Medicina (Kaunas). 2025 Dec 16;61(12):2223. doi: 10.3390/medicina61122223.
ABSTRACT
Background and Objectives: Infantile spasms (ISs), or West syndrome (WS), represent an early-onset epileptic encephalopathy in which diverse structural, genetic, metabolic, infectious, and neurocutaneous conditions converge on a shared pattern of hypsarrhythmia, clustered spasms, and later developmental impairment. Growing use of genomic diagnostics has revealed that variants in STXBP1, KCNQ2, GRIN2A, GRIN2B, and TSC-related genes are more common than previously recognized and can be linked to partially actionable pathways. This review aimed to synthesize current evidence on the multifactorial etiology, network-based pathogenesis, and evolving targeted therapies for ISs, with particular attention to TSC-related forms. Materials and Methods: A structured narrative review was undertaken of publications from 1990 to 2025 in PubMed, Scopus, Web of Science, and Embase using terms related to ISs, WS, genetics, mTOR, ACTH, vigabatrin, ketogenic diet, and precision therapies. Authoritative guidance from ILAE and AAN was incorporated. Clinical, molecular, and therapeutic data were grouped under etiological, pathogenetic, and management domains. Results: Structural causes remained the largest group, but combined genetic, genetic-structural, and metabolic etiologies accounted for about one third of contemporary cohorts. Early network disruption involving cortex, thalamus, basal ganglia, and brainstem, together with imbalances in NGF, BDNF, and IGF-1, explained why distinct primary insults produce a uniform electroclinical phenotype. Early treatment with ACTH or high dose prednisolone, with or without vigabatrin, was consistently associated with higher electroclinical remission and better developmental outcome. Everolimus and related mTOR inhibitors showed benefit in TSC-associated ISs, while agents directed at NMDA receptors or KCNQ channels are emerging for genotype defined subgroups. Conclusions: ISs should be approached as a heterogeneous but mechanistically convergent disorder in which rapid diagnosis, parallel genetic testing, and early disease modifying therapy improve prognosis. Integration of molecular profiling with standardized outcome monitoring is likely to move management from symptomatic seizure control to pathway-specific intervention.
PMID:41470225 | PMC:PMC12734430 | DOI:10.3390/medicina61122223
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