Epilepsia Open

ObjectiveStereotactic laser amygdalohippocampotomy (SLAH) is an appealing option for patients with temporal lobe epilepsy, who often require intracranial monitoring to confirm mesial temporal seizure onset. However, given limited spatial sampling, it is possible that stereotactic electroencephalography (sEEG) may miss seizure onset elsewhere. We hypothesized that sEEG seizure onset patterns (SOPs) may differentiate between primary onset and secondary spread and predict postoperative seizure control. In this study, we characterized the two-year outcomes of patients who underwent single-probe SLAH after sEEG and evaluated whether sEEG SOPs predict postoperative seizure freedom. MethodsThis retrospective five-center study included patients with or without mesial temporal sclerosis (MTS) who underwent sEEG followed by single probe SLAH between August 2014 and January 2022. Patients with causative hippocampal lesions apart from MTS or for whom the SLAH was considered palliative were excluded. A SOP catalogue was developed based on literature review. The dominant pattern for each patient was used for survival analysis. The primary outcome was two-year Engel I classification or recurrent seizures before then, stratified by SOP category. Results58 patients were included with a mean follow-up duration of 39 {+/-} 12 months after SLAH. Overall one-, two, and three-year Engel I seizure freedom probability was 54%, 36%, and 33% respectively. Patients with SOPs including low voltage fast activity or low frequency repetitive spiking had a 46% two-year seizure freedom probability, compared to 0% for patients with alpha or theta frequency repetitive spiking or theta or delta frequency rhythmic slowing (log rank test, p = 0.00015). SignificancePatients who underwent SLAH after sEEG had a low probability of seizure freedom at two years, but SOPs successfully predicted seizure recurrence in a subset of patients. This study provides proof of concept that SOPs distinguish between seizure onset and spread and supports using SOPs to improve selection of SLAH candidates. Key PointsO_LIWe described extended seizure outcomes in a five-center retrospective review of 58 patients. C_LIO_LISeizure onset patterns (SOP) were categorized as putative positive vs. negative predictors of postoperative seizure freedom. C_LIO_LILow voltage fast activity or low frequency repetitive spiking are associated with higher seizure freedom probability C_LIO_LIA 0% Engel I probability was found for patients whose dominant SOP was rhythmic slowing or repetitive spiking in the theta or alpha frequency bands. C_LI

ImportanceTo date, epilepsy surgery outcomes remain highly variable, with seizure freedom rates hovering around 50-70%, highlighting the need for a deeper understanding of the factors influencing surgical success. ObjectiveTo conduct an individual patient data meta-analysis of epilepsy surgery outcomes in drug-resistant epilepsy, leveraging granular, patient-level data to identify key clinical, demographic, and anatomical factors that influence surgical success. Data SourcesMEDLINE (via Ovid), Embase, and Scopus were searched from inception to August 9, 2024. Study SelectionPrimary studies reporting patient-level surgical outcomes and clinical information in patients with drug-resistant epilepsy. Data Extraction and SynthesisData were abstracted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Unique patient data from 385 studies were pooled, yielding 5,588 patients with outcomes, localization, demographics, pathology, and other findings. Surgical success rates were reported with 95% Wald confidence intervals. Main Outcome(s) and Measure(s)Measured outcomes were surgical success rates (% Engel 1/ ILAE 1-2) based on key patient and disease-specific factors. Statistical associations were tested with chi-squared tests (p<0.05), effect sizes measured with Cramers V, and post-hoc comparisons adjusted using the false discovery rate. ResultsSurgical success rates (Engel I/ILAE 1-2) have remained stable over the past decades (r=0.25, p=0.13), while seizure freedom rates (Engel Ia/ILAE 1) have significantly improved (r=0.59, p<0.01). This occurred alongside a rise in surgical interventions, including more complex cases, as indicated by increased stereo-EEG use, and the adoption of minimally invasive techniques. Surgical success varied significantly by lobar anatomy ({chi}2=52, p<0.01), with the highest success rates in temporal (68.6% [67.0-70.1%]) and insular lobes (66.2% [55.4-77.0%]), although only temporal outcomes were statistically significant. Multilobar resections had lower success rates, with outcomes varying significantly by lobar combination ({chi}2=25, p=0.02). Variability in outcomes were also influenced by histopathology and MRI findings ({chi}2=121, p<0.001), and the type of surgical intervention ({chi}2=30.5, p<0.001). Conclusions and RelevanceThis meta-analysis combined patient-level data from multiple studies to understand how individual patient characteristics influence surgical outcomes. Identifying these prognostic factors can guide more personalized patient selection and surgical planning, and ultimately improve rates of favorable outcomes in epilepsy surgery. Key PointsO_ST_ABSQuestionC_ST_ABSWhat are the main factors influencing surgical success in drug-resistant epilepsy patients? FindingsA systematic review of 5,588 individual patient data from 385 primary research studies showed that the anatomical region, surgical technique, and histopathological diagnosis impact epilepsy surgery outcomes, with varying success rates based on these factors interaction. MeaningPresurgical evaluations and research into potential biomarkers and treatment options should consider these patient-specific factors instead of relying on generalized, population-level outcome statistics.

