The role of neurosteroids in the pathophysiology and treatment of catamenial epilepsy

Abstract

SUMMARYCatamenial epilepsy is a multifaceted neuroendocrine condition in which seizures are clustered around specific points in the menstrual cycle, most often around perimenstrual or periovulatory period. Generally, a two-fold or greater increase in seizure frequency during a particular phase of the menstrual cycle could be considered as catamenial epilepsy. Based on this criteria, recent clinical studies indicate that catamenial epilepsy affects 31 -60% of the women with epilepsy. Three types of catamenial seizures (perimenstrual, periovulatory and inadequate luteal) have been identified. However, there is no specific drug available today for catamenial epilepsy, which has not been successfully treated with conventional antiepileptic drugs. Elucidation of the pathophysiology of catamenial epilepsy is a prerequisite to develop specific targeted approaches for treatment or prevention of the disorder. Cyclical changes in the circulating levels of estrogens and progesterone play a central role in the development of catamenial epilepsy. There is emerging evidence that endogenous neurosteroids with anticonvulsant or proconvulsant effects could play a critical role in catamenial epilepsy. It is thought that perimenstrual catamenial epilepsy is associated with the withdrawal of anticonvulsant neurosteroids. Progesterone and other hormonal agents have been shown in limited trials to be moderately effective in catamenial epilepsy, but may cause endocrine side effects. Synthetic neurosteroids, which enhance the tonic GABA-A receptor function, might provide an effective approach for the catamenial epilepsy therapy without producing hormonal side effects.

Development and Persistence of Limbic Epileptogenesis Are Impaired in Mice Lacking Progesterone Receptors

“…Relative seizure resistance in mice lacking PRs or finasterideinduced increase in seizure susceptibility in WT mice is consistent with such dual pathways. These mechanisms may be relevant to the pathophysiology of catamenial epilepsy (Scharfman and MacLusky, 2006;Reddy, 2009;Gangisetty and Reddy, 2010).…”

“…Women with epilepsy are prone to seizures in response to decreased levels of P during perimenstrual periods (Herzog et al, 1997;Reddy, 2009). However, the molecular mechanism of action of P in seizure activity is not fully understood.…”

A Mouse Kindling Model of Perimenstrual Catamenial Epilepsy

“…It is a multifaceted neuroendocrine condition attributed to numerous causes. There is growing evidence from animal experiments suggesting that enhanced seizure susceptibility in perimenstrual catamenial epilepsy is caused by the withdrawal of the progesterone-derived neurosteroids as a result of the fall in progesterone at the time of menstruation (Reddy, 2009;Pack et al, 2011). In women, there is evidence for seizure exacerbation after the inadvertent inhibition of neurosteroid synthesis (Herzog and Frye, 2003).…”

Action of adrenal and gonadal steroid hormones on kainic acid-evoked seizures in a rat model of epileptogenesis

“…The present data showed that treatment with estradiol intensified the convulsive syndrome triggered by kainic acidchallenge in the adrenalectomized and castrated male rats. Similar proconvulsant action of estradiol in castrated female rats has been reported elsewhere [24]. It is well known that estradiol could stimulate glutamate release and inhibit GABA synthesis, which is most likely the principal mechanism of its pro-convulsive action.…”