Epilepsia Open最新文献

Objective: Late-onset unexplained epilepsy (LoUE), defined as epilepsy onset after age 55 without an obvious cause, is an important risk factor for dementia. Studies have shown that 10%-25% of individuals with LoUE develop dementia within 3-4 years following their first seizure. However, the mechanisms underlying progression from LoUE to dementia remain poorly understood. The goals of the ELUCID study are to identify risk factors associated with the development of cognitive decline and dementia in LoUE and to develop tools to identify patients at a high risk for these outcomes and thereby establish a foundation for dementia prevention strategies in this population.

Methods and analysis: ELUCID is a multi-center prospective longitudinal observational study that will enroll 600 participants aged 55 or older with LoUE across seven U.S. medical centers. Participants will undergo a baseline evaluation that includes a detailed clinical history, cognitive testing, brain MRI, overnight scalp EEG, and blood biomarkers. Participants will be followed at 6-month intervals for up to 5 years, to record cognitive and neurological changes, with the primary outcomes of interest being the development of mild cognitive impairment and/or dementia. This study aims to establish LoUE disease subtypes based on biomarkers, cognitive trajectories, and imaging features and to develop a risk stratification tool for predicting cognitive decline and dementia in patients presenting with LoUE.

Ethics and dissemination: ELUCID has obtained IRB approval (no. 2023P001566, August 2023), with the Mass General Brigham IRB serving as the single IRB of record. All de-identified study data will be made publicly available on completion of the study.

Plain language summary: The ELUCID study is a research project involving several medical centers across the U.S. It will focus on older adults who have recently developed seizures without a clear cause. Participants undergo an initial evaluation that includes questions about their medical history, a brain MRI, an overnight scalp EEG (brain wave study), and a blood draw. They will be followed over time with health questionnaires and yearly tests of memory and thinking. The purpose of the study is to learn what factors increase the risk of dementia in this population and to develop tools to predict which individuals are at the highest risk.

Objective: Epileptic seizures show a rhythmic pattern, being more frequent at particular times of the day (e.g., only occurring during sleep), suggesting a role of the circadian rhythm. Clock genes regulate the circadian rhythm and might be involved in the pathophysiology of epilepsy. This systematic review sought to answer the research question: what is the relationship between clock genes and the pathophysiology of epilepsy?

Methods: For this, we used Scopus, Embase, Medline, CINHAL, and Web of Sciences to summarize the up-to-date literature on this topic and included 26 articles out of the 6364 articles identified.

Results: We describe three distinct approaches to this research: (a) the effect of clock genes knockout on the severity of epilepsy, (b) the expression of clock genes in different types of epilepsy (humans and/or animal models) and (c) the variants of clock genes in different types of epilepsy (humans). Our results show a paucity of studies with very heterogeneous methodology and outcomes, with conflicting results. Most studies suggest a protective role of clock genes in epilepsy, particularly of Clock and Bmal1, showing lowered clock gene expression in different animal models of epilepsy, in line with the increased severity of epilepsy after knockout of clock genes. There are, though, other studies with conflicting results, making this interpretation relatively weak. A few clock gene variants were also identified in epilepsy cases (humans).

Significance: This suggests the need to further clarify the implications of the dysregulation of the clock genes and of the genes encoding interacting proteins, as this might offer new insights into the circadian patterning of certain epilepsies.

Objective: Febrile seizures (FS) are common and usually self-limited, yet a subset of children develop epilepsy. Early risk stratification remains challenging, particularly in resource-limited settings with limited access to long-term neurologic follow-up. We aimed to estimate the incidence and identify the most robust predictors of epilepsy following FS in children.

Methods: In this prospective cohort study at Children's Hospital 2 (Ho Chi Minh City, Vietnam), 631 children aged 1 month to 6 years with first FS were enrolled (March 2023-March 2024) and followed through July 2025. Children with any history of seizures prior to the index FS were excluded. Epilepsy was defined per the International League Against Epilepsy (ILAE) 2014 criteria. Predictor selection used clinical reasoning and Bayesian Model Averaging (BMA), followed by multivariable Cox regression. Discrimination was evaluated using Harrell's C-index and time-dependent AUC; internal validation was performed with bootstrap resampling.

