In about 10% to 70% of female epileptics, seizures do not occur randomly, but at times related to the menstrual cycle. This is called catamenial epilepsy. The preovulatory, perimenstrual and inadequate luteal phases of the cycle are the times of increased seizure frequency. The perimenstrual pattern is the most common, followed by the periovulatory period.
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Catamenial epilepsy is quite refractory to treatment because of the underlying neurosteroid-mediated mechanisms. Most patients are not well-controlled with conventional anti-epileptic drugs, and in fact, some of these medications may increase the seizure frequency by various routes of action.
As mentioned above, three patterns are known to exist, and the exact pattern is diagnosed by keeping careful charts of the menstrual cycle and the seizure frequency, along with a serum progesterone level at the midluteal phase. This latter is to tell whether the woman is having an ovulatory or anovulatory cycle, which will help to interpret the pattern of seizure.
In most cases a seizure-vs-menstrual diary is kept. The first day of menstruation is the first day of the diary. The following phases are then identified:
- Day -3 to +3 is the menstrual phase
- Day +4 to +9 is the follicular phase
- Day +10 to +16 is the ovulatory phase
- Day +17 to -4 is the luteal phase
Over at least 2 cycles, the number of seizures is counted. If the average frequency is increased by a factor of 2 or more during one particular phase, this is equivalent to a diagnosis of catamenial epilepsy. Of course, self-reporting is made difficult by the fact that a healthy woman may have both ovulatory and anovulatory cycles, with at least 10% of cycles being anovulatory and often prolonged.
This is where the midluteal progesterone assay comes in useful. When the progesterone level falls below 5 ng/mL on any day between day 20 and day 22, the luteal phase is inadequate, and this may be confirmed by seeing an immature Graafian follicle in the ovary on pelvic ultrasound. In catamenial epilepsy, about 16% of women have seizures connected with inadequate luteal phase defects.
While there is no specific treatment of catamenial epilepsy, conventional antiepileptic drugs (AEDs) are used as the first line of treatment. However, more than one medication from this group is necessary in at least a third of subjects, because they are intractable to ordinary treatment.
It is known that many of these drugs (such as phenytoin, phenobarbital, carbamazepine, oxcarbazepine, and primidone) induce the hepatic cytochrome P450 enzyme family. This metabolism causes the concentration of estrogen and progesterone to decrease, as well as reducing the levels of free hormone by increasing the concentration of sex hormone-binding globulin in the blood.
Speeding up their metabolism results in loss of inhibition of neuronal excitability and hence decreases the seizure threshold. Valproate on the other hand inhibits this group of enzymes and leads to increased sex hormone levels.
The AEDs which do not lead to enzyme induction include pregabalin, levetiracetam, tiagabine and gabapentin. If the patient is on oral contraceptives, she may theoretically be at risk for increased seizure frequency because these drugs induce the metabolism of lamotrigine, another AED.
Benzodiazepines are allosteric modulators of the GABA-A receptor and have a broad anticonvulsant activity. The most commonly used in this condition include clonazepam and clobazam. These may be given intermittently at 2-4 days before the onset of menstrual bleeding, to avoid the induction of tolerance to its effects, which is quite common.
Hormonal therapy has been tested for several years, either by suppressing the ovarian estrogen secretion or by supplementing cyclic doses of progesterone. Estrogen suppression may be accomplished using depomedroxy progesterone (DMPA) or analogs of gonadotropin-releasing hormone.
For progesterone supplementation, either natural or synthetic progestins have been used in the luteal phase, but only the former has shown evidence of benefit in the form of reduced seizure frequencies, especially in the perimenstrual form of catamenial epilepsy which is uniquely responsive to neurosteroids.
DMPA is associated with a high risk of amenorrhea, and its efficacy is moderate with respect to suppressing seizures. This is thought to be due to its lower conversion rate to allopregnanolone, which is the active anticonvulsant metabolite of progesterone in the brain.
Neurosteroids suppress most types of seizures because of their ability to activate all isoforms of the GABA-A receptor, and producing tonic inhibition of neuronal excitability, thus increasing the seizure threshold. They do not usually build tolerance unlike benzodiazepines. They act rapidly and have a reasonable duration of action.
Other neurosteroid analogs have been tried in attempts to improve upon natural neurosteroids which are quickly metabolized to inactive forms, must be administered parenterally, and may have undesirable hormonal effects.
These include ganaxolone which is a 3-β-derivative of allopregnanolone that cannot be reconverted to its active hormonal state. It has good antiseizure activity and an impressive safety profile. More research is ongoing to assess its efficacy.
In conclusion, it is important to treat catamenial epilepsy with an aim to not only prevent seizures but also to forestall undesirable effects such as decreased bone density, menstrual irregularity and amenorrhea, emotional problems and interference with conception or dangers during pregnancy, as well as other unwanted hormonal side effects.
TSPO ligands are one form of therapy that is being researched to increase the synthesis of endogenous neurosteroids in the brain. Available agents require further investigation to allow more thorough documentation of their effectiveness and for the finetuning of their dosage and protocols of use.