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Case Reports of Women with Epilepsy

2003; Wiley; Volume: 44; Issue: s3 Linguagem: Inglês

10.1046/j.1528-1157.44.s3.1.x

1528-1167

Deborah T. Combs‐Cantrell, Mark S. Yerby,

Epilepsy research and treatment

Women with epilepsy are faced with many unique issues regarding their reproductive health. Pregnancies in women with epilepsy are considered high risk because of the increased risk for seizures, maternal complications, and adverse outcomes in the newborn. Infants of women with epilepsy have a two- to threefold increase in the rate of fetal malformations. Investigators have hypothesized that the increased risks are secondary to genetic predisposition, exposure of the fetus to seizures, and in utero exposure to antiepileptic drugs (AEDs). However, the relative contribution of each factor is undetermined. Two similar cases of women with epilepsy involving pregnancy and the risk of neural tube defects (NTDs) are presented. Although the cases are similar, they illustrate the diverse challenges faced in the care of women with epilepsy and their unborn children. A 36-year-old right-handed woman presented with a history of seizures that began at age 16. She was the product of a normal pregnancy, birth, and delivery. She had normal developmental milestones. She denied any history of febrile seizures, central nervous system infections, head injury, status epilepticus, or skin lesions and reported no family history of seizures. Her seizures were described as generalized tonic-clonic. She had been seizure free for 2 years. Originally, she received phenobarbital. The tonic-clonic seizures were controlled, but she began to have episodes of nonresponsive staring. Her medication was changed to phenytoin (PHT). PHT controlled both the staring episodes and the tonic-clonic seizures, but severe gum hypertrophy occurred. She was changed to carbamazepine, but the episodes of staring became more frequent and she developed involuntary jerking of her upper extremities. For the past 2 years, she had received 500 mg of valproate (VPA) three times per day. She reported no side effects, seizures, or other related events. Findings of computed tomography of the brain and multiple electroencephalograms (EEGs) were reported as normal. The patient's menstrual cycles were normal. At age 30, she suffered a miscarriage at 13 weeks of gestation while taking PHT. She had a 3.5-year-old son. During the pregnancy, she remained seizure free. There was no maternal or paternal history of birth defects. She was taking an oral contraceptive and had no other medical conditions. She wished to conceive in the future. She was referred by her gynecologist because of the increased risk for NTDs associated with VPA. Findings of neurological and general physical examinations were normal. Magnetic resonance imaging (MRI) of the brain, routine sleep-deprived EEG, 72-h ambulatory EEG, complete blood count, and comprehensive chemistry panel yielded normal results. The peak VPA level was 98 mg/dl and the trough level was 76 mg/dl. The patient was given folic acid 1 mg per day, calcium citrate 400 mg three times per day, selenium 30 μg per day, and zinc 30 mg per day. She was admitted for closed-circuit TV–EEG monitoring. VPA was discontinued at the time of admission. The interictal EEG was abnormal because of the presence of 4.5-Hz polyspike-and-wave formations in a generalized distribution. Three myoclonic seizures and two atypical absence seizures were recorded. She was given the diagnosis of juvenile myoclonic epilepsy. Before discharge, she was given intravenous VPA, oral VPA, and lamotrigine (LTG). She was eventually converted to LTG monotherapy in the outpatient setting. She remained seizure free without side effects while taking LTG 250 mg per day. The LTG trough level was 6 mg/dl. After 6 months of LTG monotherapy, the patient became pregnant. At 9 weeks of gestation, she began to have myoclonic jerks, and her trough LTG level was 3.5 μg/dl. LTG was increased to 300 mg per day with trough levels of 5.8 μg/dl, and she remained seizure free. The alpha-fetoprotein level and findings of level II ultrasonography were normal. At 39 weeks of gestation, a healthy male infant was born by spontaneous vaginal delivery. The infant was breastfed without complications. Three weeks postpartum, the patient complained of frequent "dizziness" after the administration of LTG, and her trough LTG levels were 8.8 μg/dl. The dose of LTG was decreased to 250 mg/day. She has remained seizure free and without side effects since that time. A 37-year-old right-handed woman