion changes (SISCOM z-scores) estimated from the acquired SISCOM map at that site. Across patients, a significant correlation (p

Objective: The recent FDA approval of the first 7T MRI scanner for clinical diagnostic use in October 2017 will likely increase the utilization of 7T for epilepsy presurgical evaluation. This study aims at accessing the radiological and clinical value of 7T in patients with pharmacoresistant focal epilepsy and 3T-visible lesions.Methods: Patients with pharmacoresistant focal epilepsy were included if they had a lesion on pre-operative standard-of-care 3T MRI and also a 7T research MRI. An epilepsy protocol was used for the acquisition of the 7T MRI. Prospective visual analysis of 7T MRI was performed by an experienced board-certified neuroradiologist and communicated to the patient management team. The clinical significance of the additional 7T findings was assessed by intracranial EEG (ICEEG) ictal onset, surgical resection, post-operative seizure outcome and histopathology. A subset of lesions were demarked with arrows for subsequent, retrospective comparison between 3T and 7T by 7 neuroradiologists using a set of quantitative scales: lesion presence, conspicuity, boundary, gray-white tissue contrast, artifacts, and the most helpful sequence for diagnosis. Conger's kappa for multiple raters was performed for chance-adjusted agreement statistics.Results: A total of 47 patients were included, with the main pathology types of focal cortical dysplasia (FCD), hippocampal sclerosis, periventricular nodular heterotopia (PVNH), tumor and polymicrogyria (PMG). 7T detected additional smaller lesions in 19% (9/47) of patients, who had extensive abnormalities such as PMG and PVNH; however, these additional findings were not necessarily epileptogenic. 3T−7T comparison by the neuroradiologist team showed that lesion conspicuity and lesion boundary were significantly better at 7T (p < 0.001), particularly for FCD, PVNH and PMG. Chance-adjusted agreement was within the fair range for lesion presence, conspicuity and boundary. Gray-white contrast was significantly improved at 7T (p < 0.001). Significantly more artifacts were encountered at 7T (p < 0.001).Significance: For patients with 3T-visible lesions, 7T MRI may better elucidate the extent of multifocal abnormalities such as PVNH and PMG, providing potential targets to improve ICEEG implantation. Patients with FCD, PVNH and PMG would likely benefit the most from 7T due to improved lesion conspicuity and boundary. Pathologies in the antero–inferior temporal regions likely benefit less due to artifacts.

Object: The objective of the study is to investigate and report our experience with extra operative intracranial EEG monitoring for evaluation of epilepsy surgery among elderly (≥60 years) patients. Methods: After IRB approval, we searched our prospectively maintained epilepsy surgery database to find patients who underwent eiEEG at the age of 60 years or older. Electronic medical records were reviewed to extract clinical and surgery-related information. Patients who underwent resective epilepsy surgery after eiEEG and had at least 1 year of clinical follow-up were assessed for seizure outcome. Categorical and continuous variables were compared using Pearson chi-square and Student's t-test, respectively. Results: A total of 21 patients, with 13 (62%) women, underwent eiEEG in our center at the age of 60 years or older. The mean age at time of implantation was 63.8 ± 2.7 years. Sub-dural grids (SDG) were implanted in five (24%) patients, whereas sixteen (76%) patients underwent stereo-EEG (SEEG) implantation. Median number of contacts in SDG were 106 (56–136) and depth electrodes in SEEG were 12 (9–14). There were 2 complications, including one mortality due to intracerebral hemorrhage. Sixteen (76%) patients underwent respective epilepsy surgery after eiEEG and eleven (69%) achieved Engel class I outcome on the last follow-up [mean follow-up duration of 2.7 (± 1.8) years]. Conclusion: We noticed an increased utilization of eiEEG in elderly patients after the introduction of SEEG at our center. Overall, we found that eiEEG can help achieve good seizure outcomes in the elderly population. However, the one eiEEG-related mortality serves a word of caution about the potential risks in this population. Keywords: Epilepsy surgery, Elderly, Intracranial recording, SEEG, Subdural electrodes, Outcome

Focal cortical dysplasia (FCD) and hemimegalencephaly (HME) are epileptogenic neurodevelopmental malformations caused by mutations in mTOR pathway genes. Deep sequencing of these genes in FCD/HME brain tissue identified an etiology in 27 of 66 cases (41%). Radiographically indistinguishable lesions are caused by somatic activating mutations in AKT3, MTOR, and PIK3CA and germline loss-of-function mutations in DEPDC5, NPRL2, and TSC1/2, including TSC2 mutations in isolated HME demonstrating a “two-hit” model. Mutations in the same gene cause a disease continuum from FCD to HME to bilateral brain overgrowth, reflecting the progenitor cell and developmental time when the mutation occurred. Single-cell sequencing demonstrated mTOR activation in neurons in all lesions. Conditional Pik3ca activation in the mouse cortex showed that mTOR activation in excitatory neurons and glia, but not interneurons, is sufficient for abnormal cortical overgrowth. These data suggest that mTOR activation in dorsal telencephalic progenitors, in some cases specifically the excitatory neuron lineage, causes cortical dysplasia.

