Epilepsia最新文献

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.

Mental health (MH) comorbidities are prevalent among people with epilepsy (PWE), but many experience challenges accessing care. To address this, suggestions have been made to integrate MH care into epilepsy care settings, yet the current approaches, benefits, and implementation determinants to MH care integration are unclear. This review aims to synthesize existing integrated MH care models for PWE to inform the development and planning of future initiatives. We searched Embase, Medline, PsycINFO, and Cochrane for articles that described any activity within a health care setting that addressed MH as routine care for PWE. Year of publication was restricted to 2000 onward. At least two authors reviewed articles and extracted data. Barriers, facilitators, and future recommendations were identified through thematic synthesis using NVivo. Study quality was assessed for articles reporting clinical outcomes. Following review of 7520 abstracts and 596 full-text articles, 65 met eligibility criteria and were included. Most (k = 43, 66%) described routine MH screening, with 11 reporting on uptake and acceptability, which was generally high. Interventions included psychological interventions (k = 23, 35%), psychoeducation (k = 9, 14%), and pharmacotherapy (k = 6, 9%). Thirteen articles (20%) reported on changes in MH outcomes, all of which indicated some improvements in MH, but 33% were rated as poor quality. Thirty-four (52%) articles reported on barriers and facilitators, and 34 (37%) articles provided recommendations for future initiatives. Overall, diverse approaches to integrated MH care for PWE were identified, with promising uptake, acceptability, and impacts on MH outcomes. Qualitative analysis informed a proposed framework for future integrated MH care initiatives. The framework outlines fundamental components of care activities, such as MH screening, psychoeducation, and care pathways, as well as key facilitators for their establishment (e.g., policies, infrastructure, staffing) and effective delivery (e.g., staff incentives, acceptability, evaluation).

Objective: Lennox-Gastaut syndrome (LGS) is typically characterized by drug-resistant epilepsy and subsequent cognitive deterioration. Surgery is a rare but viable option for the control of seizures in a subset of patients with LGS. This study aimed to describe the organization of the epileptogenic zone network (EZN) in patients with LGS using stereoelectroencephalography (SEEG) and to report the outcome of post-SEEG treatment.

Methods: A quantitative SEEG signal analysis was conducted in 14 consecutive patients with LGS, in whom a potentially localized EZN was suggested based on a comprehensive noninvasive evaluation. The EZN and the irritative zone network were identified using relevant biomarkers during ictal (epileptogenicity index and connectivity epileptogenicity index) and interictal (spikes and high-frequency oscillations) recordings. The applied post-SEEG treatments were assessed, including SEEG-guided radiofrequency thermocoagulation (RF-TC), surgery, and neurostimulation.

Results: The seizure onset patterns showed some specificity by seizure type, with 84% of tonic seizures involving low-voltage fast activity. The EZN of patients with LGS was often, but not always, complex and extensive, involving two or more lobes (79%) and both hemispheres (64%). The lateral neocortical structures, particularly the lateral premotor and dorsolateral prefrontal cortices, were identified as being most frequently involved in the EZN. Among the explored subcortical structures, only the pulvinar, central-lateral thalamic nucleus, and hypothalamic hamartoma belonged to the EZN. Twelve patients (86%) underwent SEEG-guided RF-TC, with 50% experiencing a >50% reduction in baseline seizure frequency. Four patients (29%) underwent curative surgery for significant involvement of a lesion in the EZN, and one case achieved an Engel class I outcome.

Significance: This is the first quantitative SEEG study in patients with LGS to demonstrate the utility of SEEG in identifying patients who may benefit from surgery and to perform SEEG-guided RF-TC. Nevertheless, the indications for SEEG should be carefully assessed, as localized EZN is uncommon in LGS.

Objective: Epilepsy has negative socioeconomic impacts on those affected, resulting not only from actual disability but also from social stigma. However, longitudinal studies examining occupational consequences following an epilepsy diagnosis are limited. We aimed to investigate the occupational outcomes of newly diagnosed epilepsy among Korean employees.

Methods: We conducted a nationwide population-based retrospective cohort study using the Korean National Health Insurance Service database. We included newly diagnosed people with epilepsy (PWE) aged 25 to 54 years, identified by diagnostic codes and antiseizure medication (ASM) prescriptions, who were employed at diagnosis between 2004 and 2018. The employment status of PWE was determined based on their enrollment in the employer-provided health insurance scheme. We analyzed the rates of job loss and reemployment, associated factors, and income changes following diagnosis.