ObjectiveEpilepsy surgery in the operculo-insular cortex is challenging due to the difficult delineation of the epileptogenic zone and the high risk of post-operative deficits following resections in this region. MethodsPre- and post-surgical data from 30 pediatric patients who underwent opercular-insular cortex surgery at Motol Epilepsy Center Prague from 2010 to 2022 were analyzed. ResultsFocal cortical dysplasia (FCD, n = 15) was the predominant cause of epilepsy in the patients studied, followed by epilepsy-associated tumors (n = 5) and tuberous sclerosis complex (n = 2). In eight patients where FCD was the most likely etiology, histology was negative. The epileptogenic zone was in the dominant hemisphere in 16 patients. Variability in seizure semiology and electrophysiological findings necessitated multimodal imaging and advanced post-processing for precise epileptogenic zone localization. Stereoelectroencephalography (SEEG) monitoring was used in 23 patients. The use of oblique electrodes as guides during resection proved beneficial for the neurosurgeon. At the two-year follow-up, 23 patients were seizure-free (ILAE Classification of Outcome 1), and seven experienced a seizure frequency reduction of > 50% (ILAE 4). Nineteen remained seizure-free following the definitive outcome assessment (2-13 years post-surgery). Five from 15 patients operated in posterior insula experienced pyramidal tract ischemia, leading to permanent mild hemiparesis in three patients and moderate hemiparesis in one patient. One patient experienced unexpected pontine ischemia 9 days post-surgery, leading to permanent spastic hemiparesis. Five other patients experienced transient deficits. SignificanceDespite diagnostic and surgical challenges, epilepsy surgery in the opercular-insular cortex can lead to excellent patient outcomes. A comprehensive diagnostic approach is crucial for surgical success. For surgeries in the posterior insula, ischemia in the pyramidal tract and subsequent hemiparesis of varying severity should be anticipated. However, in pediatric patients, there is a great chance for significant recovery with proper rehabilitation. Key pointsO_LIDespite the diagnostic and surgical challenges, patients who underwent operculo-insular cortex surgery achieved excellent outcomes. C_LIO_LISeizures from the operculo-insular region exhibit diverse semiology and propagation patterns (i.e., frontal, perisylvian, and temporal). C_LIO_LIAn initially negative MRI finding is common. Video EEG typically reveals an extensive finding. A multimodal diagnostic approach is crucial. C_LIO_LISEEG was necessary in a significant number of cases, and the use of oblique electrodes as guides proved beneficial for the neurosurgeon. C_LIO_LIFor surgeries in the posterior insula, ischemia in the pyramidal tract and subsequent hemiparesis of varying severity should be anticipated. C_LI

Scalp electroencephalography (EEG) may reveal bilateral independent or unclear (BI/U) ictal onset patterns in patients with focal drug-resistant epilepsy, presenting a challenge to surgical decision-making. The utility of stereo-electroencephalography (SEEG) in this subgroup, particularly the probability of delineating a single seizure onset zone (SOZ) that would permit curative resection, remains poorly understood. This study examined whether BI/U scalp EEG findings could predict SEEG outcomes in this population. We conducted a retrospective cohort study of consecutive patients with focal drug-resistant epilepsy and BI/U ictal onset on scalp EEG who underwent SEEG evaluation at the London Health Sciences Centre (Ontario, Canada) between January 2012 and December 2024. All patients had undergone non-invasive and invasive presurgical assessments. Surgical outcomes were determined using the Engel classification following at least one year of postoperative follow-up. A blinded decision validation sub-study was also performed. Blinded to actual outcomes, the team made decisions regarding SEEG and surgical interventions when patients found to have a single SEEG SOZ were presented. Responses were stratified to inform the added diagnostic value of SEEG. Of 255 SEEG cases screened, 84 patients (33%) met inclusion criteria. The cohort was 56% female, with a median seizure onset age of 12 years (IQR 6-20); 65.5% had temporal lobe epilepsy (TLE). A single SOZ was identified in 14.3% of cases (TLE: 14.5%, extratemporal: 13.8%). Patients with a single SEEG SOZ were found to have shorter recording durations (mean of 11 vs 15.79 days in those with multifocal SEEG SOZs; p=0.009). Curative focal resections were performed in 12% (n=10), with long-term Engel I outcomes achieved in one patient (1.2%). Palliative resections occurred in 26% (n=22), with Engel I outcomes in 7% (n=6). In 50% of the blinded cases, the epilepsy surgery team reported that they would not have recommended SEEG based on phase I data. These findings suggest that patients with BI/U scalp EEG SOZs may be associated with a low likelihood of identifying a single SEEG SOZ and curative outcome. Using BI/U scalp EEG ictal onset as a predictor in preoperative decision-making will assist in refining SEEG candidate selection in this large subgroup.

