In part 1 of this 2-part series on catamenial epilepsy, we featured an in-depth discussion with Andrew G. Herzog, MD, MSc, professor of neurology at Harvard Medical School, director of the Harvard Neuroendocrine Unit at Beth Israel Deaconess Medical Center in Boston.

For part 2, we conducted a joint interview with Nichole Tyson, MD, clinical associate professor in the department of obstetrics and gynecology at Stanford University School of Medicine and specialist in pediatric adolescent gynecology at Stanford Children’s Health in Sunnyvale, California and her research assistant Samuel Frank of Princeton University in New Jersey. He and Dr Tyson co-authored a recent review on the diagnosis and management of catamenial epilepsy.1

What are the current treatment approaches to catamenial epilepsy?


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Dr Tyson and Frank: Treatment of catamenial epilepsy should start with traditional anti-epileptic medications. After that, there are 2 important steps: The first step is to tailor treatment strategies towards the catamenial nature of the patient’s epilepsy, which typically involves management under the care of a neurologist and prescription for anti-epileptic medication. The second step is to optimize the catamenial nature of the seizures based on the patient’s fertility desires, menstrual concerns, and underlying medical conditions that may preclude the use of estrogen-containing hormonal contraception.

For some patients with catamenial epilepsy, anticonvulsants are not sufficient. To augment their care, certain hormonal therapies should be considered. Many small studies suggest that progestins can be used in conjunction with traditional anticonvulsants to reduce catamenial seizures. These include combined hormonal contraceptives and depot medroxyprogesterone acetate (DMPA).2-6 In addition, gonadotrophin-releasing hormone (GnRH) has shown efficacy in reducing catamenial seizures in small studies.7,8 Further research is needed to define the specific mechanisms of action and show efficacies on a population scale. 

Levonorgestrel intrauterine devices (IUDs) are an underutilized therapy in catamenial epilepsy. They are highly effective contraception, long acting, with efficacy in reducing menstrual bleeding with high rates of menstrual suppression and no interactions with antiepileptic drugs.1 They tend to not suppress ovulation as well as other methods such as the pill, patch, shot, or ring, but further studies are needed to see if there are additional benefits (with minimal risks) of the levonorgestrel IUD in patients with catamenial epilepsy. Perhaps their hormone and menstrual suppression is sufficient to improve symptoms.

What are the other alternatives that don’t involve contraception?

Dr Tyson and Frank: There are other possible solutions for patients who do not desire contraception. Progesterone in the form of micronized progesterone (Prometrium), norethindrone acetate (Aygestin), and medroxyprogesterone acetate (Provera) are not considered effective contraceptive modalities but may offer relief from catamenial seizures. Therefore, these progesterone options are ideal for those considering pregnancy while simultaneously managing their catamenial epilepsy. However, more research is needed on the effects of these specific progestins on catamenial epilepsy. 

The ethinyl estradiol in oral contraceptive pills (OCPs) can speed up breakdown of a small subset of antiepileptic medications including lamotrigine.9,10 Therefore, it is important for physicians to closely monitor patients who are taking this combination of drugs. Dosages may need to be changed or different drugs may need to be considered if seizures worsen. 

How do clinicians balance treatment against its potential effects on fertility, menstrual cycle, bone health, and cardiovascular health? 

Dr Tyson and Frank: There were some early black box warnings placed on DMPA due to bone loss, however these were quickly removed as bone mineral density loss due to DMPA has been shown to be reversible.11-15 DMPA is a convenient (now with self-administration) and popular birth control method which is uniquely helpful for controlling catamenial seizures. In fact, DMPA uniquely raises the seizure threshold for those with epilepsy, thus represents a top-tier hormonal option for patients with epilepsy. 

Cardiovascular health concerns that pertain to hormone replacement therapy in the menopausal patient are beyond the scope of this discussion. Hormone replacement therapy has definitely undergone some re-analysis and is really considered an important therapeutic option for women in menopause in the early years (with timing of treatment being a key factor), with both efficacy and safety profiles that benefit cardiovascular health. 