Results: Among the 13 122 newly diagnosed PWE, the overall first-year job loss rate across the study period was 21.7%, which was 1.62-2.54 times higher than that of the general population for each year. The excesses of job loss among PWE in safe occupations were comparable to those in safety-sensitive occupations. Central nervous system illness (adjusted hazard ratio [aHR] = 1.12), psychiatric disease (aHR = 1.19), ≥2 emergency room visits or hospitalizations (aHR = 3.00), and ≥4 ASM attempts (aHR = 1.26) increased the risk of job loss. Among individuals who lost their job during the first year, 22.4% were reemployed within 1 year, with similar risk factors hindering reemployment. The income distribution of regained jobs showed a downward shift compared to previous jobs.

Significance: Newly diagnosed PWE were at risk of job loss, irrespective of the occupational hazards related to seizures. Poor disease control and comorbidities partially contributed to unemployment. Alongside active seizure management, guidance for suitable occupations and the implementation of tailored restrictions based on occupational risk stratification are imperative to improve the job security of PWE.

Acute symptomatic seizures, occurring shortly after a central nervous system insult, constitute nearly half of all seizure cases. However, there is a conspicuous absence of clear, comprehensive, and cohesive guidelines for the management of these seizures with antiseizure medications, especially their duration of use. This lack of consensus on the optimal duration of therapy leads to prolonged treatments that may carry adverse consequences. The primary objective of this narrative review is to present the existing evidence-based literature on the management of acute symptomatic seizures within the context of the underlying pathologies that trigger them. We explore the risk of developing epilepsy for each specific etiology and identify the factors that influence this risk. Finally, to facilitate decision-making regarding treatment duration, we categorize acute seizures based on the temporal characteristics of hyperexcitability as acute, subacute, and prolonged. Such a rubric may offer clarity in an area where consensus and guidelines are lacking.

Objective: An increasing number of antiseizure medications (ASMs) are approved for monotherapy for focal epilepsy, but direct comparisons of the lifetime cost-effectiveness of all existing treatment strategies are lacking. This study aims to compare the cost-effectiveness of new ASMs and traditional ASMs as first-line monotherapy for newly diagnosed focal epilepsy.

Method: We used a Markov model to evaluate the lifetime cost-effectiveness of 10 ASMs in the treatment of focal epilepsy, with lacosamide (LCM) as a control, from the perspective of society in the United States. Effectiveness, cost data, and health state utilities were obtained from published literature. The cycle of the model is 6 months. Willingness to pay was defined as $150 000 per quality-adjusted life year (QALY). One-way and probabilistic sensitivity analyses were conducted to evaluate parameter uncertainty, and several scenario analyses were also conducted.

Results: The base case analysis showed that carbamazepine (CBZ) was the least costly ASM and more effective than valproic acid (VPA), levetiracetam (LEV), gabapentin (GBP), topiramate (TPM), and lamotrigine (LTG) from an American social perspective. In contrast, oxcarbazepine (OXC), phenytoin (PHT), phenobarbitone (PHB), LCM, and zonisamide (ZNS) were more effective than CBZ, with incremental cost-effectiveness ratios of $334 703.50, $325 610.99, $3 037 148.62, $1 178 954.91, and $108 153 360.85/QALY, respectively. The traditional ASMs were ranked as CBZ, PHT, VPA, and PHB; the new ASMs were ranked as OXC, LEV, LCM, LTG, TPM, GBP, and ZNS. When generic drugs are used, PHT, OXC, and CBZ remain the three most cost-effective options.

Significance: In terms of cost-effectiveness, CBZ monotherapy is the best option for newly diagnosed focal epilepsy, followed by OXC, PHT, VPA, LEV, PHB, LCM, LTG, TPM, GBP, and ZNS. Most traditional ASMs are more cost-effective than new ASMs; OXC is an exception.

Objective: To investigate whether local lesions created by stereo-electroencephalography (SEEG)-guided radiofrequency thermocoagulation (RFTC) affect distant brain connectivity and excitability in patients with focal, drug-resistant epilepsy (DRE).

