Etiology Of Epilepsy Research Articles

Clinical characteristics and outcomes of adults with multifocal epilepsy.

Multifocal epilepsy is an important subtype of epilepsy, but it is sometimes difficult to recognise in general clinical practice. Distinguishing (uni)focal from multifocal drug resistant epilepsy is important when considering surgical resection. The presence of multiple discrete autonomous epileptogenic zones may limit surgical options to neuromodulation or palliative resection. We describe the clinical characteristics and outcomes of a cohort of patients with multifocal epilepsy diagnosed by video-EEG monitoring. Patients with probable and possible multifocal epilepsy were identified from an Epilepsy Monitoring Unit database during a 9-year period. Clinical characteristics and long term outcomes are described. We identified 30 patients- 19 with possible and 11 with probable multifocal epilepsy based on clinical assessment and video-EEG findings. The aetiology of epilepsy was structural or of unknown cause in the majority. Prior to video-EEG monitoring, clinical assessment including ascertainment of seizure semiology or routine EEG suggested multifocal epilepsy in only 13.3% of patients. Over 95% had ongoing drug resistant seizures at last follow up. One patient died from sudden unexpected death in epilepsy over the 9-year study interval. This study highlights that multifocal epilepsy is often not recognised or diagnosed in the outpatient setting. Typically it is a diagnosis made after video-EEG monitoring. In our experience multifocal epilepsy is usually drug-resistant and often highly refractory. Recognising patients with multifocal epilepsy as a more treatment-resistant subgroup within focal epilepsy is important for counselling and management considerations.

Asymmetric dynamics of GABAergic system and paradoxical responses of GABAergicneurons in piriform seizures.

The piriform cortex (PC) plays a critical role in ictogenesis, where an excitation/inhibition imbalance contributes to epilepsy etiology. However, the epileptic dynamics of the gamma-aminobutyric acid (GABA) system and the precise role of GABAergic neurons within the PC in epilepsy remain unclear. We combined Ca2+ and GABA sensors to investigate the dynamics of Gad2-expressing neurons and GABA levels, and selectively manipulated GABAergic neurons in the PC through chemogenetic inhibition and caspase3-mediated apoptosis targeting Gad2 interneurons. GABAergic system dynamics in the PC were bidirectional and asymmetric,accompanied by PC optokindling-induced seizures, notably characterized by a robust response of Gad2 neurons but a rapid descent of GABA content during seizures. Chemogenetic inhibition of PC Gad2 neurons induced seizure-like behavior, with a discrepancy between the GABAergic neuron activities and GABA levels, signifying a transition from interictal to ictal states. Surprisingly, selective inhibition of Gad2 neurons in the PC produced paradoxical activation in a subset of Gad2 neurons. Moreover, the chronic deficiency of PC Gad2 neurons triggered spontaneous recurrent seizures. Our findings uncover the dynamic interplay within PC inhibitory components and elaborate counteractive mechanisms in seizure regulation. These insights could inform future therapeutic strategies targeting GABAergic neurons to control epileptic activity.

Association between Frequency of Seizures and Number of Antiseizure Medications (ASM) in Patients with Epilepsy.

The literature has shown the relevance of nutritional and metabolic aspects in patients with epilepsy. This study evaluated the relationship between clinical variables and plasma proteins and compared the variables between seizure frequency and neurological examination. A pilot study was carried out with eighty-four (n = 84) adults patients with epilepsy. The relationship between clinical variables of the disease (age at disease onset, neurological examination, current type and frequency of seizures, duration of disease, amount of antiseizure medications-ASM used and type and etiology of epilepsy) and plasma proteins (albumin and transferrin) was investigated. In the statistical analysis, the chi-square, Fisher, Mann-Whitney, Kruskal-Wallis tests, Spearman coefficient and univariate logistic regression were used. There was a significant association between the use of antiseizure medications (ASM) (p = 0.0105) and altered neurological examination (p = 0.0049), compared with the frequency of seizures, and between albumin and gender (p = 0.0005), and albumin and etiology of epilepsy (p = 0.0186). There was a significant low-intensity and inverse linear correlation (coefficient = -0.31363, p = 0.0037) between albumin and disease duration. In the logistic regression model, a significant association was only observed between the number of ASM and the frequency of seizures (p = 0.0120; OR = 3.368; 95% CI = 1.305-8.691). There was no association between plasma proteins and the outcomes of seizure frequency and neurological examination. The number of ASM and not protein metabolism was associated with frequency of seizures in patients with epilepsy.

