Epilepsia最新文献

Electroencephalography (EEG) has been instrumental in epilepsy research for the past century, both for basic and translational studies. Its contributions have advanced our understanding of epilepsy, shedding light on the pathophysiology and functional organization of epileptic networks, and the mechanisms underlying seizures. Here we re-examine the historical significance, ongoing relevance, and future trajectories of EEG in epilepsy research. We describe traditional approaches to record brain electrical activity and discuss novel cutting-edge, large-scale techniques using micro-electrode arrays. Contemporary EEG studies explore brain potentials beyond the traditional Berger frequencies to uncover underexplored mechanisms operating at ultra-slow and high frequencies, which have proven valuable in understanding the principles of ictogenesis, epileptogenesis, and endogenous epileptogenicity. Integrating EEG with modern techniques such as optogenetics, chemogenetics, and imaging provides a more comprehensive understanding of epilepsy. EEG has become an integral element in a powerful suite of tools for capturing epileptic network dynamics across various temporal and spatial scales, ranging from rapid pathological synchronization to the long-term processes of epileptogenesis or seizure cycles. Advancements in EEG recording techniques parallel the application of sophisticated mathematical analyses and algorithms, significantly augmenting the information yield of EEG recordings. Beyond seizures and interictal activity, EEG has been instrumental in elucidating the mechanisms underlying epilepsy-related cognitive deficits and other comorbidities. Although EEG remains a cornerstone in epilepsy research, persistent challenges such as limited spatial resolution, artifacts, and the difficulty of long-term recording highlight the ongoing need for refinement. Despite these challenges, EEG continues to be a fundamental research tool, playing a central role in unraveling disease mechanisms and drug discovery.

Objective: First unprovoked seizures and acute seizures are common and can develop into epilepsy. The risk of epilepsy following these seizures in community samples is not well established, and it is unclear whether the probability of subsequent unprovoked seizures following these seizures reaches the International League Against Epilepsy's threshold of 60%.

Methods: We followed participants initially classified as having first unprovoked seizures, having acute seizures, or without seizures in a community-based survey conducted in 2003 to estimate the subsequent risk of epilepsy in 2008 and 2021. The diagnosis of epilepsy in 2008 and 2021 was based on data from a community survey and health care visits to Kilifi County Hospital and the epilepsy clinic. Poisson regression models were used to compute incident risk ratios (IRRs) for epilepsy and population-attributable risk (PAR); population-attributable risk fractions (PAFs) were computed from contingency tables.

Results: In the 5-year follow-up (censored in 2008 survey), the IRR for epilepsy was 23.3 (95% confidence interval [CI] = 14.2-38.2) for first unprovoked seizures and 10.4 (95% CI = 5.6-19.5) for acute seizures compared to the no-seizure group. By 2021 (including 2008), the IRR was 18.4 (95% CI = 11.9-28.5) for first unprovoked seizures and 7.9 (95% CI = 4.3-14.5) for acute seizures compared to the no-seizure group. The PAR for first unprovoked seizures and acute seizures was 29.0 and 8.0/1000 persons in the long-term follow-up. The PAF was 56.3% for first unprovoked seizures and 26.3% for acute seizures in the long-term follow-up. There was a high probability that a person with acute seizures (72%) or first unprovoked seizures (92%) developed epilepsy earlier than a person from the comparison group.

Significance: First unprovoked seizures and acute seizures are associated with high risk for developing epilepsy. Neurological correlates for epilepsy risk following first unprovoked seizures should be investigated to inform epilepsy diagnosis and treatment.

Objective: In 2021, the US Food and Drug Administration issued a safety warning concerning lamotrigine use in patients with underlying cardiac disorders. This warning was based on in vitro data that predicted class Ib antiarrhythmic activity for lamotrigine. Therefore, we investigated the proarrhythmic potential of lamotrigine in the murine heart and compared its effect with flecainide.

Methods: Murine hearts were perfused with clinically relevant concentrations of lamotrigine 3.8 μg/mL (15 μmol·L^-1) or flecainide .4 μg/mL (1 μmol·L^-1).