Results: Over a median follow-up of 2.0 years, 35 children (5.5%) developed epilepsy, corresponding to an incidence of 29 per 1000 person-years. After BMA, four independent predictors were retained: neurodevelopmental delay (HR = 8.78), family history of epilepsy (HR = 2.66), focal seizures (HR = 3.23), and each additional FS recurrence (HR = 1.50). The predictor set showed strong discrimination (C-index: 0.87; AUC at 24 months: 0.89 with 95% CI: 0.82, 0.95).

Significance: This parsimonious set of clinical predictors may support early counseling and targeted follow-up of children with FS, especially where pediatric neurology resources are limited. Model development and validation are ongoing.

Plain language summary: We followed 631 children after their first febrile seizure to see who might later develop epilepsy. About 5.5% of children developed epilepsy within 2 years. Children with developmental delay, focal seizures, a family history of epilepsy, or repeated FS were at higher risk. Using these four simple factors may help doctors give families clearer advice and closer follow-up, especially where access to pediatric neurologists is limited.

Objective: This study aims to investigate the causal relationship between cathepsins and epilepsy, using Mendelian randomization (MR) and mediation analysis.

Methods: Publicly accessible summary statistics on epilepsy were obtained from FinnGen and the International League Against Epilepsy Consortium. Cathepsin genome-wide association data were provided by the IEU OpenGWAS. To evaluate the causal relationship between epilepsy and cathepsins, we conducted a bidirectional two-sample Mendelian randomization (MR) and mediation analysis.

Results: The results of the MR analysis revealed that elevated cathepsin E levels correlated with a higher likelihood of developing generalized epilepsy (odds ratio: 1.304, 95% confidence interval: 1.127-1.508, p: 0.0004, p adjusted for false discovery rate: 0.044). The mediation analysis identified a disintegrin and metalloproteinase with thrombospondin motifs 4 as having a notable impact (mediation effect: 23.5%) in the causal link between cathepsin E and generalized epilepsy.

Significance: This study provides evidence of a causal relationship between cathepsin E and generalized epilepsy, suggesting that elevated cathepsin E levels may increase the risk of developing this condition. The identification of a disintegrin and metalloproteinase with thrombospondin motifs 4 as a mediator offers insight into the molecular mechanisms underlying this association, which could guide future research into potential therapeutic targets for epilepsy.

Plain language summary: Epilepsy is a common neurological disorder, but some patients do not respond to standard treatments. This study looks at a protein family called cathepsins and how they might be linked to epilepsy. We found that higher levels of cathepsin E are associated with a higher chance of generalized epilepsy. Our results suggest that cathepsin E could play a key role in causing epilepsy, which could lead to new treatment options for patients who do not respond to current therapies.

Objective: Dravet syndrome (DS) is a rare disease with a high clinical and socioeconomic impact on patients, society, and the healthcare system. The recent approval of therapies such as fenfluramine (FFA) has transformed the treatment landscape; however, data on their cost-effectiveness are still scarce. This study evaluates the real-world cost-effectiveness of adding FFA to existing therapies for DS patients from the Italian National Healthcare System perspective.

Methods: This retrospective multicenter observational study included 124 Italian DS patients initiating FFA as add-on treatment between February 2017 and August 2022 and followed until December 2022 or disenrollment (post-FFA period). Data on drug treatments, healthcare resource utilization, and main outcomes-rescue medication, hospital admission, and status epilepticus (SE) episodes-were collected both in the post-FFA period and in a pre-FFA period matching each patient's follow-up duration (median 2.9 years). Annual per-patient rates and costs, with 95% confidence intervals (CI), were determined for each outcome in both periods. Incremental cost-effectiveness ratios (ICERs) with 95% CIs and cost-effectiveness acceptability curves (CEACs) were also calculated.

Results: The median age at FFA initiation was 8.5 years. Mean annual healthcare cost of patients with DS was €5740 (95% CI 2896-9930) in the pre-FFA period. FFA introduction added an annual per-patient drug acquisition cost of €16 476, but it significantly reduced frequency and costs associated with hospital admissions and acute events. ICERs were €2187 per rescue medication avoided, €12 935 per hospital admission avoided, and €17 301 per SE episode avoided.

Significance: This real-world study demonstrates that despite increased drug acquisition costs, FFA provides clinical and economic benefits by reducing acute events and related healthcare costs. The investment required to reduce acute events is justifiable given the young age of DS patients and its impact on the healthcare system, families, and caregivers. Future research should incorporate indirect costs and a broader societal perspective.

