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

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Summary

Catamenial 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 twofold 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.

Introduction

Epilepsy is one of the most common chronic neurological disorders characterized by the unpredictable occurrence of seizures. However, there is a form of epilepsy, called catamenial epilepsy, which does not adhere to this lack of pattern. Catamenial epilepsy, derived from the Greek word katomenios, meaning “monthly”, is characterized by seizures that cluster around specific points in the menstrual cycle (Fig. 1). Catamenial epilepsy affects from 10 to 70% of women with epilepsy (Dickerson, 1941, Rosciszewska, 1980, Tauboll et al., 1991, Duncan et al., 1993, Towanabut et al., 1998, Herzog et al., 2004, Gilad et al., 2008). The large variation in prevalence of catamenial epilepsy is partly because of methodological differences such as the criteria used for defining seizure exacerbation in relation to menstrual cycle, patients self-reporting, diaries, and other inaccurate records of seizures relating to menses (Duncan et al., 1993, Herzog et al., 2004, Bazan et al., 2005, El-Khayat et al., 2008). Despite such high incidence and increased awareness, there is no widely accepted definition of catamenial epilepsy.

Section snippets

Definition of catamenial epilepsy

Catamenial epilepsy is commonly defined as the cyclical increase in seizures around the time of menses or at other phases of the menstrual cycle. According to Duncan et al. (1993), catamenial epilepsy is defined based upon the criteria of having at least 75% of the seizures during a 10-day period of the menstrual cycle beginning 4 days before menstruation. In the seminal study, Herzog et al. (1997) defined catamenial epilepsy as a greater than average seizure frequency during perimenstrual or

Types of catamenial epilepsy

Studies on the frequency of catamenial epilepsy demonstrate the complexity of the condition and the difficulty in studying it. The need to develop better diagnostic tools of catamenial epilepsy and catamenial types has been widely recognized. Herzog et al. (1997) have described three distinct types of catamenial epilepsy: perimenstrual (C1), periovulatory (C2), and inadequate luteal-phase (C3) catamenial seizures (Table 1). However, these authors observed that the conventional perimenstrual

Association of catamenial seizures and epileptic syndromes

Catamenial seizures are more common among women with focal epilepsy, especially temporal lobe epilepsy, compared with those who have generalized epilepsy but it is associated with every epilepsy syndrome (Marques-Assis, 1981, Morrell, 1999, Foldvary-Schaefer and Falcone, 2003). Catamenial seizures are seen in women with idiopathic, cryptogenic or symptomatic epilepsy and in subjects showing focal and generalized seizures (El-Khayat et al., 2008). Catamenial seizures are observed in women who

Role of hormones and neurosteroids in catamenial epilepsy

Steroid hormones play a key role in the neuroendocrine control of neuronal excitability and brain function. As illustrated in Fig. 1, cyclical changes of ovarian hormones estrogens and progesterone are now widely believed to be important in the pathogenesis of catamenial epilepsy. Generally, progesterone is anticonvulsant, while estrogen is proconvulsant. There is emerging evidence that changes in endogenous neurosteroids, including those derived from adrenal steroid hormones and circulating

Animal models of catamenial epilepsy: implications for understanding the pathophysiology

Animal models of epilepsy play a key role in the characterization of pathophysiology and discovery of AEDs. Conventional seizure models, which are largely based on the utilization of acutely induced seizures in naive animals, are not suitable because they do not allow testing of specific therapies that are targeted to catamenial epilepsy. These models are clearly different from such models as kindling, pilocarpine or chronic kainic acid that induce severe damage and remodeling response in the

The hormonal and non-hormonal treatment of catamenial epilepsy

Presently there is no specific treatment for catamenial epilepsy. The conventional AEDs are the mainstay for the management of catamenial seizures in women. Approximately one third of women with epilepsy use more than one AED appropriate to their seizure type. This is partly because catamenial seizures are often refractory to conventional AEDs. Many of these drugs are prescribed for treatment of catamenial epilepsy without direct studies of effectiveness, with their use based primarily on

Neurosteroids

There is emerging evidence that neurosteroids represent a novel class of agents with potential utility in catamenial epilepsy therapy (Rogawski and Reddy, 2004). Neurosteroid allopregnanolone withdrawal-induced seizure susceptibility appears to simulate perimenstrual catamenial epilepsy (Reddy et al., 2001). During this seizure-prone state, the activity of conventional antiepileptic drugs, including diazepam and sodium valproate, is reduced in an animal model of catamenial epilepsy (Reddy and

Conclusions and future perspectives

Catamenial epilepsy is a multifaceted neuroendocrine condition. Although ovarian hormones play a central role, the exact cause of catamenial epilepsy is unknown. Experimental studies to this point have indicated a clear role of estrogen, progesterone and endogenous neurosteroids in the pathophysiology of the three types of catamenial epilepsy (see summary, Table 6). Whether there are abnormalities in hormonal dynamics that predispose to catamenial epilepsy is not known. There is emerging

Acknowledgement

This work was supported by U.S. National Institutes of Health (NIH/NINDS) grants NS051398 & NS052158 (to DSR).

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