ObjectiveLennox-Gastaut Syndrome (LGS) is a severe, often treatment-resistant epilepsy syndrome typically diagnosed in early childhood. Many have seizures before diagnosis. Some have periods of seizure freedom before treatment resistance, i.e., a "gap." Review of these gaps may identify early candidate biomarkers of LGS and/or highlight opportunities for intervention. MethodsWe reviewed charts of children diagnosed with LGS born in 2008-2010 and diagnosed with LGS by 2014 at five academic medical centers in New York City using the RENYC (Rare Epilepsies in New York City) database. We collected dates of events of potential biomarkers by chart abstraction, including onset of slow spike-and-wave (SSW) and onset and offset of seizure freedom. Seizure-free periods ("gaps") were defined as greater than 30 days without unprovoked seizures. ResultsThirty-three children had LGS (52% male; etiology 33% structural-acquired, 6% structural-congenital, 3% genetic-structural, 24% genetic, 33% unknown). Twenty-two (67%) had a gap before diagnosis. Eight of these twenty-two (36%) had SSW described before the gap, five (23%) during the gap, and six (27%) after the gap. A history of infantile epileptic spasms syndrome (IESS), age at seizure onset, and age of tonic seizure onset were not different between those with and without a gap. Of 20 (61%) with a history of IESS, 10 (30% of the full cohort) had not received recommended therapy (i.e., ACTH, prednisolone, or vigabatrin) as first-line treatment. ConclusionsThe appearance of SSW, even in seizure-free children, may herald the development of LGS in high-risk children. Further studies on its predictive value are warranted. Our findings also highlight use of recommended first-line therapy for infantile spasms as a potentially modifiable treatment gap in children who subsequently develop LGS.

BackgroundSurgical treatment is a highly effective option for drug-resistant temporal lobe epilepsy (TLE). When non-invasive exploration is insufficient to localize the epileptogenic zone, anatomo- electroclinical (AEC) hypotheses can be interrogated by stereoelectroencephalography (SEEG) methodology. To facilitate more effective exploration and intervention, we developed a classification system of AEC hypotheses for temporal lobe SEEG explorations: Mesial lateral temporal (MLT), temporal basal occipital (TBO), anterior perisylvian (AP), and perisylvian (P). MethodsIn a cohort of 60 patients with drug-resistant TLE who underwent SEEG, we collected demographic data, clinical/epilepsy history, neuroimaging, seizure semiology, and the analysis of the multidisciplinary epilepsy patient management conference. We identify and describe the 4 patterns of hypotheses, analyze the semiological and structural features, and validate the proposed classification system using a random forest classifier machine learning algorithm. FindingsUsing this approach, we identify the features most predictive of each classification, and demonstrate an overall 90% classification accuracy using semiological features and 97% accuracy using electrode location. Age, sex, and the presence of an MRI abnormality did not vary by classification. We qualitatively explain the features of each classification with case examples. Finally, we specifically provide indirect targeting coordinates for each electrode to facilitate reproducible SEEG explorations. Following SEEG exploration, 94% patients underwent surgical intervention (82% selective resection, 12% neuromodulation). In resection patients, one-year seizure freedom rate was 73% and did not vary significantly by classification (MLT: 86%, TBO: 71%, AP: 75%, P: 68%; p=0.9) with overall 26% verbal memory decline. InterpretationThe patterns of explorations, grounded in semiology and cortical cytoarchitectonic and functional features, guided volumetrically-restricted resections that resulted in a high rate of seizure freedom. This approach guides both a theoretical approach to TLE and a practical realization that can be tailored to the individual patient. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSWe searched the MEDLINE database from inception to June 1, 2024 using the terms ("temporal lobe epilepsy", "mesial temporal lobe epilepsy", "anatomo-electroclinical hypothesis", "stereo EEG", "neuropsychological outcome", "surgical strategy", "intracranial exploration", and/or "seizure freedom". We supplemented this with search of Google Scholar and reference list. After review, we selected 1 randomized controlled trial (RCT), 17 cohort studies, 9 technical reports, 1 epidemiological report, and 2 systematic reviews. The RCT compared surgical treatment of temporal lobe epilepsy vs. medical management using a standardized temporal lobectomy approach in all patients and demonstrated significant benefit for surgical treatment. However, it did not address the process of anatomo-electroclinical hypotheses to guide intracranial exploration and selective temporal resections nor did it address neuropsychological outcomes. The cohort studies varied in focus, but described various semiological features, surgical approaches, and neuropsychological outcomes. Despite these reports, a systematic approach to intracranial exploration using SEEG and detailed analysis of seizure freedom and neuropsychological outcomes is lacking. Added value of this studyOur study addresses this limitation in one of the largest cohorts of TLE patients with SEEG explorations to date. Using semiological observations and a detailed cytoarchitectonic analysis, we propose a novel hypothesis classification system of four hypotheses in TLE and describe this in detail. We quantitatively validate this approach using a machine learning based approach and provide details to facilitate a practical implementation. Finally, we demonstrate a high rate of seizure freedom with excellent neuropsychological outcomes using this approach. Implications of all of the available evidenceIn this study, we demonstrate that that an appropriately designed intracranial exploration (based on the proposed hypothesis classification) can provide excellent results without necessitating a standard temporal lobectomy. This challenges the prior selective vs. standard temporal dichotomy in the literature but builds on several themes previously reported. This precision and patient-centered approach integrates multimodal information and multidisciplinary discussion resulting in more selective surgical interventions that maximize seizure freedom while minimizing neuropsychological morbidity.