Plain language summary: Dravet syndrome is a severe and rare type of epilepsy that can be very hard on patients and their families. It also puts a great burden on healthcare systems. A new treatment, fenfluramine (FFA), helps better control seizures. Although FFA increases drug treatment costs, this cost is actually balanced out by reduced emergency visits and hospital stays for severe seizures, leading to overall lower healthcare expenses.

Objective: This study evaluated the long-term risk of major cardiovascular diseases (CVDs) in patients with epilepsy using a nationwide cohort, aiming to address critical gaps in population-based evidence on brain-heart interactions.

Methods: Data from the Korean National Health Insurance Service (2002-2013) were analyzed. For each cardiovascular outcome, an independent matched cohort was constructed, comprising 1740 to 3164 patients with newly diagnosed epilepsy and corresponding 10-fold matched controls. The primary outcomes included six CVDs: hypertension (HTN), ischemic heart disease (IHD), cardiac arrhythmia (CA), heart failure (HF), atherosclerosis (AS), and peripheral artery disease (PAD). Incidence rate ratios (IRRs) and adjusted hazard ratios (aHRs) were calculated using multivariable Cox regression models.

Results: Epilepsy was significantly associated with increased risk of all six CVDs. The highest aHRs were observed for CA (2.02 [95% CI, 1.70-2.39]), IHD (1.71 [95% CI, 1.50-1.95]), and HF (1.64 [95% CI, 1.28-2.10]). Risk was higher in patients aged <60 years and in men. Notably, younger patients showed substantially elevated risks for CA (2.61 [95% CI, 1.99-3.42]) and AS (2.06 [95% CI, 1.47-2.89]). The sex-specific difference was most prominent for HF, with higher aHRs in men (1.86 [95% CI, 1.29-2.67]) than in women (1.49 [95% CI, 1.07-2.09]).

Significance: Patients with epilepsy have a significantly increased long-term risk of CVD, especially CA, IHD, and HF. Risk is disproportionately elevated in younger individuals and men, suggesting the need for targeted cardiovascular surveillance and prevention in these subgroups.

Plain language summary: People with epilepsy may face a higher risk of heart and blood vessel diseases such as heart attack, irregular heartbeat, and heart failure. This study analyzed national health data from Korea and found that epilepsy patients had more cardiovascular problems than those without epilepsy, especially younger men. These results suggest that doctors should monitor heart health more closely in people living with epilepsy.

Objective: Early response to anti-seizure medication (ASM) is associated with a favorable prognosis in patients with epilepsy. Research is required to confirm existing data on the clinical use of perampanel as first adjunctive therapy in different patient groups and different regions. Here, we present a post hoc analysis of four post-marketing studies to examine side by side the efficacy and safety of perampanel administered as the first adjunctive ASM across different geographic settings.

Methods: Data from patients receiving first adjunctive perampanel were included in this post hoc analysis from Study 412 (NCT02726074, South Korea), Study 410 (NCT03288129, US), Study 509 (NCT04202159, Germany), and Study 501 (NCT04257604, Italy). Assessments included the median percent reduction from baseline/screening in seizure frequency, seizure-freedom rate, retention rate, and safety.

Results: A total of 170 patients who received first adjunctive perampanel were included in this study, including 102 patients from Study 412, 44 from Study 410, 13 from Study 509, and 11 from Study 501. At the latest time point in each study, 50% responder rates were ≥62.5% (range, 62.5%-100.0%) across seizure types, while seizure-freedom rates ranged from 25.0% to 100.0% (median, 51.6%). Retention rates were ≥61.8% at Month 6 in all studies and ≥54.5% at Month 12 in Studies 410 and 501 where these data were available. Overall, 46.2%-90.9% of patients experienced ≥1 treatment-emergent adverse event (TEAE) and 13.7%-27.3% discontinued perampanel due to TEAE(s). The most common TEAEs reported across each study were dizziness (≤50.0%), somnolence (≤36.4%), and fatigue (≤13.6%).

Significance: The results from this post hoc analysis demonstrated that perampanel as first adjunctive therapy had a good treatment response with no new safety signals observed. Limitations included the post hoc nature of the analysis and the inability to pool data due to study design differences. Overall, these data support the use of perampanel as an early-line treatment in patients with epilepsy.

