Anup D. Patel

Rapid advances in disease-modifying therapies (DMTs) for epilepsy, including gene-based therapies, antisense oligonucleotides, and stem cell-derived approaches, are reshaping the treatment landscape. As these therapies move through clinical trials and toward regulatory review, they introduce complex clinical, operational, ethical, and equity considerations that extend well beyond traditional antiseizure medication management. Successful integration will require careful attention to patient selection, genetic and biomarker testing, multidisciplinary care models, infrastructure readiness, referral pathways, long-term safety monitoring, informed consent for novel and potentially irreversible interventions, access to clinical trials, and cost and reimbursement challenges. Significant investments in personnel, systems, and facilities may be necessary, raising important questions about implementation across diverse practice settings and the risk of widening disparities in care. Here, we review the evolving therapeutic pipeline and outline key considerations for safe, ethical, and equitable implementation.

Objective: Lennox–Gastaut Syndrome (LGS) is a severe developmental and epileptic encephalopathy characterized by multiple seizure types, cognitive impairment, and distinct electroencephalographic (EEG) findings. However, evolving diagnostic criteria, heterogeneous clinical features, and inconsistent electronic health record (EHR) documentation complicate accurate diagnosis and cohort identification. As part of a Patient‐Centered Outcomes Research Institute‐sponsored study developing EHR‐based computable phenotypes for LGS, we established a reference standard through retrospective chart review and epileptologist classification. Methods: A multicenter retrospective chart review was conducted across seven pediatric epilepsy centers. Stratified sampling using PCORnet data selected patients based on the International Classification of Diseases, 10th Revision diagnosis code for LGS or other intractable epilepsy diagnoses between 2016 and 2022. Clinical teams abstracted seizure history, EEG findings, developmental status, and treatment history. Two epileptologists independently reviewed each case as classic LGS, pragmatic LGS, or not LGS. Discordant cases underwent adjudication by a senior epileptologist. Cases with incomplete or unclear data underwent repeat abstraction and review. Results: Of 997 identified patients, 935 underwent classification after exclusions. Initial epileptologist disagreement occurred in 105 cases (11%, unweighted Cohen kappa = 82%). Following adjudication, 130 cases underwent reabstraction to retrieve additional EEG reports and clinical details. Rereview reclassified 67 cases initially considered “not LGS”: 33 classic LGS, 12 pragmatic LGS, and 22 excluded for insufficient data. Key EHR challenges included inconsistent EEG reporting, incomplete seizure type characterization, fragmented documentation of cognitive impairment, unclear age at onset, and variable terminology across institutions and providers. Slow spike‐and‐wave EEG findings were the most frequently missing diagnostic element. Significance: Validating LGS diagnoses using EHR data is complex and resource intensive. Standardized terminology, structured documentation, and rigorous multicenter validation may improve diagnostic accuracy, research cohort identification, computable phenotype development, and longitudinal care for individuals with LGS. Our results highlight important operational lessons for multicenter rare epilepsy studies and underscore the need for improved diagnosis pathways and longitudinal care systems for those with LGS and their families.

Consumer wearable devices are commonly used by patients and consumers for several reasons with increasing application as new technologies are developed. Use of these devices is an emerging issue in Neurology because of increased adoption and the additional data reported to providers by patients. Understanding of possible functions, limitations, and effect on patients of non-US Food and Drug Administration (FDA)-cleared wearable technology to inform neurologic care is needed. A common theme in people with neurologic conditions regarding consumer wearables and associated tracking applications is that there is significant promise in these tools, but adherence (days per use/per week), continued engagement (attrition), and unintended consequences such as heightened anxiety remain important issues. Further understanding and validation of these devices is needed within the field of Neurology before full use and confidence can be achieved. Below, we provide examples of non-FDA-cleared wearable devices used in Neurology in the areas of epilepsy, headache, cardiac monitoring, and sleep.

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: Nonadherence to antiseizure medications in pediatric epilepsy affects ~60% of youth. The aim of this multisite two‐stage sequential, multiple assignment, randomized trial (SMART) was to evaluate the effectiveness of mHealth intervention strategies for improving adherence in caregivers of young children with epilepsy, particularly those who are underserved. It was hypothesized that participants initially randomized to treatment would exhibit significantly greater improvements in adherence compared to an active control group at the end of stage 1. Secondary outcomes included longitudinal adherence, seizure freedom/severity, and health‐related quality of life. Methods: Participants across four epilepsy centers were recruited ( n = 461, mean age = 7.6 ± 3.0 years, 51% males, 62% White non‐Hispanic, 71% underserved). Baseline questionnaires were completed, and electronic adherence monitors were provided. Three intervention strategies were embedded in this SMART: (1) active control (mHealth education + automated digital reminders), (2) treatment (mHealth education + automated digital reminders + individualized adherence feedback) in stage 1 continuing in stage 2 regardless of responsiveness in stage 1, and (3) treatment in stage 1 continuing in stage 2 if patient is responsive in stage 1 or augmented by problem‐solving if patient is nonresponsive in stage 1. Active intervention was 5 months, with two posttreatment follow‐ups. Standard analysis of covariance was conducted for the primary aim. Secondary analyses compared mean change from baseline associated with each intervention strategy. Results: The treatment group had significantly better mean adherence percentage change from baseline to the end of stage 1 compared to the active control group (13.2% vs. 3.1% change, t = 2.82, p = .005, d = .37). Adherence rates declined over time across all SMART strategies. An increased probability of seizure freedom at 6 and 12 months across all SMART strategies was found. Significance: This pediatric epilepsy SMART trial demonstrated adherence improvements for the treatment group that did not persist over time. Improvements in seizure freedom that were independent of SMART strategy were also identified. mHealth education, automated digital reminders, and individualized adherence feedback appear to have been efficacious.

Approximately one-third of children with epilepsy develop intractable epilepsy and require multiple-day hospital admission for EEG and neuroimaging to determine other interventions for seizure reduction (Phase 1). Of note, children with epilepsy are at increased risk of autism spectrum disorder (ASD); however, prolonged hospitalization may be difficult due to developmental delays, sensory sensitivities, and challenging behavior. Challenging behavior during or reluctance to complete admission may lead to delayed or incomplete information about seizures and interfere with treatment. To address this need, we created a multidisciplinary team and a novel program, the Phase 1 ASD and epilepsy intervention program. We used quality improvement (QI) methodology, and our aim was to increase the percentage of patients with ASD and epilepsy who participated in a treatment program before Phase 1 admission from 0% to 80% in the first year. Participants included children with ASD and epilepsy who were referred for Phase 1 at a large children's hospital with a level 4 epilepsy center. After referral, caregivers were called to complete an intake and gather information about the child's development, preferences, and needs for admission. The program includes individualized planning for admission based on the child's needs, team communication about patient characteristics and needs, and behavior intervention. The intervention was implemented and monitored using QI methodology. All children with ASD referred for Phase 1 were enrolled in the program, and we achieved a centerline shift in the first 2 years, which has been sustained for 5 years (68 of 81 participants, 83.9%). The age of patients ranged from 2 to 18, with a mean age of 10.7 years. Seventy percent were male, and 66.7% were White. All children who participated completed the multiple-day EEG and all required medical procedures. Our work demonstrates the feasibility of the program, which is now standard of care at our hospital. Similar interventions can be implemented for Phase 2 admissions or other medical procedures. Children with ASD who participate in a multidisciplinary intervention program can successfully complete potentially challenging hospital admissions, allowing them equitable access to critical care.