Women’s Issues in Epilepsy

Globally, 15 million females of reproductive potential are living with epilepsy with significant sex and gender influences that span their lifespan. A multitude of considerations result from the multidirectional interactions of exogenous and endogenous hormones, seizures, and antiseizure medications that together affect important aspects of a female’s life, including menstruation, contraception, pregnancy, breastfeeding, and bone health. Practitioners must maintain knowledge of these specialized topics and provide regular counseling to optimize epilepsy care.

Catamenial Epilepsy

Seizure exacerbation during the menstrual cycle is common with catamenial epilepsy affecting one-third of women with epilepsy (WWE) of reproductive age, though a wide range of prevalence has been reported (10%–78%), reflecting early inconsistencies in its classification. Currently, catamenial epilepsy is defined as a doubling of seizures or seizures occurring almost exclusively during specific times of the menstrual cycle. This is attributed to the neuroactive properties of female sex steroids and their cyclical variation where estrogens mainly act as a proconvulsant, while progesterone and its metabolites have anticonvulsant properties. Three seizure patterns of catamenial epilepsy have been recognized, namely, perimenstrual (C1 pattern), periovulation (C2 pattern), and anovulatory cycles (C3 pattern), during which there is a heightened estrogen-to-progesterone ratio favoring a proconvulsant state (see Fig. 13.1 for catamenial patterns). In females with refractory seizures, catamenial epilepsy should be considered and investigated with a menstrual and seizure diary; if diagnosed, it has important management implications. Approaches include both hormonal and antiseizure medication (ASM) interventions and depend on pattern and patient preference. For instance, supplemental progesterone during the luteal phase in a C1 pattern, hormonal contraceptives for suppression of menstruation to avoid cyclic variation, and increasing a background ASM dose or adding adjuncts such as clobazam or acetazolamide around the time of heightened risk are potential strategies.

Types of catamenial epilepsy. Day 1 is the first day of menstrual flow; day 14 is ovulation. (A) The C1 pattern represents perimenstrual seizure exacerbation, and the C2 pattern represents periovulatory seizure exacerbation. (B) The C3 pattern represents catamenial epilepsy in anovulatory cycles.

F , Follicular phase; L , luteal phase; M , perimenstrual; O , periovulatory phase.

Reprinted with permission from Herzog AG, Klein P, Ransil BJ. Three patterns of catamenial epilepsy. Epilepsia 1997;38(10):1082–1088.

Contraception

Contraceptive counseling should be offered to WWE of childbearing potential, as neurologists can positively influence the use of reliable contraceptive methods while incorporating patient preferences and maintaining epilepsy control. Interactions between various antiseizure medications and hormonal birth control can alter the efficacy of contraception and seizure stability. Specifically, hepatic enzyme-inducing medications through cytochrome P450 may induce metabolism of hormonal birth control, while estrogen induces glucuronidation, resulting in enhanced metabolism of lamotrigine and to a lesser degree valproate and oxcarbazepine (see Table 13.1 for ASM and contraception interactions). Copper and progestin intrauterine devices (IUDs) have become the preferred recommended contraceptive method, as they are reliable and reversible and exert localized effects without systemic interactions or alterations of drug metabolism. In women who prefer an alternative method or in whom IUDs are contraindicated, other forms include the combined oral contraceptive pill, progestin-only formulations, and surgical nonhormonal measures such as vasectomy and tubal ligation. However, using these methods may have reduced efficacy or require dose adjustments due to increased clearance of either the contraceptive or antiseizure medication, depending on the combination.

Fertility

Fertility in WWE is challenging to study in isolation due to confounding psychosocial and biological causes. Biological reasons for infertility in WWE include central dysregulation of the hypothalamic-pituitary-ovarian axis, premature ovarian failure, and polycystic ovarian syndrome. Hepatic enzyme-inducing ASMs may contribute to menstrual dysfunction through increased metabolism of hormones, increased production of sex hormone binding globulin causing lower free bioactive hormones, and valproate (VPA) related effects of hyperandrogenism and weight gain. In WWE, polytherapy is consistently identified as a risk factor for infertility, while other factors have less reliably been reproduced, such as epilepsy severity, childhood-onset epilepsy, metabolic epilepsy, and lesional epilepsy (epilepsy characterized by a structural brain lesion as the underlying cause of recurrent seizures). Reassuringly, in the absence of preexisting risks of infertility, a recent study showed no difference in fertility rate or time to conception in WWE compared to controls, though avoidance of polytherapy and VPA may increase the chances of conceiving.

