BACKGROUND
Epilepsy of infancy with migrating focal seizures (EIMFS) is among the most severe developmental and epileptic encephalopathies (DEEs), marked by intractable multifocal seizures migrating across both hemispheres, profound developmental arrest, and high early mortality. Advances in next-generation sequencing have revealed a heterogeneous genetic architecture dominated by KCNT1 gain-of-function variants across more than 30 implicated genes, creating opportunities for precision therapeutics.
OBJECTIVE
To systematically map published evidence on the clinical, electrophysiological, neuroimaging, genetic, and therapeutic landscape of EIMFS, and to delineate critical knowledge gaps and future research priorities.
METHODS
A scoping review was conducted following the Arksey and O'Malley framework, searching PubMed, Ovid MEDLINE, Embase, Cochrane Library/CENTRAL, and ClinicalTrials.gov.
RESULTS
Of 643 articles screened, 89 met inclusion criteria. Beyond confirmation of the canonical electroclinical phenotype, several gaps emerged: neonatal versus post-neonatal onset stratification by genetic etiology remains largely uncharacterized; genotype-specific EEG biomarkers are lacking except for a single small KCNT1 study; and the clinical significance of atypical EEG features-including burst suppression and hypsarrhythmia-is undefined. Neuroimaging literature documents progressive cerebral atrophy and myelination abnormalities without quantitative volumetry, diffusion tractography markers, or attribution to seizure burden, medication effects, or underlying etiology. Genetic diagnostic yield was 70-80%, with KCNT1 accounting for 30-50% of solved cases; however, genotype-outcome stratification is limited. Seizures were broadly refractory; potassium bromide, ketogenic diet, cannabidiol, and quinidine (in KCNT1-confirmed cases) showed partial efficacy. Emerging precision approaches include sodium channel blockers for SCN2A gain-of-function variants, novel small molecules, fluoxetine, antisense oligonucleotides, and divalent siRNA targeting KCNT1. Systemic-to-pulmonary collateral circulation causing severe cardiopulmonary complications was reported across multiple cases, yet no consensus screening protocol exists.
CONCLUSIONS
EIMFS remains one of the most refractory epilepsy syndromes of infancy. Precision genetic diagnosis is essential to guide targeted therapy. International collaborative registries, standardized outcome measures, genotype-stratified biomarker studies, and rapid point-of-care genomic testing are urgently needed to advance evidence-based care for this highly vulnerable population.
Early infantile developmental and epileptic encephalopathy (EIDEE) is among the most severe epilepsy syndromes, with onset before three months of age and an estimated incidence of approximately 10 per 100,000 live births. The 2022 International League Against Epilepsy classification unified the historically distinct Ohtahara syndrome and early myoclonic encephalopathy under a single diagnostic framework defined by frequent drug-resistant tonic and/or myoclonic seizures, an abnormal neurological examination, and an abnormal interictal electroencephalogram-most characteristically a burst-suppression pattern. This narrative review synthesizes the clinical, electrophysiological, neuroimaging, genetic, and therapeutic literature within the EIDEE framework. The clinical phenotype is characterized by central hypotonia, postnatal microcephaly, cortical visual impairment, and age-dependent syndromic evolution toward infantile epileptic spasms syndrome or Lennox-Gastaut syndrome in the majority of patients. Electroencephalography remains essential for syndromic classification, while systematic metabolic screening and early trio whole-exome or whole-genome sequencing are central to the etiologic workup, achieving diagnostic yields of 60-65%. The most commonly identified genetic causes include STXBP1, KCNQ2, and SCN2A variants. Outcomes are poor overall and strongly etiology-dependent: vitamin-responsive disorders carry a substantially more favorable prognosis, whereas mortality reaches 25% in genetic cohorts. Genotype-guided pharmacotherapy is now applicable to a clinically meaningful subset of patients, with sodium channel blockers, potassium channel openers, and emerging antisense oligonucleotide therapies representing important therapeutic advances. Gene therapy trials are underway but have encountered early safety signals, underscoring the vulnerability of this population. Critical unmet needs include earlier molecular diagnosis, precision therapies targeting developmental outcomes beyond seizure control, and prospective international registries to characterize the long-term natural history of EIDEE.
Debopam Samanta· Brain & development (Tokyo....· 0 citations
OBJECTIVE
Surgery is an effective, yet underutilized treatment for children with drug-resistant epilepsy. Although predictors of surgical outcomes are well described, the decision to recommend surgery varies by institution. We aim to evaluate the rates of not recommending surgery, identify associated patient characteristics, and quantify variability across centers.
