Epilepsia Open最新文献

Objective: Variants in KCNQ2 encoding the voltage-gated potassium channel K_V7.2 are associated with developmental and epileptic encephalopathy (DEE) of varying severity. This study examined the relationship of KCNQ2 variant dysfunction with the neurodevelopmental phenotype of individuals with KCNQ2-DEE.

Methods: A parent-reported survey gathered clinical and genetic data for individuals with KCNQ2-DEE. Several clinical features were analyzed separately and as a composite non-seizure phenotype severity score (PSS) for six features (mobility, communication, hand use, eating, scoliosis, cerebral visual impairment). The effect of variants on K_V7.2 channel function was determined by voltage-clamp recording in heterologous cells co-expressing K_V7.3. Functional effects were classified as severe loss of function (SLOF), loss of function (LOF), wild-type-like (WTL), and gain of function (GOF).

Results: The study included 48 individuals each heterozygous for one of 38 unique variants. Median seizure-onset age was 1 day. Complete or significant seizure reduction was reported in 7/13 with carbamazepine, 13/17 with oxcarbazepine, 10/13 with phenytoin, and 3/4 with retigabine. The median PSS was 1 (interquartile range 1-3). On the participant level, 29 had SLOF variants, 13 had LOF variants, and the remaining participants had variants with GOF (3) or exhibited WTL (2) function. There were no significant associations of variant function with individual phenotypes in the PSS; however, the PSS itself was higher in those with SLOF versus LOF variants (p = 0.02). Among individuals with SLOF or LOF variants, there was an intriguing lower prevalence of epileptic spasms among individuals with dominant-negative variants.

Significance: Multiple and severe neurodevelopmental impairments are common in KCNQ2-DEE. There was a modest correlation between K_V7.2 channel dysfunction and overall non-seizure phenotype severity in this cohort. These findings suggest that factors other than differences in channel dysfunction contribute to variable clinical severity in KCNQ2-DEE.

Plain language summary: We examined how changes in the KCNQ2 gene, which affect the function of a brain potassium channel, relate to developmental and seizure features in children with KCNQ2-related epilepsy. Using parent surveys and lab studies of gene variants, we found that variants causing the channel to lose most of its function were linked to slightly worse overall development. Our results suggest that while channel dysfunction plays a role, other biological or environmental factors likely influence how severely children are affected.

Objective: To examine the clinical features of new-onset focal seizures in children and investigate clinical associations and predictors of underlying etiology and drug resistance.

Methods: Data were gathered from The Children's Hospital at Westmead admissions for patients aged 1 month to 18 years who presented with new-onset focal seizures between 2018 and 2022 (n = 140). Seizure characteristics, etiology, clinical comorbidities, investigations, and antiseizure medications were analyzed. Clinical associations between etiologies and comorbidities/treatment outcomes were investigated using nonparametric tests and hierarchical cluster analysis. Multivariable logistic regression was performed to identify predictors of drug resistance.

Results: The median age of seizure onset was 4.7 years (IQR 1.9-8.1). The etiologies included unknown (n = 53, 39%) followed by structural (n = 36, 26%), self-limited childhood focal epilepsy (n = 21, 15%), genetic (n = 12, 9%), inflammatory (n = 12, 9%), and metabolic (n = 3, 2%). The explosive seizure-onset seizures (p = 0.04), focal neurological abnormalities (p = 0.04), younger age at seizure onset (p = 0.01), abnormal neuroimaging findings (p < 0.001), and drug resistance (p < 0.001) were associated with known etiology. Regression analysis showed the drug resistance risk increased with the presence of known genetic (OR 6.7; 95% CI 1.6-31.8), structural (OR 6.4; 95% CI 2.3-19.5), and inflammatory (OR 4.6; 95% CI 1.0-21.2) etiologies.

Significance: Our study examines the important associations and predictors of etiology and drug resistance in children with new-onset focal seizures. The significance of known etiologies as risk factors for drug resistance promotes the need for improved monitoring and etiology-driven treatment.

Plain language summary: This study looked at children who had focal seizures for the first time. In many cases, the cause was unknown, but a large portion was linked to structural brain changes, childhood epilepsies that usually resolve, or genetic, inflammatory, and metabolic conditions. Children with a known cause, especially genetic, structural, or inflammatory, were more likely to have seizures that did not improve with anti-seizure medications. Identifying the cause early can help doctors choose better treatments and provide closer monitoring for patients.

Objective: Status epilepticus (SE) is a neurological emergency requiring immediate treatment. Although intravenous lacosamide (LCM) is used for the management of epilepsy, its effectiveness in treating SE remains unclear. We aimed to compare the in-hospital outcomes between intravenous LCM and levetiracetam (LEV) as an early adjunctive therapy for SE using a nationwide inpatient Japanese database.