BackgroundMany genetic epilepsy disorders are characterized by focal epilepsy or exhibit focal or lateralized features, which make individuals with such conditions potential surgical candidates. However, surgical outcomes in epilepsy caused by germline genetic variants and value of genetic testing in presurgical assessment remains unclear. MethodsThis retrospective cross-sectional study included people with germline genetic epilepsy and non-genetic epilepsy identified among 2879 people with epilepsy who underwent resective surgery or laser ablation at Cleveland Clinic in years 1997-2022. We separated individuals with germline genetic epilepsies into mTORopathies (clinically or genetically diagnosed tuberous sclerosis and genetically diagnosed GATOR-related epilepsies) and other genetic etiologies. We compared clinical variables between the groups using Kruskal-Wallis and Fisher tests as appropriate. We analyzed cumulative seizure recurrence risk over 5 years with Kaplan-Meier curves and used Cox proportional hazards model for univariate and multivariate analysis. We repeated the analysis after matching both genetic sub-groups to non-genetic group 1:1 by propensity scores estimated by a generalized linear model. ResultsWe included 49 individuals with genetic epilepsies (32 individuals with mTORopathies and 17 individuals with other genetic etiologies) and 585 individuals with non-genetic epilepsy. Individuals with genetic epilepsies in both groups were younger at seizure onset (p<0.001) and at surgery (p<0.001), had a higher preoperative seizure frequency (p<0.001), higher rate of developmental delay (p<0.001), lower rate of focal interictal (p=0.005) and ictal (p<0.001) findings on EEG, and more extratemporal and extensive resections (p<0.001). At the last follow-up, individuals with other genetic etiologies had a lower rate of seizure freedom than individuals with mTORopathies and non-genetic etiologies; still, 70.6% achieved seizure reduction. Individuals with other genetic etiologies had a higher cumulative risk of seizure recurrence at 5 years both in univariate (HR 3.07, 95% CI 1.4-6.74) and multivariate (HR 3.81, 95% CI 1.69-8.62, p=0.001) analyses, which was reproducible in a matched cohort analysis. ConclusionsPeople with germline genetic epilepsy across multiple etiologies could be surgical candidates. However, seizure recurrence may be faster in genetic epilepsies other than mTORopathies. Further studies are required to clarify surgical candidacy in different genetic epilepsy disorders and establish value of presurgical genetic testing.

Epilepsy care has largely improved across the United States in the past decades, as reflected in Epilepsy Monitoring Units (EMU) bed availability, admissions, neurological procedures, and epileptologists. However, this has not been evident in many underserved areas. The vast majority of National Association of Epilepsy Centers (NAEC) accredited centers are located in major metropolitan areas, and some states lack epilepsy centers entirely. Kern Medical (KM) is the public safety-net hospital in Bakersfield, California (CA) that serves Kern and surrounding counties in the Central Valley. In 2018, an epilepsy center at KM was established with the support of the USC Epilepsy Care Consortium and received NAEC Level III accreditation to serve the over 34,000 patients who suffer from epilepsy in Kern County alone. Here, we review the initial 4-year experience of the KM Epilepsy Center by retrospectively analyzing a prospectively maintained database in light of the general NAEC data from 2012-2019. This experience demonstrates that epilepsy care can be coordinated across complex and competing health systems and socioeconomic barriers separated by large geographic distances through creative, physician-driven strategies of resource sharing and goal alignment across the health care ecosystem. However, considerable challenges remain in providing the requisite care to patients in need, even in highly resourced states like CA. This experience can inform future efforts to integrate epilepsy care across the region and beyond.

ImportanceStereoelectroencephalography (SEEG) is more frequently being used in the pre-surgical evaluation of children with focal epilepsy. Many factors affect the rate of identification of a definable seizure onset zone (SOZ) and subsequent seizure freedom following SEEG-guided epilepsy surgery, which have not been systematically examined in multi-centre studies. ObjectivesDetermine the rates and factors that predict (a) whether or not a definable putative SOZ was identified on SEEG and (b) subsequent seizure freedom following surgical intervention. DesignRetrospective cohort study SettingMulticentre study involving 6 of 7 UK Childrens Epilepsy Surgery Service centres that perform paediatric SEEG in the UK. ParticipantsAll children undergoing SEEG from 2014 - March 2019 were included. Demographic, non-invasive evaluation, SEEG and operative factors were collected retrospectively from patient records. Main OutcomesThe two main outcome measures were (a) whether or not a definable putative SOZ was identified on SEEG (binary yes/no outcome) and (b) subsequent seizure freedom following surgical intervention (Engel classification) FindingsOne hundred and thirty-five patients underwent 139 SEEG explorations using a total of 1767 electrodes. A definable SOZ was identified in 117 patients (85.7%); odds of successfully finding a SOZ were 6.4x greater for non-motor seizures compared to motor seizures (p=0.02) and 3.6x more if [&ge;] 4 seizures were recorded during SEEG (p=0.03). Of 100 patients undergoing surgical treatment, 47 (47.0%) had an Engel class I outcome at a median follow-up of 1.3 years; the only factor associated with outcome was indication for SEEG (p=0.03). SEEG was safe with one (0.7%) haematoma requiring surgical evacuation and no long-term neurological deficits as a result of the procedure. Conclusions and RelevanceThis large nationally representative cohort illustrates that, in these patients who may not have otherwise been offered resective surgery, SEEG-guided surgery can still achieve high rates of seizure freedom. Seizure semiology and the number of seizures recorded during SEEG are important factors in the identification of a definable SOZ and the indication for SEEG is an important factor in post-operative outcomes.

