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

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.

Fig. 1

The neuroendocrine (A) and limbic (B), stress-activated CRH–ACTH-steroid loops. (A) Stress-conveying signals rapidly activate CRH-expressing neurons of the central nucleus of the amygdala (ACe). Rapid CRH release in the ACe activates CRH-expression in the hypothalamic paraventricular nucleus (PVN) to secrete CRH into the hypothalamo-pituitary portal system, inducing ACTH and glucocorticoid (steroid) secretion from the pituitary and adrenal, respectively. Steroids exert a negative feedback on the production of CRH in the hypothalamus (directly and via the hippocampus), yet activate CRH gene expression in the amygdala, potentially promoting further CRH release and seizure-promoting actions in this region. (B) CRH-expressing GABAergic interneurons (dark cells) in the principal cell layers of the hippocampal CA1, CA3 and the dentate gyrus (DG) are positioned to control excitability of the pyramidal and granule cells, respectively. These neurons may be influenced by stress-evoked release of CRH from the ACe, via connections in the entorhinal cortex. For both panels, thick and thin arrows denote established or putative potentiating and inhibitory actions, respectively. Arrows do not imply mono-synaptic connections. (Modified and published with permission, from Baram and Hatalski [15]).