Seizure Freedom Research Articles

Effectiveness analysis of three-drug combination therapies for refractory focal epilepsy

Selecting appropriate antiseizure medications (ASMs) for combination therapy in patients with drug-resistant epilepsy (DRE) is a complex task that requires an empirical approach, especially in patients receiving polytherapy. We aimed to analyze the effectiveness of various three-drug combinations in a group of patients with DRE under real-world conditions. This single-center, longitudinal observational study investigated patients with drug-resistant focal epilepsy who received three-drug regimens in the outpatient clinic of Tongji Hospital from September 2019 to December 2022. The effectiveness of each triple regimen was evaluated by the seizure-free rate and within-patient ratio of the seizure frequency (a seizure frequency ratio [SFR]<1 indicated superior efficacy). The independent t-test or Mann–Whitney U test was used for effectiveness analysis, and P values were adjusted by the Benjamini–Hochberg method for multiple comparisons. A total of 511 triple trials comprising 76 different regimens were conducted among 323 enrolled patients. Among these triple regimens, lamotrigine (LTG)/valproic acid (VPA)/topiramate (TPM) was the most frequently prescribed (29.4%, n ​= ​95). At the last clinical visit, 14.9% (n ​= ​48) of patients achieved seizure freedom after receiving triple therapy. LTG/VPA/TPM and LTG/VPA/levetiracetam (LEV) exhibited the highest seizure-free rates at 17.9% and 12.8%, respectively. These two regimens also had significantly lower median SFRs of 0.48 (interquartile range [IQR], 0.17–0.85; adjusted P ​< ​0.001) and 0.63 (IQR, 0.21–1.04; adjusted P ​< ​0.01), respectively. LTG/VPA/perampanel (PER) was another promising regimen that showed marginal effectiveness (median SFR ​= ​0.67; adjusted P ​= ​0.053). LTG/VPA/phenobarbital had the highest incidence of regimen-specific side effects (40.0%, 4/10), while the incidence of side effects from LTG/VPA/LEV was minimal (5.1%, 2/39). In conclusion, LTG/VPA/TPM and LTG/VPA/LEV exhibited superior efficacy and good tolerability in treating patients with DRE. Our results provide preliminary insights into the selection of ASMs for three-drug combination therapies in this clinically challenging population.

Generalisability of epileptiform patterns across time and patients

The complexity of localising the epileptogenic zone (EZ) contributes to surgical resection failures in achieving seizure freedom. The distinct patterns of epileptiform activity during interictal and ictal phases, varying across patients, often lead to suboptimal localisation using electroencephalography (EEG) features. We posed two key questions: whether neural signals reflecting epileptogenicity generalise from interictal to ictal time windows within each patient, and whether epileptiform patterns generalise across patients. Utilising an intracranial EEG dataset from 55 patients, we extracted a large battery of simple to complex features from stereo-EEG (SEEG) and electrocorticographic (ECoG) neural signals during interictal and ictal windows. Our features (n = 34) quantified many aspects of the signals including statistical moments, complexities, frequency-domain and cross-channel network attributes. Decision tree classifiers were then trained and tested on distinct time windows and patients to evaluate the generalisability of epileptogenic patterns across time and patients, respectively. Evidence strongly supported generalisability from interictal to ictal time windows across patients, particularly in signal power and high-frequency network-based features. Consistent patterns of epileptogenicity were observed across time windows within most patients, and signal features of epileptogenic regions generalised across patients, with higher generalisability in the ictal window. Signal complexity features were particularly contributory in cross-patient generalisation across patients. These findings offer insights into generalisable features of epileptic neural activity across time and patients, with implications for future automated approaches to supplement other EZ localisation methods.

Disparities in seizure outcomes revealed by large language models.

Large-language models (LLMs) can potentially revolutionize health care delivery and research, but risk propagating existing biases or introducing new ones. In epilepsy, social determinants of health are associated with disparities in care access, but their impact on seizure outcomes among those with access remains unclear. Here we (1) evaluated our validated, epilepsy-specific LLM for intrinsic bias, and (2) used LLM-extracted seizure outcomes to determine if different demographic groups have different seizure outcomes. We tested our LLM for differences and equivalences in prediction accuracy and confidence across demographic groups defined by race, ethnicity, sex, income, and health insurance, using manually annotated notes. Next, we used LLM-classified seizure freedom at each office visit to test for demographic outcome disparities, using univariable and multivariable analyses. We analyzed 84675 clinic visits from 25612 unique patients seen at our epilepsy center. We found little evidence of bias in the prediction accuracy or confidence of outcome classifications across demographic groups. Multivariable analysis indicated worse seizure outcomes for female patients (OR 1.33, P ≤ .001), those with public insurance (OR 1.53, P ≤ .001), and those from lower-income zip codes (OR ≥1.22, P ≤ .007). Black patients had worse outcomes than White patients in univariable but not multivariable analysis (OR 1.03, P = .66). We found little evidence that our LLM was intrinsically biased against any demographic group. Seizure freedom extracted by LLM revealed disparities in seizure outcomes across several demographic groups. These findings quantify the critical need to reduce disparities in the care of people with epilepsy.

