AT AES 2017

WASHINGTON (FRONTLINE MEDICAL NEWS)– The high rate of new onset epilepsy during the period surrounding menarche has been strengthened in a data analysis that suggests surging hormones may be a treatable trigger of epileptogenic activity, according to a new analysis of the Epilepsy Birth Control Registry (EBCR) presented at the annual meeting of the American Epilepsy Society.

“The evidence connecting neuroactive sexual maturation hormones with the onset of epilepsy and seizure activity is becoming strong enough that we can at least conceptualize how hormonal interventions might be used for prevention or treatment,” reported Andrew G. Herzog, MD , director of the neuroendocrine unit at Beth Israel Deaconess Hospital, Boston.

The temporal relationship between menarche and onset of epilepsy has long been recognized, but the EBCR, which has collected data on 1,144 women with epilepsy, is permitting this relationship to be evaluated in more detail. In the most recent analysis of data from this registry, which has now been the source of multiple studies, including one that correlated seizure activity over the course of the menstrual cycle ( Epilepsia. 2015;56:e58-62 ), the mean age of new onset epilepsy was evaluated in relationship to menarche.

Confirming previous observations, new onset epilepsy was more likely to occur in the year of menarche than in any other year, and the rate, 8.3%, was approximately four times greater than an expected rate of 2.1% (P less than .0001), Dr. Herzog reported. However, the association was even stronger when a cluster analysis was performed to widen the window in which sexual maturation hormones begin to surge.

“Menarche is a single event along a continuum of sexual maturation that involves hormonal surges that begin much earlier,” Dr. Herzog explained. He suggested that adrenarche is a better term to capture the relationship between increasing hormone levels and risk of new onset epilepsy. Adrenarche describes a period in which sex steroids released by the adrenal cortex drive puberty and secondary sexual characteristics, such as growth of pubic hair.

In the cluster analysis, the most common period of new onset epilepsy occurred in a span stemming from 2 years before the onset of menarche to 6 year after onset. Almost half of new onset epilepsy in the EBCR occurred in this 8-year period, and it was more than double the rate that would have been expected if new onset epilepsy were distributed evenly by age (49.3% vs. 18.9%; P less than .0001).

“This implicates the onset of puberty and the massive increase in neuroactive steroids that modulate neurohormonal activity and seizures,” said Dr. Herzog, who noted that some neuroactive steroids increase 10-fold during this period. He suggested that the fact that there is also an increased rate of new onset epilepsy in males during the same period does not weaken this association but is likely related to the same phenomenon of neuroactive steroid release.

These data are consistent with a wide variety of other evidence from the EBCR that has linked hormones involved in sexual maturation with change in epilepsy risk, according to Dr. Herzog. He noted, for example, that his group has shown that the release of unopposed estrogen in anovulatory cycles experienced by adolescent girls in the early years of menstruation produces a higher rate of seizures than does ovulatory cycles in which both estrogen and progesterone are released. This is consistent with evidence that estrogen is associated with increased and progesterone with reduced risk of seizure activity.

The relationship between steroid release and risk of new onset epilepsy or seizure activity in patients who already have epilepsy is becoming sufficiently strong that Dr. Herzog believes that efforts should now turn to considering how this information might lead to new interventions. Although clinical trials are not near, he suggested that it might make sense to pursue medications that inhibit neuroactive hormones to prevent seizures in girls at high risk for new onset epilepsy or treat seizures suspected of being hormone related.

Dr. Herzog reports no potential conflicts of interest related to this topic. The study was partially funded by Lundbeck.