Methods: We conducted an observational study using data extracted from the Japanese Diagnosis Procedure Combination database. Patients admitted for SE who received intravenous diazepam or lorazepam on the day of admission and were discharged between April 2019 and March 2023 were enrolled. Patients were categorized into those who received intravenous LCM or LEV on the day of admission. We compared the in-hospital outcomes (in-hospital mortality, length of hospital stay, total hospitalization costs, and proportion of patients with a Glasgow Coma Scale score [GCS] ≤9 at discharge) between the groups using propensity score overlap weighting.

Results: Among the 4605 eligible patients, 227 received LCM and 4378 received LEV. In the propensity score overlap-weighted cohort, in-hospital mortality (4.0% vs. 4.6%, adjusted risk difference [aRD], -0.28%; 95% confidence interval [CI], -3.3% to 2.7%), length of hospital stay (22.4 vs. 22.3 days; difference, 0.011; 95% CI, -3.9 to 3.9), and total hospitalization costs (1 167 798 JPY vs. 1 177 497 JPY; difference, 9699 JPY; 95% CI, -196 269 to 176 872 JPY) did not differ significantly between the LCM and LEV groups. The proportion of patients with GCS scores ≤9 at discharge was lower in the LCM group than in the LEV group (0.6% and 2.4%; aRD, -2.1%; 95% CI, -3.3% to -0.9%).

Significance: LCM and LEV did not yield significantly different in-hospital mortality rates when used for early adjunctive treatment of SE. However, LCM may reduce poor neurological status at discharge. These results highlight the potential utility of LCM in the early management of SE.

Plain language summary: This study compared two intravenous antiseizure medications, levetiracetam (LEV) and lacosamide (LCM), as early add-on therapy for status epilepticus (SE), using data from a large Japanese inpatient database. The in-hospital mortality, length of hospital stay, or total medical costs did not differ significantly between the groups. However, patients treated with LCM had a lower chance of having a poor neurological status at discharge. While LEV is a well-established treatment for SE, this study suggests that LCM may be similarly effective and could offer an advantage, although more research is needed.

Accurate seizure documentation is essential in guiding treatment decisions in epilepsy but still heavily relies on highly subjective and sometimes unreliable patient reports. We report a case of medically refractory mesial temporal lobe epilepsy where subcutaneous EEG revealed persistence of seizures following add-on antiseizure medication despite the patient's self-report of seizure freedom. Thus, ultralong-term EEG subcutaneous monitoring provided valuable information on medical refractoriness and supported the decision to proceed to surgical intervention. Subcutaneous EEG monitoring was continued after resective surgery and has shown no further seizures to this date. To our knowledge, this is the first reported case utilizing subcutaneous EEG for objective seizure documentation both pre- and post-surgery. PLAIN LANGUAGE SUMMARY: Making the right treatment decisions depends on knowing the seizure frequency of a person with epilepsy, but patients' reports are often inaccurate. In our case, we describe a patient in which seizures were only detected because of a small electrode implanted under the skin to record brain activity (subcutaneous EEG). Based on this information, the patient received brain surgery, and the device was left in place after surgery, showing no further seizures. To our knowledge, this is the first reported case where this type of EEG device was used to track seizures both before and after epilepsy surgery.

Objective: The long-term effects of epilepsy surgery (ES) or vagus nerve stimulation (VNS) on antiseizure medication (ASM) usage and status epilepticus (SE) diagnosis in real-world pediatric drug-resistant epilepsy (DRE) populations remain unclear. This study aimed to provide a more comprehensive understanding of how VNS and ES affect ASM usage and SE manifestations in pediatric DRE.

Methods: We conducted a nationwide, retrospective cohort study using the Korean Health Insurance Review and Assessment Service database from January 1, 2007, to December 31, 2022. Pediatric patients (<18 years) diagnosed with DRE were categorized into ASM-only, VNS, and ES groups. Changes in ASM usage and SE diagnostic rates were assessed.

Results: A total of 6075 pediatric patients with DRE were included (ASM-only, n = 5407; VNS, n = 217; ES, n = 451). Although the VNS and ES groups had more severe epilepsy at baseline, both interventions significantly reduced ASM usage, albeit with distinct trajectories. ES led to a sharp reduction in ASM usage immediately postoperatively, followed by stabilization, with approximately one-third of the patients discontinuing ASM by the end of follow-up. VNS stabilized ASM usage rather than reducing it, with fewer than 10% of patients discontinuing ASM. Both interventions were associated with significant decreases in SE diagnostic rates after the intervention (p = 0.007 and 0.02, respectively), but no statistically significant difference was found in the overall SE rates among the three groups (p = 0.18).