Predictors of medical intractability in children with epilepsy onset during the first two years of life, excluding infantile epileptic spasm syndrome

PurposeEarly childhood epilepsy presents a significant challenge, with approximately 30 % of individuals experiencing treatment failure. This study aimed to identify predictors of medical intractability in children with epilepsy onset during the first two years of life, excluding infantile epileptic spasm syndrome. MethodsA total of 323 children were retrospectively evaluated. The analyses included a review of medical records for demographic, laboratory, radiological, and electroencephalographic (EEG) findings. Children were diagnosed with drug-resistant epilepsy (DRE) according to the ILAE diagnostic criteria. Twenty-one potential prognostic predictors were examined in relation to medical intractability. ResultsAmong the 323 children (56.7 % male), 119 (36.8 %) had unknown epilepsy, 131 (40.6 %) had structural epilepsy, 53 (16.4 %) had genetic epilepsy, and 20 (6.2 %) had metabolic epilepsy. Over a median follow-up of 68 months, 55.4 % of the children achieved ≥6 months of seizure freedom, 33.1 % developed DRE, and the remaining 11.5 % had rare ongoing seizures but did not meet the criteria for DRE because they were only treated with one antiseizure medication at the last follow-up. Univariate logistic regression analyses identified ten risk factors significantly associated with DRE. Multivariate logistic regression analyses revealed that the presence of developmental delay at epilepsy onset (p = 0.000; OR 7.890; 95 %CI 2.713 to 22.945), history of status epilepticus (p = 0.000; OR 8.247; 95 %CI 3.619 to 18.793), number of antiseizure medications (ASMs) at the sixth month of diagnosis (p = 0.000; OR 20.585; 95 %CI 8.993 to 47.117), and initial EEG findings (p = 0.046; OR 2.366; 95 %CI 1.015 to 5.518) were predictors of medical intractability. Nineteen (5.9 %) children died during follow-up for various reasons, including progressive neurogenetic or neurodegenerative disorders. ConclusionDevelopmental delay at epilepsy onset, a history of status epilepticus, the use of two or more ASMs in the sixth month of diagnosis, and abnormal initial EEG findings were associated with medical intractability.

The efficacy and safety of novel antiepileptic drugs in treatment of epilepsy of patients with brain tumors.

This meta-analysis aimed to assess the effectiveness and safety of novel antiepileptic drugs (AEDs) in treating epilepsy in patients with brain tumors (BTRE). A search was conducted on PubMed, EMBASE, Web of Science, and the Cochrane Library from inception to February 2023, with English language restriction. In this meta-analysis, 18 clinical trials involving 755 BTRE patients were included to assess the efficacy and safety of novel AEDs in BTRE treatment. At the last follow-up, a ≥50% reduction in seizure frequency was experienced by 72% of patients (random-effects model, 95% CI = 0.64-0.78) using novel AEDs. At the last follow-up, seizure freedom was experienced by 34% of patients (random-effects model, 95% CI = 0.28-0.41) using novel AEDs. The pooled incidence of AEs was found to be 19% (95% CI: 13%-26%), with a withdrawal rate due to adverse effects of only 3%. Comparable efficacy and incidence of adverse effects were observed between lacosamide and perampanel. This meta-analysis suggests that novel antiepileptic drugs are deemed effective for seizure control in brain tumor patients, particularly when used as adjunctive therapy. Although lacosamide and perampanel received more focus in studies, no significant difference was observed in the efficacy and adverse reactions of these two drugs in seizure control. Further randomized controlled trials are deemed necessary to validate our findings.

Efficacy and safety of modified medium-chain triglyceride ketogenic diet in patients with drug-resistant epilepsy

