Abstract
AIM: To review the aetiopathogenesis of infantile epileptic spasms syndrome (IESS) and mechanisms of action of adrenocorticotrophin hormone (ACTH)/corticosteroids established in humans. METHOD: MEDLINE, PubMed, and Embase were systematically searched from inception to December 2023 to identify studies related to IESS aetiology and treatment response. Mechanistic themes were identified and through consensus meetings refined and grouped into five overarching hypotheses. RESULTS: Five hypotheses were generated from 17 mechanistic themes: (1) gene and epigenetic regulation altering expression of 'vulnerability' genes; (2) stress and hypothalamic-pituitary-adrenal axis activation; (3) neuroinflammation and altered immune function; (4) altered neuronal transmission and pathways; and (5) dysfunction of metabolic pathways. INTERPRETATION: The evidence that ACTH/corticosteroids alter these processes remains limited. It is plausible that these processes interact with one another, rather than existing independently, and affect maturational and regulatory processes in the central nervous system, consistent with proposals that IESS is a neurodevelopmental disorder. Understanding how ACTH/corticosteroids work in IESS may facilitate disease-modifying treatments and improve neurodevelopmental outcomes.