Cognitive and behavioral impact of antiseizure medications, neuromodulation, ketogenic diet, and surgery in lennox-gastaut syndrome: A comprehensive review

Epilepsy & Behavior, Journal Year: 2025, Volume and Issue: 164, P. 110272 - 110272

Published: Jan. 23, 2025

Language: Английский

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Expanded clinical phenotype spectrum correlates with variant function in SCN2A-related disorders

Brain, Journal Year: 2024, Volume and Issue: 147(8), P. 2761 - 2774

Published: April 23, 2024

Abstract SCN2A-related disorders secondary to altered function in the voltage-gated sodium channel Nav1.2 are rare, with clinically heterogeneous expressions that include epilepsy, autism and multiple severe profound impairments other conditions. To advance understanding of clinical phenotypes their relationship function, 81 patients (36 female, 44%, median age 5.4 years) 69 unique SCN2A variants were systematically phenotyped assessed. Participants recruited through FamileSCN2A Foundation. Primary phenotype (epilepsy neonatal onset, n = 27; infant 18; later onset 24; without seizures, 12) was strongly correlated a non-seizure severity index (P 0.002), which based on presence gross motor, fine communication abilities, gastrostomy tube dependence diagnosis cortical visual impairment scoliosis. Non-seizure greatest neonatal-onset group least 0.002). Children lowest indices still severely impaired, as reflected by an average Vineland Adaptive Behavior composite score 49.5 (>3 standard deviations below norm-referenced mean test). Epileptic spasms significantly more common infant-onset (67%) than (22%) or later-onset (29%) epilepsy 0.007). also variant < 0.0001); gain-of-function mixed predominated shifting moderate loss complete groups. Exploratory cluster analysis identified five groups, representing: (i) primarily loss-of-function low indices; (ii) mostly but higher (iii) late-onset only, (mostly zero) severe/complete variants. Two exclusively clusters distinguished from each largely scores secondarily function. The between primary emphasizes role developmental factors differential expression effects depends combination at seizure (primary phenotype) As precision therapies for towards trials, knowledge disease will be valuable identifying appropriate these trials selecting efficient outcomes.

Language: Английский

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Clinical trials for Lennox–Gastaut syndrome: Challenges and priorities

Annals of Clinical and Translational Neurology, Journal Year: 2024, Volume and Issue: 11(11), P. 2818 - 2835

Published: Oct. 23, 2024

Abstract Objective: Lennox‐Gastaut syndrome (LGS) is a severe, childhood‐onset epilepsy that typically refractory to treatment. We surveyed the current landscape of LGS treatment, aiming identify challenges development efficacious therapies, and articulate corresponding priorities toward clinical trials improve outcomes. Methods: The Special Interest Group Pediatric Epilepsy Research Consortium integrated evidence from literature expert opinion, into narrative review. Results: provide an overview approved emerging medical, dietary, surgical neuromodulation approaches for LGS. note quality care could be improved by standardizing treatment based on consensus empirical data. Whereas natural history incompletely understood, prospective studies use large retrospective datasets understand across lifespan would enable address these dynamics. Recent discoveries related pathophysiology should disease‐modifying which are currently lacking. Finally, have focused chiefly seizures involving “drops,” but incorporate additional patient‐centered outcomes, using measures adapted people with Interpretation: Clinicians researchers enact priorities, goal tailored history.

Language: Английский

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FDA Patient-Focused Drug Development Guidances

Neurology, Journal Year: 2023, Volume and Issue: 102(1)

Published: Dec. 15, 2023

Developmental and epileptic encephalopathies (DEE) are rare, often monogenic neurodevelopmental conditions. Most affected individuals have refractory seizures. All multiple severe impairments which can be as life-limiting or more limiting than the seizures themselves. Mechanism- gene-targeted therapies for these individually genetic conditions hold hope treatment, amelioration of disease expression, even cure. The near absence fit-for-purpose (FFP) clinical outcome assessments (COA) to establish benefits nonseizure outcomes new in trials poses significant challenges drug development. Food Drug Administration Patient-Focused Development guidance series provides direction how overcome ensure FFP measures available trials. goal is that address importance patients caregivers, reliably accurately measure spectrum abilities target disease, sensitive meaningful change over time. guidances identify 3 primary strategies: (1) directly adopting implementing measures; (2) creating de novo; (3) a middle path adapting modifying existing measures. Emphasized throughout indispensable extensive role patient caregiver assuring having fit achieved. This review specifically considers difficulties COAs severely impaired groups ways adapt modify encouraged guidances. Adaptations include alternative scoring, use out-of-intended age ranges, modifications with sensory motor impairments. Some additional considerations may facilitate achieving adequate measures, especially rare diseases, personalized endpoints, merging COAs, developing consortium DEE advocates researchers fitness adapted across groups. FDA help targeting outcomes, populations, will adequately valid turn strengthen ability provide informative tests whether treatments therapeutic efficacy.