BackgroundMedium-chain triglyceride ketogenic diet (MCTKD) is previously less commonly used in China. This study was aimed to assess the efficacy and safety of the modified MCTKD in the treatment of drug-resistant epilepsy in Chinese patients.MethodsPatients with drug-resistant epilepsy were enrolled to receive treatment with modified MCTKD in Guangdong Sanjiu Brain Hospital during December 2020 and September 2022. The modified MCTKD contained fat that provided 50–70% of the total energy, as well as proteins and carbohydrates that provided 20–30% and 20% of energy, respectively. The fat component was composed of 20–30% medium-chain triglycerides (MCTs) and 30–40% long-chain triglycerides. The efficacy and safety of the diet were assessed at 1, 3 and 6 months.ResultsA total of 123 patients aged 2.5 to 65 years, were included in this study. The response rates at 1, 3 and 6 months were 49.6%, 43.1%, and 30.9%, respectively. The seizure freedom rates at 1, 3 and 6 months were 12.2%, 10.6%, and 6.5%, respectively. The retention rates at 1, 3 and 6 months were 98.4%, 65.0% and 33.3% respectively. Side effects occurred in 21.14% of patients, which were predominantly gastrointestinal symptoms such as abdominal pain, diarrhea, vomiting, and constipation, and most of them resolved after dietary adjustments. A total of 82 patients (66.7%) discontinued the treatment with the reason of refusing to eat (8.1%), poor efficacy (35.0%), poor compliance (4.9%), and inability to follow-up (9.8%). Only 4 patients (3.3%) withdrew the diet due to side effects.ConclusionsThe modified MCTKD with MCTs providing 20–30% of energy has a good safety in patients with drug-resistant epilepsy, but its effectiveness needs to be enhanced. Further modifications of MCTKD with an optimal energy ratio are required to achieve a better efficacy and safety.

Effectiveness and tolerability of brivaracetam in patients with epilepsy stratified by comorbidities and etiology in the real world: 12-month subgroup data from the international EXPERIENCE pooled analysis

ObjectiveTo assess the effectiveness and tolerability of brivaracetam (BRV) in adults with epilepsy by specific comorbidities and epilepsy etiologies.MethodsEXPERIENCE/EPD332 was a pooled analysis of individual patient records from several non-interventional studies of patients with epilepsy initiating BRV in clinical practice. Outcomes included ≥ 50% reduction from baseline in seizure frequency, seizure freedom (no seizures within prior 3 months), continuous seizure freedom (no seizures since baseline), BRV discontinuation, and treatment-emergent adverse events (TEAEs) at 3, 6, and 12 months. Analyses were performed for all adult patients (≥ 16 years of age) and stratified by comorbidity and by etiology at baseline (patients with cognitive/learning disability [CLD], psychiatric comorbidity, post-stroke epilepsy, brain tumor−related epilepsy [BTRE], and traumatic brain injury−related epilepsy [TBIE]).ResultsAt 12 months, ≥ 50% seizure reduction was achieved in 35.6% (n = 264), 38.7% (n = 310), 41.7% (n = 24), 34.1% (n = 41), and 50.0% (n = 28) of patients with CLD, psychiatric comorbidity, post-stroke epilepsy, BTRE, and TBIE, respectively; and continuous seizure freedom was achieved in 5.7% (n = 318), 13.7% (n = 424), 29.4% (n = 34), 11.4% (n = 44), and 13.8% (n = 29), respectively. During the study follow-up, in patients with CLD, psychiatric comorbidity, post-stroke epilepsy, BTRE, and TBIE, 37.1% (n = 403), 30.7% (n = 605), 33.3% (n = 51), 39.7% (n = 68), and 27.1% (n = 49) of patients discontinued BRV, respectively; and TEAEs since prior visit at 12 months were reported in 11.3% (n = 283), 10.0% (n = 410), 16.7% (n = 36), 12.5% (n = 48), and 3.0% (n = 33), respectively.ConclusionsBRV as prescribed in the real world is effective and well tolerated among patients with CLD, psychiatric comorbidity, post-stroke epilepsy, BTRE, and TBIE.

Perampanel for the treatment of epilepsy with genetic aetiology: Real-world evidence from the PERMIT Extension study

Genetic factors contribute to the aetiology of epilepsy in >50% of cases, and information on the use of antiseizure medications in people with specific aetiologies will help guide treatment decisions. The PERMIT Extension study pooled data from two real-world studies (PERMIT and PROVE) to investigate the effectiveness and safety/tolerability of perampanel (PER) when used to treat people with focal and generalised epilepsy in everyday clinical practice. This post-hoc analysis of PERMIT Extension explored the use of PER when used to treat individuals presumed to have epilepsy with a genetic aetiology. Assessments included retention rate (evaluated at 3, 6 and 12 months), effectiveness (responder and seizure freedom rates; evaluated at 3, 6, 12 months and the last visit [last observation carried forward) and tolerability (adverse events [AEs]). Of the 6822 people with epilepsy included in PERMIT Extension, 1012 were presumed to have a genetic aetiology. The most common genetic aetiologies were idiopathic generalised epilepsy (IGE; 58.2%), tuberous sclerosis (1.1%), Dravet syndrome (0.8%) and genetic epilepsy with febrile seizures plus (GEFS+; 0.5%). Retention rates at 3, 6 and 12 months in the total genetic aetiology population were 89.3%, 79.7% and 65.9%, respectively. In the total genetic aetiology population, responder rates at 12 months and the last visit were 74.8% and 68.3%, respectively, and corresponding seizure freedom rates were 48.9% and 46.5%, respectively. For the specific aetiology subgroups, responder rates at 12 months and the last visit were, respectively: 90.4% and 84.4% (IGE), 100% and 57.1% (tuberous sclerosis), 100% and 71.4% (Dravet syndrome), and 33.3% and 20.0% (GEFS+). Corresponding seizure freedom rates were, respectively: 73.1% and 64.6% (IGE), 33.3% and 22.2% (tuberous sclerosis), 20.0% and 28.6% (Dravet syndrome), and 0% and 0% (GEFS+). The incidence of AEs was 46.5% for the total genetic aetiology population, 48.8% for IGE, 27.3% for tuberous sclerosis, 62.5% for Dravet syndrome, and 20% for GEFS+. Tolerability findings were consistent with PER’s known safety profile. PER was effective and generally well tolerated when used in individuals with a presumed genetic epilepsy aetiology in clinical practice. PER was effective across a wide range of genetic aetiologies.