presented with a history of seizures that began at age 14. She was the product of a normal pregnancy, birth, and delivery. She had normal developmental milestones. She denied any history of febrile seizures, central nervous system infections, head injury, skin lesions, or status epilepticus. Her maternal grandmother and brother had seizure disorders. The description of her seizures was consistent with myoclonic, generalized tonic-clonic, and absence seizures. Findings of general physical and neurological examinations and an MRI scan of the brain were normal. Routine EEG was abnormal because of 4-Hz polyspike-and-wave formations. The patient was diagnosed with juvenile myoclonic epilepsy. Originally, when her seizures began at age 14, she was given VPA sprinkles 250 mg three times per day, folic acid 1 mg per day, zinc 30 mg per day, selenium 30 μg per day, and calcium 400 mg twice per day. VPA peak levels were 80 μg/dl and a trough level was 68 μg/dl. She remained seizure free and without side effects for >12 years. Menstrual cycles were normal. She was taking an oral contraceptive and had no other medical conditions. She had suffered two spontaneous miscarriages within the first 8 weeks of gestation. There was no maternal history of defects, but her husband had spina bifida occulta. She wished to change her AED regimen before conception. She made the informed decision to change to LTG monotherapy. Crossover to LTG monotherapy was successful. However, despite increasing dosages of LTG, she had frequent myoclonic seizures. Alternative AEDs were discussed, but she asked to return to her previous regimen of VPA. She was converted to her original VPA regimen and, in addition, was given folic acid 4 mg per day, zinc 30 mg per day, selenium 80 μg per day, and calcium 400 mg three times per day. She had three pregnancies with normal-term infants born by spontaneous vaginal delivery. Each child was breastfed successfully. She has remained seizure free without side effects. These cases highlight that, despite the increased risks of pregnancy in women with epilepsy, with appropriate clinical management >90% of women with epilepsy can have successful pregnancies and healthy children. AED selection in women with epilepsy of reproductive age should be based on efficacy, tolerability, drug interactions, and teratogenicity. Available data should be used to formulate clinical care plans for women with epilepsy that are unique and specific to each individual. These cases have important lessons for us. Fundamental understanding of the pathophysiology, epidemiology, and genetics of NTDs, as well as comorbid conditions, allows for the planning of specific interventions and risk reduction. However, patients should be treated individually, considering that the number of variables (such as race, age, gender, weight, and body mass index) is large. In these two cases, both patients are women with juvenile myoclonic epilepsy. However, they are quite different clinically. The first woman had myoclonic, generalized tonic-clonic, and absence seizures. Her diagnosis was confirmed by EEG, which demonstrated generalized 4.5-Hz polyspike-and-wave discharges. All of these seizure types responded well to LTG. This permitted her physician to reduce the potential risk for NTDs by using LTG as an alternative to VPA. The other patient was historically and clinically similar in terms of seizure types. She also had "classic" generalized 4.0-Hz polyspike-and-wave discharges. Unlike the first woman, she did not respond to LTG and in fact had a significant worsening of her myoclonus. Exacerbations of myoclonic seizures have been described with LTG (1,2). It was therefore appropriate for her to be returned to her original VPA regimen to have her seizures controlled. Congenital malformations are unfortunate pregnancy outcomes. Modern technology permits us to diagnose the vast majority relatively early in gestation. It is estimated that anatomic ultrasonography is >95% accurate at 16 weeks of gestational age. This may still leave parents with the uncomfortable decision of whether to terminate a pregnancy. This is always a difficult choice, one that we would like our patients to be able to avoid. Although the risk for NTDs is only 1–2% with VPA exposure, it is clear that alternative AEDs with the broad spectrum and clinical efficacy of VPA but without this risk are needed. Several newer AEDs, including LTG, levetiracetam, topiramate, and zonisamide, appear to be effective in a variety of epilepsy types, although their impact on myoclonus and absence has yet to be clearly established. Our experience with their