BackgroundComplete resection of focal malformations of cortical development (MCD) has been recognized as crucial for the success of epilepsy surgery. However, many of these lesions escape detection using even state-of-the-art epilepsy protocol MRI imaging. This study evaluates the concurrence of radiographic and histopathologic findings of MCD in patients with refractory temporal lobe epilepsy (TLE) and defines the predictive value of EEG findings in the detection of MCD. Materials and MethodsPre-operative MRI, scalp VEEG, and post-operative surgical pathology reports from 34 consecutive patients treated for refractory TLE by surgical resection over a ten year period were included in analysis. Radiographic findings of MCD were correlated with histopathologic findings of MCD and compared against pre-operative interictal scalp EEG findings. Results66.7% of focal cortical dysplasias (FCD) identified on pathology and all cases of mild MCD (mMCD) were missed on pre-operative MRI. The description of a rhythmic or continuous interictal abnormality on pre-operative VEEG corresponds to a sensitivity of 73.1% and a specificity of 62.5% in detecting either FCD or mMCD. Of the patients who had a radiographically occult FCD, 80% had either a continuous or rhythmic interictal abnormality described in the interpretation of their pre-operative VEEG. ConclusionThis study highlights the high prevalence of MCDs in refractory TLE and the high rate of missed MCDs on pre-operative MRI. Findings here suggest that pre-operative scalp EEG may be able to provide additional information in the pre-operative detection of MCDs and therefore inform surgical decision making.

ObjectiveProtocadherin-19 (PCDH19)-clustering epilepsy (PCE) is a severe genetic epilepsy that manifests with early-onset cluster seizures often triggered by fever, intellectual disability, autistic features, and later neuropsychiatric risk. PCDH19 is an X-linked gene critical for brain development. PCE predominantly affects females and rare mosaic males, but not hemizygous males, likely due to cellular mosaicism arising from random X-inactivation and resultant segregation of wild-type and mutant neurons (so-called cellular interference) during development. We generated a novel PCE mouse model and explored neuronal segregation, seizure susceptibility and cortical interneuron distributions. MethodsFemale Pcdh19+/- mice were crossed with X-GFP males to visualize random X-inactivation patterns. Seizure susceptibility was assessed in juvenile mice using hyperthermia and flurothyl exposure. Behavioral testing evaluated cognitive domains. Interneuron distribution in hippocampus and cortex was examined histologically by immunolabeling and crosses with parvalbumin reporter mice. ResultsJuvenile Pcdh19+/- females lacked spontaneous seizures but displayed lower seizure thresholds and more severe seizures during hyperthermia. Seizure susceptibility did not differ from controls after flurothyl exposure. Pcdh19+/- females also exhibited segregation of GFP+ cells in the cortex, hippocampal CA1 region and medial ganglionic eminence, with a marked reduction of parvalbumin-positive interneurons in the CA1 hippocampal region. Although parvalbumin interneuron density was unchanged in the Pcdh19+/- female cortex overall, localized decreases arose in GFP- (Pcdh19 knockout) cortical stripes. InterpretationJuvenile PCE mice exhibit seizure susceptibility to hyperthermia and disrupted the distribution of parvalbumin-expressing interneurons in the hippocampus and cortex. These findings suggest focal parvalbumin interneuron alterations may contribute to PCE pathophysiology.