Systematic 1 Hz direct electrical stimulation for seizure induction: A reliable method for localizing seizure onset zone and predicting seizure freedom

ObjectiveTo prospectively investigate the utility of seizure induction using systematic 1 Hz stimulation by exploring its concordance with the spontaneous seizure onset zone (SOZ) and relation to surgical outcome; comparison with seizures induced by non-systematic 50 Hz stimulation was attempted as well. MethodsProspective cohort study from 2018 to 2021 with ≥ 1 y post-surgery follow up at Yale New Haven Hospital. With 1 Hz, all or most of the gray matter contacts were stimulated at 1, 5, and 10 mA for 30–60s. With 50 Hz, selected gray matter contacts outside of the medial temporal regions were stimulated at 1–5 mA for 0.5–3s. Stimulation was bipolar, biphasic with 0.3 ms pulse width. The Yale Brain Atlas was used for data visualization. Variables were analyzed using Fisher's exact, χ2, or Mann–Whitney test. ResultsForty-one consecutive patients with refractory epilepsy undergoing intracranial EEG for localization of SOZ were included. Fifty-six percent (23/41) of patients undergoing 1 Hz stimulation had seizures induced, 83% (19/23) habitual (clinically and electrographically). Eighty two percent (23/28) of patients undergoing 50 Hz stimulation had seizures, 65% (15/23) habitual. Stimulation of medial temporal or insular regions with 1 Hz was more likely to induce seizures compared to other regions [15/32 (47%) vs. 2/41 (5%), p < 0.001]. Sixteen patients underwent resection; 11/16 were seizure free at one year and all 11 had habitual seizures induced by 1 Hz; 5/16 were not seizure free at one year and none of those 5 had seizures with 1 Hz (11/11 vs 0/5, p < 0.0001). No patients had convulsions with 1 Hz stimulation, but four did with 50 Hz (0/41 vs. 4/28, p = 0.02). SignificanceInduction of habitual seizures with 1 Hz stimulation can reliably identify the SOZ, correlates with excellent surgical outcome if that area is resected, and may be superior (and safer) than 50 Hz for this purpose. However, seizure induction with 1 Hz was infrequent outside of the medial temporal and insular regions in this study.

Efficacy, tolerability and safety of add-on third-generation antiseizure medications in treating focal seizures worldwide: a network meta-analysis of randomised, placebo-controlled trials

Adjunctive newer antiseizure medications (ASMs) are being used in patients with treatment-resistant focal-onset seizures (FOS). An updated network meta-analysis (NMA) was necessary to compile evidence in this critical area. We systematically searched PubMed, Embase, Cochrane Library, Web of Science, and Scopus from their inception until 17 January 2024, evaluating the efficacy, tolerability, and safety of rufinamide (RUF), brivaracetam (BRV), cenobamate (CNB), eslicarbazepine (ESL), lacosamide (LCM), retigabine (RTG), and perampanel (PER) as adjunctive treatments for FOS. Efficacy outcomes included seizure response and seizure freedom. Tolerability was assessed by discontinuation due to adverse events (AEs). Safety outcomes were evaluated based on the number of patients experiencing at least one AE and serious adverse events (SAEs). This review is registered with PROSPERO (CRD42023485130). A total of 29 studies involving 11,750 participants were included. For seizure response, all ASMs were significantly superior to placebo, with RTG ranking highest, followed by CNB. Considering dosage, CNB 400mg/d was top-ranked, followed by RTG 1200mg/d. For seizure freedom, BRV was highest-ranked, followed by CNB, with BRV 100mg/d leading, followed by CNB 400mg/d. Regarding tolerability, LCM 600mg/d had the lowest ranking, followed by CNB 400mg/d. For the safety outcome of AEs, ESL 1200mg/d was ranked lowest, followed by CNB 400mg/d. Regarding SAEs, LCM 400mg/d was ranked lowest, followed by RTG 1200mg/d. ASMs at different dosages have varying efficacy and tolerability profiles. We have provided hierarchical rankings of ASMs for efficacy and safety outcomes. Our findings offer the most comprehensive evidence available to inform patients, families, physicians, guideline developers, and policymakers about the choice of ASMs in patients with treatment-resistant FOS. None.

