Neurosteroid Replacement Therapy for Catamenial Epilepsy

Perimenstrual catamenial epilepsy, the cyclical occurrence of seizure exacerbations near the time of menstruation, affects a high proportion of women of reproductive age with drug-refractory epilepsy. Enhanced seizure susceptibility in perimenstrual catamenial epilepsy is believed to be due to the withdrawal of the progesterone-derived GABA(A) receptor modulating neurosteroid allopregnanolone as a result of the fall in progesterone at the time of menstruation. Studies in a rat pseudopregnancy model of catamenial epilepsy indicate that after neurosteroid withdrawal there is enhanced susceptibility to chemoconvulsant seizures. There is also a transitory increase in the frequency of spontaneous seizures in epileptic rats that had experienced pilocarpine-induced status epilepticus. In the catamenial epilepsy model, there is a marked reduction in the antiseizure potency of anticonvulsant drugs, including benzodiazepines and valproate, but an increase in the anticonvulsant potency and protective index of neurosteroids such as allopregnanolone and the neurosteroid analog ganaxolone. The enhanced seizure susceptibility and benzodiazepine-resistance subsequent to neurosteroid withdrawal may be related to reduced expression and altered kinetics of synaptic GABA(A) receptors and increased expression of GABA(A) receptor subunits (such as alpha 4) that confer benzodiazepine insensitivity. The enhanced potency of neurosteroids may be due to a relative increase after neurosteroid withdrawal in the expression of neurosteroid-sensitive delta-subunit-containing perisynaptic or extrasynaptic GABA(A) receptors. Positive allosteric modulatory neurosteroids and synthetic analogs such as ganaxolone may be administered to prevent catamenial seizure exacerbations, in what we call neurosteroid replacement therapy.