Low statistical power is a recognized problem in many fields. We performed a systematic review to determine the median statistical power of studies of epilepsy surgery outcomes. We performed a PubMed search for studies reporting epilepsy surgery outcomes for the years 1980-2020, focusing on studies using stereoelectroencephalography (SEEG). We extracted patient count data for comparisons of surgical outcome between two groups, based on a reported prognostic factor. We defined a clinically meaningful difference as the difference in seizure freedom for MRI positive (66.9%) versus negative (45.5%) from the largest study found. Based on 69 studies of surgery outcomes in patients undergoing SEEG, the median sample size was 38 patients, and the median statistical power was 24%. This implies at least a 17% chance a study with a significant result is false, assuming 1:1 pre-test odds. Results from simulation studies suggest that, if a typical SEEG study finds a significant effect, then the median observed effect size will be more than double the true effect size. We conclude that studies of epilepsy surgery outcomes using SEEG are often statistically underpowered, which limits the reproducibility and reliability of the literature. We discuss how statistical power could be improved. SHORT SUMMARYWe performed a systematic review to determine the median statistical power of studies of epilepsy surgery outcomes, focused on stereoelectroencephalography. We extracted patient count data for comparisons of outcomes between two groups. We defined a clinically meaningful difference as the prognostic value of a normal versus abnormal MRI. Based on 69 studies, the median sample size was 38 patients, and the median statistical power was 24%. Underpowered studies will overestimate the size of true effects and are more likely to report false positive results. We discuss how statistical power, and thus reproducibility and reliability of results, can be improved.

Cortical tubers are benign lesions that develop in patients with tuberous sclerosis complex (TSC), often resulting in drug-resistant epilepsy. Surgical resection may be required for seizure control, but the extent of the resection required is unclear. Many centres include resection of perituberal cortex, which may be associated with neurological deficits. Also, patients with tubers in eloquent cortex may be excluded from epilepsy surgery.\n\nOur electrophysiological and MRI studies indicate that the tuber centre is the source of seizures, suggesting that smaller resections may be sufficient for seizure control. Here we report five epilepsy surgeries in four children with TSC and focal motor seizures from solitary epileptogenic tubers in the sensorimotor cortex in whom the resection was limited to the tuber centre, leaving the tuber rim and surrounding perituberal cortex intact. Seizures were eliminated in all cases, and no functional deficits were observed. On routine histopathology we observed an apparent increase in density of dysmorphic neurons at the tuber centre, which we confirmed using unbiased stereology which demonstrated a significantly greater density of dysmorphic neurons within the resected tuber centre (1951 {+/-} 215 cells/mm3) compared to the biopsied tuber rim (531 {+/-} 189 cells/mm3, n = 4, p = 0.008).\n\nTaken together with our previous electrophysiological and MRI studies implicating the tuber centre as the focus of epileptic activity, and other electrophysiological studies of dysmorphic neurons in focal cortical dysplasia, this study supports the hypothesis that dysmorphic neurons concentrated at the tuber centre are the seizure generators in TSC. Furthermore, our results support limiting resection to the tuber centre, decreasing the risk of neurological deficits when tubers are located within eloquent cortex.

BackgroundIntractable or drug-resistant epilepsy (DRE) is a condition where seizures cannot be adequately controlled through antiepileptic medications. In the setting where resective surgery is ineffective, neuromodulation therapy, or vagus nerve stimulation (VNS), is a safe and approved solution. Nonetheless, the efficacy has yet to be clear. We conducted this systematic review and meta-analysis to evaluate the clinical benefit and response of VNS on seizure frequency reduction in intractable epilepsy. MethodsFour databases (PubMed, Elsevier, Google Scholar, Neurology Journals) were searched from inception to November 2024. RCTs and observational studies that analyzed the effect of vagus nerve stimulation in intractable epilepsy patients were included. Review manager (RevMan 5.4) was used for data analysis with random effects model based on heterogeneities. ResultsFive cohort studies (three prospective and two retrospective) were included in the quantitative analysis, involving 244 participants with intractable epilepsy. The pooled analysis revealed a significantly increased likelihood of seizure reduction with VNS (RR = 13.55, 95% CI = 4.95-37.05; p <0.001). Adverse events, reported in three studies, were generally mild to moderate. Two studies assessing the relationship between seizure type and VNS response consistently demonstrated a better response in cases of generalized epilepsy. One study found a positive response of VNS therapy after prior surgery in focal resection group (>60%), followed by corpus callosotomy (33%). However, no study reported a significant reduction in AED usage following VNS therapy. ConclusionVNS is considered a favorable therapy for patients with intractable epilepsy, notably in generalized epilepsy.

IntroductionSince the initial description of CACNA1A-related hemiplegic migraine (HM), the phenotypic spectrum has expanded from mild episodes in neurotypical individuals to potentially life-threatening events frequently seen in individuals with developmental and epileptic encephalopathies. However, the overall longitudinal course throughout childhood remains unknown. MethodsWe analyzed HM and seizure history in individuals with CACNA1A-related HM, delineating frequency and severity of events in monthly increments through a standardized approach. Combining these data with medication prescription information, we assessed the response of HM to different agents. ResultsOur cohort involved 15 individuals between 3 and 29 years (163 patient years) and included 11 unique and two recurrent variants (p.R1349Q and p.V1393M; both n=2). The age of first confirmed HM ranged from 14 months to 13 years (average 3 years). 25% of all HM events were severe (lasting >3 days) and 73% of individuals had at least 1 severe occurrence. Spacing of HM events ranged from 1 month to 14 years and changes in HM severity over time of showed increases or decreases of >2 severity levels in 12/122 events. Eight individuals had epilepsy, but severity of epilepsy did not correlate with frequency and severity of HM events. While levetiracetam (n=6) and acetazolamide (n=5) were the most frequently used medications, they did not show efficacy in HM prevention or HM severity reduction. However, verapamil (n=3) showed efficacy in preventing HM episodes (OR 2.68, CI 1.39-5.67). SignificanceThe longitudinal course of CACNA1A-related HM lacks recognizable patterns for timing and severity of HM events or correlation with seizure patterns. Our data underscores the unpredictability of CACNA1A-related HM, highlighting the need for close surveillance for reoccurring HM events even in individuals with symptom-free periods. Key pointsO_LI24% of hemiplegic migraines (HM) in CACNA1A-related disorders are severe, involving cerebral edema and greater than 4 days to recover C_LIO_LITiming and severity of HM are unpredictable, with large changes in severity between events, and age of onset ranging from 1-13 years C_LIO_LIEpilepsy occurred in 53% of individuals, with neither the timing nor severity of seizures correlated with HM C_LI

