Madison M. Berl

Objectives: Focal cortical dysplasia (FCD) is the most common etiology of drug‐resistant epilepsy in children. Focal to bilateral tonic–clonic seizures (FBTCS) mark a high risk of drug‐resistant epilepsy and involve thalamocortical circuitry in their generation and propagation. Using FCD as a model of focal epilepsy, we examined the integrity of thalamocortical circuitry to characterize thalamo‐lesional connectivity signatures of FBTCS. Methods: Forty‐three patients (14 with FBTCS) range 5–22 years, and 116 age‐ and sex‐matched healthy controls were included. A network‐driven thalamic functional parcellation was developed in healthy controls using Yeo 7‐network atlas. We calculated z ‐scored thalamo‐lesional functional connectivity between thalamic functional parcels and dysplasia masks in reference to controls, which was used to classify the presence of FBTCS. Clinical associations of thalamo‐lesional connectivity were evaluated. Results: Z ‐scored thalamo‐lesional connectivity classified the presence of FBTCS with a median accuracy of 0.72. The thalamic parcel preferentially connected to the somatomotor‐network (SMN), comprising ventral‐posterolateral, pulvinar‐medial and intralaminar nuclei, contributed most to classification. Lower ipsilateral SMN‐thalamus connectivity was related to postsurgical seizure freedom and preserved ipsilateral thalamic volume. Significance: Thalamocortical circuitry was examined between the seizure generator (lesion) and the amplifier (thalamus) in FCD patients. FBTCS are associated with thalamo‐lesional connectivity abnormalities that correlate to postsurgical outcomes, and demonstrate the SMN‐thalamus as a primary gatekeeper for secondary generalization. The successful implementation of our classifier suggests that these thalamo‐lesional signatures can serve as a potential neuromarker for seizure phenotyping, marking a step toward network‐informed, personalized treatment.

This study examined associations between neighborhood context (quality of resources/conditions important for healthy child development) and IQ in youth presenting for neuropsychological evaluations. Participants included 4,633 DC Metro Area youth (ages 2-22) who underwent neuropsychological evaluation. Neighborhood opportunity was assessed with the Child Opportunity Index (COI) 2.0 (Metro norms). Multiple regression analyses examined associations between COI and IQ and explored moderation of age, sex, and medical condition. Controlling for age, sex, and medical condition, neighborhood opportunity was positively associated with IQ, with the model accounting for approximately 10-14% of the variance in cognitive outcomes (full scale IQ: β = 0.198; verbal IQ: β = 0.202; non-verbal IQ: β = 0.148, p's < 0.001). Age moderated the association between COI and cognitive outcomes (full scale IQ: β = 0.005, p = 0.018; verbal IQ: β = 0.005, p = 0.043; non-verbal IQ: β = 0.005, p < 0.001) with stronger association at older ages. Cognitive outcomes were associated with educational (p < 0.01) and social/economic (p < 0.001) but not health/environmental opportunity (p = 0.553). Children living in higher opportunity neighborhoods showed higher performance on measures of IQ. A child's neighborhood resources (especially educational and social/economic) are an important consideration when interpreting cognitive performance of children. These findings support the need for advocacy to improve community resources as a path toward addressing inequities that may impact cognitive development.

