Epilepsia Open

Background and ObjectivesIndividuals with disease-causing variants in STXBP1 frequently have epilepsy onset in the first year of life with a variety of seizure types, including epileptic spasms. However, the impact of early-onset seizures and anti-seizure medication (ASM) on the risk of developing epileptic spasms and impact on their trajectory is poorly understood, limiting informed and anticipatory treatment, as well as trial design. MethodsWe retrospectively reconstructed seizure and medication histories in weekly intervals for individuals with STXBP1-related disorders with epilepsy onset in the first year of life and quantitatively analyzed longitudinal seizure histories and medication response. ResultsWe included 61 individuals with early onset seizures, 29 of whom had epileptic spasms. Individuals with neonatal seizures were likely to have continued seizures after the neonatal period (25/26). The risk of developing epileptic spasms was not increased in individuals with neonatal seizures or early infantile seizures (21/41 vs. 8/16; OR 1, 95% CI 0.3-3.9, p = 1). We did not find any ASM associated with the development of epileptic spasms following prior seizures. Individuals with prior seizures (n = 16/21, 76%) had a higher risk to develop refractory epileptic spasms (n = 5/8, 63%, OR =1.9, 95% CI 0.2-14.6, p = 0.6). Individuals with refractory epileptic spasms had a later onset of epileptic spasms (n = 20, median 20 weeks) compared to individuals with non-refractory epileptic spasms (n = 8, median 13 weeks; p = 0.08). When assessing treatment response, we found that clonazepam (n = 3, OR 12.6, 95% CI 2.2-509.4; p < 0.01), clobazam (n=7, OR 3, 95% CI 1.6-6.2; p < 0.01), topiramate (n=9, OR 2.3, 95% CI 1.4-3.9; p < 0.01), and levetiracetam (n=16, OR 1.7, 95% CI 1.2-2.4; p < 0.01) were more likely to reduce seizure frequency and/or to maintain seizure freedom with regards to epileptic spasms than other medications. DiscussionWe provide a comprehensive assessment of early-onset seizures in STXBP1-related disorders and show that the risk of epileptic spasms is not increased following a prior history of early-life seizures, nor by certain ASM. Our study provides baseline information for targeted treatment and prognostication in early-life seizures in STXBP1-related disorders.

Neonatal seizures are challenging to diagnose due to subtle clinical presentations and require video-EEG for confirmatory diagnosis. However, video-EEG is not always available, so clinicians must sometimes decide to treat neonatal seizures prior to diagnostic confirmation. The extent of this gap in clinical care is not previously described. This retrospective study examined anti-seizure medication (ASM) use in 115 infants who underwent video-EEG at Mount Sinai. Of 46 infants treated with ASMs, 59% received loading doses before EEG. Among these, 89% showed epileptiform activity and 52% (14/27) had seizures on EEG. Mortality among treated infants was high (30%). These findings highlight the significant reliance on clinical judgment without EEG when treating neonatal seizures. Our data support future work to develop scalable, accessible tools to improve timely and accurate treatment of neonatal seizures.

IntroductionSince the initial description of CACNA1A-related hemiplegic migraine (HM), the phenotypic spectrum has expanded from mild episodes in neurotypical individuals to potentially life-threatening events frequently seen in individuals with developmental and epileptic encephalopathies. However, the overall longitudinal course throughout childhood remains unknown. MethodsWe analyzed HM and seizure history in individuals with CACNA1A-related HM, delineating frequency and severity of events in monthly increments through a standardized approach. Combining these data with medication prescription information, we assessed the response of HM to different agents. ResultsOur cohort involved 15 individuals between 3 and 29 years (163 patient years) and included 11 unique and two recurrent variants (p.R1349Q and p.V1393M; both n=2). The age of first confirmed HM ranged from 14 months to 13 years (average 3 years). 25% of all HM events were severe (lasting >3 days) and 73% of individuals had at least 1 severe occurrence. Spacing of HM events ranged from 1 month to 14 years and changes in HM severity over time of showed increases or decreases of >2 severity levels in 12/122 events. Eight individuals had epilepsy, but severity of epilepsy did not correlate with frequency and severity of HM events. While levetiracetam (n=6) and acetazolamide (n=5) were the most frequently used medications, they did not show efficacy in HM prevention or HM severity reduction. However, verapamil (n=3) showed efficacy in preventing HM episodes (OR 2.68, CI 1.39-5.67). SignificanceThe longitudinal course of CACNA1A-related HM lacks recognizable patterns for timing and severity of HM events or correlation with seizure patterns. Our data underscores the unpredictability of CACNA1A-related HM, highlighting the need for close surveillance for reoccurring HM events even in individuals with symptom-free periods. Key pointsO_LI24% of hemiplegic migraines (HM) in CACNA1A-related disorders are severe, involving cerebral edema and greater than 4 days to recover C_LIO_LITiming and severity of HM are unpredictable, with large changes in severity between events, and age of onset ranging from 1-13 years C_LIO_LIEpilepsy occurred in 53% of individuals, with neither the timing nor severity of seizures correlated with HM C_LI