ObjectivesWe comprehensively characterised a large paediatric cohort with histologically confirmed focal cortical dysplasia (FCD) type 1 to demonstrate the role of advanced multimodal pre-surgical evaluation and identify predictors of postsurgical outcomes. MethodsThis study comprised a systematic re-analysis of clinical, electrophysiological, and radiological features. The results of this re-analysis served as independent variables for subsequent statistical analyses of outcome predictors. ResultsAll children (N = 31) had drug-resistant epilepsy with varying impacts on neurodevelopment and cognition (presurgical intelligence quotient (IQ)/developmental quotient scores: 32-106). Low presurgical IQ was associated with abnormal slow background electroencephalogram (EEG) activity and disrupted sleep architecture. Scalp EEG showed predominantly multiregional and often bilateral epileptiform activity. Advanced epilepsy magnetic resonance imaging (MRI) protocols identified FCD-specific features in 74.2% of patients (23/31), 17 of whom were initially evaluated as MRI-negative. In six out of eight MRI-negative cases, fluorodeoxyglucose positron emission tomography (FDG-PET) and subtraction ictal single-photon emission computed tomography co-registered to MRI (SISCOM) helped localise the dysplastic cortex. Sixteen patients (51.6%) underwent stereoelectroencephalography (SEEG). Twenty-eight underwent resective surgery, and three underwent hemispheral disconnection. Seizure freedom was achieved in 71.0% of patients (22/31) by the last follow-up, including seven of the eight MRI-negative patients. Anti-seizure medications (ASMs) were reduced in 21 patients, with complete withdrawal in 5 individuals. Seizure outcome was predicted by a combination of the following descriptors: age at epilepsy onset, epilepsy duration, long-term invasive EEG, and specific MRI, and PET findings. SignificanceThis study highlights the broad phenotypic spectrum of FCD type 1, which spans far beyond the narrow descriptions of previous studies. Combining advanced MRI protocols with additional neuroimaging techniques helped localise the epileptogenic zone in many previously non-lesional cases. Complex multimodal presurgical approaches (including SEEG) could enhance postsurgical outcomes in these complex patients. Key pointsO_LIThe phenotypic spectrum of paediatric patients with FCD type 1 spans beyond the narrow description of previous studies C_LIO_LIMRI-negative patients benefit from enhanced precision in localising the epileptogenic zone, facilitated by FDG-PET, SISCOM, and SEEG C_LIO_LIA complex multimodal presurgical approach could enhance postoperative seizure outcomes in patients with FCD type 1 C_LIO_LIPaediatric patients with suspected FCD type 1 should be referred to epilepsy surgery centres as soon as possible C_LI

ObjectiveTo determine the impact of epilepsy duration and interictal spikes on functional connectivity in children with Self-Limited Epilepsy with Centrotemporal Spikes (SeLECTS). MethodsConnectivity was calculated from electroencephalograms (EEGs) of 68 children with SeLECTS and 65 age and sex-matched controls using the weighted phase lag index. SeLECTS EEGs were categorized by epilepsy duration (shorter or longer than 6 months) to assess progressive connectivity changes. To investigate the impact of spikes on connectivity, 19 SeLECTS patients who underwent two EEGs were analyzed longitudinally, comparing those whose spikes persisted versus resolved over time. Analyses focused on connectivity during sleep. ResultsConnectivity increased with epilepsy duration, being lowest in controls, intermediate in patients with shorter epilepsy duration, and highest in those with longer duration. Changes were initially greatest within the right occipital region and became more widespread with longer epilepsy duration. Longitudinally, patients with persistent spikes showed increasing connectivity over time, while those with spike resolution demonstrated decreasing connectivity, resulting in significant between-group differences. ConclusionsFunctional connectivity in SeLECTS increases progressively with epilepsy duration and spike exposure, suggesting that ongoing spikes drive neural network alterations. SignificanceSpikes are a potential treatment target to prevent progressive brain network disruption and preserve cognitive outcomes.