Mesial temporal lobe epilepsy (MTLE) caused by hippocampal sclerosis is one of the most frequent focal epilepsies in adults. It is characterized by focal seizures that begin in the hippocampus, sometimes spread to the insulo-perisylvian regions and may progress to secondary generalized seizures. Morphological alterations in hippocampal sclerosis are well defined. Among them, hippocampal sclerosis is characterized by prominent cell loss in the hilus and CA1, and abnormal mossy fiber sprouting (granular cell axons) into the dentate gyrus inner molecular layer. In this review, we highlight the role of mossy fiber sprouting in seizure generation and hippocampal excitability and discuss the response of alternative treatment strategies in terms of MFS and spontaneous recurrent seizures in models of TLE (temporal lobe epilepsy).

Status epilepticus (SE) is one of the most serious manifestations of epilepsy. Systemic inflammation and damage of blood-brain barrier (BBB) are etiologic cofactors in the pathogenesis of pilocarpine SE while acute osmotic disruption of the BBB is sufficient to elicit seizures. Whether an inflammatory-vascular-BBB mechanism could apply to the lithium–pilocarpine model is unknown. LiCl facilitated seizures induced by low-dose pilocarpine by activation of circulating T-lymphocytes and mononuclear cells. Serum IL-1β levels increased and BBB damage occurred concurrently to increased theta EEG activity. These events occurred prior to SE induced by cholinergic exposure. SE was elicited by lithium and pilocarpine irrespective of their sequence of administration supporting a common pathogenetic mechanism. Since IL-1β is an etiologic trigger for BBB breakdown and its serum elevation occurs before onset of SE early after LiCl and pilocarpine injections, we tested the hypothesis that intravenous administration of IL-1 receptor antagonists (IL-1ra) may prevent pilocarpine-induced seizures. Animals pre-treated with IL-1ra exhibited significant reduction of SE onset and of BBB damage. Our data support the concept of targeting systemic inflammation and BBB for the prevention of status epilepticus.

Frontal lobe epilepsy (FLE) surgery is the second most common surgery performed to treat pharmacoresistant epilepsy. Yet, little is known about long-term seizure outcome following frontal lobectomy. The aim of this study is to investigate the trends in longitudinal outcome and identify potential prognostic indicators in a cohort of FLE patients investigated using modern diagnostic techniques. We reviewed 70 patients who underwent a frontal lobectomy between 1995 and 2003 (mean follow-up 4.1 ± 3 years). Data were analysed using survival analysis and multivariate regression with Cox proportional hazard models. A favourable outcome was defined as complete seizure-freedom, allowing for auras and seizures restricted to the first post-operative week. The estimated probability of complete seizure-freedom was 55.7% [95% confidence interval (CI) = 50–62] at 1 post-operative year, 45.1% (95% CI = 39–51) at 3 years, and 30.1% (95% CI = 21–39) at 5 years. Eighty per cent of seizure recurrences occurred within the first 6 post-operative months. Late remissions and relapses occurred, but were rare. After multivariate analysis, the following variables retained their significance as independent predictors of seizure recurrence: MRI-negative malformation of cortical development as disease aetiology [risk ratio (RR) = 2.22, 95% CI = 1.40–3.47], any extrafrontal MRI abnormality (RR = 1.75, 95% CI = 1.12–2.69), generalized/non-localized ictal EEG patterns (RR = 1.83, 95% CI = 1.15–2.87), occurrence of acute post-operative seizures (RR = 2.17, 95% CI = 1.50–3.14) and incomplete surgical resection (RR = 2.56, 95% CI = 1.66–4.05) (log likelihood-ratio test P-value < 0.0001). More than half of patients in favourable prognostic categories were seizure-free at 3 years, and up to 40% were seizure-free at 5 years, compared to <15% in those with unfavourable outcome predictors. These data underscore the importance of appropriate selection of potential surgical candidates. [ABSTRACT FROM AUTHOR]