Assisted reproductive technology (ART) remains an option for WWE who are struggling with fertility and has similar reported efficacy as in the general population. However, associated risks from exogenous hormones that heighten the estrogen-to-progesterone ratio or interact with ASMs exist. The ART process may include administration of gonadotropins that stimulate ovaries, resulting in a large surge of estrogen, or involve direct administration of estrogen, both theoretically inducing a proconvulsant state. Current evidence for epilepsy management in this context is limited, but serum drug levels at baseline and during hormonal therapy, along with adjunctive pretreatment with clobazam, may be considered.

Preconception Care

In the United States, more than 50% of pregnancies in WWE are unplanned. This emphasizes the need for early reproductive counseling and family planning, as preparation can improve outcomes by mitigating the risk of seizure destabilization and teratogenicity. The best predictor of seizure control during pregnancy is indicated by baseline seizure frequency in the 9–12 months prior to conception and prepregnancy efforts should be aimed at optimizing stability. The risk of major congenital malformations (MCMs) with ASM exposure in pregnancy is two to five times higher than that in the general population; the risk is both drug and dose dependent, the highest risk being associated with polytherapy and high-dose VPA (≥1500 mg total daily dose). A transition to lamotrigine, levetiracetam, or oxcarbazepine should be discussed, as these drugs have the lowest reported rates of teratogenicity observed across multiple international pregnancy registries (see Fig. 13.2 for the prevalence of MCMs with ASMs). Less is currently known about newer ASMs such as perampanel, eslicarbazepine, lacosamide, and brivaracetam. In addition to in utero exposure to VPA causing structural defects, VPA has been linked to impairment in cognitive and behavioral outcomes, also with a dose-dependent relationship. In considering a drug switch, shared decision must be employed to balance multiple factors, including patient preference, type of epilepsy, risk of seizure destabilization, and risks of teratogenicity and poor neurodevelopmental outcomes. A preconception drug serum level should be measured to establish a baseline for subsequent titrations as drug levels fall during pregnancy.

Prevalence of major congenital malformations of antiseizure medication compared with lamotrigine ≤325 mg/d. CBZ , Carbamazepine; CI , confidence interval; LEV , levetiracetam; LTG , lamotrigine; OXC , oxcarbazepine; PB , phenobarbital; PHT , phenytoin; Ref , reference; TPM , topiramate; VPA , valproate.

From Tomson T, Battino D, Perucca E. Teratogenicity of antiepileptic drugs. Curr Opin Neurol . 2019;32(2):246–252.

Periconceptional folic acid supplementation is recommended in all WWE of reproductive age to minimize risks of major congenital malformations, neural tube defects, and adverse neurodevelopmental outcomes. The optimal dosing has not been established, but folic acid typically is prescribed in the range of 1–4 mg daily at least 3 months prior to conception. A higher range of dosing may be considered for patients who are on VPA, carbamazepine, or polytherapy or who have a history of previous open neural tube defects. Recent evidence has demonstrated an association of high-dose folic acid and negative impacts including lower psychomotor scale scores and increased risk of cancer in children of mothers with epilepsy. Therefore, supratherapeutic dosing is not advised.

Pregnancy Care in Epilepsy

Pregnancy care for WWE involves balancing seizure control with in utero fetal drug exposure. Seizures in pregnancy have been associated with maternal injury and perinatal complications such as fetal hypoxia, preterm delivery, and low birth weight, while in utero ASM exposure has the potential for major congenital malformations, neural tube defects, and adverse neurodevelopmental outcomes. Therapeutic drug monitoring is an important tool that should be implemented if available to mitigate these risks with a baseline preconception level and then monthly monitoring following conception. Levels of all ASMs decrease due to physiologic changes in pregnancy, though the extent and timing are drug dependent. There is a prominent decline of levetiracetam and lamotrigine early in the first trimester, whereas clearance of oxcarbazepine and topiramate is greatest in the second trimester, and carbamazepine and lacosamide show minor changes (see Fig. 13.3 for ASM levels during pregnancy). As a general guideline, if levels fall by >35% of preconception levels, women are at greater risk for breakthrough seizures, and a dose titration should be considered. If drug levels are not available, a dose increase of 30%–50% should be considered after the first trimester if it is a drug with a known pregnancy-associated decline, if the patient is on the lowest effective dose at the onset of pregnancy, or if the patient has a history of severe or breakthrough seizures. Reassuringly, the majority of pregnant WWE have a stable course that is attributable in part to carefully considered drug adjustments and monitoring.