Significance: These findings demonstrate that VNS and CES positively impact ASM usage, reduce the incidence of SE, and underscore the need for timely intervention to optimize outcomes.

Plain language summary: We studied children with drug-resistant epilepsy who were treated with either vagus nerve stimulation (VNS) or brain surgery for epilepsy. We found that brain surgery often led to a large and lasting reduction in seizure medication, whereas VNS helped stabilize medication use. Both treatments were linked to fewer cases of status epilepticus, a severe type of seizure emergency. These findings suggest that VNS and surgery may help reduce medication burden and protect against serious seizures in children with hard-to-treat epilepsy.

Objective: Dravet syndrome (DS) is a severe developmental and epileptic encephalopathy with a high seizure burden and mortality risk. Stiripentol, one of the first DS-specific therapies, received FDA approval in 2018 but its real-world use and impact post-approval in the USA remain insufficiently characterized. The STIRUS study aimed to assess treatment patterns, clinical efficacy, and quality of life outcomes associated with stiripentol in a contemporary US cohort.

Methods: STIRUS was a retrospective, multicenter chart review of 98 DS patients who initiated stiripentol after FDA approval and were treated for at least 3 months. Data were collected from 10 USA epilepsy centers on seizure types and frequency, status epilepticus (SE), rescue medication use, emergency room visits, and quality of life, at baseline and during the first and final 3 months on stiripentol. Changes over time were assessed using generalized estimating equation models.

Results: Initiation of stiripentol was associated with a significant reduction in bilateral convulsive seizure frequency (OR = 2.16, p < 0.006) and a nearly 50% decrease in SE episodes (OR = 2.9, p < 0.003). Importantly, there was a marked decline in rescue medication use and seizure-related hospital visits: the proportion of patients requiring no rescue medications increased from 23% to over 53%, and those needing frequent emergency interventions dropped from 39% at baseline to 14% during the final 3 months. Quality of life improved in more than half of patients and caregivers.

Significance: The STIRUS study supports the real-world efficacy of stiripentol in reducing seizure burden and healthcare utilization in DS. Despite its demonstrated benefits and approval for use in infants, stiripentol remains underutilized and often introduced late in the treatment course. Early and broader adoption may help improve clinical outcomes and quality of life in this vulnerable population.

Plain language summary: The STIRUS study found that stiripentol, an anti-seizure medication specifically approved for Dravet Syndrome, helped reduce seizures and hospital visits for children living with this severe form of epilepsy. Patients had fewer convulsive seizures, needed fewer rescue medicines, and reported better quality of life. Despite these benefits, stiripentol is still not widely used and often started too late in treatment, suggesting earlier use could further improve outcomes.

The management of drug-resistant epilepsy (DRE) in the pediatric population using neurostimulation of the centromedian (CM) nucleus of the thalamus (CMN) has been reported to be effective and safe. We present a case series of pediatric patients treated with responsive neurostimulation (RNS) and report on contact localization in relation to preliminary outcomes, specifically seizure reduction rates. Thirteen pediatric patients treated with RNS underwent direct targeting of the CMN based on Magnetization-Prepared 2 Rapid Gradient-Echo (MP2RAGE) scans, using ClearPoint neuronavigation. The implanted electrodes were co-registered to a probabilistic anatomical model of the thalamic nuclei (Freesurfer) for secondary confirmation of contact localization. Ten out of the 12 patients with extra-temporal multifocal or generalized DRE (83.3%) had over 50% reduction in seizures, benefiting from an 80.4% seizure reduction rate. The average follow-up interval was 25.2 months, with no patients experiencing stimulation-related side effects. The analysis of post-operative images revealed that out of the 24 CM-processed electrodes, 23 (95.8%) had at least two contacts in the nucleus, based on patient-specific segmentation of the thalamus. The preliminary outcomes suggest a robust response to central neurostimulation and no stimulation-related side effects in pediatric patients suffering from multifocal or generalized DRE when implementing high-accuracy direct targeting. PLAIN LANGUAGE SUMMARY: We are reporting our experience in the management of the most challenging types of pediatric epilepsy, involving seizures originating from multiple and/or poorly defined brain areas. We surgically implanted a responsive neurostimulation device (RNS) in central areas of the brain that function as connection hubs between different brain regions. These devices are designed to detect early signs of abnormal brain activity, and respond with electrical pulses to prevent progression to clinical seizures. Using our approach, we reduced the seizure rates by an average of 80% in 83% of the pediatric patients who received this treatment.

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.