METHODS
We queried the Pediatric Epilepsy Research Consortium Surgery database, a prospective multicenter cohort of children (0-18 years) undergoing initial evaluation for epilepsy surgery. Patients with documented surgical decisions were included. Demographic, clinical, and presurgical evaluation variables were compared by surgical recommendation status. Logistic regression identified factors associated with not recommending surgery. Mixed-effects models quantified between-center variability.
RESULTS
Among 2480 patients across 29 centers, 532 (21%) were not recommended epilepsy surgery (median center rate 17%, interquartile range [IQR] 10%-28%). After accounting for patient characteristics associated with surgical candidacy, substantial variation in decision-making remained across centers, with a median twofold difference in the odds of not recommending surgery between otherwise similar patients evaluated at different institutions (Median Odds Ratio = 2.25; Intraclass Correlation Coefficient = .18). The clinical characteristics most strongly associated with not recommending surgery included monthly or less frequent seizures (odds ratio [OR] 2.17, 95% confidence interval [CI] 1.75-2.69), non-structural etiology (OR 2.02, 95% CI 1.56-2.61), and taking ≤2 anti-seizure medications (ASMs) (OR 1.67, 95% CI 1.34-2.08, all p's < .01). These characteristics showed minimal clustering across centers (ICCs < .05).
SIGNIFICANCE
One in five children evaluated for epilepsy surgery are not recommended to pursue surgical treatment. Although clinical factors influence decision-making, they do not explain the substantial variation in recommendations across pediatric epilepsy centers. Similar children evaluated at different institutions had significant differences in the odds of not being recommended surgery, suggesting that institutional decision-making contributes importantly to surgical candidacy.
A. Caraway, Nancy A Mcnamara, Andrew T. Knox et al.· Epilepsia· 0 citations
BACKGROUND AND OBJECTIVES
Despite its proven effectiveness, epilepsy surgery for drug-resistant epilepsy (DRE) remains underutilized and frequently delayed. Previous studies of epilepsy duration before surgery-using variable delay thresholds (2-20 years)-were small, single-center cohorts focused mainly on temporal/frontal lobe epilepsy, showed better seizure freedom with earlier surgery, but did not distinguish total epilepsy duration from DRE duration. As contemporary epilepsy surgery now includes broader indications and emphasizes faster evaluation, the timing and impact of evaluation across this wider population remain unclear. We examined factors associated with evaluation timing from DRE diagnosis and its effect on surgical outcomes in a large multicenter cohort.
METHODS
Using a prospective database across 29 US centers, we analyzed associations between patient and epilepsy factors and DRE-to-evaluation interval-defined as the interval from DRE diagnosis to phase 1 video-EEG admission, categorized as shorter (<1 year) or longer (≥1 year)-and compared seizure freedom between groups using multivariable logistic regression adjusted for etiology, seizure type, neuroimaging, and surgical factors.
RESULTS
Among 1,310 children, 720 (55%) had shorter and 590 (45%) longer DRE-to-evaluation intervals. Shorter interval was associated with lesional epilepsy (OR 1.65, 95% CI 1.30-2.08), focal seizures (2.80, 2.13-3.70), and normal neurologic exams (1.86, 1.49-2.33). Structural congenital and acquired etiologies were linked to shorter interval, while genetic etiologies (1.73, 1.30-2.32) were linked to longer interval. Among 624 surgical patients (357 shorter, 267 longer), seizure freedom occurred in 53% vs 27% (3.04, 2.17-4.29; p < 0.01). After adjustment, longer interval remained independently associated with lower seizure freedom (0.59, 0.35-1.00; p = 0.0497). DRE-to-evaluation interval, not total epilepsy duration, predicted outcomes.
DISCUSION
In this first large multicenter study across diverse epilepsy types applying a 1-year benchmark, nearly half of pediatric patients experienced delays, particularly those with MRI-negative, generalized, or genetic epilepsies. Delays from DRE diagnosis were independently associated with reduced seizure freedom, supporting presurgical evaluation within 1 year as an evidence-based quality benchmark.
Debopam Samanta, A. Caraway, Andrew T. Knox et al.· Neurology Clinical Practice· 0 citations
A comprehensive narrative review of studies indexed in PubMed/MEDLINE, Embase, Cochrane Library, ClinicalTrials.gov, and American Epilepsy Society proceedings through January 2026 positions STXBP1-RD as a leading test case for precision medicine in DEEs.
A rapidly advancing precision-therapy pipeline-including antisense oligonucleotides to upregulate the intact allele, AAV-based gene replacement, CRISPR-mediated transcriptional activation, epigenetic modulators, and rational pathway-targeted small molecules-offers realistic prospects for disease modification.