Quality of life, epilepsy advances, and the evolving role of anticonvulsants in women with epilepsy.

In the United States, approximately 1.1 million women of childbearing age have epilepsy. Even though antiepileptic drugs (AEDs) control the seizures of about 80% of patients with epilepsy, the management of women with epilepsy (WWE) presents physicians with unique problems, ranging from the cosmetic consequences of some AEDs (e.g., changes in weight) to the seizures of catamenial epilepsy (apparently related to a relative lack of progesterone during the luteal phase of the menstrual cycle). In addition, the effectiveness of hormonal contraceptives can be reduced by enzyme-inducing AEDs. The pregnancies of WWE present a greater risk for complications: one-quarter to one-third of WWE experience an increase in seizure frequency. In addition, difficulties during labor and adverse outcomes (e.g., fetal mortality and malformations, neonatal hemorrhage, low birth weight, and developmental delay) are more likely. The practitioner must choose a course that both prevents seizures and minimizes fetal exposure to AEDs.

Antiepileptic drug disposition during pregnancy.

A significant proportion of women with epilepsy have an increase in their seizure frequency during pregnancy. Multiple factors may be involved in this phenomenon, but changes in antiepileptic drug (AED) concentration appear to be the most significant. AED concentration declines as pregnancy progresses, due primarily to dynamic changes in plasma protein binding. Total concentrations of all first-line AEDs (carbamazepine, phenytoin, phenobarbital, and valproic acid) fall significantly during pregnancy, compared to baseline. Free or unbound drug concentrations, however, fall significantly only for phenobarbital. Valproate free concentrations actually increase by 25% by delivery. Women taking carbamazepine, phenytoin, or valproate may be relatively protected by adequate free concentrations of these compounds. When managing pregnant women with epilepsy, measurement of free AED concentrations and appropriate dose adjustment to maintain therapeutic ranges will permit more effective clinical management than using total concentration values.

Progressive dementia and epilepsy in a young adult: unusual intraneuronal inclusions.

A 30-year-old woman had a syndrome of dementia, dystonia, myoclonus, and intention tremor. Brain biopsy showed PAS-positive inclusions of Lafora's disease, but electronmicroscopy demonstrated that the inclusions differed from previously reported Lafora bodies. This may represent a previously undescribed disorder.

Serum prolactins in the diagnosis of epilepsy: sensitivity, specificity, and predictive value.

Serum prolactin levels rise after generalized tonic-clonic and partial complex seizures, but not after pseudoepileptic seizures. The criteria for a significant elevation in serum prolactin vary with individual investigators. The prevalence of pseudoseizures in the population studied determines the predictive value of serum prolactin determinations. In populations where most patients have epilepsy, a rise in serum prolactin is highly predictive for true epilepsy, but no increase in serum prolactin is not predictive for pseudoseizures.

Epilepsy in pregnancy: developmental outcome of offspring at 12 months.

Women were enrolled in our prospective cohort study of epilepsy and pregnancy to determine the developmental outcome of offspring and the immediate outcome of pregnancy. Women with epilepsy (case group) were enrolled before conception or during the first trimester, and women without epilepsy or chronic illness (control group) were recruited during pregnancy. We have now completed 12-month evaluation for 43 children in the case group and 41 in the control group. We found no difference in growth parameters between the groups. The children in the case group had a higher mean number of minor anomalies than did those in the control group, and their features were consistent with those previously reported for children exposed to AEDs in utero. Developmental differences between the two groups varied, with some differences reaching statistical significance. The findings reported here are preliminary, since the children will be evaluated through 3 years of age.

A new method of measuring brain atrophy: the effect of aging in its application for diagnosing dementia.

A new method of measuring cerebral atrophy using a ratio of brain parenchyma to ventricular and subarachnoid space is described. It uses digitized brain CT. This ratio was measured prospectively on 117 consecutive elderly patients referred for evaluation of cognitive dysfunction. Diagnosis was determined by preestablished criteria and confirmed by follow-up. Despite the improved accuracy and reproducibility of this method, its ability to differentiate persons with senile dementia of the Alzheimer's type (SDAT) from those suffering from pseudodementia was confounded by age, and was hence of limited utility. We conclude that even with sophisticated measures of cerebral atrophy, CT is unable to discriminate among common causes of cognitive dysfunction in the elderly.

Management issues for women with epilepsy: a review of the literature.

OBJECTIVE: A review of literature referable to management issues for women with epilepsy (WWE) was undertaken for the development of a practice parameter. BACKGROUND: Epilepsy is a common neurologic condition with gender-related management implications. Although reviews of this topic often focus on pregnancy-related issues for WWE, specific health concerns for WWE are present throughout all phases of reproductive life. METHODS: An OVID MEDLINE literature search was conducted for 1965 to 1997 using the following key words/phrases and cross referencing: epilepsy/ seizures and pregnancy, anticonvulsants, antiepileptic drugs (AEDs), teratogenesis, oral contraceptives, birth defects, folate/folic acid, vitamin K, metabolic bone disease, and breast-feeding. RESULTS: Pregnancy outcome literature for WWE spans several decades. Methodology varies and interpretation is complicated by modern management strategies. Contributions of socioeconomic factors, AEDs, maternal epilepsy, and seizures during pregnancy to adverse pregnancy outcomes have not been clearly delineated. There is a biologic basis for recommendations concerning contraception, folate supplementation, vitamin K use in pregnancy, breast-feeding, metabolic bone disease, catamenial epilepsy, and reproductive endocrine disorders, but no outcome studies afford a strong evidence base for practice recommendation. CONCLUSIONS: WWE face health issues for which there is no available outcome literature to guide decision making. The urgent need for studies in many of these areas is highlighted by expanded treatment options with new AEDs and epilepsy surgery.