Variants in the GATOR1 complex gene DEPDC5 disrupt mTORC1 pathway regulation, driving cortical malformations and focal epilepsy. DEPDC5 is the most common genetic cause of focal epilepsy, often linked to focal cortical dysplasia (FCD). However, reduced penetrance complicates genetic counselling and risk prediction. This study analysed the largest DEPDC5-related epilepsy cohort, synthesising data from 170 families and 586 variant carriers. Epilepsy penetrance was estimated at 64.9% (n=380/586), with median seizure onset at 5 years. By age 10, 76.1% of individuals experienced seizures. Drug resistance occurred in 48.3% (n=101/209) of cases, and cortical malformations were present in 28% (n= 49/175) of MRIs. SUDEP accounted for 16% (n= 4/25) of deaths among affected individuals. Early seizure onset correlated strongly with drug resistance, intellectual disability, and MRI abnormalities, underscoring its role as a severity marker. Surgical intervention in drug-resistant cases (34.7% [n= 35/101]) achieved favourable outcomes (Engel I or II) in 88% (n= 29/33) of individuals, with pathology confirming cortical malformations in 92.6% (n=25/27) of those with abnormal MRIs. This study advances the understanding of DEPDC5-related epilepsy, providing critical insights into penetrance, phenotype, and treatment outcomes to inform precision care and genetic counselling.

Febrile infection-related epilepsy syndrome (FIRES) is a severe childhood epilepsy with refractory status epilepticus after a typically mild febrile infection. The etiology of FIRES is largely unknown, and outcomes in most individuals with FIRES are poor. Here, we reviewed the current state-of-the art genetic testing strategies in individuals with FIRES. We performed a systematic computational analysis to identify individuals with FIRES and characterize the clinical landscape using the Electronic Medical Records (EMR). Among 25 individuals with a confirmed FIRES diagnosis over the last decade, we performed a comprehensive review of genetic testing and other diagnostic testing. Management included use of steroids and intravenous immunoglobulin (IVIG) in most individuals, followed by the ketogenic diet, and, after 2014, an increasing use of immunosuppressants, IVIG, and plasma exchange (PLEX). Genetic testing was performed on a clinical basis in almost all individuals and was non-diagnostic in all patients. We compared FIRES with both status epilepticus (SE) and refractory status epilepticus (RSE) as a broader comparison cohort and identified genetic causes in 36% of patients with RSE. In summary, despite the absence of any identifiable etiologies in FIRES, we performed an unbiased analysis of the clinical landscape, identifying a heterogeneous range of treatment strategies and characterized real-world clinical practice. FIRES remains one of the most enigmatic conditions in child neurology without any known etiologies to date despite significant efforts in the field, suggesting a clear need for further studies and novel diagnostic and treatment approaches. Furthermore, the difference in genetic signatures between FIRES and RSE suggest distinct underlying etiologies.