ВЛИЯНИЕ ЭПИЛЕПСИИ НА ТЕЧЕНИЕ И ИСХОДЫ БЕРЕМЕННОСТИ

A retrospective analysis was conducted in 82 women with epilepsy. The course of pregnancy was analyzed in 58 women with epilepsy who took antiepileptic drugs during pregnancy - the main group, the comparison group - 24 pregnant women with drug-free remission of epilepsy. The etiology, pathogenesis, type and form of epilepsy were examined in the study groups. In the presence of epilepsy, other concomitant somatic pathology was present in 54 (93,1 %) pregnant women of the main and 21 (87,5 %) comparison groups, and the analyzed groups did not differ in terms of the two factors (p=0,409). There were no statistically significant differences between the groups in the incidence of anemia in pregnant women (59,6 % and 33,3 % (p=0,053), threatened miscarriage 39,7 % and 33,3 % (p=0,592), fetal growth restriction 12,1 % and 4,2 % (p=0,273). Chronic placental insufficiency in the main group was 11 (18,9 %) and 7 (29,2 %) in the comparison group (p=0,473), which indicated timely prevention in women of the main group

The role of genetic testing in adult patients with unexplained epilepsy.

Genetic causes are often overlooked in patients with epilepsy of unknown etiology, particularly in adults. We aimed to evaluate clinical features of genetic epilepsy and the utility of genetic testing. We retrospectively screened consecutive unrelated adult epilepsy patients at an epilepsy clinic from April 2022 to May 2023. Patients with unknown etiology or special brain lesions were classified as unexplained epilepsy. In them, patients with young-onset seizures or family history of seizures who were recommended for and ultimately underwent genetic testing using either panel next-generation sequencing (NGS) or whole-exome sequencing (WES) were enrolled. A definite or probable genetic diagnosis was established through genotype-phenotype correlation. We compared the demographic characteristics between genetic epilepsy and other etiologies. Of the 374 adult epilepsy patients, 258 were classified as unexplained epilepsy, 129 were suspected of having genetic epilepsy due to young-onset seizures or a positive family history, 33 underwent genetic testing; 13 harbored variants classified as pathogenic, and 6 reached a definite genetic diagnosis, resulting in a yield of 18%. Among the 27 patients without a definite genetic diagnosis, 7 had a nongenetic structural etiology. Patients with genetic etiology exhibited greater multisystem involvement particularly multiple structural anomalies and early childhood-onset seizures, but wasn't directly correlated with young-onset seizures or a positive family history. The diagnostic yield was comparable between panel NGS and WES. In adult patients with unexplained epilepsy, genetic epilepsy is more associated with multisystem involvement and multiple structural anomalies but not family history of seizures or young-onset seizures.

Epilepsy in children and anesthesia

Epilepsy, also called seizure disorder, is the most common childhood brain disorder in the United States. The aetiology of epilepsy in children is multifactorial with congenital, metabolic, infective, and problems associated with prematurity being common causes. Nearly 3 million Americans have epilepsy. About 450,000 of them are under 17 years old. About 1 in 200 children (0.5%) have epilepsy, a neurological condition where children have a predisposition to recurrent, unprovoked seizures. There are many different types of epilepsy, especially in infancy, childhood and adolescence. Epilepsy can be thought of in terms of either: the site of seizure origin in the brain (generalised or focal seizures), or the underlying cause. Genetic epilepsies (formerly called idiopathic or primary epilepsies) occur in an otherwise normal person and are due to a genetic predisposition to seizures. Some epilepsies are due to an underlying abnormality of the brain structure or chemistry (formerly called symptomatic or secondary epilepsies). Other epilepsies have no known cause. Epilepsy is commonly diagnosed in children and can be confused with other conditions. An accurate diagnosis is essential. A seizure is an excessive surge of electrical activity in the brain that can cause a variety of symptoms, depending on which parts of the brain are involved. Seizures can be provoked or unprovoked. Provoked seizures, caused by fever in a young child or severe hypoglycemia, are not considered to be forms of epilepsy. Unprovoked seizures have no clear cause but can be related to genetics or brain injury. When a child has two or more unprovoked seizures, epilepsy is often the diagnosis. Despite advances in antiepileptic medication therapy, a significant number of pediatric patients with epilepsy have seizures that are not well controlled. Antiepileptic medications interact with anesthetic agents, and common anesthetics can precipitate or suppress seizure activity. There are important pharmacokinetic and pharmacodynamic interactions between AEDs and drugs commonly used in anaesthesia. These affect both drug efficacy and the risk of seizure activity intraoperatively.

Isoaspartate formation and irreversible aggregation of collapsin response mediator protein 2: implications for the etiology of epilepsy and age-related cognitive decline.

