Several investigators have explored the relationship between these life epochs and epilepsy. Rosciszewska49 was the first clinician to suggest a relationship between menopause and a change in seizure pattern. Abbasi et al.50 performed a questionnaire study on their population of perimenopausal and menopausal women with epilepsy and found that 41% (20 out of 49) of women reported a worsening of seizures as they became menopausal.
Harden et al.51 studied the course of epilepsy specifically during menopause and perimenopause. Perimenopause was defined as the onset of irregular menses with or without "hot flashes," and natural menopause was defined as at least 1 year without menstruation. In this study, perimenopause was associated with an increase in seizures in the majority of subjects. A reported history of a catamenial seizure pattern was significantly associated with seizure increase during perimenopause. A catamenial seizure pattern was defined in this study as an exclusively premenstrual and/or midcycle (ovulatory) seizure increase.52
Of the menopausal women with epilepsy, one-third of subjects each reported an increase, a decrease, or no change in their seizure frequency after the cessation of menses. Notably, subjects who reported a catamenial pattern during their reproductive years were significantly more likely to have a decrease in seizures during menopause, implying that the seizure-producing influence of reproductive hormonal cycling had subsided.
Remarkably, these findings have a clear neuroendocrine explanation, based on the excitatory action of estrogen in the brain, and an inhibitory action of progesterone. Although estrogen levels decline as ovarian function diminishes, progesterone declines before estrogen, with resulting elevation of the serum ratio of estrogen to progesterone.53,54 Early in the perimenopause, for example, anovulatory cycles may develop and lead to increased ratios of estrogen to progesterone, which would be expected to promote the occurrence of seizures, as was reported. Later, however, estrogen production by the ovaries may become essentially undetectable, with a potentially beneficial effect on seizures.
These findings indicate that women with epilepsy who have a hormonal influence on seizure occurrence during their cycling years may also be particularly affected by hormonal changes during perimenopause and menopause. During perimenopause, seizure increase may be expected, especially for those women with a history of a catamenial seizure pattern. During menopause, a history of a catamenial seizure pattern may indicate the potential for seizure decrease.
Estrogen replacement therapy is often considered the treatment of choice for preventing osteoporosis and maintaining bone health in menopausal women.55-58 Practically speaking, since the recent WHI report showing an increased risk of breast cancer after 5 years of treatment, hormone replacement therapy (HRT) is most frequently prescribed for brief periods to treat symptoms of estrogen withdrawal, especially hot flashes and atrophic urogenital changes.59,60
In the study by Harden and colleagues,51 a significant proportion of menopausal and perimenopausal women with epilepsy reported that HRT, either estrogen alone or combined with progesterone, produced an increase in seizures or auras. Therefore, although it seems that many menopausal women with epilepsy have taken HRT safely, it may adversely affect seizures for some patients.
The age of menopause and perimenopause may also be influenced by epilepsy. Klein et al. reported a significant risk of early onset of perimenopause in women with epilepsy compared to controls, as measured by symptom report and serum hormone levels.61 This increased risk was found in women with both primary generalized epilepsy and localization-related epilepsy.
A recent study of 68 menopausal women with epilepsy found that women with high seizure frequency (several seizures monthly) experienced menopause at an early age, with cessation of menses occurring at 46 to 47 years. Menopause occurred approximately 3 years later for women with well-controlled epilepsy, even when factors that produce early menopause, such as smoking, were controlled for. Type or duration of antiepileptic drug use did not influence this result.62
Therefore, high seizure frequency may be associated with an age of menopause as much as 4 to 5 years earlier than the population normative menopausal age of 51 years. These findings suggest that central nervous system factors are most important in the relationship of epilepsy to menopause, although a direct effect of epilepsy on the ovaries could also be occurring.
Revised April 2004 by Cynthia Harden, MD, Weill Cornell Medical College.
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