ReviewThe role of neurosteroids in the pathophysiology and treatment of catamenial epilepsy
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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Molecular mechanisms of sex differences in epilepsy
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2021, Neuroscience LettersCitation Excerpt :Progesterone acts as an anticonvulsant agent through three primary mechanisms: negatively impacting glutamatergic (excitatory) transmission, binding to progesterone receptors (PRs), and metabolization to the inhibitory neurosteroid AP. [42,52,53]. This occurs through sequential A-ring reductions and allows AP to act as a positive allosteric modulator of GABAA receptors [39,45,54,55]. Progesterone is also metabolized to 5α-dihydroprogesterone, which is known to inhibit seizures.
The interactions between reproductive hormones and epilepsy
2021, Handbook of Clinical NeurologyCitation Excerpt :Also in studies in Purkinje cells from rat cerebellum both progesterone itself and several of its metabolites, including 3α-5α-THP, decreased glutamate responsiveness after either systemic or topical application (Smith et al., 1987a,b,c). Progesterone itself may act via genomic mechanisms to exert antiseizure effects and antagonize estradiol effects (Taubøll and Lindström, 1993; Reddy, 2009, 2018) (Fig. 11.1). Clinically, Bäckström et al. (1984) found that intravenous infusion of progesterone, sufficient to produce luteal phase serum levels, was associated with a significant decrease in interictal spike frequency in four of seven women with focal-onset seizures.
Seizure burden fluctuates with the female reproductive cycle in a mouse model of chronic temporal lobe epilepsy
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