Collapsin response mediator protein 2 (CRMP2) functions in the genesis and activity of neuronal connections in mammalian brain. We previously reported that a protein coincident with CRMP2 on 2D-gels undergoes marked accumulation of abnormal L-isoaspartyl sites in brain extracts of mice missing the repair enzyme, protein L-isoaspartyl methyltransferase (PIMT). To conflrm and explore the signiflcance of isoaspartyl damage in CRMP2, we expressed and purifled recombinant mouse CRMP2 (rCRMP2). A polyclonal antibody made against the recombinant protein precipitated CRMP2 from brain extracts of PIMT-KO mice, but not from WT mice, suggesting that (1) the rCRMP2 antigen underwent signiflcant isoAsp formation in the process of antibody production and (2) the isoAsp form of CRMP2 is considerably more immunogenic than the native protein. In vitro aging of rCRMP2 at pH 7.4, 37°C for 0-28 days led to robust accumulation of isoAsp sites that were repairable by PIMT, and also induced a progressive accumulation of apparent dimers and higher-mass oligomers as judged by SDS-PAGE. A similar pattern of CRMP2 aggregation was observed in mice, with levels increasing throughout the lifespan. We conclude that CRMP2 is indeed a major target of PIMT-mediated protein repair in the brain; that isoAsp forms of CRMP2 are highly immunogeni; and that CRMP2 dysfunction makes a signiflcant contribution to neuropathology in the PIMT-KO mouse.

Adeno-Associated Viral Vectors in the Treatment of Epilepsy.

Epilepsy is a brain disorder characterized by a persistent predisposition to epileptic seizures. With various etiologies of epilepsy, a significant proportion of patients develop pharmacoresistance to antiepileptic drugs, which necessitates the search for new therapeutic methods, in particular, using gene therapy. This review discusses the use of adeno-associated viral (AAV) vectors in gene therapy for epilepsy, emphasizing their advantages, such as high efficiency of neuronal tissue transduction and low immunogenicity/cytotoxicity. AAV vectors provide the possibility of personalized therapy due to the diversity of serotypes and genomic constructs, which allows for increasing the specificity and effectiveness of treatment. Promising orientations include the modulation of the expression of neuropeptides, ion channels, transcription, and neurotrophic factors, as well as the use of antisense oligonucleotides to regulate seizure activity, which can reduce the severity of epileptic disorders. This review summarizes the current advances in the use of AAV vectors for the treatment of epilepsy of various etiologies, demonstrating the significant potential of AAV vectors for the development of personalized and more effective approaches to reducing seizure activity and improving patient prognosis.

BRIVA-ONE study: 12-month outcomes of brivaracetam monotherapy in clinical practice.

This study investigated the effectiveness and tolerability of brivaracetam (BRV) monotherapy in a large series of patients with epilepsy. This was a multicenter, retrospective, observational, non-interventional study in 24 hospitals across Spain. Patients aged ≥18 years who started on BRV monotherapy, either as first-line or following conversion, at least 1 year before database closure were included. Patients were evaluated at baseline and at 3, 6 and 12 months after initiation of BRV monotherapy, in accordance with usual clinical practice at these centers. Data were collected retrospectively from patients' individual charts by participating physicians. The primary effectiveness and safety endpoints were the percentage of seizure-free patients 1 year after initiation of BRV monotherapy and the proportion of patients reporting adverse events (AEs) over the complete follow-up period. Retention rates and subpopulation analysis (levetiracetam switchers, elderly and different etiologies) were also investigated. A total of 276 patients were included (48 with BRV as first-line monotherapy and 228 who converted to BRV monotherapy). The overall retention rate in monotherapy at 12 months was 89.9% (87.5% for first-line monotherapy group; 90.4% for conversion-to-monotherapy group). Seizure-freedom rates at 12 months were 77.8% (75% for first-line monotherapy group; 78.4% for conversion-to-monotherapy group). AEs occurred in 39.5% of patients at 12 months (35.4% for first-line monotherapy group; 40.4% for conversion-to-monotherapy group). Most AEs were mild-to-moderate. The most frequent AEs were irritability (12.3%) and dizziness (10.1%). The most frequent AEs leading to BRV withdrawal were dizziness (1.8%) and memory problems (1.4%). Similar outcomes in terms of effectiveness and tolerability of BRV monotherapy were observed in patients switching from levetiracetam, those with different epilepsy etiologies, and elderly patients. BRV was effective and well tolerated both as first-line monotherapy and following conversion to monotherapy in a real-world setting of patients with epilepsy. The goal of the medical treatment of epilepsy is to ensure best possible patient quality of life, by maximizing seizure control and minimizing medication toxicity. Brivaracetam (BRV) is a new-generation epilepsy treatment that is well tolerated by patients. In our study, monotherapy with BRV reduced seizures in patients who had not received other treatments and in patients who switched from a previous treatment to BRV monotherapy. BRV was well tolerated and also effective in sensitive patients (i.e., the elderly and those who had epilepsy caused by a brain tumor or a brain injury).