Outcome of Epilepsy Surgery in MRI-Negative Patients Without Histopathologic Abnormalities in the Resected Tissue.

Patients with presumed nonlesional focal epilepsy-based on either MRI or histopathologic findings-have a lower success rate of epilepsy surgery compared with lesional patients. In this study, we aimed to characterize a large group of patients with focal epilepsy who underwent epilepsy surgery despite a normal MRI and had no lesion on histopathology. Determinants of their postoperative seizure outcomes were further studied. We designed an observational multicenter cohort study of MRI-negative and histopathology-negative patients who were derived from the European Epilepsy Brain Bank and underwent epilepsy surgery between 2000 and 2012 in 34 epilepsy surgery centers within Europe. We collected data on clinical characteristics, presurgical assessment, including genetic testing, surgery characteristics, postoperative outcome, and treatment regimen. Of the 217 included patients, 40% were seizure-free (Engel I) 2 years after surgery and one-third of patients remained seizure-free after 5 years. Temporal lobe surgery (adjusted odds ratio [AOR]: 2.62; 95% CI 1.19-5.76), shorter epilepsy duration (AOR for duration: 0.94; 95% CI 0.89-0.99), and completely normal histopathologic findings-versus nonspecific reactive gliosis-(AOR: 4.69; 95% CI 1.79-11.27) were significantly associated with favorable seizure outcome at 2 years after surgery. Of patients who underwent invasive monitoring, only 35% reached seizure freedom at 2 years. Patients with parietal lobe resections had lowest seizure freedom rates (12.5%). Among temporal lobe surgery patients, there was a trend toward favorable outcome if hippocampectomy was part of the resection strategy (OR: 2.94; 95% CI 0.98-8.80). Genetic testing was only sporadically performed. This study shows that seizure freedom can be reached in 40% of nonlesional patients with both normal MRI and histopathology findings. In particular, nonlesional temporal lobe epilepsy should be regarded as a relatively favorable group, with almost half of patients achieving seizure freedom at 2 years after surgery-even more if the hippocampus is resected-compared with only 1 in 5 nonlesional patients who underwent extratemporal surgery. Patients with an electroclinically identified focus, who are nonlesional, will be a promising group for advanced molecular-genetic analysis of brain tissue specimens to identify new brain somatic epilepsy genes or epilepsy-associated molecular pathways.

Stereotactic Electroencephalogram Recordings in Temporal Lobectomy Patients Demonstrates the Predictive Value of Interictal Cross-Frequency Correlations: A Retrospective Study.

Positive correlations between low- and high-frequency spectra from stereotactic electroencephalogram (SEEG) recordings have been implicated in pathological brain activity interictally and have been used for ictal detection in both focal and network models. We evaluated SEEG signals in patients who ultimately underwent temporal lobectomy to evaluate their utility in seizure localization and prediction of seizure freedom post-resection. We retrospectively analyzed cross-frequency correlations between beta and high gamma (HG) interictal SEEG signals from 22 patients. We compared signals based on temporal versus extra-temporal locations, seizure-free (SF) versus non-seizure-free (NSF) outcomes, and mesial (M) versus mesial temporal-plus (M+) onset. Positive cross-correlations were increased in temporal areas. NSF patients showed a higher proportion of positive electrodes in temporal areas. SF patients had a greater proportion of significant channels in mesial versus lateral temporal areas. HG/Beta correlations in mesial versus lateral temporal areas predicted seizure freedom better than ictal SEEG seizure onset localization to M or M+ locations. We present preliminary data that local HG/Beta correlations may predict epilepsy focus and surgical outcome and may have utility as adjunct methods to conventional SEEG analysis. Further studies are needed to determine strategies for prospective studies and clinical use.

Keto Clarity: A Comprehensive Systematic Review Exploring the Efficacy, Safety, and Mechanisms of Ketogenic Diet in Pediatric Epilepsy.