Hypothalamic hamartomas (HH) are rare brain lesions associated with epilepsy and numerous comorbidities. Worldwide treatment is varied. There is a paucity of high-quality evidence to guide treatment. This study aimed to establish expert consensus on the evaluation and management of HH. A modified Delphi survey was designed by the Medical Advisory Board of Hope for Hypothalamic Hamartomas and was conducted among 17 International League Against Epilepsy level II epilepsy surgery centers. The survey included 257 questions in round 1 and 81 refined questions in round 2, covering domains of diagnosis, imaging, medical and surgical treatment, neuropsychological and psychiatric evaluation, and care. Consensus was defined as ≥75% agreement using a 9-point Likert scale. Consensus was achieved on 82% of the questions. Key findings include the following: Diagnosis: Gelastic and dacrystic seizures are strongly associated with HH; 3T epilepsy protocol MRI is essential. Evaluation: Preoperative neuropsychological and endocrinologic assessments are important. Evaluation with further imaging (PET, SPECT, and magnetoencephalography) and intracranial EEG is not useful. Treatment: No consensus was achieved on first-line, second-line, or third-line antiseizure medications (ASMs). Surgical evaluation should begin at the start of the first ASM, with surgery recommended after failure of 2 ASMs. LITT is preferred for Delalande II and III HH. Postoperative care: MRI follow-up at 6-12 months recommended. Preoperative and postoperative cognitive, behavioral, psychosocial, and endocrinologic evaluations are emphasized. Domains: IQ, language, attention, executive function, academic achievement, adaptive function, and behavior (tantrums, rage, anxiety, and depression) are important. This Delphi process highlights an international consensus on aspects of HH management. Gelastic/dacrystic seizures are important at diagnosis. A 3T epilepsy protocol MRI is essential. Early epilepsy surgery evaluation is advised. Surgery should be pursued either by disconnective, ablative, or resective techniques. HH location, size, and surgical experience are essential for good outcomes. Postoperative MRI should be obtained 6-12 months and/or if ongoing seizures. Neuropsychological testing should be obtained at baseline, and 6-12 months postsurgically. Findings support a multidisciplinary, protocol-driven approach to optimize outcomes in patients with HH. Areas lacking consensus, such as specific endocrine testing and timing of certain interventions, warrant further research and standardization.

Objective: Focal cortical dysplasia (FCD) is the most common cause of surgically treatable, drug‐resistant epilepsy in children. Anxiety and depression are frequent comorbidities in epilepsy. This study examined whether FCD overlap with large‐scale functional networks, the default mode network (DMN) and the limbic network, is associated with parent‐reported anxiety or depressive symptoms. Methods: Sixty‐nine patients with FCD‐related epilepsy completed the Child Behavior Checklist (CBCL), among whom 56 finished the 6 to 18 years version of CBCL (CBCL _6–18 ). FCD overlap (%) with Yeo 7‐networks was calculated. General linear models tested FCD _DMN or FCD _limbic overlap with CBCL Diagnostic and Statistical Manual of Mental Disorders – Fifth Edition (DSM)‐Anxiety Problems or DSM‐Depressive Problems Scores controlling for age and gender. Results: Fifty‐six patients had preoperative CBCL _6–18 (median age = 12.8 years, 55% male patients). FCD _DMN overlap (B = 0.08, 95% confidence interval [CI] = 0.002–0.16, partial η ² = 0.086, p = 0.045) and female gender were associated with higher DSM‐Depressive Problems T‐scores. This lesion‐network depressive‐symptoms effect was stronger in an adolescent‐only model (52% male patients): FCD _DMN overlap (B = 0.19, 95% CI = 0.068–0.32, partial η ² = 0.37, p = 0.004). Network overlap was not associated with DSM‐Anxiety Problems in any age group. Interpretation: FCD _DMN overlap is associated with increased depressive symptoms, particularly for adolescents, whereas FCD _limbic overlap is not. These findings underscore the importance of lesion‐network colocalization contributing to depression vulnerability in developmental epilepsy and highlight DMN colocalization involvement as a potential neurobiological marker of depressive risk. ANN NEUROL 2026;100:84–94