Maternal pre-gestational and gestational diabetes and risk of offspring epilepsy: A cohort study

Abstract Background Despite growing evidence linking maternal diabetes to impaired brain physiology and neurodevelopment in offspring, evidence on its effect on epilepsy remains scarce. This study aims to determine if intrauterine exposure to maternal pre-existing and gestational diabetes mellitus is associated with risk of offspring epilepsy. Methods We studied >2.3 million singletons live-born in Sweden between 1998 and 2021, with final follow up until October 31, 2023. The Swedish Medical Birth Register was linked to the National Patient Register to identify gestational diabetes (GDM), maternal pre-gestational type 1 (T1DM) and type 2 diabetes (T2DM), and offspring epilepsy. The incidence of epilepsy, comparing offspring of mothers with versus without diabetes, was calculated as hazard ratios (HR), adjusting for maternal education, smoking, body mass index, hypertension, epilepsy and other important confounders. Paternal T1DM and T2DM were additionally analysed as negative control exposures to assess genetic confounding. Results Of the 2,335,245 offspring analysed (48.9% female), 13,883 (0.6%) were exposed to maternal T1DM, 4477 (0.2%) to T2DM, and 37,253 (1.6%) to GDM. During a median follow up of 13 years (range 0-26 years), 18,732 offspring were diagnosed with epilepsy. Maternal T1DM (HR 1.27, 95% confidence intervals [CI] 1.08-1.49) and T2DM (HR 1.34, 95% CI 1.00-1.49) were associated with higher hazards of epilepsy in offspring, compared with no exposure to maternal diabetes. Preterm birth and birth-asphyxia jointly mediated 63% and 39% of these associations, respectively. No association was found between maternal GDM and epilepsy. Paternal T1DM and T2DM did not show association with epilepsy. Conclusions In this nationwide population-based cohort study, children of mothers with T1DM or T2DM showed an elevated risk of epilepsy. The results from paternal comparison and mediation analyses suggest a key role of the intrauterine environment in the aetiology of epilepsy. Key messages • Maternal pre-existing T1DM and T2DM might be risk factors for epilepsy in offspring and are likely to influence the risk through the intrauterine environment independent of genetic mechanisms. • In the context of a globally rising prevalence of diabetes in women who get pregnant, it is crucial that the diabetes is well-regulated and birth complications associated with diabetes are prevented.

Factors impacting time to genetic diagnosis for children with epilepsy.

Molecular diagnosis for pediatric epilepsy patients can impact treatment and health supervision recommendations. However, there is little known about factors affecting the time to receive a diagnosis. Our objective was to characterize factors affecting the time from first seizure to molecular diagnosis in children with epilepsy. A retrospective, population-based review was used to analyze data from pediatric patients with a genetic etiology for epilepsy over a 5 year period. A subgroup of patients with seizure onset after 2016 was evaluated for recent trends. We identified 119 patients in the main cohort and 62 in a more recent (contemporaneous) subgroup. Sex, race, and ethnicity were not significantly associated with time to molecular diagnosis. A greater number of hospitalizations was associated with a shorter time to diagnosis (p < 0.001). Developmental delay was associated with a longer time to diagnosis (p = 0.002). We found no association for time to diagnosis with a diagnosis of autism, utilization of free genetic testing, or epilepsy type. In the recent subgroup analysis, commercial insurance was associated with decreased time to diagnosis (p = 0.02). Developmental delay, public insurance, or patients in the outpatient setting had longer times to molecular diagnosis. These findings suggest that there may be opportunities to implement interventions aimed at accelerating the provision of genetic testing in pediatric epilepsy. PLAIN LANGUAGE SUMMARY: Genetic diagnosis for pediatric epilepsy patients can impact treatment and care. This study looked at factors that affect how long it takes a pediatric epilepsy patient to receive a genetic diagnosis. We found that sex, race and ethnicity, epilepsy type, and whether the patient had autism did not affect how long it took the patient to receive a diagnosis. However, we found that patients with developmental delay, fewer hospitalizations, and public insurance took a longer time to receive a diagnosis. Our findings suggest potential strategies for reducing the time to receive a genetic diagnosis.

Diagnosis and Classification of Pediatric Epilepsy in Sub-Saharan Africa: A Comprehensive Review.

