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EEC 2022 | The influence of the ovarian cycle on seizure severity in epilepsy

Bruna Nucera, MD, Hospital of Merano, Merano-Meran, Italy, discusses the influence of the ovarian cycle on seizure occurrence. Reproductive health and epilepsy are tightly intertwined, in both men and women. Catamenial epilepsy, defined as a pattern of seizures that changes in severity during particular phases of the menstrual cycle, is seen in as many as 60% of all women with epilepsy. Seizures get more severe or more frequent during certain times of their cycle, commonly perimenstrually (C1 pattern), at ovulation (C2 pattern), or during the luteal phase (C3 pattern). Estradiol and progesterone are the major players underlying catamenial epilepsy, exerting pro-convulsant and anti-convulsant influences, respectively. Current treatment practices include the use of pulsed hormonal (e.g. progesterone) and non-hormonal treatments (e.g. clobazam). Dr Nucera explains how alterations in gonadotropin-releasing hormone (GnRH) secretion in women with temporal lobe epilepsy can cause polycystic ovarian syndrome, hypothalamic amenorrhea, or menstrual cycle abnormalities, depending on the epileptogenic focus. Not only epilepsy, but the administration of anti-seizure medications can also influence reproductive function. This interview took place at the 14th European Epilepsy Congress (EEC) 2022 in Geneva, Switzerland.

Transcript (edited for clarity)

Catamenial epilepsy is defined as an exacerbation of seizure before or during the cycle. This condition is very important also because it’s a very frequent condition, it normally affects 60% of women patients with epilepsy. So in general, people don’t think also that epidemiology of this condition is very, very high.

Catamenial epilepsy is defined and classified by Herzog, it’s consisting three different patterns...

Catamenial epilepsy is defined as an exacerbation of seizure before or during the cycle. This condition is very important also because it’s a very frequent condition, it normally affects 60% of women patients with epilepsy. So in general, people don’t think also that epidemiology of this condition is very, very high.

Catamenial epilepsy is defined and classified by Herzog, it’s consisting three different patterns. We have the perimenstrual pattern, C1, call it C1, the periovulatory pattern, call it C2, when we have an exacerbation in the seizure during perimenstrual and periovulatory in normal cycle. However, we noted women with epilepsy could also have inadequate luteal phase and amenorrhea, so in this case we have also the C3 catamenial epilepsy pattern, when we have an exacerbation of seizures in the second half of the cycle.

The hormone in this condition play an important role. In fact, in general we know that two hormone, estradiol and progesterone, play together a key role in this condition. Estradiol is considered in general a proconvulsive hormone, this hormone has a proconvulsive effect. On the other hand, progesterone has an anticonvulsive effect. In fact, in the treatment of catamenial epilepsy also the hormone have an important role. In fact the treatment of this condition includes non-hormonal therapy, for example antiseizure medication such as clobazam or acetazolamide, and hormonal therapy with the cyclic progesterone. So it’s really important to discuss this condition for its high frequency and for management of women with epilepsy with this condition.

There is an important linking between the cycle and, in general, epilepsy. We know in reproductive health, for example, in general women but also men with epilepsy could develop alterations in reproductive health. For example, in women with epilepsy it’s more frequent to see conditions such as polycystic ovarian syndrome and abnormal menstrual cycle, as I said before. And also men with epilepsy could also have alteration in spermatogenesis and sexual disorder.

Regarding the cycle in women with epilepsy, we noted the hypothalamus regulate this and control ovarian folliculogenesis with releasing of the gonadotropin-releasing hormone. In particular, regarding this topic, in the literature we know that women, in particular with temporal lobe epilepsy, could develop polycystic ovarian syndrome and amenorrhea. In a study in 2003, women with left or right temporal lobe epilepsy was described and the study demonstrated that women with left temporal lobe epilepsy have dysregulation in the gonadotropin-releasing hormone pulses that was higher than normal control. On the other hand, in women with right temporal lobe epilepsy, we have fewer pulses.

And this could explain also the development of the two conditions, polycystic ovarian syndrome for one hand and on the other hand amenorrhea. In fact, if you increase gonadotropin-releasing factor you have more follicular stimulating hormone, and so we have so much follicular that don’t ovulate and they develop, for example, as small ovarian cysts, and this is the polycystic ovarian syndrome. On the other hand, when we have a decrease of gonadotropin-releasing hormone, you have fewer follicular maturation, you have a failure of follicular maturation and menstrual cycle, and you get amenorrhea. So you get hypothalamic amenorrhea in the right temporal lobe epilepsy, and polycystic ovarian syndrome in the left temporal lobe epilepsy.

Also, we know that antiseizure medication could have a role in change in reproductive hormones. For example, we know that valproate is generally considered the antiseizure medication with the most adverse effect in reproductive health, also is the hormone that is more teratogenic in women with pregnancy. And in particular, valproate retard folliculogenesis in animal studies, but also in human studies, and could develop polycystic ovarian syndrome in women that take valproate. So these are really linking between these hormones, menstrual cycle, but also not solely epilepsy per se but also anti-seizure medication could play a role in this topic, in this condition.

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