However, cardiovascular risk is not applicable to the woman using hormonal contraception or progesterone managing catamenial epilepsy. The main risk of estrogen-containing hormonal contraception is venous thromboembolic events. These are quite rare but elevated in patients using hormonal contraception with estrogen compared to those who are not. However, in this context, one must also weigh the risk of pregnancy and postpartum, which also increases – even more so than birth control – the risk of blood clots to legs and lungs.       

Another consideration for catamenial epilepsy patients who are trying to get pregnant is that some antiepileptic drugs are associated with teratogenicity, and therefore, optimizing treatment modalities prior to planning pregnancy is a particularly important consideration for the patient with epilepsy.

In addition to the role of birth control on seizures, it is important to consider the role of anticonvulsants on birth control. 

Why women with catamenial epilepsy consider the role of anticonvulsants on birth control?

Dr Tyson and Frank: Liver enzyme-inducing anticonvulsants can reduce the anti-fertility efficacy of combination hormonal contraceptives. The American College of Obstetrics and Gynecology (ACGO) Committee letter therefore suggests increasing the dose of OCPs, increasing the cycle of OCPs, and decreasing the hormone free period of OCPs.16 Additionally, the birth control patch, ring, shot, IUD, or implant should also be considered as ideal contraceptive options for patients with epilepsy.17

Why do you believe research on this topic is so limited?    

Dr Tyson and Frank: This is a very important question. One major reason is that catamenial epilepsy sits in a corner between neurology and gynecology. Many times, these patients solely see a neurologist and never have discussions about menstrual cycles, pregnancy planning, or contraceptive needs. 

In addition, there are challenges and variables in the diagnosis of catamenial epilepsy. In practice, it is not always consistent across neurologists, documentation in charts (for things like retrospective chart reviews), or in the neurology literature. 

In some studies, the progesterones used with some efficacy in treating catamenial epilepsy (for example, progesterone lozenges) are only available for study protocols and not available for use in the US or even by prescription.

As mentioned, there is a large gap in care for women with epilepsy in the realm of contraception and preconception counseling. It is important that we focus on the complexity of the whole patient rather than focusing on managing the seizure disorder alone. A much more holistic approach needs to be provided for the teen or young woman with epilepsy.

What should clinicians know about caring for adolescents with epilepsy?

Dr Tyson and Frank: Adolescents with epilepsy, like their peers without epilepsy, have menstrual cycles, have sex, and have reproductive considerations that all need to be addressed to optimize their care. We always champion having adolescents with epilepsy consult pediatric and adolescent gynecologists (as young women), as we are experts in caring for this unique population’s specific reproductive health concerns.

Many girls do not meet a gynecologist until they are 21 and are due for their first pap smear. ACOG recommends consultation with a gynecologist at age 13-15 for all girls.18 We certainly endorse this recommendation in the world of Pediatric and Adolescent Gynecology (PAG) and would encourage consultation with a PAG provider at time of menarche for girls with epilepsy. 

What changes in standard of care for catamenial epilepsy would you like to see?

Dr Tyson and Frank: The main change we would like to see is increased awareness of catamenial epilepsy among pediatricians, neurologists, and adult gynecologists alike. This includes an increase in awareness of the condition, hormonal modalities to optimize treatment, and provision of preconception counseling. These patients have higher risks of fetal teratogenicity with certain anti-epileptics which should be addressed and reviewed with the patient.

If pregnancy is desired, anti-epileptics should be tailored to the patient’s reproductive plans to minimize risk, and folic acid should be discussed. If pregnancy is not desired, birth control counseling should be provided within the framework of shared decision-making, including the patient’s individualized risks, benefits, and alternatives, all within the framework of shared decision-making. 

In practice, patients with catamenial epilepsy often interact primarily or solely with neurologists. It is important – some would say imperative – for neurologists and gynecologists to collaborate to optimize the care of the patient with catamenial epilepsy. 