Results: Ex vivo electrocardiography revealed a high prevalence of ventricular tachycardia (VT) in lamotrigine-perfused hearts (7/9 hearts), whereas only two hearts exposed to flecainide evidenced VT. Optical voltage mapping showed that lamotrigine preferentially decreased ventricular conduction velocity (CV) in the longitudinal direction at all pacing frequencies tested (-22% ± 8.6%, -30% ± 15.4%, and -33% ± 13.3% for pacing frequency of 200-ms, 180-ms, and 150-ms cycle length, respectively, p ≤ .05) compared to the transverse direction, which only slowed CV at the fastest pacing frequency (-15% ± 16% for pacing frequency of 150-ms cycle length, p ≤ .01). Notably, the preferential CV slowing in the longitudinal direction altered the anisotropic ratio, giving rise to a functional substrate for reentrant VT. In contrast, flecainide slowed CV uniformly in both longitudinal and transverse directions (-30% ± 8.5% vs. -27% ± 5.3%, -32% ± 9.4% vs. -29% ± 6.9%, and - 29% ± 8.3% vs. -27% ± 10% for pacing frequency of 200-ms, 180-ms, and 150-ms cycle length, respectively, p ≤ .05).

Significance: Our findings provide mechanistic insight into the proarrhythmic impact of lamotrigine.

Objective: The ketogenic diet has been the mainstay of treatment of drug-resistant epilepsy (DRE). No comparative trials have been conducted to assess the efficacy of the two less strict ketogenic diets: modified Atkins diet (MAD) and low glycemic index treatment (LGIT). This study assesses the non-inferiority of LGIT compared with MAD.

Methods: This was an open-label randomized non-inferiority trial. Children with DRE were randomized to receive either MAD or LGIT as an add-on to anti-seizure medications. The primary endpoint was percentage seizure reduction at the end of 24 weeks of therapy compared to the baseline. The non-inferiority margin of -15% was predefined to calculate the sample size.

Results: Ninety-one children were enrolled and randomized to receive either MAD (n = 45) or LGIT (n = 46). Intention-to-treat analysis done at the end of 24 weeks of therapy showed a mean (±standard deviation [SD]) percentage seizure reduction of 60.7% (±41.3) in the MAD sub-group and 57% (±39.4) in the LGIT sub-group (p = 0.664). The absolute difference between the means of percentage seizure reduction was -3.7 (-20.5 to 13.2) and crossed the non-inferiority margin. Ten children in the MAD group and nine children in the LGIT group did not complete 24 weeks of therapy. Adverse effects were comparable between the arms (MAD, 66.6%; LGIT, 50%), although serious adverse effects were higher in the MAD arm. The most common adverse effect was decreased acceptance (24.2%) followed by decreased satiety (9.9%), vomiting (9.9%), weight loss (5.5%), constipation (5.5%), and diarrhea (3.3%). Dyslipidemia was more commonly seen in the MAD group (MAD, six; LGIT, one). One death in the LGIT arm was unrelated to therapy. Although there was no statistically significant difference in improvement in cognition, behavior, and quality of life scales, improvement was noted from baseline scores.

Significance: LGIT may be non-inferior to MAD in the treatment of children with DRE with the advantage of increased acceptance and fewer adverse effects.

Objective: This study aims to improve genetic diagnosis in childhood onset epilepsy with neurodevelopmental problems by utilizing RNA sequencing of fibroblasts to identify pathogenic variants that may be missed by exome sequencing and copy number variation analysis.

Methods: We enrolled 41 individuals with childhood onset epilepsy and neurodevelopmental problems who previously had inconclusive genetic testing. Fibroblast samples were cultured and analyzed using RNA sequencing to detect aberrant expression, aberrant splicing, and monoallelic expression using the Detection of RNA Outlier Pipeline (DROP) pipeline. Detected events were correlated with phenotypes, and long-read genome sequencing was performed on individuals with strong candidate events to identify the causal genomic variant. A systematic literature review on RNA sequencing in rare disorders was conducted to contextualize our findings.