Background/Objectives: Epilepsy is a major public health issue in Sub-Saharan Africa, particularly among children, due to limited healthcare resources, socioeconomic inequalities, and cultural stigma that often result in underdiagnosis and undertreatment. This review examines pediatric epilepsy's diagnosis, classification, and management in this setting, highlighting the need for culturally appropriate interventions to improve care quality and address these challenges. Methods: A review of the literature was conducted using MEDLINE, Embase, Scopus, and Web of Science databases to identify pertinent studies published between 2013 and 2024. This review included studies examining the epidemiology, seizure classification and etiologies of epilepsy among children in Sub-Saharan Africa. Results: This review revealed higher incidence and prevalence of epilepsy in Sub-Saharan Africa compared to high-income countries, primarily attributable to factors such as infectious diseases, perinatal injuries, and limited diagnostic resources. The most frequently reported types of epilepsy were generalized and focal seizures, with significant etiological contributions from structural and infectious causes, including nodding syndrome and HIV-related epilepsy. The treatment gap remains considerable, with up to 80% of children not receiving appropriate antiseizure medications. Conclusions: The diagnosis and treatment of epilepsy in pediatric populations in Sub-Saharan Africa is complicated by several factors, including cultural stigma and the lack of adequate healthcare infrastructure. There is an urgent need for culturally tailored diagnostic tools, improved access to affordable treatments, and public health initiatives aimed at reducing stigma. Addressing these gaps through enhanced research, improved healthcare access, and targeted educational campaigns is crucial for improving the quality of life for children with epilepsy.

Circulating microRNAs and isomiRs as biomarkers for the initial insult and epileptogenesis in four experimental epilepsy models: The EPITARGET study.

Structural epilepsies can manifest months or years after the occurrence of an initial epileptogenic insult, making them amenable for secondary prevention. However, development of preventive treatments has been challenged by a lack of biomarkers for identifying the subset of individuals with the highest risk of epilepsy after the epileptogenic insult. Four different rat models of epileptogenesis were investigated to identify differentially expressed circulating microRNA (miRNA) and isomiR profiles as biomarkers for epileptogenesis. Plasma samples were collected on day 2 and day 9 during the latency period from animals that did or did not develop epilepsy during long-term video-electroencephalographic monitoring. miRNAs and isomiRs were identified and measured in an unsupervised manner, using a genome-wide small RNA sequencing platform. Receiver operating characteristic analysis was performed to determine the performance of putative biomarkers. Two days after an epileptogenic insult, alterations in the levels of several plasma miRNAs and isomiRs predicted epileptogenesis in a model-specific manner. One miRNA, miR-3085, showed good sensitivity (but low specificity) as a prognostic biomarker for epileptogenesis in all four models (area under the curve = .729, sensitivity = 83%, specificity = 64%, p < .05). Identified plasma miRNAs and isomiRs are mostly etiology-specific rather than common prognostic biomarkers of epileptogenesis. These data imply that in preclinical and clinical studies, it may be necessary to identify specific biomarkers for different epilepsy etiologies. Importantly, circulating miRNAs like miR-3085 with high negative predictive value for epileptogenesis in different etiologies could be useful candidates for initial screening purposes of epileptogenesis risk.

Beyond seizure freedom: Reduction in anti-seizure medication after epilepsy surgery

IntroductionPatients considering therapeutic epilepsy surgery often seek to decrease the number of anti-seizure medications (ASMs) they need. Predicting such reductions remains challenging. Although predictors of seizure freedom after epilepsy surgery are well-established, long-term outcomes remain modest and factors associated with ASM reduction, even in the absence of seizure freedom, may improve surgical planning to align with patient goals. MethodsWe studied a large multi-institutional cohort of patients who underwent epilepsy surgery between 2001 and 2022, with a minimum of two years follow-up. Preoperative features, including duration of epilepsy, epilepsy etiology, non-invasive investigation data, and total number of ASMs prescribed immediately prior to surgery were extracted for each patient. Primary endpoints included likelihood of ASM reduction and ASM freedom at multiple post-operative time points up to 15 years and stratified by seizure control. ResultsA total of 250 patients were followed for a median of 6.0 (range 2, 22) years after intracranial EEG (iEEG) surgery. Significant ASM reduction was only observed in those who underwent subsequent resection, whereas those undergoing neuromodulation saw their ASM usage maintained. Engel I outcomes were the strongest driver of ASM reduction. In patients with persistent seizures, patients with lateralized seizure onset zones (SOZs) also achieved sustained ASM reduction over time. Similarly, an increased number of preoperative ASMs also corresponded to a higher likelihood of ASM reduction across all follow-up periods. Other preoperative factors, including seizure etiology, did not independently influence ASM reduction. ConclusionsEven patients with persistent seizures after epilepsy surgery can observe meaningful ASM reduction during long-term follow-up. ASM reduction may be a relevant secondary outcome measure for epilepsy surgery.