Projected decrease of antiseizure medication concentrations during pregnancy if no dose changes are made.

Reprinted with permission from Li Y, Meador KJ. Epilepsy and Pregnancy. Continuum (Minneap Minn) 2022;28:34–54.

Postpartum and Breastfeeding

WWE are particularly vulnerable to seizures in the postpartum period due to an increase in stress and sleep deprivation. Reported rates of hospital readmission and incidence of mental health comorbidities are also higher, emphasizing the importance of judicious follow-up for maternal health and well-being, including screening for postpartum depression. Anticipatory drug adjustments of ASMs changed in pregnancy are also required, as many ASM levels increase with return to prepregnancy physiology and metabolism.

Postpartum-specific epilepsy safety measures include ensuring maternal social supports, encouraging adequate periods of restful sleep (the National Sleep Foundation recommends at least 7 hours of sleep each night) with family helping with nocturnal feeds, changing and feeding the infant near ground level, childproofing medications, using strollers rather than infant carriers, and avoiding cosleeping and bathing the infant alone.

Breastfeeding is safe and should be recommended to WWE, as it provides many benefits to infants and mothers. Transfer of antiseizure medications into breastmilk is an area that has been extensively studied with evidence showing minimal accumulation. In breastfed infants, serum drug concentrations for carbamazepine, oxcarbazepine, lamotrigine, levetiracetam, topiramate, valproic acid, and zonisamide remain low compared to maternal serum drug concentrations. If feasible, WWE should be reassured and encouraged to breastfeed without altering their antiseizure medication regimen.

Bone Health

Sex and gender disparities are prevalent in bone health, particularly in females over 50 years of age, who face higher rates of osteoporosis, risk of falls, and lifetime risk of fractures. Osteoporosis is four times more common in females, due to lower bone density and faster rate of bone loss, which can be exacerbated by postmenopausal estrogen decline. Risk of osteoporosis is further heightened by epilepsy and chronic exposure to ASMs, independent of drug mechanism of action; emerging evidence indicates that many ASMs accelerate osteoporosis onset, including those that induce cytochrome P450 as well as those that act via nonenzyme induction mechanisms. Therefore, WWE should be screened for vitamin D deficiency and bone loss and should be counseled on bone-protective measures such as weight-bearing exercises, avoidance of smoking and alcohol, and maintenance of a well-balanced and/or supplemented diet with adequate vitamin D and calcium. The current recommended intakes are 600 IU daily of vitamin D and 700–1300 mg daily of calcium, though WWE likely require higher doses, given the accelerated effects of epilepsy and chronic ASM use on osteoporosis incidence.

Sleep Disturbances in Women

Inherent sex differences of circadian rhythms between males and females have been reported, implicating a role of reproductive hormones in sleep physiology. This is further reflected in the higher prevalence of many sleep disorders in females, particularly during periods of hormonal change such as menstruation, pregnancy, or menopause.

Restless Leg Syndrome

Restless leg syndrome (RLS) is a sleep-related movement disorder that is frequently encountered in clinical practice and is twice as common in females. It is characterized by an uncomfortable urge and sensation to move the lower extremities that worsens at night when at rest. Studies of RLS pathophysiology have consistently identified central iron deficiency as a biological abnormality, which corresponds to symptom exacerbation during menses and pregnancy, when iron stores are reduced. It is also increased during menopause, during which estrogen and progesterone levels decline, though the role of sex steroids in RLS remains unclear. Pregnancy increases the risk of both debut and worsening of RLS with increasing prevalence in each trimester (8% in T1, 16% in T2, and 22% in T3), in part attributable to physiologic changes and blood volume expansion. Interestingly, higher parity is also associated with increasing risk of RLS later in life. Treatment in pregnancy should be aimed at replenishing iron stores and nonpharmacologic interventions (exercise, massage, avoidance of caffeine and stimulants, withdrawal of exacerbating drugs), but typically RLS resolves postpartum. According to the 2018 guidelines, if the ferritin level is <300 ng/mL and transferrin saturation is <45%, supplementation is recommended, though normal peripheral iron studies do not rule out central iron deficiency. Pharmacologic symptomatic strategies in nonpregnant females include α2δ ligands (e.g., gabapentin or pregabalin) as first-line therapy, given that dopamine agonists may cause augmentation with long-term use.