ObjectiveWhile epilepsy research has largely focused on medical management and clinical outcomes, less attention has been given to the unmet psychosocial, and everyday needs of people with epilepsy (PWE), particularly in low- and middle-income countries. The Global Epilepsy Needs Study (GENS) aims to explore these needs, which are integral to quality of life, by capturing both shared and context-specific experiences. MethodsGENS employed a patient-centered approach and mixed-methods design, integrating a cross-sectional survey and semi-structured interviews in 15 countries. The survey, available in 12 languages, captured experiences across 10 life domains (n=5296). Interviews, analysed thematically using a phenomenological approach and Colaizzis Method, explored lived experiences in depth (n=75). To ensure meaningful involvement and diverse representation, national patient associations, healthcare professionals, researchers and people with lived experience guided each stage of the research process, from study design to manuscript development. ResultsQuantitative and qualitative data were integrated using a joint display method. This analysis generated 5 Generalised Themes across all life domains: 1) Managing uncertainty and redefining daily life; 2) Living with risk, social exclusion, and misunderstanding; 3) Challenges in navigating inaccessible systems; 4) Consequences of inaccessible or inadequate information; and 5) Complex epilepsy needs demand more than standard approaches. SignificanceThis first-of-its-kind global study offers a comprehensive picture of the psychosocial and everyday challenges faced by PWE. It establishes a critical evidence base for epilepsy organisations, highlights the need for healthcare systems to adopt holistic, multidisciplinary approaches, and calls on policymakers to invest in systemic reforms that safeguard dignity, inclusion, and life opportunities. Future research should explore the needs of underserved groups, including caregivers, individuals with complex epilepsy, women, and those in low-income or rural settings. Plain Language SummaryThis study looked at the everyday challenges faced by people with epilepsy in different parts of the world. It showed that many people struggle with fear, stigma, poor access to services, and a lack of clear information and support. Women, people in rural areas, and those in low-income settings often face the greatest challenges. The study calls for better education, more support for caregivers, and improvements across health, work, school, and transport systems. It also shows the need for more research to understand and respond to the real-life needs of people most impacted by epilepsy.

Background: People of childbearing potential with epilepsy in regions endemic for Taenia solium, where neurocysticercosis (NCC) is highly prevalent, represent a vulnerable population due to the elevated burden of epilepsy and resource limitations. Clinical practice in these settings remains poorly characterized. This study characterized anti-seizure medication (ASM) prescribing patterns by medication risk profiles among people of childbearing potential with epilepsy in Northern Peru, a region highly endemic for T. solium. Methods: Participants were drawn from a prospective, population-based epilepsy cohort in Tumbes, Peru (2006 to 2020). The analytic population included females with epilepsy aged 15 to 49 years. The primary outcome was pregnancy-associated ASM risk of congenital malformations and adverse neurodevelopmental outcomes. ASMs were classified as ''Established Low Risk'' (lamotrigine, levetiracetam), ''Possible Risk/Inadequate Data'' (carbamazepine, phenobarbital, phenytoin), and ''Established High Risk'' (valproic acid). Prescription patterns were examined in relation to demographic and clinical characteristics. Results: Among 1,975 individuals with epilepsy, 685 were people of childbearing potential. Approximately 34.9% met criteria for probable or definite NCC. Most ASM prescriptions were in the ''Possible Risk/Inadequate Data'' category (87.0%), and 12.8% received ''Established High Risk'' medications. In multivariable analysis, high-risk prescribing was associated with prior ASM use and polytherapy. Discussion: People of childbearing potential with epilepsy were predominantly treated with carbamazepine, phenytoin, phenobarbital, and valproate, reflecting local ASM availability. Despite evidence supporting lamotrigine and levetiracetam in pregnancy, prescribing patterns reflect local formulary constraints. These findings highlight a gap between guideline recommendations and real-world prescribing in resource-limited settings, underscoring the need for context-specific treatment strategies.

BackgroundPatients with epilepsy often present with multiple comorbidities, which can exacerbate the progression of the disease and reduce their quality of life. Despite the clinical significance, there is a scarcity of collective data to estimate the prevalence of comorbidities among patients with epilepsy in the Asian setting. MethodsWe conducted a comprehensive literature search in PubMed, Scopus, and Google Scholar to identify observational studies conducted in Asia that reported the prevalence of comorbidities among patients diagnosed with epilepsy. Only studies focusing on epilepsy patients were included, and participants were required to have epilepsy confirmed through clinical diagnosis or International Classification of Diseases (ICD) codes. Other neurological conditions, such as non-epileptic seizures, brain tumors, or stroke without concurrent epilepsy, were excluded from this analysis to maintain focus on epilepsy-specific outcomes. ResultsA total of nine studies were included in the meta-analysis based on inclusion criteria. The most prevalent comorbidities among patients with epilepsy in Asia were hypertension (28.6%, 95% CI: 25.3%-32.0%) and diabetes mellitus (16.2%, 95% CI: 12.5%-20.2%). Factors such as gender, alcohol use, family history, and education level were significantly lower in comparison to other factors. ConclusionsOur study identified hypertension and diabetes mellitus as the most common comorbid conditions among epilepsy patients in Asian settings. These findings highlight the necessity for targeted interventions and comprehensive management strategies to address the high prevalence of comorbidities, ultimately improving patient outcomes. Further research is warranted to explore the underlying mechanisms and develop effective prevention strategies.