Epilepsy, a widespread neurological disorder characterized by recurrent seizures, affects millions globally, with a significant impact on the pediatric population. Antiepileptic drugs (AEDs) constitute the primary treatment; however, drug-resistant epilepsy (DRE), especially in children, poses a therapeutic challenge. Alternative interventions, such as surgery, vagus nerve stimulation, and the ketogenic diet (KD), have been explored.This systematic review aims to investigate various types of KDs, their distinctions, their effectiveness, and their safety concerning the reduction of seizure frequency, achieving seizure freedom, and the occurrence of adverse events. The study adheres to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines. A comprehensive search was conducted using databases such as PubMed Central (PMC), MedLine, and Science Direct to identify relevant articles. Eligibility criteria and quality assessment tools were applied to evaluate the potential risk of bias and select 11 articles for inclusion in this review. The selected articles encompassed four randomized controlled trials (RCTs), two systematic reviews, and five narrative reviews. The data collected for this review was completed on October 2, 2023. Challenges, such as palatability, cultural factors, and adherence difficulties, were identified. Family or caregiver involvement plays a pivotal role in treatment success. Despite numerous RCTs and reviews, information gaps persist, hindering conclusive outcomes. Evaluating the risk-benefit ratio is crucial, considering potential side effects. The highly individualized nature of KD therapy, influenced by diverse seizure types and syndromes, necessitates a trial-and-error approach monitored by a multidisciplinary team. Long-term safety and efficacy demand continuous real-life patient data review. In summary, while KD presents a promising alternative for DRE, its success relies on meticulous planning, individualized implementation, and ongoing research to address existing challenges and information gaps.

Deep Brain Stimulation of Bilateral Centromedian Thalamic Nuclei in Pediatric Patients with Lennox-Gastaut Syndrome: An Institutional Experience

IntroductionSurgical management of pediatric patients with non-lesional, drug-resistant epilepsy (DRE), including patients with Lennox-Gastaut Syndrome (LGS), remains a challenge given the lack of resective targets in most patients, and demonstrates seizure freedom rates <50% at 5-years. The efficacy of deep brain stimulation (DBS) is less certain in children than adults. This study examined clinical and seizure outcomes for pediatric patients with LGS undergoing DBS targeting of the centromedian thalamic nuclei (CMTN). MethodsIRB-approved retrospective analysis of patients ≤19-years with clinical diagnosis of LGS undergoing bilateral DBS placement to the CMTN from 2020-2021 by a single surgeon. ResultsFour females and 2 males, aged 6-19 years were identified. Before surgery, each child experienced at least 6-years of refractory seizures; 4 children experienced seizures since infancy. All took antiseizure medications at time of surgery. Five children had prior placement of a vagus nerve stimulator, 2 had previous corpus callosotomy. Mean length of stay following DBS was 2-days. No children experienced adverse neurological effects from implantation; mean follow-up time was 16.3 months. Four patients had >60% reduction in seizure frequency following surgery, 1 patient experienced 10% reduction, 1 patient demonstrated no change. No children reported worsening seizure symptoms post-surgery. ConclusionsOur study contributes to the sparse literature describing CMTN DBS for children with DRE from LGS. Our results suggest that CMTN DBS is a safe and effective therapeutic modality that should be considered as alternative or adjuvant therapy for this challenging patient population. Further studies with larger patient populations are warranted.

EANM practice guidelines for an appropriate use of PET and SPECT for patients with epilepsy

Epilepsy is one of the most frequent neurological conditions with an estimated prevalence of more than 50 million people worldwide and an annual incidence of two million. Although pharmacotherapy with anti-seizure medication (ASM) is the treatment of choice, ~30% of patients with epilepsy do not respond to ASM and become drug resistant. Focal epilepsy is the most frequent form of epilepsy. In patients with drug-resistant focal epilepsy, epilepsy surgery is a treatment option depending on the localisation of the seizure focus for seizure relief or seizure freedom with consecutive improvement in quality of life. Beside examinations such as scalp video/electroencephalography (EEG) telemetry, structural, and functional magnetic resonance imaging (MRI), which are primary standard tools for the diagnostic work-up and therapy management of epilepsy patients, molecular neuroimaging using different radiopharmaceuticals with single-photon emission computed tomography (SPECT) and positron emission tomography (PET) influences and impacts on therapy decisions. To date, there are no literature-based praxis recommendations for the use of Nuclear Medicine (NM) imaging procedures in epilepsy. The aims of these guidelines are to assist in understanding the role and challenges of radiotracer imaging for epilepsy; to provide practical information for performing different molecular imaging procedures for epilepsy; and to provide an algorithm for selecting the most appropriate imaging procedures in specific clinical situations based on current literature. These guidelines are written and authorized by the European Association of Nuclear Medicine (EANM) to promote optimal epilepsy imaging, especially in the presurgical setting in children, adolescents, and adults with focal epilepsy. They will assist NM healthcare professionals and also specialists such as Neurologists, Neurophysiologists, Neurosurgeons, Psychiatrists, Psychologists, and others involved in epilepsy management in the detection and interpretation of epileptic seizure onset zone (SOZ) for further treatment decision. The information provided should be applied according to local laws and regulations as well as the availability of various radiopharmaceuticals and imaging modalities.