Obstructive Sleep Apnea

Obstructive sleep apnea (OSA) is a sleep-related breathing disorder with repetitive airway closures, oxygen desaturation, and disrupted sleep. It is often overlooked in females, who more commonly report nonspecific symptoms of headache, depression, anxiety, fatigue, and insomnia in comparison to males, who characteristically present with snoring and apnea. The reported overall prevalence in females is 6%–19% (compared to 13%–33% in males) with a narrowing of the sex gap with advancing age, as evidenced by a significant increase in postmenopausal females. If undiagnosed, OSA can lead to negative outcomes, including worsening of cardiovascular, psychiatric, and neurologic disorders along with reduced quality of life. Specific risk factors in females include pregnancy, hyperandrogenism and polycystic ovarian syndrome, and menopause, with increased body mass index and hormonal alterations as contributors (see Fig. 13.4 for pregnancy-related physiologic changes that predispose females to OSA). Importantly, untreated OSA in pregnancy has been associated with poorer maternal-fetal outcomes. This emphasizes the importance of implementing screening tools and standardized evaluation of patients at risk with polysomnography or home sleep apnea testing. OSA is a treatable condition with a variety of interventions, though positive airway pressure therapy remains the gold standard if tolerated.

Anatomic and physiologic changes during pregnancy that predispose females to sleep disturbances. During pregnancy, changes such as weight gain, increased uterine volume, and hormonal changes occur, which have been linked to the development of sleep disorders such as obstructive sleep apnea.

CC by 4.0) (From Martin H, Antony KM, Kumar S. Obstructive sleep apnea in pregnancy – development, impact and potential mechanisms. J Women’s Health Dev . 2020;3(4):446–469.

Definitions

Migraine without aura (MO) is defined by at least five episodes of unilateral throbbing headache with associated phonosensitivity and photosensitivity and nausea and/or vomiting of moderate to severe intensity lasting 4–72 hours that is not explained by another diagnosis. Migraine with aura (MA) requires at least two typical aura events usually visual, sensory, or language, lasting 15–60 minutes preceding the headache. The other criteria are the same as those of MO. Menstrual migraine (MM) is defined as migraine that occurs only in close relationship to the onset of menstruation, starting 2 days prior to 2 days after the first day of menses or withdrawal bleeding. Females with menstrually related migraine (MRM) have characteristics similar to those of females with MM, but migraines may occur at other times of their cycle as well.

Stroke Risk

Females who have MA have a small but real increased risk of stroke. Data have shown that the risk for stroke is 2.0–2.5 times greater in females with MA. This is not true for those with MO. The reasons for this increased risk are complex and may have to do with the pathophysiology of cortical-spreading depression, predilection for endothelial injury, migraineur’s association with having patent foramen ovale, and genetic risks, as migraine is associated with neurologic disorders that involve increased stroke risk (e.g., cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy). These stroke risks increase with age and the presence of other traditional stroke factors such as hypertension and smoking.

Hormonal Contraceptives

Estrogen in combined hormonal contraceptives (CHC) confers an independent risk of stroke. For this reason, the American College of Obstetrics and Gynecology guidelines state that CHC should be avoided in females who have MA. This decision should be nuanced and individualized to determine the risks and benefits for a particular patient, including the indication and dose of CHC. For example, the need for CHC may be supported by a woman who has MA but no other traditional stroke risks and who needs estrogen for endometriosis.

MO is the more hormonally driven headache, so are those most likely to have either MM or MRM. In this subset of migraineurs, continuous CHC without placebo may be helpful to decrease the menstrual exacerbation of migraine and may be an excellent choice for females with MO who also want an oral contraceptive method. Other strategies include increasing the preventive medication dose premenstrually and mini-prophylaxis regimens ( Box 13.1 ).