ObjectiveLennox-Gastaut Syndrome (LGS) is a severe, often treatment-resistant epilepsy syndrome typically diagnosed in early childhood. Many have seizures before diagnosis. Some have periods of seizure freedom before treatment resistance, i.e., a "gap." Review of these gaps may identify early candidate biomarkers of LGS and/or highlight opportunities for intervention. MethodsWe reviewed charts of children diagnosed with LGS born in 2008-2010 and diagnosed with LGS by 2014 at five academic medical centers in New York City using the RENYC (Rare Epilepsies in New York City) database. We collected dates of events of potential biomarkers by chart abstraction, including onset of slow spike-and-wave (SSW) and onset and offset of seizure freedom. Seizure-free periods ("gaps") were defined as greater than 30 days without unprovoked seizures. ResultsThirty-three children had LGS (52% male; etiology 33% structural-acquired, 6% structural-congenital, 3% genetic-structural, 24% genetic, 33% unknown). Twenty-two (67%) had a gap before diagnosis. Eight of these twenty-two (36%) had SSW described before the gap, five (23%) during the gap, and six (27%) after the gap. A history of infantile epileptic spasms syndrome (IESS), age at seizure onset, and age of tonic seizure onset were not different between those with and without a gap. Of 20 (61%) with a history of IESS, 10 (30% of the full cohort) had not received recommended therapy (i.e., ACTH, prednisolone, or vigabatrin) as first-line treatment. ConclusionsThe appearance of SSW, even in seizure-free children, may herald the development of LGS in high-risk children. Further studies on its predictive value are warranted. Our findings also highlight use of recommended first-line therapy for infantile spasms as a potentially modifiable treatment gap in children who subsequently develop LGS.

OBJECTIVEThis study aimed to further examine the impact of epileptic seizures on neurocognitive outcomes in KBG syndrome, a rare genetic neurodevelopmental disorder characterized by pathogenic variants in the gene ANKRD11. METHODSA single clinician interviewed a cohort of individuals with genetically confirmed cases of KBG syndrome. Medical records and other relevant data were collected for each participant. To evaluate participants adaptive functioning, trained professionals conducted assessments using the Vineland-3 Adaptive Behavior Scales. The assessment compared individuals with epilepsy to those without seizures and covered the domains of communication, daily living skills, socialization, and maladaptive behaviors. Further comparisons were drawn based on insights from interviews and information extracted from participants medical records. RESULTSThirty-nine individuals (22 males, 17 females) with KBG syndrome, confirmed through genetic analysis, were interviewed via videoconferencing by a single physician, followed by Vineland-3 assessment by trained raters. Individuals with KBG syndrome came from 36 unique families spanning 11 countries. While the KBG cohort displayed lower overall adaptive behavior composite scores compared to the average population, several members displayed standard scores at or higher than average, as well as higher scores compared to those with the neurodevelopmental disorder Ogden syndrome. Within the KBG cohort, males consistently scored lower than females across all domains, but none of these categories reached statistical significance. While the group with epilepsy exhibited overall lower scores than the non-seizure group in every category, statistical significance was only reached in the written communication subdomain. We predict this lack of significance is limited by low sample size, reducing study power. CONCLUSIONSDue to the rarity of KBG syndrome, our research provides valuable insights that can aid in epilepsy screening and inform assessment strategies for neurocognitive functioning in those with this condition. The cohort performed overall higher than expected with outliers existing in both directions. Although our results suggest that seizures might influence the trajectory of KBG syndrome, the approaching but overall absence of statistical significance between study groups underscores the necessity for a more extensive cohort to discern subtle variations in functioning. Conducting Vineland-3 assessments in the KBG syndrome population can enhance research insights regarding differences between those with and without epilepsy. Given the data collected, we recommend vigilant monitoring for seizures following a KBG diagnosis, with consideration for performing baseline EEG assessments.