The importance of routine genetic testing in pediatric epilepsy surgery.

Genetic variants in relevant genes coexisting with MRI lesions in children with drug-resistant epilepsy (DRE) can negatively influence epilepsy surgery outcomes. Still, presurgical evaluation does not include genetic diagnostics routinely. Here, we report our presurgical evaluation algorithm that includes routine genetic testing. We analyzed retrospectively the data of 68 children with DRE operated at a mean age of 7.8 years (IQR: 8.1 years) at our center. In 49 children, genetic test results were available. We identified 21 gene variants (ACMG III: n = 7, ACMG IV: n = 2, ACMG V: n = 12) in 19 patients (45.2%) in the genes TSC1, TSC2, MECP2, DEPDC5, HUWE1, GRIN1, ASH1I, TRIO, KIF5C, CDON, ANKD11, TGFBR2, ATN1, COL4A1, JAK2, KCNQ2, ATP1A2, and GLI3 by whole-exome sequencing as well as deletions and duplications by array CGH in six patients. While the results did not change the surgery indication, they supported counseling with respect to postoperative chance of seizure freedom and weaning of antiseizure medication (ASM). The presence of genetic findings leads to the postoperative retention of at least one ASM. In our cohort, the International League against Epilepsy (ILAE) seizure outcome did not differ between patients with and without abnormal genetic findings. However, in the 7/68 patients with an unsatisfactory ILAE seizure outcome IV or V 12 months postsurgery, 2 had an abnormal or suspicious genetic finding as a putative explanation for persisting seizures postsurgery, and 3 had received palliative surgery including one TSC patient. This study highlights the importance of genetic testing in children with DRE to address putative underlying germline variants as genetic epilepsy causes or predisposing factors that guide patient and/or parent counseling on a case-by-case with respect to their individual chance of postoperative seizure freedom and ASM weaning. PLAIN LANGUAGE SUMMARY: Genetic variants in children with drug-resistant epilepsy (DRE) can negatively influence epilepsy surgery outcomes. However, presurgical evaluation does not include genetic diagnostics routinely. This retrospective study analyzed the genetic testing results of the 68 pediatric patients who received epilepsy surgery in our center. We identified 21 gene variants by whole-exome sequencing as well as deletions and duplications by array CGH in 6 patients. These results highlight the importance of genetic testing in children with DRE to guide patient and/or parent counseling on a case-by-case with respect to their individual chance of postoperative seizure freedom and ASM weaning.

Sequential levetiracetam and phenytoin in electroencephalographic neonatal seizures unresponsive to phenobarbital: a multicenter prospective observational study in India

Although levetiracetam and phenytoin are widely used antiseizure medications (ASM) in neonates, their efficacy on seizure freedom is unclear. We evaluated electroencephalographic (EEG) seizure freedom following sequential levetiracetam and phenytoin in neonatal seizures unresponsive to phenobarbital. We recruited neonates born ≥35 weeks and aged <72h who had continued electrographic seizures despite phenobarbital, from three Indian hospitals, between 20 June 2020 and 31 July 2022. The neonates were treated with intravenous levetiracetam (20mg/kg x 2 doses, second line) followed by phenytoin (20mg/kg x 2 doses, third line) if seizures persisted. The primary outcome was complete seizure freedom, defined as an absence of seizures on EEG for at least 60min within 40min from the start of infusion. Of the 206 neonates with continued seizures despite phenobarbital, 152 received levetiracetam with EEG. Of these one EEG was missing, 47 (31.1%) were in status epilepticus, and primary outcome data were available in 145. Seizure freedom occurred in 20 (13.8%; 95% CI 8.6%-20.5%) after levetiracetam; 16 (80.0%) responded to the first dose and 4 (20.0%) to the second dose. Of the 125 neonates with persisting seizures after levetiracetam, 114 received phenytoin under EEG monitoring. Of these, the primary outcome data were available in 104. Seizure freedom occurred in 59 (56.7%; 95% CI 46.7%-66.4%) neonates; 54 (91.5%) responded to the first dose and 5 (8.5%) to the second dose. With the conventional doses, levetiracetam was associated with immediate EEG seizure cessation in only 14% of phenobarbital unresponsive neonatal seizures. Additional treatment with phenytoin along with levetiracetam attained seizure freedom in further 57%. Safety and efficacy of higher doses of levetiracetam should be evaluated in well-designed randomised controlled trials. National Institute for Health and Care Research (NIHR) Research and Innovation for Global Health Transformation (NIHR200144).