safety in pregnancy is unfortunately limited; however, the data are greatest for LTG. The International Lamotrigine Pregnancy Registry has identified 334 first-trimester pregnancy outcomes in women exposed to LTG monotherapy or polytherapy. The malformation rates when LTG is used as monotherapy, as polytherapy without VPA, and as polytherapy with VPA are 1.8, 4.3, and 10.0%, respectively (3). These results suggest that LTG is relatively safe, but with low-frequency outcomes such as NTDs, even these sample sizes have modest power. In general, there is an inherent potential for sample bias in registries, and this registry cannot be considered a random sample of women taking LTG. Nevertheless, it is a very positive thing that we have this information for LTG: data for the other medications are extremely limited, so much so that no estimate of the risk of those agents in pregnancy can be made. Another useful observation from these case reports is the demonstration of the sharp decline in plasma concentration that occurs in pregnancy. While this phenomenon has been well documented for most "older" AEDs, it is useful to remember that newer agents are not immune to increased clearance and decreased plasma levels. Careful monitoring is required to ensure that the drug levels remain in the therapeutic range and that the patient is thus protected from seizures. Folic acid supplementation is clearly appropriate for all women. However, its protective effect is not absolute, and thus careful planning and pregnancy management are still critical if outcomes are to be optimized. The American Academy of Neurology has developed guidelines (4) to assist clinicians in treating patients: these guidelines have great utility but require flexibility. The American Academy of Neurology's Guidelines for pregnant women with epilepsy are summarized below. In view of the risks of epilepsy and pregnancy for mother and fetus, the fact that no single AED is safer than any other for use in pregnancy (with the exception of trimethadione), and the fact that both seizures and AEDs have the potential for harm, the following guidelines are recommended: Women of childbearing age should be counseled early and educated about the risks of pregnancy and adverse pregnancy outcomes. Included in the educational counseling of the patient should be information regarding the increased risk of seizures during pregnancy, as well as the increased risk of adverse pregnancy outcomes. The importance of monotherapy should be emphasized with the patient and attempts to switch to monotherapy made if withdrawal from the patient's AED is not recommended. Preconceptional supplementation has been recommended by the Centers for Disease Control for all women of childbearing age. The recommended dosage is 0.4 mg/day. This should be encouraged for women with epilepsy. The patient, her family, and the obstetrician should be educated about the risks of AED use during pregnancy. The patient should ideally have AED concentrations monitored monthly. The measurement of unbound levels may be necessary to adequately monitor the patient. The patient should continue folate supplementation during pregnancy. Supplemental vitamin K (10 mg/day) should be given during the last 2 weeks of pregnancy. The patient and fetus should be monitored for evidence of malformations and growth retardation, ideally with ultrasound. AEDs should be changed only if it is necessary to do so to improve seizure control. AED concentrations should be monitored through the eighth postpartum week. The patient should be counseled on how to deal with seizures while managing child care. Breastfeeding can generally be performed safely in term infants. These cases illustrate the importance of precise diagnosis, without which one has no foundation on which to develop a treatment plan. Second, they illustrate that even when patients appear similar clinically (both had juvenile myoclonic epilepsy), they may still be divergent in their response to AEDs. We report outcomes in terms of relative risk. Relative risk is just that, relative. There is no study to date with enough statistical power to give clear and accurate rates for individual AED exposure. This, coupled with the variables of race, occupation, geography, and pharmacogenetics, makes individual case prediction extremely difficult. We can lower but not eliminate risks. One must be willing to modify one's approach to meet the needs of individual patients. The large body of collective medical information allows us to generalize about patients and their conditions, but we care for them as individuals, one at a time.