Filling a Therapeutic Need: Potential of Perampanel to Treat Catamenial Epilepsy

Katherine A. Zarroli, MD

CATAMENIAL EPILEPSY DESCRIBES a worsening of seizures in relation to the menstrual cycle and may affect approximately 40% of women with epilepsy. Current treatment of catamenial epilepsy depends on whether a woman has regular or irregular menstrual periods. If a woman has regular periods, hormonal and nonhormonal treatments taken prior to and during a period may be used. In women who do not have regular periods and therefore cannot predict their period days, treatment options include using synthetic hormones or gonadotropin-releasing hormone analogues to stop periods.¹

Perampanel (Fycompa; Eisai Co, Ltd), an FDA-approved medication for focal onset seizures, is currently being assessed in a pilot study (NCT05201703) of women with perimenstrual (C1 pattern) catamenial epilepsy (TABLE). This phase 4 study, which began in March 2022, includes 55 women aged 18 to 50 years with at least 2 unprovoked seizures per month despite drug trials with at least 1 first-line antiepileptic drug (AED).²

Individuals in the study must show a C1 catamenial pattern in 2 of 3 documented cycles. C1 pattern will be defined as a 2-fold increase in average daily seizure frequency during the menstrual phase, compared with the follicular and luteal phases of the ovulation cycle, in 2 of 3 documented cycles. Of note, the menstrual phase will be defined as days –3 to +3 of the menstrual cycle. The study will exclude those with a progressive neurologic or systemic disorder, individuals who used a systemic hormonal contraception during the 3 months prior to enrollment, pregnant or breastfeeding women, or those with active suicidal or homicidal ideation.

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The study is being led by Katherine A. Zarroli, MD, a clinical neurophysiologist and epilepsy physician at UF Health Jacksonville, in Florida. Study participants are randomly assigned to either perampanel 4 mg daily or perampanel 4 mg daily with a boost to 6 mg daily 1 week before the start of their menstrual cycle until day 4 of their cycle. The study will use responder rates, otherwise considered at least a 50% reduction in seizures, as the primary outcome of the study. Additional procedures of the study include a questionnaire to determine the risks of perampanel use and the collection of blood and urine for a pregnancy test.

Like many seizure medications, perampanel is usually started at a low dose and slowly increased. It has been used to treat temporal lobe epilepsy, focal impaired awareness or complex partial seizures, secondarily generalized seizures or bilateral tonic clonic seizures, focal aware onset seizures, and tonic-clonic seizures. The therapy comes as an oral suspension at a dose of 0.5 mg for each mL, with an adaptor and syringe to measure each dose.³

Catamenial epilepsy, like many other conditions with seizures, is diagnosed through an electroencephalogram. MRI and CT scans have been used as well to study the condition and locate where the seizure is happening in the brain. Typically, women with epilepsy are instructed to keep a record of their seizures and menstrual cycle in case there is a potential connection between the two. A drop in progesterone, a hormone in the body, just before menstruation may trigger seizures in women with catamenial epilepsy. The rise in estrogen during ovulation may also trigger seizures in this patient population.

Since its original approval, perampanel has been studied in several settings, including a 2021 study of patients with comorbid epilepsy and migraine. Migraine, the most common form of disabling headache, affects 3 times more women than men. Led by Claudio Liguori, MD, a neurologist at the Epilepsy Center at the University of Rome, in Italy, the observational study included 31 adults with epilepsy and comorbid migraine who started perampanel to better control epileptic seizures and were followed up for 12 months.⁴

The mean age of the cohort was 40.13 years (±13.13), and the cohort was mostly made up of women (n = 21; 67.7%). Fourteen patients (45.2%) started perampanel with 1 concomitant antiseizure medication (ASM), and 17 patients started the study drug in association with 2 ASMs (54.8%). At 12 months, most patients (n = 27; 87.1%) were still on treatment, whereas 2 patients discontinued because of lack of efficacy and 2 because of adverse events. Treatment with perampanel over a year resulted in seizure freedom for 11 patients. Seven patients experienced at least 75% reductions, 3 at least 50%, 1 at least 25%, and 5 remained unchanged. There was also a significant difference in epileptic seizure frequency means across baseline and at the 6- and 12-month follow-up visits (X2 = 33.767; P < .001).⁴

REFERENCES
1. Maguire MJ, Nevitt SJ. Treatments for seizures in catamenial (menstrual-related) epilepsy. Cochrane Database Syst Rev. 2021;9(9):CD013225. doi:10.1002/14651858.CD0132225.pub3
2. Fycompa in catamenial epilepsy. ClincialTrials.gov. Updated June 8, 2023. Accessed July 12, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT05201703
3. Perampanel. Epilepsy Foundation. Updated February 2, 2023. Accessed July 12, 2023. https://www.epilepsy.com/tools-resources/seizure-medication-list/perampanel
4. Fernandes M, Dono F, Dainese F, et al. Perampanel may represent an effective treatment for the prevention of migraine comorbid with epilepsy. EpilepsBehav. 2021;125:108391. doi:10.1016/j.yebeh.2021.108391