Methods: Ten patients with focal DRE underwent SEEG implantation and subsequently 1 Hz bipolar repetitive electrical stimulation (RES) for 30 s before and after RFTC. Root mean square (RMS) of cortico-cortical evoked potentials (CCEPs) was calculated for 15 ms to 300 ms post-stimulation with baseline correction. Contact pairs were categorized as both coagulated, hybrid, or both non-coagulated. The data were divided into nine categories based on the stimulating and recording contact pair combinations. RMS of CCEPs was compared before and after (<12 h) RFTC using a two-sample t test (Hochberg corrected, p < 0.05) for each patient. Boost score, indicating power increase during seizures before RFTC relative to baseline, was analyzed in 4 s windows with 1 s overlap during seizure duration.

Results: RFTC altered connectivity across all categories. Of interest, decreases and increases in RMS were observed in connections between non-coagulated contacts distant from coagulation site (range: 1.09-85 mm, median = 17.7 mm, interquartile range [IQR] 10.1-32.3). Contact pairs involved in significantly altered non-coagulated connections showed a higher boost score correlation in the theta, beta, and gamma bands, as well as a stronger maximum correlation with coagulated sites in the delta band than contacts for which connectivity did not change after RFTC.

Significance: This study highlights how local lesions alter distant brain connectivity, providing insights for future research on epilepsy network changes and seizure outcomes following RFTC.

We propose and prioritize important outcome domains that should be considered for future research investigating long-term outcomes (LTO) after new onset refractory status epilepticus (NORSE). The study was led by the international NORSE Institute LTO Working Group. First, literature describing the LTO of NORSE survivors was identified using a PubMed search and summarized to identify knowledge gaps. Subsequently, a consensus-building process was performed to prioritize and rank important LTO domains for further research. The prioritization of LTO domains was qualitative, enabling the expert panel to generate ideas, share opinions, and provide reasons for the rankings. A second round took place to allow expansion and agreement regarding specific details for each domain. Outcomes were classified into eight main domains: (1) Function: Neuropsychological, Neurological (other than seizures), and Psychiatric (mood and behavior); (2) Quality of Life; (3) Epilepsy; (4) Nonneurological (medical); (5) Social; (6) Caregiver Burden; (7) Long-Term Mortality; and (8) Health Care System Impact. In addition, the working group suggested obtaining outcome measures for each domain at 6 months and 1 year after discharge and annually thereafter until stability has been reached. There are no currently established time frames set for when LTO in NORSE begin or plateau, and previously there existed no consensus regarding which LTO should be considered. This consensus process identifies and recommends NORSE LTO domains that should be considered in future research studies to provide more consistent results that can be compared between studies. Survivors of NORSE should be evaluated serially and at fixed points over time to maximize our understanding of the recovery trajectory for all LTO domains. Establishing reliable and standardized data describing LTO (beyond seizures) after NORSE will support discussions with families during the acute stages, prognostication, the development of targeted management strategies for survivors, and future comparative research globally helping to identify biomarkers that may predict LTO.

Objective: To assess whether social determinants of health (SDOHs) are associated with the first antiseizure medication (ASM) prescribed for newly diagnosed epilepsy.

Methods: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) standards were followed, and the protocol registered (CRD42023448998). Embase, Medline, and Web of Science were searched up to July 31, 2023. Two reviewers independently screened studies and reached mutual consensus for inclusion. Studies reporting the first ASM prescribed for patients with new epilepsy in all age groups, countries, and languages were eligible for inclusion. Review articles, conference abstracts, and studies with fewer than 15 participants were not eligible for inclusion. Studies were meta-analyzed using fixed-effects models. Quality assessment was performed using the Newcastle-Ottawa Scale.

Results: Thirteen studies (total participants = 380,785) contained SDOH data and their association with the first ASM prescription after epilepsy diagnosis. Meta-analysis of studies with compatible data revealed that Black (pooled odds ratio [OR] .94, 95% confidence interval [CI] .90-.98) and Hispanic (pooled OR .89, 95% CI .82-.97) patients with U.S. Medicare/Medicaid had a lower odds of receiving a newer ASM compared to White patients. Three studies revealed that rural epilepsy patients had a lower odds of receiving new ASMs compared to urban patients (pooled OR .84, 95% CI .80-.89). The relationship between income levels and ASM prescription patterns differed across countries, highlighting inconsistencies that warrant further investigation. Among studies identified for inclusion, relatively few had combinable data, thereby limiting the scope of our meta-analysis to two SDOHs.

Significance: Significant disparities exist in first-line ASM prescription for non-White and rural persons with epilepsy. There exist few data on other SDOHs including gender identity and socioeconomic background. Future work leveraging large data sets may reveal additional ASM prescription inequities. Developing care pathways to rectify known prescribing disparities may improve health equity among PWE.