IntroductionPathogenic mutations in STXBP1 and SLC6A1 can cause developmental delay and epilepsy. 4-phenylbutyrate (4PB), a drug used for urea cycle disorders, rescues dysfunction in pre-clinical models for both genes, suggesting an opportunity for drug repurposing. MethodsWe conducted a single-treatment group, multiple-dose, open-label study of 4PB (as glycerol phenylbutyrate) in children with pathogenic STXBP1 and SLC6A1 mutations at two centers (NCT04937062). Enrolled participants were monitored for 4 weeks (baseline) then received 4PB for 10 weeks, with an option for extended use. Endpoints were safety and tolerability (primary) as well as seizure burden, EEG abnormalities, quality of life, development, behavior, and sleep (exploratory). We report safety, tolerability, EEG, and seizure outcomes. ResultsWe enrolled 20 children (10 STXBP1, 10 SLC6A1; median age 5 years, absolute range 4 months to 11 years; 14 males; all White, 2 Hispanic). There were six serious adverse events, one attributed to 4PB (hospitalization for metabolic acidosis). Other common adverse events included a honey-like odor, sedation, and anorexia. After one participant initially withdrew for metabolic acidosis (SLC6A1), 18 of the 19 remaining participants opted for extended use. Of these 18, 17 (94%) continued 4PB within 10% of the target dose (11.2 mL/m^2/day) at the last clinical visit (2-3 years). At baseline, every child had abnormal EEG findings (seizures, paroxysmal or generalized slowing, or epileptiform discharges). For STXBP1, EEG improvements after one year of 4PB include (1) six with EEG seizures before 4PB versus two after and (2) nine with epileptiform discharges on initial EEGs versus four after. For SLC6A1, there was no clear pattern of EEG evolution. After 10 weeks of 4PB, seizures (or spells) were reduced in STXBP1 for six (60%), and in SLC6A1 for seven (70%). Seizure outcomes at the last visit were as follows. For STXBP1, three children were seizure-free and six had seizures daily to monthly; for SLC6A1, eight had sustained reduction in seizures, typically with seizure freedom and brief relapses that resolved after weight adjustment of the 4PB dose. ConclusionThis case series found 4PB was safe and well-tolerated and reduced seizures for STXBP1 and SLC6A1 disorders. KEY POINTSO_ST_ABSQuestionC_ST_ABSIs 4-phenylbutyrate (4PB; a drug used for urea cycle disorders) safe, tolerable, and effective for people with developmental delay and seizures due to mutations in STXBP1 or SLC6A1? FindingsIn a single-treatment group, multiple-dose, open-label study of 4PB at two centers, treatment of 20 children (10 STXBP1 and 10 SLC6A1) with 4PB (as glycerol phenylbutyrate) was safe (no new side effects) and well tolerated (19 enrolled in extended use). For both disorders, seizures improved in the short term (6 STXBP and 7 SLC6A1 with fewer seizures after 6 weeks) and long term (3 STXBP1 and 8 SLC6A1 with sustained seizure reduction after 2-3 years of use). Meaning4PB is a safe and well-tolerated repurposed drug that may improve seizure control in STXBP1 and SLC6A1.

BackgroundHow different thalamic sites are recruited during seizure propagation remains poorly understood. Simultaneous recordings from multiple thalamic sites in patients with focal seizures provide a rare opportunity to investigate the spatiotemporal pattern of thalamic involvement during human epilepsy. ObjectiveTo characterize the recruitment patterns of mediodorsal (MD) thalamic subregion during seizures and their generalization to the contralateral hemisphere. MethodsWe analyzed 119 seizures from 23 patients (12 male, age range: 20-57y) undergoing multisite thalamic recordings. In accordance with current clinical standards, we determined the spatial and temporal features of thalamic seizure activity by visually reviewing intracranial EEG recordings from different seizure types in each individual patient. ResultsThe procedure of multisite thalamic recordings had no complications. In total, we captured seizures originating from temporal lobes (63%), orbitofrontal (11%), frontotemporal (8%), occipital (8%), lateral frontal (4%), parietal (3%), and cingulate (2%) regions. Seizures were focal (76% in 21 patients), focal-to-bilateral tonic-clonic (FBTC, 9% in nine patients), or only electrographic (15% in six patients). Thalamic engagement was seen in 100% of patients occurring typically early during seizure evolution (83% within 15 seconds of seizure onset). Majority of FBTC seizures (73%) had faster thalamic recruitment, often within the first 5 seconds. The pulvinar (PLV) subregion was the most common first-activated thalamic site, particularly in temporal lobe seizures. Although the MD was involved in most seizures (88.2%), it was rarely the initial or sole thalamic structure engaged and more often followed anterior (ANT) and/or PLV sites. Contralateral propagation occurred in 66% of seizures and was strongly linked to MD involvement: the ipsilateral and contralateral MDs were engaged in about 95% of these cases. When ipsilateral MD engagement was absent, contralateral spread of seizures was uncommon. In majority of seizures (60%) that generalized to the contralateral hemisphere, the ipsilateral MD was involved before or simultaneously with the contralateral cortical sites. Importantly, seizures that first activated the MD originated mainly from the medial temporal lobes, whereas those spreading primarily to the contralateral cortex were mostly neocortical in onset. ConclusionsThe thalamic MD subregion was often involved after the other thalamic sites, but the MD sites, along with the massa intermedia connecting the two thalami, were significantly involved when seizures spread to contralateral hemisphere. Our findings suggest that a single thalamic lead capturing both MD subregions may yield important clinical information about laterality, origin, and generalization of seizures.