Baseline characteristics and predictors for early implantation of vagus nerve stimulation therapy in people with drug-resistant epilepsy: Observations from an international prospective outcomes registry (CORE-VNS).

Vagus nerve stimulation (VNS) Therapy is routinely indicated for people with drug-resistant epilepsy (DRE). We analyzed the baseline characteristics of individuals receiving the recently released VNS models and identified factors associated with early or late implantation. The Comprehensive Outcomes Registry of subjects with Epilepsy (CORE-VNS), a prospective observational study evaluating the clinical and psychosocial outcomes of VNS Therapy®, is following participants for up to 60 months after VNS implantation. In this analysis, we used Cox proportional hazards model to identify baseline characteristics associated with the time from diagnosis to first implantation. Of the 819 enrolled, 792 (96.7%) participants implanted with a VNS device were evaluated. 529 (64.6%) underwent the first implantation and 263 (32.1%) a re-implantation. Participants' median age at first implant was 24 years; 492 (62.1%) were ≥18 years old and 166 (20.3%) were < 12 years old. The average number of failed ASMs prior to VNS implantation was 7.1, and 145 (17.7%) had undergone previous epilepsy-related surgery. Epilepsy was classified as focal in 47.7% of participants, generalized in 16.1% and combined focal and generalized in 34.2%. Many of the participants (40.9%) had epilepsy of unknown etiology. The median time from diagnosis to first implantation was 10.33 years and was significantly shorter in participants with combined focal and generalized epilepsy compared to those with focal epilepsy alone, and in participants with genetic and immune epilepsy compared to those with unknown etiologies. In people with DRE, VNS Therapy is provided after multiple failures of ASMs and after failure of epilepsy surgery in one in six individuals. Time from diagnosis to first implantation is associated with epilepsy type and etiology, likely reflecting variable treatment pathways. Clearer guidelines on when and how non-drug therapies should be deployed in people with DRE related to different epilepsy factors are needed. Neuromodulation can be a very helpful treatment in people who have seizures that do not respond to medications. The most widely utilized neuromodulation therapy is vagus nerve stimulation (VNS). We present data from a large, global study to show that people use an average of seven anti-seizure medications before attempting VNS Therapy and that it takes about 10 years for people to get their first VNS implant. We advocate for clearer treatment guidelines on how and when to consider VNS Therapy in people with seizures that are resistant to medication.

Deep brain stimulation targets in drug-resistant epilepsy: Systematic review and meta-analysis of effectiveness and predictors of response

PurposeAnterior nucleus of the thalamus (ANT) is the only deep brain stimulation (DBS) target that is approved by the FDA for treatment of drug-resistant epilepsy (DRE). Hippocampus (HC) and centromedian nucleus (CMN) have been reported as potential DBS targets for DRE. This study aimed to assess the effectiveness and predictors of response among DRE patients treated with DBS in general and among ANT, HC and CMN DBS-targets. MethodsA systematic search was executed on PubMed, SCOPUS and the Cochrane Central Register of Controlled Trials (CENTRAL) electronic databases between Jan 1, 2000 and June 29, 2020. Patients with DRE who underwent DBS treatment with at least three months of follow-up were included. Individual patient data (IPD) meta-analysis was conducted on DBS studies with available IPD. Response was defined as ≥50 % reduction in seizures frequency. Responders group was compared with non-responders group in terms of demographics, epilepsy/seizure characteristics, MRI findings, and DBS targets and duration of use. Subsequently, predictors of response to different DBS targets were investigated. ResultsThirty-nine studies with a total of 296 patients (ANT: 69 %, HC: 11 %, CMN: 21 %) were included. The responders group constituted of 209 patients (70.6 %). The response was significantly higher in patients with generalized seizures compared to those with focal seizures (93.2% vs 63.9 %; p < 0.001). Response was significantly higher with CMN (83.9 %) and HC (77.4 %) compared with ANT (65.5 %) as DBS targets (p = 0.014). Response was also significantly associated with longer duration of DBS use (p = 0.008). The responder rate was higher among the patients with lesional MRIs (76.7 %) than those with non-lesional MRIs (66.7 %), but with no statistically significant difference (p = 0.134). Age, gender, epilepsy etiology, onset zone of focal seizures, and previous use of VNS had no significant differences between the responders and non-responders. A binary logistic regression including the seizure type, MRI findings, DBS targets, and DBS duration showed, after controlling for confounders, that the duration of DBS use was the only significant predictor of response (adjusted OR 1.061; 95 % CI 1.019–1.106; p = 0.005). Regarding DBS targets, the response rate in patients with symptomatic etiology was significantly higher with HC or CMN targets than the ANT (p = 0.003). In patients with non-lesional MRI, response rate was significantly higher with the CMN target compared to the other two targets (p = 0.008). ConclusionDBS proves to be effective in DRE, with progressive success upon longer treatment and possibility of improving quality of life. In addition to focal seizures, DBS has potential for treating generalized seizures as well. While the ANT stands as the most utilized and only approved DBS target for DRE, CMN and HC are alternative targets with high seizure control potential. Patients with symptomatic etiology showed significant seizure reduction when HC or CMN were targeted. Studies revealed noticeable effectiveness of CMN-DBS in treating patients with non-lesional MRI. Despite ANT prominence in research, our findings suggest promising outcomes with CMN and HC, emphasizing the need for future larger-scale comparative clinical trials to better understand the efficacy of different DBS targets.