Results: RNA sequencing identified five strong candidate events in four individuals, affecting the genes QRICH1, TSC1, SMARCA1, GNAI1, and PTEN. (Likely) pathogenic genomic variants affecting expression of QRICH1, TSC1, and SMARCA1 were detected, resulting in a diagnostic yield of 7% (3/41). Two variants were not covered in the initial exome sequencing data but were revealed through long-read sequencing. The identification of a pathogenic TSC1 variant led to a previously unrecognized diagnosis of tuberous sclerosis complex. This prompted guideline-based screening, which revealed tuberous sclerosis lesions in the brain and lung, directly impacting clinical care. Notably, two of the three pathogenic events would not have been detected using whole blood due to the lack of expression of the involved genes. The lower yield of this study compared to studies in other rare disorders reflects the genetic heterogeneity of epilepsy and neurodevelopmental disorders, and the inaccessibility of affected tissue.

Significance: This research underscores RNA sequencing of cultured fibroblasts as a valuable tool in genetic diagnostics for childhood onset epilepsy, particularly when conventional methods fail. Expanding the control dataset with age-matched samples and incorporating RNA sequencing with nonsense-mediated decay inhibition could further enhance diagnostic yield.

Clinical practice guidelines (CPGs) and consensus-based recommendations (CBRs) require considerable effort, collaboration, and time-all within the constraints of finite resources. Professional societies, such as the International League Against Epilepsy (ILAE), must prioritize what topics and questions to address. Implementing evidence-based care remains a crucial challenge in clinical practice. Using rigorous processes to ensure that the best available research evidence informs health care recommendations is of the utmost importance. We aimed to develop a structured and transparent process for prioritizing future CPGs and CBRs supported by the ILAE. A multidisciplinary group of researchers and experts from the ILAE Prioritization Task Force conducted a scoping review to identify prioritization approaches for CPG and CBR development. This scoping review was reported according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) and Cochrane recommendations. A Problem/population, Concept, and Context (PCC) strategy was applied to the literature search and selection of the studies. We searched Medline/PubMed, Embase, Web of Science, and Scopus without time or language limits. The findings were synthesized qualitatively. A consensus-based process was followed to develop a prioritization scoring tool for CPGs and another for CBRs. Thirty-nine participants, including clinicians, experts in the field, methodologists, and other relevant stakeholders, contributed to developing the final instrument (based on a 5-point Likert scale). Of 721 unique citations, 8 papers reporting prioritization approaches for guideline development were included. Based on these, we developed an initial tool with 10 criteria. It was iteratively optimized and revised by the ILAE Standards and Best Practice Council, which unanimously approved the instrument. The ILAE Executive Committee subsequently approved its final version. The ILAE Prioritization Tool is intended to standardize the prioritization processes and optimize the ILAE's use of resources to select CPGs and CBRs for endorsement.

Seizure detection devices (SDDs) offer promising technological advancements in epilepsy management, providing real-time seizure monitoring and alerts for patients and caregivers. This critical review explores user perspectives and experiences with SDDs to better understand factors influencing their adoption and sustained use. An electronic literature search identified 34 relevant studies addressing common themes such as usability, motivation, comfort, accuracy, barriers, and the financial burden of these devices. Usability emerged as the most frequently discussed factor, with patients and caregivers also emphasizing the importance of ease of use, long battery life, and waterproof design. Although validated devices showed high user satisfaction, technical challenges, false negatives, and false positives need much improvement. Motivation to use SDDs was driven by enhanced safety, symptom tracking, and health care professional recommendations. Comfort and wearability were also critical aspects, with users favoring lightweight, breathable, and discreet designs for long-term wear. Users reported the devices as "comfortable" and preferring wrist or arm-worn devices for the long term. Accuracy-particularly minimizing false positives and false negatives-was a priority for users. Barriers to adoption included device cost, limited insurance reimbursement, discomfort, and concerns about data privacy. Despite these challenges, many users were willing to use SDDs. Recommendations from health care professionals significantly increased user motivation. This review highlights the need for SDD designs that address user concerns regarding usability, comfort, looks, and accuracy, while also reducing financial and technical barriers. Enhancing clinical involvement and tailoring devices to specific patient needs may be crucial to promoting wider SDD adoption. Further research is needed to evaluate the impact of SDDs on quality of life and to explore ways to mitigate challenges in long-term use.