PurposePerinatal ischemic stroke (PIS) is a frequent cause for perinatal brain structure defects resulting in epilepsy, cerebral palsy and disability. Since the severity of symptoms is variable, the aim of this study was to evaluate the outcome of children with PIS and seizures/epilepsy to aid parental counseling and therapy decisions. MaterialWe studied retrospectively patients with arterial PIS and structural epilepsy or seizures in the newborn treated at a single center in 2000-2019. Specifically, signs and symptoms of cerebral palsy (CP), developmental and motor delay, epilepsy and thrombophilia were assessed. ResultsFrom the identified 69 individuals with arterial PIS, we only included the 50 patients (64% male) who had structural epilepsy at the time of investigation or previously in their medical history.The mean age of the included patients was 7.1 years (range 0.08-22) at last consultation. Infarct localisation was predominantly unilateral (86%), left sided (58%) and affecting the middle cerebral artery (94%). Genetic thrombophilia was identified in 52% of the patients examined with genetic testing. More than half of the individuals had CP (52%), and 38.5% had a cognitive outcome below average. First seizures occurred in the neonatal period in 58% of patients and developed into drug-refractory epilepsy in 24.1%. Children with late-onset of epilepsy were twice as likely to develop drug-refractory epilepsy (52.4%). DiscussionOur study shows that patients with PIS and seizures as common sequela often also develop CP. Children with later onset of epilepsy have a worse outcome. Patients with seizure onset in the neonatal period and reccuring seizures have a good response to treatment. Therefore, early diagnosis, follow-up examination and adequate therapy are important. Most children need intensive physiotherapy and speech therapy; however, participation in life is usually age-appropriate.

BackgroundThe ZFHX3 gene plays vital roles in embryonic development, cell proliferation, neuronal differentiation, and neuronal death. This study aims to explore the relationship between ZFHX3 variants and epilepsy. MethodsWhole-exome sequencing was performed in a cohort of 378 patients with partial (focal) epilepsy. A Drosophila Zfh2 knockdown model was used to validate the association between ZFHX3 and epilepsy. ResultsCompound heterozygous ZFHX3 variants were identified in eight unrelated cases. The burden of ZFHX3 variants was significantly higher in the case cohort, shown by multiple/specific statistical analyses. In Zfh2 knockdown flies, the incidence and duration of seizure-like behavior were significantly greater than those in the controls. The Zfh2 knockdown flies exhibited more firing in excitatory neurons. All patients presented partial seizures. The five patients with variants in the C-terminus/N-terminus presented mild partial epilepsy. The other three patients included one who experienced frequent nonconvulsive status epilepticus and two who had early spasms. These three patients had also neurodevelopmental abnormalities and were diagnosed as developmental epileptic encephalopathy (DEE), but achieved seizure-free after antiepileptic-drug treatment without adrenocorticotropic-hormone/steroids. The analyses of temporal expression (genetic dependent stages) indicated that ZFHX3 orthologs were highly expressed in the embryonic stage and decreased dramatically after birth. ConclusionZFHX3 is a novel causative gene of childhood partial epilepsy and DEE. The patients of infantile spasms achieved seizure-free after treatment without adrenocorticotropic-hormone/steroids implies a significance of genetic diagnosis in precise treatment. The genetic dependent stage provided an insight into the underlying mechanism of the evolutional course of illness. WHAT IS ALREADY KNOWN ON THIS TOPICThe ZFHX3 protein plays an essential role in neurodevelopment. The relationship between ZFHX3 variants and human diseases remains unknown. WHAT THIS STUDY ADDSEight pairs of compound heterozygous ZFHX3 variants were identified in eight unrelated patients with partial epilepsy, including two who evolved from early spasms. HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICYThe ZFHX3 gene is a novel pathogenic gene of childhood partial epilepsy and developmental epileptic encephalopathy. The development-dependent expression pattern of ZFHX3 explains the evolutional course of the illness, potentially being helpful in the management of the patients.