Systemic lupus erythematosus and epilepsy: A Mendelian randomization study.

Numerous observational studies have found a relationship between systemic lupus erythematosus (SLE) and epilepsy; however, their causal relationship remains unclear. This study aimed to investigate the causal role of SLE in epilepsy or any of its subtypes using a two-sample Mendelian randomization (MR) analysis. Single nucleotide polymorphisms (SNPs) linked to SLE were utilized as instrumental variables in MR analysis to assess their causal impact on epilepsy. The primary MR findings were derived using the inverse variance weighted (IVW) method, which was further supported by the weighted median and MR-Egger regression techniques. Additionally, sensitivity analyses, including Cochran's Q test and pleiotropy tests, were conducted to evaluate the influence of these SNPs on epilepsy, particularly looking for signs of horizontal pleiotropy and heterogeneity. We selected 43 SNPs that reached genome-wide significance from genome-wide association studies (GWASs) on SLE to serve as instrumental variables in this study. The IVW method showed no evidence to support a causal association between SLE and epilepsy (all epilepsy: odds ratio (OR) = 1.006, 95% confidence interval (CI) = 0.994-1.018; focal epilepsy: OR = 1.006, 95% CI = 0.994-1.019; generalized epilepsy: OR = 1.015, 95% CI = 0.996-1.035). Other MR complementary methods revealed consistent results. Furthermore, there was no evidence indicating heterogeneity or horizontal pleiotropy. The findings of MR analysis did not support a genetically predicted causal relationship between SLE and epilepsy, but emphasized the need for further research on shared pathophysiological mechanisms, particularly the role of immune system abnormalities and potential influences such as chronic inflammation and therapeutic interventions. The etiology of epilepsy is complex and diverse, including immune factors. Through a Mendelian randomization analysis, we did not find evidence of a genetic causal relationship between systemic lupus erythematosus and epilepsy. However, this does not invalidate epidemiological evidence, and further exploration is needed to investigate factors influencing the relationship between the two.

Utility of Various Activation Procedures in Provoking Ictal and Interictal Patterns, during Routine Electroencephalogram (rEEG) Recording.

Activation procedures (APs) are adopted during routine electroencephalography (rEEG) to provoke interictal epileptiform abnormalities (EAs). This study aimed to observe interictal and ictal (EAs) of different EEG patterns, provoked by various APs. This cross-sectional study was performed in the neurology department of King Fahd hospital of university, Saudi Arabia. The EEGs and medical records of patients who presented for EEG recordings were screened initially, then 146 EEGs provoked EAs due to utilization of APs, were included for analysis. Among all EEGs with provoked EAs, Non-rapid eye movement sleep (NREM) provoked EAs in 93 (63.7%) patients with following patterns, focal spike wave discharges (FSWDs) 45 (P= 0.01), focal spike wave discharges with bilateral synchrony (FSWDBS) 27 (P=0.03) and generalized spike wave discharges (GSWDs) 46 (P=0.01). Intermittent photic stimulation (IPS) most significantly provoked FSWDs in 07 patient (P =0.01) and GSWDs in 30 patients (P=<0.001) 7 patients (P = 0.01) and GSWDs in 30 patients (P < 0.001). Hyperventilation (HV) was associated with a higher occurrence of GSWDs in 37 patients (P =0.01). Female sex 7 (P = 0.02), provoked GSWDs 3 (P = 0.03), NREM sleep 8 (P = 0.04), prolonged EEG record 3 (P = 0.02), clinical events during recording 5 (P ≤ 0.01), diagnosis of genetic 05 (P = 0.03), and immune-mediated epilepsies 2 (P = 0.001) were associated with the provocation of ictal EAs; however, in multiple logistic regression analysis, no statistically significant association of these variables (P ≥ 0.05 each) was noted. The provocation of EAs in rEEG with different APs varies according to circumstances, including seizure types, epilepsy etiology, and the type of AP applied. These clinical and procedural parameters affect the diagnostic yield of rEEG and need careful consideration during rEEG recordings. APs adopted during rEEG recording can induce FSWDs, FSWDBS, and GSWDs in the form of either interictal or ictal EAs in various etiologies of epilepsy. Ictal EAs may appear in the form of GSWDs, during NREM sleep, in prolonged EEG records; however, their independent association needs to be evaluated in larger sample studies. Further, prospective cohort studies with adequate sample sizes are warranted.