Language: Английский

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Operational definition of developmental and epileptic encephalopathies to underpin the design of therapeutic trials

Epilepsia, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 27, 2025

Abstract Developmental and epileptic encephalopathies (DEEs) are the most severe group of epilepsies, characterized by drug‐resistant seizures developmental slowing or regression. DEEs encompass many epilepsy syndromes, although not all patients with a DEE can be classified into specific syndrome. Our understanding etiologies has been revolutionized next‐generation sequencing, more than 900 genes implicated, in addition to structural causes. It is therefore now possible consider precision medicine novel therapeutic approaches for these devastating diseases trials repurposed new drugs, including gene therapies. Trials being designed target either broadly, genetic DEEs. To serve this purpose, clear operational definition needed ensure that appropriate selected precisely defined, targeted outcome measures. Herein we propose set stage development

Language: Английский

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Dravet syndrome: From neurodevelopmental to neurodegenerative disease?

Epilepsia, Journal Year: 2025, Volume and Issue: unknown

Published: March 4, 2025

Abstract Objective Dravet syndrome (DS) is a severe developmental and epileptic encephalopathy caused by SCN1A haploinsufficiency in the majority of cases. Caregivers adults with DS often complain about loss previously acquired skills. We set out to explore these perceptions determine whether abnormalities reported were detectable validated tests. also investigated possible correlations between symptoms, age, exposure sodium channel blockers (SCBs). Methods This cross‐sectional, multicenter study used Vineland Adaptive Behavior Scales, 3rd edition (raw scores) for behavior analyses Moss–Psychiatric Assessment Schedules checklist screen psychiatric symptoms. The Social Communication Questionnaire screened social communication deficits. Parkinsonian features evaluated modified Unified Parkinson's Disease Rating Scale. For gait evaluation, we use home videos, using instrumental analysis subgroup patients, then videos remainder. Results A total 92 patients enrolled (age range = 18–51 years, mean 27.93 ± 8.59 years). Sixty percent caregivers observed decline skills, including intelligence, speech, interaction others, ability climb stairs walk without support, hand coordination. parkinsonian worse older those exposed SCBs longer periods time. Fourteen positive affective disorders, 11.6% dementia, 10.5% psychotic disorder. Fifty‐three Significance largest group be systematically evaluated. They had nonseizure Older age associated adaptive gait, parkinsonism. Some depression dementia. identified functional activities daily living (ADLs). Taken together, risk perform mastered ADLs support that some may developing neurodegenerative

Language: Английский

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Gross Motor Function in Individuals With SCN2A-Related Disorders

Neurology Clinical Practice, Journal Year: 2025, Volume and Issue: 15(3)

Published: May 2, 2025

SCN2A-related disorders (RDs) are genetic conditions characterized by severe to profound impairments in multiple domains including gross motor function, which could serve as a nonseizure outcome precision medicine therapy trials. This study evaluated specific properties of the Vineland Adaptive Behavior Scales-3 (VABS3) and other assessments for their fitness use trials SCN2A-RDs. Sixty-five families recruited through FamileSCN2A foundation enrolled affected children ("participants," 28 female, median age 6.4 years, interquartile range [IQR] 4.1-10.5) 1-year, longitudinal study. Assessments were administered at 0 (study entry), 6, 12 months. included VABS3, Assessment System 0-5 years (ABAS), modified Functional Mobility Scale (FMS), Activities Questionnaire-Walking Level (FAQ-WL). The VABS3 composite score (34 [IQR 26-46]) indicated overall adaptive function >4 SDs below normative mean. Forty percent participants aged 2 or older required wheelchairs home distances, 28% not take any steps. standardized scores (SSs) domain (20 20-32]) subdomain (1 1-2]) reflected performance floor measures. Standardized discriminated poorly among with different levels mobility (FAQ-WL FMS) markers diseases severity (presence epilepsy, history epileptic spasms, number seizure medications). Cross-sectionally, SSs declined increasing age. By contrast, raw ABAS growth scale values (GSVs) had relatively little effects. They distinguished well between based on FAQ-WL FMS those disease markers. Test-retest inter-rater reliability all excellent. No changed significantly over time analyses. Gross people SCN2A-RDs is so severely impaired that it cannot be adequately measured norm-referenced (standardized) scores. GSVs alternative scoring used out intended have superior promising psychometric features this group, they should considered future similarly severe, rare disorders.

Language: Английский

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What does better look like in individuals with severe neurodevelopmental impairments? A qualitative descriptive study on SCN2A-related developmental and epileptic encephalopathy

Quality of Life Research, Journal Year: 2023, Volume and Issue: 33(2), P. 519 - 528

Published: Dec. 8, 2023

There are limited psychometric data on outcome measures for children with Developmental Epileptic Encephalopathies (DEEs), beyond measuring seizures, and no to describe meaningful change. This study aimed explore parent perceptions of important differences in functional abilities that would guide their participation clinical trials.

Language: Английский

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Adapting a measure of gross motor skills for individuals with CDKL5 deficiency disorder: A psychometric study

Epilepsy Research, Journal Year: 2024, Volume and Issue: 200, P. 107287 - 107287

Published: Jan. 18, 2024

Language: Английский

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ENVISIONing a critical period to preserve development: communication delays in SCN1A+ dravet syndrome

Epiliepsy currents/Epilepsy currents, Journal Year: 2024, Volume and Issue: 24(5), P. 342 - 344

Published: Oct. 1, 2024

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Language: Английский

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