Early acquired brain injury is a major risk factor for infantile epileptic spasms syndrome (IESS), which may impair cognitive development, especially if diagnosis and treatment are delayed. However, individual-level prediction of which infants will develop IESS is currently not possible. We assessed whether high-frequency oscillations (HFOs) in scalp EEG or recurrent interictal epileptiform discharges (IED) during the first months of life could predict forthcoming IESS. Our population-based cohort included 36 infants with cortical injury due to infarction, haemorrhage, infection or trauma involving a large cortical area ([&ge;] anterior/posterior cerebral artery territory or [&ge;] half of the middle cerebral artery territory), or hypoxic-ischaemic encephalopathy with cortical and deep grey matter involvement. The infants underwent repeated EEGs during the first year of life until 12 months of age or until IESS diagnosis. HFOs during sleep were scored both visually and automatically, whereas IEDs were assessed visually only. We tested whether HFO rate increased during the first year of life using a mixed-effects model with within- and between-subject random effects. Using only EEGs recorded prior to IESS diagnosis, we evaluated whether HFO rate or recurrent IEDs could predict IESS development by training a ridge-regularized logistic regression model with exhaustive leave-2-subjects-out cross-validation. Eleven infants (31%) developed IESS. HFO rate increased with age in both groups but more steeply in the IESS group [within person slope {beta} = 2.43 (IESS) vs. 0.06 (no-IESS) units/month, P < 0.001]. The logistic regression model showed that both HFO rate [AUC 0.801 (95% CI 0.668, 0.936)] and recurrent IEDs [AUC 0.826 (95% CI 0.720, 0.932)] were able to predict forthcoming IESS. However, in a multivariable model, only recurrent IEDs remained independently associated with IESS, and HFO rate did not add predictive value. The marked increase in HFO rate toward IESS diagnosis supports their role as a biomarker of epileptogenesis. During the first months of life, HFOs and recurrent IEDs performed equally well in predicting subsequent IESS. However, IEDs are easier to apply to clinical practice.

BackgroundIntractable or drug-resistant epilepsy (DRE) is a condition where seizures cannot be adequately controlled through antiepileptic medications. In the setting where resective surgery is ineffective, neuromodulation therapy, or vagus nerve stimulation (VNS), is a safe and approved solution. Nonetheless, the efficacy has yet to be clear. We conducted this systematic review and meta-analysis to evaluate the clinical benefit and response of VNS on seizure frequency reduction in intractable epilepsy. MethodsFour databases (PubMed, Elsevier, Google Scholar, Neurology Journals) were searched from inception to November 2024. RCTs and observational studies that analyzed the effect of vagus nerve stimulation in intractable epilepsy patients were included. Review manager (RevMan 5.4) was used for data analysis with random effects model based on heterogeneities. ResultsFive cohort studies (three prospective and two retrospective) were included in the quantitative analysis, involving 244 participants with intractable epilepsy. The pooled analysis revealed a significantly increased likelihood of seizure reduction with VNS (RR = 13.55, 95% CI = 4.95-37.05; p <0.001). Adverse events, reported in three studies, were generally mild to moderate. Two studies assessing the relationship between seizure type and VNS response consistently demonstrated a better response in cases of generalized epilepsy. One study found a positive response of VNS therapy after prior surgery in focal resection group (>60%), followed by corpus callosotomy (33%). However, no study reported a significant reduction in AED usage following VNS therapy. ConclusionVNS is considered a favorable therapy for patients with intractable epilepsy, notably in generalized epilepsy.

We examined seizure semiology and response to medications in 28 children (9 female, 19 male) with likely pathogenic and pathogenic SCN2A-related epilepsy. Parents reported seizure onset, seizure semiology, genetic variants, therapies used for seizures, and response to treatment. 27 children experienced defined seizures and 1 reported no seizure history. The most common initial seizures were focal or hemi-convulsions (n=8). Tonic seizures were the most common reported seizure type while febrile and atonic or drop seizures were the least common. Most patients experienced multiple seizures daily or were entirely seizure-free, with no difference based on age at seizure onset. The proportion of effective trials of the 8 most commonly reported medications ranged from 4 of 26 trials (levetiracetam) to 5 of 10 trials (valproic acid). Phenytoin was the most commonly reported effective treatment (N=4). Topiramate was reported to be the most effective treatment in combination with another treatment (N=6). We found a wide phenotypic spectrum of SCN2A-related disorders and a possible correlation between genotype and seizure onset, semiology, and treatment response. Gain-of-function mutations in early-onset SCN2A epilepsies responded well to sodium channel blockers. Further exploration of SCN2A pathogenic variants are needed to identify mediation mechanisms of action in SCN2A-related epilepsy.