BackgroundThe ZFHX3 gene plays vital roles in embryonic development, cell proliferation, neuronal differentiation, and neuronal death. This study aims to explore the relationship between ZFHX3 variants and epilepsy. MethodsWhole-exome sequencing was performed in a cohort of 378 patients with partial (focal) epilepsy. A Drosophila Zfh2 knockdown model was used to validate the association between ZFHX3 and epilepsy. ResultsCompound heterozygous ZFHX3 variants were identified in eight unrelated cases. The burden of ZFHX3 variants was significantly higher in the case cohort, shown by multiple/specific statistical analyses. In Zfh2 knockdown flies, the incidence and duration of seizure-like behavior were significantly greater than those in the controls. The Zfh2 knockdown flies exhibited more firing in excitatory neurons. All patients presented partial seizures. The five patients with variants in the C-terminus/N-terminus presented mild partial epilepsy. The other three patients included one who experienced frequent nonconvulsive status epilepticus and two who had early spasms. These three patients had also neurodevelopmental abnormalities and were diagnosed as developmental epileptic encephalopathy (DEE), but achieved seizure-free after antiepileptic-drug treatment without adrenocorticotropic-hormone/steroids. The analyses of temporal expression (genetic dependent stages) indicated that ZFHX3 orthologs were highly expressed in the embryonic stage and decreased dramatically after birth. ConclusionZFHX3 is a novel causative gene of childhood partial epilepsy and DEE. The patients of infantile spasms achieved seizure-free after treatment without adrenocorticotropic-hormone/steroids implies a significance of genetic diagnosis in precise treatment. The genetic dependent stage provided an insight into the underlying mechanism of the evolutional course of illness. WHAT IS ALREADY KNOWN ON THIS TOPICThe ZFHX3 protein plays an essential role in neurodevelopment. The relationship between ZFHX3 variants and human diseases remains unknown. WHAT THIS STUDY ADDSEight pairs of compound heterozygous ZFHX3 variants were identified in eight unrelated patients with partial epilepsy, including two who evolved from early spasms. HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICYThe ZFHX3 gene is a novel pathogenic gene of childhood partial epilepsy and developmental epileptic encephalopathy. The development-dependent expression pattern of ZFHX3 explains the evolutional course of the illness, potentially being helpful in the management of the patients.

We examined seizure semiology and response to medications in 28 children (9 female, 19 male) with likely pathogenic and pathogenic SCN2A-related epilepsy. Parents reported seizure onset, seizure semiology, genetic variants, therapies used for seizures, and response to treatment. 27 children experienced defined seizures and 1 reported no seizure history. The most common initial seizures were focal or hemi-convulsions (n=8). Tonic seizures were the most common reported seizure type while febrile and atonic or drop seizures were the least common. Most patients experienced multiple seizures daily or were entirely seizure-free, with no difference based on age at seizure onset. The proportion of effective trials of the 8 most commonly reported medications ranged from 4 of 26 trials (levetiracetam) to 5 of 10 trials (valproic acid). Phenytoin was the most commonly reported effective treatment (N=4). Topiramate was reported to be the most effective treatment in combination with another treatment (N=6). We found a wide phenotypic spectrum of SCN2A-related disorders and a possible correlation between genotype and seizure onset, semiology, and treatment response. Gain-of-function mutations in early-onset SCN2A epilepsies responded well to sodium channel blockers. Further exploration of SCN2A pathogenic variants are needed to identify mediation mechanisms of action in SCN2A-related epilepsy.

ObjectiveMore than one-third of the people with focal epilepsy do not achieve seizure freedom with medication, neuromodulation, or neurosurgery therapies. Palliative care with the goal of reducing epilepsy burden is an alternative for these patients. Minimizing severe seizures is essential for reducing morbidity. Existing seizure severity scales are qualitative and rely on patient reports, limiting our ability to rigorously track and intervene to curb severe seizures. The goal of this study is to develop and validate a quantitative metric for seizure severity. MethodsWe retrospectively analyzed preictal and ictal intracranial-EEG (iEEG) recordings from 54 people with drug-resistant epilepsy undergoing pre-surgical evaluation. We developed a new metric that objectively combines seizure duration, spread, and semiology to quantify seizure severity. We calculated preictal iEEG network features and fit a linear mixed-effects model to quantify patient-specific associations between preictal networks and seizure severity. ResultsWe evaluated 256 seizures from 54 patients using the quantitative seizure severity score. Seizure severity was consistent with clinical seizure type. Medication taper strategy was associated with seizure severity (p = 0.018, 97.5% confidence interval = [-1.242, -0.116]) and lower pre-surgical seizure severity was associated with better post-surgical seizure outcome (U = 465, p = 0.042). A linear mixed-effects model with preictal network features as regressors and seizure severity as response revealed a group-level positive trend. In 12 out of 14 patients with multiple types of seizures, more severe seizures were preceded by more abnormal preictal networks. SignificanceWe present a quantitative metric for seizure severity that correlates with clinical and electrographic features. We found that the seizure severity score was associated with abnormal preictal networks. We propose this measure to holistically capture patient condition and guide incremental changes in therapy to improve patient outcome over time.