Neuroendocrine aspects of catamenial epilepsy

Abstract

This article is part of a Special Issue "Hormones & Neurotrauma".

This review describes the neuroendocrinological aspects of catamenial epilepsy, a menstrual cycle-related seizure disorder in women with epilepsy. 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. Three types of catamenial seizures (perimenstrual, periovulatory and inadequate luteal) have been identified. The molecular pathophysiology of catamenial epilepsy remains unclear. Cyclical changes in the circulating levels of estrogens and progesterone (P) play a central role in the development of catamenial epilepsy. Endogenous neurosteroids such as allopregnanolone (AP) and allotetrahydrodeoxycorticosterone (THDOC) that modulate seizure susceptibility could play a critical role in catamenial epilepsy. In addition, plasticity in GABA-A receptor subunits could play a role in the enhanced seizure susceptibility in catamenial epilepsy. P-derived neurosteroids such as AP and THDOC potentiate synaptic GABA-A receptor function and also activate extrasynaptic GABA-A receptors in the hippocampus and thus may represent endogenous regulators of catamenial seizure susceptibility. Experimental studies have shown that neurosteroids confer greater seizure protection in animal models of catamenial epilepsy, especially without evident tolerance to their actions during chronic therapy. In the recently completed NIH-sponsored, placebo controlled phase 3 clinical trial, P therapy proved to be beneficial only in women with perimenstrual catamenial epilepsy but not in non-catamenial subjects. Neurosteroid analogs with favorable profile may be useful in the treatment of catamenial epilepsy.

Introduction

Epilepsy is one of the most common chronic neurological disorders characterized by the unpredictable occurrence of seizures that differ in type, cause, and severity. However, seizures do not occur randomly in many women with epilepsy. Seizure clusters occur with a temporal periodicity following circadian or lunar periodicity. In women with epilepsy, seizure periodicity may conform to the menstrual cycle according to a “menstrual clock” provided by a common phase marker of the onset of menses (Gowers, 1881). 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 is a multifaceted neuroendocrine condition in which seizures are most often clustered around perimenstrual or periovulatory period. Epilepsy affects an estimated 1.3 million women in the United States (Kaplan et al., 2007, Pennell, 2008). Catamenial epilepsy affects from 10 to 70% of women with epilepsy (Bazan et al., 2005, Gilad et al., 2008, Herzog et al., 2004, Reddy, 2009). The large variation in the 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-report, diaries, and other records of seizures relating to menses. Overall, these studies support the prevailing notion that at least 1 in every 3 women with epilepsy shows catamenial seizure exacerbation. Catamenial epilepsy is a form of intractable epilepsy because catamenial seizures are often quite resistant to available drug treatments. Presently, there is no effective prevention or cure for catamenial epilepsy. There is a large gap in our understanding of what changes occur in the brain in relation to the hormonal fluctuations associated with catamenial epilepsy and how these changes alter sensitivity to anticonvulsant drugs. Thus, a detailed understanding of the patterns and pathophysiology is essential for the development of rational approaches for the prevention or treatment of catamenial epilepsy.

Three types of catamenial seizures, perimenstrual (C1), periovulatory (C2), and inadequate luteal-phase (C3), have been identified (Herzog et al., 1997) (Fig. 1; Table 1). The perimenstrual type is the most common clinical type. Perimenstrual and periovulatory types are illustrated in Fig. 1. The specific pattern of catamenial epilepsy can be identified simply by charting menses and seizures and obtaining a mid-luteal phase serum progesterone (P) level to distinguish between normal and inadequate luteal phase cycles (Herzog et al., 2008, Quigg et al., 2009). The diagnosis of catamenial epilepsy is mainly based on the assessment of menstruation and seizure records (Foldvary-Schaefer and Falcone, 2003, Herzog, 2006). The simple approach of evaluation of catamenial epilepsy, that is, whether the patient's seizures tend to worsen at certain points of the menstrual cycle, is to record seizure diary in relation to menstrual cycle. Using the first day of menstrual bleeding as the first day of the cycle, the menstrual cycle is divided into four phases: (a) menstrual phase, days − 3 to + 3; (b) follicular phase, days + 4 to + 9; (c) ovulatory phase, days + 10 to + 16; and (d) luteal phase, days + 17 to − 4 (see Fig. 1). The number of seizures in each phase is counted for at least 2 cycles and a two-fold or greater increase in frequency during a particular phase of the menstrual cycle can be used as diagnostic criteria of catamenial epilepsy as demonstrated by a mathematical waveform (cosinor) analysis (Quigg et al., 2009).

In the primary clinical type, perimenstrual catamenial epilepsy (C1), women with epilepsy experience an increase in seizure activity before, during or after the onset of menstruation (Reddy, 2009). Catamenial epilepsy is observed in women with ovulatory or anovulatory cycles. Women with ovulatory cycles could experience either the perimenstrual or periovulatory catamenial types or even both within a single cycle (Bauer, 2001, Bauer et al., 1998). The diagnosis of ovulatory or anovulatory cycles is often made by estimating the midluteal phase P levels. P levels lower than 5 ng/ml during days 20 through 22 of the cycle would certainly indicate inadequate luteal phase. Subjects can be examined by pelvic-abdominal ultrasound to measure the size of mature graffian follicle as a sign of ovulation. About 16.5% of cycles in study subjects are found to be anovulatory (Herzog et al., 2004), and these women showed a third type, referred to as inadequate luteal-phase or anovulatory luteal seizures.

This review describes the neuroendocrinological aspects of catamenial epilepsy. It focuses on the role of hormones and GABA-A receptor-modulating neurosteroids in the pathophysiology of catamenial epilepsy. It also summarizes the promise of neurosteroid analogs as specific treatment for catamenial seizures in women with epilepsy.