References

1. Frank S, Tyson NA. A clinical approach to catamenial epilepsy: A Review. Perm J. Published online December 2, 2020. doi:10.7812/TPP/19.145

2. Herzog AG. Intermittent progesterone therapy and frequency of complex partial seizures in women with menstrual disorders. Neurology. 1986;36(12):1607-1610. doi:10.1212/wnl.36.12.1607

3. Herzog AG. Progesterone therapy in women with complex partial and secondary generalized seizures. Neurology. 1995;45(9):1660-1662. doi:10.1212/wnl.45.9.1660

4. Herzog AG, Fowler KM, Smithson SD, et al; Progesterone Trial Study Group. Progesterone vs placebo therapy for women with epilepsy: A randomized clinical trial. Neurology. Published online May 2, 2012. doi:10.1212/WNL.0b013e318259e1f9

5. Mattson RH, Cramer JA, Caldwell BV, Siconolfi BC. Treatment of seizures with medroxyprogesterone acetate: preliminary report. Neurology. 1984;34(9):1255-1258. doi:10.1212/wnl.34.9.1255

6. Zimmerman AW, Holden KR, Reiter EO, Dekaban AS. Medroxprogesterone acetate in the treatment of seizures associated with menstruation. J Pediatr. 1973;83(6):959-963. doi:10.1016/s0022-3476(73)80529-3

7. Bauer J, Wildt L, Flügel D, Stefan H. The effect of a synthetic GnRH analogue on catamenial epilepsy: a study in ten patients. J Neurol. 1992;239(5):284-286. doi:10.1007/BF00810354

8. Haider Y, Barnett DB. Catamenial epilepsy and goserelin. Lancet. 1991;338(8781):1530. doi:10.1016/0140-6736(91)92354-5

9. Sabers A, Ohman I, Christensen J, Tomson T. Oral contraceptives reduce lamotrigine plasma levels. Neurology. Published online August 26, 2003. doi:10.1212/01.wnl.0000076485.09353.7a

10. Reimers A, Helde G, Brodtkorb E. Ethinyl estradiol, not progestogens, reduces lamotrigine serum concentrations. Epilepsia. Published online September 1, 2005. doi:10.1111/j.1528-1167.2005.10105.x

11. Scholes D, LaCroix AZ, Ichikawa LE, Barlow WE, Ott SM. Injectable hormone contraception and bone density: results from a prospective study. Epidemiology. 2002;13(5):581-587. doi:10.1097/00001648-200209000-00015

12. Clark MK, Sowers M, Levy B, Nichols S. Bone mineral density loss and recovery during 48 months in first-time users of depot medroxyprogesterone acetate. Fertil Steril. Published online September 25, 2006. doi:10.1016/j.fertnstert.2006.05.024

13. Kaunitz AM, Miller PD, Rice VM, Ross D, McClung MR. Bone mineral density in women aged 25-35 years receiving depot medroxyprogesterone acetate: recovery following discontinuation. Contraception. Published online May 24, 2006. doi:10.1016/j.contraception.2006.03.010

14. Harel Z, Johnson CC, Gold MA, et al. Recovery of bone mineral density in adolescents following the use of depot medroxyprogesterone acetate contraceptive injections. Contraception. Published online December 14, 2009. doi:10.1016/j.contraception.2009.11.003

15. Kaunitz AM, Arias R, McClung M. Bone density recovery after depot medroxyprogesterone acetate injectable contraception use. Contraception. Published online January 7, 2008. doi:10.1016/j.contraception.2007.10.005

16. The American College of Obstetricians and Gynecologists. Gynecologic management of adolescents and young women with seizure disorders: ACOG Committee Opinion Summary, Number 806. Obstet Gynecol. 2020;135(5):1242-1243. doi:10.1097/AOG.0000000000003828

17. Bounds W, Guillebaud J. Observational series on women using the contraceptive Mirena concurrently with anti-epileptic and other enzyme-inducing drugs. J Fam Plann Reprod Health Care. 2002;28(2):78-80. doi:0.1783/147118902101195992

18. American College of Obstetricians and Gynecologists’ Committee on Adolescent Health Care. The Initial Reproductive Health Visit: ACOG Committee Opinion, Number 811. Obstet Gynecol. 2020;136(4):e70-e80. doi:10.1097/AOG.0000000000004094