How do the many etiologies of West syndrome lead to excitability and seizures? The corticotropin releasing hormone excess hypothesis

West syndrome (WS) is associated with diverse etiological factors. This fac t has suggested that there must be a 'final common pathway' for these etiol ogies, which operates on the immature brain to result in WS only at the mat urational state present during infancy. Any theory for the pathogenesis of WS has to account for the unique features of this disorder. For example, ho w can a single entity have so many etiologies? Why does WS arise only in in fancy, even when a known insult had occurred prenatally, and why does it di sappear? Why is WS associated with lasting cognitive dysfunction? And, impo rtantly, why do these seizures - unlike most others - respond to treatment by a hormone, ACTH? The established hormonal role of ACTH in human physiolo gy is to function in the neuroendocrine cascade of the responses to all str essful stimuli, including insults to the brain. As part of this function, A CTH is known to suppress the production of corticotropin releasing hormone (CRH), a peptide that is produced in response to diverse insults and stress ors. The many etiologies of WS all lead to activation of the stress response, in cluding increased production and secretion of the stress-neurohormone CRH. CRH has been shown, in infant animal models, to cause severe seizures and d eath of neurons in areas involved with learning and memory. These effects o f CRH are restricted to the infancy period because the receptors for CRH, w hich mediate its action on neurons, are most abundant during this developme ntal period. ACTH administration is known to inhibit production and release of CRH via a negative feedback mechanism. Therefore, the efficacy of ACTH for WS may depend on its ability to decrease the levels of the seizure-prom oting stress-neurohormone CRH. This CRH-excess theory for the pathophysiology of WS is consistent not only with the profile of ACTH effects, but also with the many different 'causes ' of WS, with the abnormal ACTH levels in the cerebrospinal fluid of affect ed infants and with the spontaneous disappearance of the seizures. Furtherm ore, if CRH is responsible for the seizures, and CRH-mediated neuronal inju ry contributes to the worsened cognitive outcome of individuals with WS, th en drugs which block the actions of CRH on its receptors may provide a bett er therapy for this disorder. (C) 2001 Published by Elsevier Science B.V.