Objective: Gain-of-function variants in the KCNT1 gene, which encodes a sodium-activated potassium ion channel, drive severe early onset developmental epileptic encephalopathies including epilepsy of infancy with migrating focal seizures and sleep-related hypermotor epilepsy. No therapy provides more than sporadic or incremental improvement. Here, we report suppression of seizures in a genetic mouse model of KCNT1 epilepsy by reducing Kcnt1 transcript with divalent small interfering RNA (siRNA), an emerging variant of oligonucleotide technology developed for the central nervous system.

Methods: The ATL-201 molecule is two identical synthetic double-stranded siRNAs, covalently linked, with 100% nucleotide base pair match to sequence present in both human KCNT1 and mouse Kcnt1 that does not contain any known pathogenic variant. ATL-201 activity was tested in cortical neurons cultured from wild-type mice and in mice homozygous for Kcnt1-Y777H, the mouse ortholog to the human pathogenic KCNT1-Y796H missense variant. Seizures and nest-building behavior were measured in freely behaving Kcnt1-Y777H mice. The number and duration of seizures were measured by electrocorticography in mice dosed with ATL-201 or phosphate-buffered saline in a 6-month durability study and in a 2-month dose-efficacy study.

Results: In vitro, ATL-201 reduced KCNT1 transcript from whole-cell lysate and eliminated potassium currents from KCNT1 channels in heterologous expression. ATL-201 also eliminated sodium-activated potassium currents recorded from individual cortical neurons. In vivo, ATL-201 suppressed seizures in Kcnt1-Y777H homozygous mice in a dose-dependent manner with near-complete suppression from 2 weeks to at least 4 months. Kcnt1-Y777H mice had defects in nest building, whereas in ATL-201-treated mice nest building was equivalent to wild-type mice.

Significance: Patients with KCNT1-driven epilepsy experience up to hundreds of seizures per day and have severe impairment in cognitive, motor, and language development and high mortality. The dose-dependent efficacy and long durability of ATL-201 in mice show promise for ATL-201 as a disease-modifying treatment of KCNT1 epilepsy.

Objective: This study aimed to identify prescribing behaviors in women of childbearing potential (WOCP) with epilepsy already taking valproate (VPA), and to investigate the relationship between VPA maintenance, substitution, reduction, or withdrawal as part of polytherapy, and seizure worsening or relapse.

Methods: We retrospectively reviewed the prescription behaviors and seizure outcomes in WOCP (16-50 years of age) with epilepsy, referred to eight Italian epilepsy centers, who were taking VPA for at least 1 year between 2014 and 2019.

Results: Among 750 women (~12% of all WOCP), 528 (70.4%) maintained VPA unchanged throughout the observation period, 103 (13.7%) replaced VPA with another antiseizure medication (ASM), 90 (12%) reduced VPA, and 29 (3.9%) discontinued VPA in polytherapy. Focal epilepsy was most strongly associated with VPA withdrawal (odds ratio [OR] 2.96, 95% confidence interval [CI] 1.38-6.38), whereas generalized epilepsy was most associated with its non-withdrawal (reduction/switch/maintenance) (OR .31, 95% CI .14-.68). Intellectual disability, higher seizure frequency, and higher VPA doses were linked to VPA continuation. VPA withdrawal from polytherapy was associated with a higher risk of tonic-clonic seizure worsening (OR 2.91, 95% CI 1.09-7.77) compared to non-withdrawal.

Significance: VPA was rarely withdrawn or substituted in WOCP with epilepsy, in secondary and tertiary care settings following European regulatory restrictions. This likely reflects a population with severe epilepsies where VPA is difficult to replace; whereas women with milder epilepsies likely discontinued VPA earlier, as evidenced by its low overall prescription frequency. Withdrawal of VPA from a polytherapy regimen was associated with a threefold increased risk of seizure exacerbation.