Analysis of factors influencing the efficacy of vagus nerve stimulation for the treatment of drug-resistant epilepsy in children and prediction model for efficacy evaluation.

Vagus nerve stimulation (VNS) has been widely used in the treatment of drug-resistant epilepsy (DRE) in children. We aimed to explore the efficacy and safety of VNS, focusing on factors that can influence the efficacy of VNS, and construct a prediction model for the efficacy of VNS in the treatment of DRE children. Retrospectively analyzed 45 DRE children who underwent VNS at Qilu Hospital of Shandong University from June 2016 to November 2022. A ≥50% reduction in seizure frequency was defined as responder, logistic regression analyses were performed to analyze factors affecting the efficacy of VNS, and a predictive model was constructed. The predictive model was evaluated by receiver operating characteristic curve (ROC), calibration curves, and decision curve analyses (DCA). A total of 45 DRE children were included in this study, and the frequency of seizures was significantly reduced after VNS treatment, with 25 responders (55.6%), of whom 6 (13.3%) achieved seizure freedom. There was a significant improvement in the Quality of Life in Childhood Epilepsy Questionnaire (15.5%) and Seizure Severity Score (46.2%). 16 potential factors affecting the efficacy of VNS were included, and three statistically significant positive predictors were ultimately screened: shorter seizure duration, focal seizure, and absence of intellectual disability. We developed a nomogram for predicting the efficacy of VNS in the treatment of DRE children. The ROC curve confirmed that the predictive model has good diagnostic performance (AUC = 0.864, P < 0.05), and the nomogram can be further validated by bootstrapping for 1,000 repetitions, with a C-index of 0.837. Besides, this model showed good fitting and calibration and positive net benefits in decision curve analysis. VNS is a safe and effective treatment for DRE children. We developed a predictive nomogram for the efficacy of VNS, which provides a basis for more accurate selection of VNS patients.

Endoscopic callosotomy as a minimally invasive approach to treat paediatric refractory epilepsy: case series.

Endoscopic callosotomy has emerged as a promising and minimally invasive technique for the treatment of refractory epilepsy. This paper aims to review the clinical outcomes and advancements associated with endoscopic callosotomy as a therapeutic option. This study includes 14 Paediatric patients diagnosed and managed at Al-azhar university hospitals. Those 14 patients were studied over 2 years. All patients underwent a corpus callosotomy using the bimanual endoscopic technique. Endoscopic anterior corpus callosotomy was done in 13 patients while one case underwent endoscopic complete callosotomy. The most frequent complication was transient disconnection syndrome followed by transient Urinary incontinence and one case had minor CSF leak. As regard seizure freedom outcome (Engel's Outcome Scale): 4 cases (28.6%) became seizure free (Engle class I), 5 cases (35.7%) with Engle class II, 1 case (7.1%) with Engle class III and 4 cases (28.6%) classify as Engle class IV. As a minimally invasive technique with a favorable impact on cognitive function, less complications and a significant reduction in seizure frequency and severity in the majority of paediatric patients, endoscopic corpus callosotomy offeres substantial benefits in managing refractory epilepsy in paediatric.

The impact of ketogenic diet on drug-resistant epilepsy in children: A comprehensive review and meta-analysis.

The ketogenic diet (KD), characterized by high-fat and low-carbohydrate intake, is currently gaining widespread popularity as a treatment for drug-resistant epilepsy (DRE). In addition to the traditional ketogenic diet, several variants have been introduced to enhance compliance and flexibility, such as the modified Atkins diet (MAD) and the low glycemic index diet (LGID). These adaptations aim to provide patients with more manageable and sustainable options while harnessing the potential therapeutic benefits of DRE. The objective of this study is to evaluate the efficacy and safety of the KD in pediatric patients who exhibit DRE. In this study, we conducted a thorough review of existing literature by searching Cochrane, Embase, Medline, and PubMed. Our approach involved predefined criteria for data extraction and the assessment of study quality. Eleven RCTs with 788 participants were included in this study. The pooled effect estimates revealed a significant association between dietary interventions and seizure frequency reduction of > 50% (OR 6.68, 96% CI 3.52, 12.67) and > 90% (OR 4.37, 95% CI 2.04, 9.37). Dietary interventions also increased the odds of achieving seizure freedom (OR 4.13, 95% CI 1.61, 10.60). The common adverse effects included constipation (39.07%) and vomiting (10%). In conclusion, dietary interventions, notably the KD, hold promise for pediatric DRE, reducing seizures and achieving freedom. These non-pharmacological options improve the quality of life of non-responsive and non-surgical patients. The KD has emerged as a potential therapeutic approach. Further research is needed to address the limitations and investigate their long-term effects.