Abstract
West syndrome (WS) is associated with diverse etiological factors. This fact has suggested
that there must be a ‘final common pathway’ for these etiologies, which operates on
the immature brain to result in WS only at the maturational state present during infancy.
Any theory for the pathogenesis of WS has to account for the unique features of this
disorder. For example, how can a single entity have so many etiologies? Why does WS
arise only in infancy, even when a known insult had occurred prenatally, and why does
it disappear? Why is WS associated with lasting cognitive dysfunction? And, importantly,
why do these seizures – unlike most others – respond to treatment by a hormone, ACTH?
The established hormonal role of ACTH in human physiology is to function in the neuroendocrine
cascade of the responses to all stressful stimuli, including insults to the brain.
As part of this function, ACTH is known to suppress the production of corticotropin
releasing hormone (CRH), a peptide that is produced in response to diverse insults
and stressors.
The many etiologies of WS all lead to activation of the stress response, including
increased production and secretion of the stress-neurohormone CRH. CRH has been shown,
in infant animal models, to cause severe seizures and death of neurons in areas involved
with learning and memory. These effects of CRH are restricted to the infancy period
because the receptors for CRH, which mediate its action on neurons, are most abundant
during this developmental 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-promoting 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 affected infants and with the spontaneous
disappearance of the seizures. Furthermore, if CRH is responsible for the seizures,
and CRH-mediated neuronal injury contributes to the worsened cognitive outcome of
individuals with WS, then drugs which block the actions of CRH on its receptors may
provide a better therapy for this disorder.
Keywords
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Article info
Publication history
Received in revised form:
June 11,
2001
Received:
May 8,
2001
Identification
Copyright
© 2001 Published by Elsevier Inc.