Hemispherectomy at The Hospital for Sick Children: expanded indications and lessons learned over 35 years

OBJECTIVE Functional hemispherectomy is an effective surgical intervention for select patients with drug-resistant epilepsy. The last several decades have seen dramatic evolutions in preoperative evaluation, surgical techniques, and postoperative care. Here, the authors present a retrospective review of the medical records of 146 children who underwent hemispherectomy between 1987 and 2022 at The Hospital for Sick Children, providing a unique overview of the evolution of the procedure and patient outcomes over 35 years. METHODS The medical records of all children who underwent hemispherectomy at The Hospital for Sick Children between 1987 and 2022 were reviewed. Demographic information, preoperative clinical features, short-term and long-term seizure outcomes, and details regarding postoperative complications were recorded. RESULTS The seizure outcomes of 146 children were analyzed. There were 68 females and 78 males with a mean age of 5.08 years, 123 of whom demonstrated seizure freedom (Engel class IA) in the short-term postoperative follow-up period and 89 in the long term. The effectiveness of hemispherectomy in achieving long-term seizure control has improved over time (β = 0.06, p &lt; 0.001). Factors associated with overall seizure freedom included younger age at the time of hemispherectomy and stroke as the etiology of seizures, as well as complete disconnection during the first surgery. Additionally, the etiologies of epilepsy for which hemispherectomy is performed have expanded over time, while complication rates have remained unchanged. CONCLUSIONS Hemispherectomy is an increasingly effective treatment for certain cases of drug-resistant epilepsy. The etiologies of epilepsy for which hemispherectomy is performed are broadening, with no change in its safety profile. Seizure outcomes are better when the etiology of epilepsy is an ischemic injury, and the most common complication after the procedure is hydrocephalus. These findings reinforce the ongoing use of hemispherectomy as a safe and effective treatment option for certain individuals with drug-resistant epilepsy, support its application to a broader range of etiologies, and highlight areas of future investigation.

Exploring the Genetic Etiology of Pediatric Epilepsy: Insights from Targeted Next-Generation Sequence Analysis

Introduction: Epilepsy is a group of neurologic disorders with clinical and genetic heterogeneity. Epilepsy often affects children; thus, early diagnosis and precise treatment are vital to protecting the standard of life of a child. Progress in epilepsy-related gene discovery has caused enormous novelty in specific epilepsy diagnoses. Genetic testing using next-generation sequencing is now reachable, leading to higher diagnosis ratios and understanding of the disease’s underlying mechanisms. The study’s primary aim was to identify the genetic etiology based on targeted next-generation sequence analysis data and to calculate the diagnostic value of the epilepsy gene panel in the 0–17 age-group diagnosed with epilepsy. The secondary aim was to demonstrate the significance of periodic reinterpretation of variant of uncertain significance (VUS) variants and genotype-phenotype correlation. Methods: This retrospective study comprised 107 patients with epilepsy aged 8 months to 17 years, for whom a targeted gene panel covered 110 genes. VUS variants were reanalyzed, and genotype-phenotype correlation was performed. Results: In the initial evaluation, causal variants were described in 23 patients (21.5%). After reinterpretation of VUS, we detected causal variants in 30 out of 107 patients (28%). By reinterpreting the VUS and evaluating genotype-phenotype correlations, we enhanced our diagnostic value by 30.32%. After reinterpretation of VUS variants, the ACMG classification of 36 variants, including 15 benign (31%), 15 likely benign (31%), 5 likely pathogenic (10%), and 1 pathogenic (2%), were redefined. We most frequently detected causal variants in TSC2 (n = 5), GRIN2A (n = 4), and ALDH7A1 (n = 4) genes. Conclusion: The predictive value for epilepsy panel testing was 28% in the cohort. Our study revealed the importance of reanalysis of VUS variants and contributed to enriching the mutation spectrum in epilepsy.