Objective: To assess long‐term safety of antiseizure medication (ASM) discontinuation after resolution of acute provoked neonatal seizures and prior to hospital discharge. Methods: Prospective, observational, comparative effectiveness cohort study of neonates with acute provoked seizures born from July 2015 to March 2018, and followed until September 2024, at nine U.S. Neonatal Seizure Registry centers with Level IV neonatal intensive care units and Level IV pediatric epilepsy programs. Duration of ASM treatment was quantified as (1) discontinuation before discharge from the neonatal seizure admission or (2) maintenance at the time of hospital discharge. Outcomes were adjusted for propensity to receive ASM at discharge. Propensity for ASM maintenance was defined among enrolled participants by a logistic regression model including seizure etiology, gestational age, therapeutic hypothermia, worst electroencephalography (EEG) background, days of EEG seizures, and discharge neurological exam (all p ≤ .1 in a joint model, except etiology, which was included for face validity). The primary outcome was non‐inferiority of cognition (Wechsler Preschool and Primary Scale of Intelligence assessed at age 5–6 years). Secondary outcomes were non‐inferiority of functional development (Vineland Adaptive Behavior Scale, 3rd Edition, assessed at 3–8 years) and post‐neonatal epilepsy (assessed at 1–8 years). Results: Among 284 children with at least one follow‐up, outcomes were similar in the discontinued vs maintained ASM groups for full‐scale IQ at age 5 years (adjusted difference +10 points), functional development at ages 3–8 years (adjusted difference 0 points), and post‐neonatal epilepsy at ages 1–8 years (adjusted hazard ratio .93, 95% confidence interval [CI] .48–1.80). Significance: Prolonged administration of ASM for several months after resolution of acute provoked neonatal seizures may expose infants to unnecessary medications. These results provide additional evidence for safety of discontinuing ASM for most neonates soon after the resolution of acute provoked seizures—a practice that is recommended in the International League Against Epilepsy (ILAE) guideline for neonatal seizure management.

Objective: Dravet syndrome (DS) is the prototypic developmental and epileptic encephalopathy, characterized by drug‐resistant seizures, developmental slowing, and many other morbidities. Detailed characterization of behavioral phenotypes and social–emotional skill development are limited. Methods: We prospectively assessed behavioral and social–emotional problems in the ENVISION natural history study (NCT04537832) of children with DS associated with SCN1A pathogenic variants ( SCN1A + DS) enrolled at p = .002). SDQ Hyperactivity scores worsened over time ( p = .013), whereas emotional difficulties remained stable. VABS‐3 Socialization domain scores, which were already more than 1 SD below the normative mean at baseline, decreased further, particularly in younger participants. Correlation analyses showed that poorer communication abilities were associated with increased problematic behaviors ( R = −.55 for CBCL Total Problems and VABS‐3 Communication scores). Mixed‐effects modeling identified age as the strongest predictor of worsening behavioral outcomes. Significance: We found that behavioral and social–emotional problems are inherent components of DS that present in toddlerhood and worsen throughout early childhood. This highlights the need to diagnose and manage these issues early. Targeted therapy may alleviate the wide‐ranging morbidities that are intrinsic to DS, including the social–emotional and behavior problems that frequently emerge.

Objective: Despite being safe and effective, surgery for pediatric epilepsy is underutilized. Social determinants of health (SDoH) are important to consider when examining this treatment gap. This study examined the potential systemic inequities at three different stages in the journey toward epilepsy surgery across the Pediatric Epilepsy Research Consortium (PERC). Methods: Any youth in the PERC prospective surgery database (≤18 years) was eligible and included if sociodemographic factors were also available. We examined if there were differences in disparity factors in: (1) referral to Phase I evaluation, (2) offering of surgery, and (3) completion of surgery. Results: Of 1309 patients, the majority were male (53%, p = .04), White (82.2%, p < .001), not Hispanic or Latino (84.3%, p < .001), and privately insured (56.3%, p < .001). Of the youth who were offered surgical treatment ( n = 1103, 84.3%), there were no significant differences in race/ethnicity or sex. Those with a structural lesion were more likely to be offered surgery, and historically marginalized youth were more likely to have a lesion. Of patients who completed surgery ( n = 927, 84.0%), White patients were 1.88 times (95% confidence interval [CI]: 1.14–3.04) more likely than Black patients to complete surgery ( p = .01). Significance: Youth who began surgery evaluation are not representative of the demographics of those with epilepsy in the United States, with greater representation of White, non‐Hispanic male individuals. In addition, youth who began surgery evaluation disproportionally have private insurance. At the next stage of offering surgery, there were no differences based on SDoH. However, there is evidence that underrepresented youth that were magnetic resonance negative were less likely to be referred for surgical workup and that Black youth were less likely to undergo surgery. Therefore, efforts to provide equitable opportunity for all youth with refractory epilepsy should be concentrated at the referral for surgery evaluation point of care; however, additional efforts are also needed at later stages.