Access to and delivery of quality surgical epilepsy care remains a challenge in both safety-net and private hospital systems. Underserved populations are more likely to utilize safety-net hospital systems, but there are few data on epilepsy surgery outcomes in this setting. We aimed to analyze and compare surgical epilepsy care in a safety-net versus private hospital system. We prospectively collected evaluation and treatment data in patients undergoing resective surgery for epilepsy at a safety-net hospital system and a collaborating private hospital system between 2010-2017. Seizure characteristics, pre-surgical evaluation, perioperative complications, and seizure outcomes were prospectively recorded. Data from 102 patients in the safety-net and 145 patients in the private hospital system were analyzed. There were higher proportions of African American (p=.02) and Hispanic patients (p= .03) in the safety-net hospital system. There was no difference in mean time from epilepsy onset to surgery between groups (p=.54). The presurgical evaluation was equivalent (p>.18), except for more frequent use of magnetoencephalography in the private system (p=.02). Seizure freedom outcomes were excellent, and complication rates were low with no significant differences between groups (p=.95 and p>.22, respectively). However, patients from safety-net hospital systems were more likely to be lost to follow up (p=.04). Quality and equitable surgical epilepsy care can be delivered in a safety-net hospital system despite the higher-minority demographics and intrinsic factors of safety-net hospitals. Partnership of safety-net hospital systems with established comprehensive epilepsy centers and the expansion of these services is essential for healthcare equity in modern epilepsy care.

Purpose: DNM1-related disorder is a rare developmental and epileptic encephalopathy. The current understanding of the clinical spectrum is based on sparse patient descriptions. Here, we compile the largest DNM1 cohort to date, to characterize the genotypic and phenotypic landscape of the disorder. Methods: Phenotypic data was manually curated from 95 individuals from multiple sources and harmonized using the Human Phenotype Ontology framework. Results: Disease-causing variants in DNM1 cluster in mutational hotspots within the gene, which achieve Strong and Moderate evidence for pathogenicity based on ACMG guidelines. The overall DNM1 phenotype was homogeneous compared to other genetic epilepsy conditions: SCN2A, SCN8A, STXBP1, and SYNGAP1. The p.R237W (n=15) variant was associated with bilateral tonic-clonic seizures, infantile spasms, and dystonia. The p.I398_R399insCR (n=14) variant was associated with severe hypotonia, profound global delay, and cortical visual impairment. Five individuals with homozygous loss-of-function variants were clinically similar to dominant-negative DNM1-related disorder, but microcephaly and brain MRI abnormalities were more common in this group. Conclusion: A harmonized cohort of individuals with DNM1-related disorder was analyzed to define mutational hotspots and reveal novel genotype-phenotype correlations. Due to the homogeneous phenotype, disease mechanism, and high proportion of recurrent variants, DNM1 represents an attractive target for targeted therapy development.

BackgroundComplete resection of focal malformations of cortical development (MCD) has been recognized as crucial for the success of epilepsy surgery. However, many of these lesions escape detection using even state-of-the-art epilepsy protocol MRI imaging. This study evaluates the concurrence of radiographic and histopathologic findings of MCD in patients with refractory temporal lobe epilepsy (TLE) and defines the predictive value of EEG findings in the detection of MCD. Materials and MethodsPre-operative MRI, scalp VEEG, and post-operative surgical pathology reports from 34 consecutive patients treated for refractory TLE by surgical resection over a ten year period were included in analysis. Radiographic findings of MCD were correlated with histopathologic findings of MCD and compared against pre-operative interictal scalp EEG findings. Results66.7% of focal cortical dysplasias (FCD) identified on pathology and all cases of mild MCD (mMCD) were missed on pre-operative MRI. The description of a rhythmic or continuous interictal abnormality on pre-operative VEEG corresponds to a sensitivity of 73.1% and a specificity of 62.5% in detecting either FCD or mMCD. Of the patients who had a radiographically occult FCD, 80% had either a continuous or rhythmic interictal abnormality described in the interpretation of their pre-operative VEEG. ConclusionThis study highlights the high prevalence of MCDs in refractory TLE and the high rate of missed MCDs on pre-operative MRI. Findings here suggest that pre-operative scalp EEG may be able to provide additional information in the pre-operative detection of MCDs and therefore inform surgical decision making.