Plain language summary: This analysis looked at a medicine called perampanel and how well it works for people with epilepsy when it was one of the first medicines added to their regular seizure treatment. Data were collected from four separate studies that were done in South Korea, the United States, Germany, and Italy. Most patients had fewer seizures across all four studies after 6 months of treatment. The most common side effects reported in patients included dizziness and sleepiness. Perampanel worked well when used early during treatment, and most people were able to keep taking perampanel without significant difficulties.

Epilepsy affects 65 million people worldwide, and is a World Health Organization priority disease as highlighted in their 2022-2031 Intersectoral Global Action Plan (IGAP) on Epilepsy and other Neurological Disorders. IGAP's objectives include improving epilepsy treatment and care. Patient-reported outcomes measures (PROMs) may assist with this. PROMs are self-report instruments that assess the lived experience of disease, for example, quality of life, mood, and treatment adverse effects. Regulatory agencies recommend including PROMs in clinical trials, and incorporating PROMs into routine clinical practice may improve patient outcomes. We conducted a narrative review of PubMed and health regulatory agencies' guidelines to identify PROMs used in clinical epilepsy research and practice. We identified 390 unique PROMs used in epilepsy settings. We summarize the practical considerations for PROMs selection, including the various psychometric properties that can be used to measure how "good" a PROM is; the role for generic, neurology-specific, and epilepsy-specific PROMs; and ways to optimize the collection of PROMs in clinical settings. This review discusses the strengths and limitations of 22 PROMs, covering four domains (health-related quality of life, disability and seizure severity, mood, and antiseizure medication adverse effects), that are commonly used in clinical epilepsy research and practice. This article may serve as a useful reference for researchers and clinicians when selecting PROMs for use in clinical epilepsy trials and routine clinical practice, and complements the recently published report from the International Consortium for Health Outcomes Measurement that recommends five specific PROMs assessing quality of life, depression, anxiety, cognition, and sleep. The judicious selection and application of PROMs may lead to better understanding of patient experiences, inform clinical decision-making, and ultimately improve outcomes. PLAIN LANGUAGE SUMMARY: Patient-reported outcome measures (PROMs) are questionnaires completed by patients, assisting with communication of their lived experience of disease with clinicians. PROMs cover topics such as quality of life, disability, mood, and treatment side effects. PROMs may improve patient satisfaction and communication with healthcare providers, detect hitherto undisclosed issues, and can be used to monitor treatment response. This current review summarizes the strengths and limitations of 22 PROMs that are commonly used in clinical epilepsy research and practice.

Objective: To compare the effectiveness and safety of Perampanel (PER) and Levetiracetam (LEV) as monotherapy in Chinese patients with focal-onset seizures (FOS).

Methods: This is a single-center, ambispective, open-label, real-world observational study. The PER arm of the study prospectively enrolled patients aged ≥4 years with FOS who visited Nanjing Brain Hospital during January 2020 to December 2021. These patients received PER monotherapy and were prospectively followed until January 2024. For the LEV arm, data were retrospectively collected from patients with FOS who started LEV monotherapy during January 2019 to December 2021, and these patients were retrospectively followed until January 2024. The primary endpoint was seizure-freedom rate (SFR) after 24 months of treatment. Treatment-emergent adverse events (TEAEs) were recorded.

Results: Seventy patients in the PER group and 77 patients in the LEV group were enrolled. The PER group had a non-significant trend of higher SFR than the LEV group at 24 months (58.6% vs. 41.3%, p = 0.06). At 6 and 12 months, PER showed significantly higher SFRs than LEV (69.8% vs. 48.6%, p = 0.01; 68.3% vs. 38.8%, p < 0.001, respectively). The two groups had comparable retention rates. The PER group had a significantly higher incidence of TEAEs than the LEV group (37.1% vs. 11.7%, p < 0.001) because of the significantly higher incidence of dizziness in the PER group. None of the TEAEs was serious.

Significance: Patients with FOS receiving PER monotherapy were more likely to achieve seizure freedom and had a higher incidence of dizziness than those receiving LEV monotherapy.

Plain language summary: This study compared the effectiveness and safety of PER and LEV as monotherapy in Chinese patients with focal-onset seizures (FOS), in which 70 patients receiving PER monotherapy and 77 patients receiving LEV monotherapy were enrolled. Compared with LEV, PER had significantly higher seizure-freedom rates (SFRs) at 6 and 12 months and a non-significant trend of higher SFR at 24 months. The two treatments had comparable retention rates. Chinese patients with FOS receiving PER monotherapy were more likely to achieve seizure freedom and had a higher incidence of dizziness than LEV.