Aetiopathogenesis of infantile epileptic spasms syndrome and mechanisms of action of adrenocorticotrophin hormone/corticosteroids in children: A scoping review

Emily A Innes; Velda X Han; Shrujna Patel; Michelle A Farrar; Deepak Gill; Shekeeb S Mohammad; Russell C Dale

doi:10.1111/dmcn.16273

Aetiopathogenesis of infantile epileptic spasms syndrome and mechanisms of action of adrenocorticotrophin hormone/corticosteroids in children: A scoping review

Dev Med Child Neurol. 2025 Aug;67(8):1004-1025. doi: 10.1111/dmcn.16273. Epub 2025 Feb 28.

Authors

Emily A Innes^{1

2}, Velda X Han^{1

3

4}, Shrujna Patel^{1

5}, Michelle A Farrar^{6

7}, Deepak Gill^{1

5

8}, Shekeeb S Mohammad^#^{1

5

8}, Russell C Dale^#^{1

5

8}

Affiliations

¹ Kids Neuroscience Centre, The Children's Hospital at Westmead, University of Sydney, NSW, Australia.
² Sydney Medical School, The University of Notre Dame Australia, Sydney, NSW, Australia.
³ Khoo Teck Puat-National University Children's Medical Institute, National University Health System, Singapore.
⁴ Yong Loo Lin School of Medicine, National University Singapore, Singapore.
⁵ Sydney Medical School, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia.
⁶ Neurology Department, Sydney Children' Hospital at Randwick, Sydney, NSW, Australia.
⁷ Discipline of Paediatrics, School of Women's and Children's Health, UNSW Medicine, The University of New South Wales, NSW, Australia.
⁸ TY Nelson Department of Neurology and Neurosurgery, The Children's Hospital at Westmead, Sydney, NSW, Australia.

^# Contributed equally.

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.

Publication types

Scoping Review
Review

MeSH terms

Adrenal Cortex Hormones* / pharmacology
Adrenocorticotropic Hormone* / metabolism
Child
Humans
Hypothalamo-Hypophyseal System
Infant
Spasms, Infantile* / drug therapy
Spasms, Infantile* / etiology
Spasms, Infantile* / metabolism
Spasms, Infantile* / physiopathology

Substances

Adrenocorticotropic Hormone
Adrenal Cortex Hormones

Grants and funding

APP1193648/Petre Foundation