Pregnancy and Postpartum

Females who have MO, particularly those with a hormonal exacerbation, often have worsening in their migraine frequency during the first trimester. However, over 80% have a remission in their migraines by early in the second trimester. This time course is less predictable with females who have MA; where only 44% improve during pregnancy. Postpartum, there is often a migraine exacerbation due to changes in estrogen, sleep deprivation, and stress. Migraineurs have an increased risk for preeclampsia, and they should be counseled in this regard.

Females of reproductive age should be asked the key question “Are you planning pregnancy?” If they are, then a discussion about their migraine medication safety during pregnancy, the natural history of migraine during pregnancy, and postpartum and appropriate management of their headache disorder can ensue. During pregnancy, migraine management shifts to an increased use of nonmedical therapies (physical therapy, acupuncture, and stress management) and symptomatic medications ( Table 13.2 ). This is due to both the expected improvement of migraines during pregnancy and the fact that most preventive medications carry some level of risk ( Table 13.3 ).

Postpartum migraine management depends on the frequency and severity of headaches and whether or not the patient is breastfeeding.

Menopause

Females with hormonally exacerbated migraine may have an exacerbation during the menopausal transition. The approach to treatment is the same as that for any migraine patient. For females who have MA and need hormonal therapy for their vasomotor symptoms, estrogen therapy is deemed safe, especially the transdermal estrogen patch. This is because the amount of delivered estrogen is low, and for females younger than 60 years of age, the absolute risk of stroke from standard dose hormonal therapy is rare (two additional strokes per 10,000 person-years of use).

Definition and Prevalence

Multiple sclerosis (MS) is a demyelinating inflammatory autoimmune disease of the central nervous system that affects primarily the myelin sheath but also injuring the underlying axons. It is characterized by either relapses and remissions of neurologic deficits or a more progressive decline in neurologic function. In the United States, about 1 million people are affected by MS, with females affected three times more than males.

Contraception

Females with MS who do not want to become pregnant should be counseled on effective contraception. All contraceptive methods are available to these patients; therefore, the focus should be effective methods and ease of reversibility.

Prenatal Counseling

Prior to pregnancy there are multiple issues that should be discussed with females who are planning pregnancy. They should know that there is a small genetic risk such that if one partner has MS, the risk of an offspring developing MS is 2%–4%, and if both parents are affected, the risk is increased to around 20%. These females should be on both prenatal vitamins and vitamin D supplementation. (The recommended vitamin D3 dose is 4000 IU/day.) Females with MS need to understand that achieving disease stability prior to pregnancy is important, as those with stable disease are much more likely to have fewer relapses intrapartum as well as postpartum. Further, there needs to be a discussion about managing their disease-modifying therapy (DMT), as many patients require a washout ( Box 13.2 ). In addition, there are specific concerns about discontinuation of natalizumab and fingolimod, as they carry a high risk of rebound of MS activity. Expert opinion now recommends continuing natalizumab treatment during pregnancy, timing administration in pregnancy to late first trimester to end around gestation week 32 with infusions every 6–8 weeks. Prepregnancy washout for natalizumab is not recommended.

Box 13.2

Multiple Sclerosis Therapies: Washout Period/Label

• •
  

  Interferons and glatiramer acetate

  
  
  
  
  • •
    

    No washout

  
  
  
  
• •
  

  Teriflunomide

  
  
  
  
  • •
    

    8 months or rapid elimination protocol

  
  
  
  
• •
  

  Fingolimod

  
  
  
  
  • •
    

    2-month washout

  
  
  
  
• •
  

  Dimethyl fumarate

  
  
  
  
  • •
    

    No washout

  
  
  
  
• •
  

  Alemtuzumab

  
  
  
  
  • •
    

    4-month washout

  
  
  
  
• •
  

  Cladribine

  
  
  
  
  • •
    

    3-month washout

  
  
  
  
• •
  

  Ocrelizumab

  
  
  
  
  • •
    

    6 months washout

  
  
  
  
• •
  

  Natalizumab

  
  
  
  
  • •
    

    3 months washout

  
  

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