Antiepileptics and the development of congenital anomalies.

We are conducting a prospective cohort study of epilepsy and pregnancy to determine the nature and extent of adverse pregnancy outcomes in infants of mothers with epilepsy (IME). Women with epilepsy were enrolled no later than the first trimester and were matched with controls; their infants were examined at 8 weeks by pediatricians blinded to maternal status. A number of variables were compared between case and control infants: birth weight, length, gestational age, head circumference, Apgar scores, feeding difficulties, neonatal irritability, and presence of major malformations and minor anomalies. The number of minor anomalies per infant was greater for IME than for controls (mean, 5.05 and 3.65, p less than 0.0001 per infant, respectively). Prominent occiput was the only anomaly seen significantly more often in IME than in controls (p less than 0.05).

The validity of 3 clinical diagnostic criteria for Alzheimer's disease.

To examine the validity of criteria-based (clinical) diagnosis of Alzheimer's disease (AD), 4 physicians experienced in the evaluation of dementia patients applied 3 sets of diagnostic criteria to each of 62 patients based on standardized medical record information. Diagnostic outcome was validated by neuropathologic examination (completed previously) for all (43) demented patients and 4 nondemented patients and by follow-up in the remainder (15) with no dementia. Raters were blind to the composition of the study group as well as to the clinical and pathologic diagnoses. We evaluated 3 diagnostic criteria sets for AD: the American Psychiatric Association diagnostic criteria from the Diagnostic and Statistical Manual (DSM-III), the NINCDS-ADRDA Work Group criteria for the diagnosis of Alzheimer's disease (NINCDS), and the Eisdorfer and Cohen research diagnostic criteria for primary neuronal degeneration (ECRDC). ECRDC had the highest specificity (0.88) but also the greatest odds of false-negative diagnosis (LRneg = 0.61, sensitivity = 0.46). NINCDS had the best sensitivity (0.92, specificity = 0.65), and DSM-III showed intermediate values (sensitivity = 0.76, specificity = 0.80). We conclude that the investigator or clinician who wishes to ensure that patients classified as AD are more likely to be AD should choose DSM-III, whereas the investigator who wishes to include the greatest number of AD cases, seldom assigning a diagnosis of no AD to a true case, should choose NINCDS.

Special considerations for women with epilepsy.

Women with epilepsy present health care providers with unique problems and opportunities for advancement of care. The fundamentals of epileptic pathophysiology are similar in both sexes. There are, however, some significant differences. Cosmetic effects of antiepileptic drugs (AEDs) may have different implications for women. Women who have seizures associated with their menstrual cycle may need special attention regarding their cyclic hormonal changes and AED selection. Antiepileptic drugs may reduce the effectiveness of hormonal contraception. Women with epilepsy have higher rates of infertility and an increased prevalence of reproductive and endocrine disorders. The majority of women with epilepsy have normal, healthy children, but their pregnancies are considered high risk due to an increase in seizure frequency, metabolic alterations of AEDs (which complicate management), and an increased risk of adverse pregnancy outcomes. These issues and an approach to optimize the management of women with epilepsy are discussed.

The use of anticonvulsants during pregnancy.

Antiepilepsy (AED) medications have revolutionized the treatment of epilepsy, transforming it from a chronic progressive disease with inevitable cognitive and motor decline to a disorder in which most effected persons operate largely in a normal fashion. As with all medications adverse experiences can occur. However, it has been clear that the alternative of uncontrolled seizures are more hazardous than pharmacological therapies. However, physicians are faced with a dilemma when treating fertile or pregnant women with epilepsy. Many AED impair the effectiveness of oral contraceptives. There is evidence that some AED may effect fertility. AED metabolism changes in pregnancy, making management of women with epilepsy more difficult. AED exposure in early pregnancy increases the risk of congenital malformations, and exposure during other phases may increase the risk of developmental delay and neonatal hemorrhage. AED can be secreted in breast milk, thus extending the exposure into infancy. The exclusion of women of childbearing age from clinical trials limits our ability to collect information on the pharmacokinetics and potential adverse experiences of AED in pregnancy. Thus, when new medications are marketed, clinicians and their patients have no information on how to best manage conception, pregnancy, and lactation. This article discusses these issues in detail and describes our current understanding of the use of AED in women of childbearing age.

Use of unbound drug concentrations to determine neonatal anticonvulsant exposure.

Unbound and total concentrations of several anticonvulsant drugs were measured by liquid chromatography in maternal and neonatal cord serum collected at birth from 16 women being treated for epilepsy and their newborns. Maternal and neonatal unbound drug concentrations agreed closely for phenobarbital (n = 6), phenytoin (n = 7), carbamazepine (n = 8), and its epoxide metabolite. Mean maternal total drug concentrations were higher than neonatal concentrations in the cases of phenobarbital, carbamazepine, its epoxide and diol metabolites. The differences were due to greater protein binding in maternal serum. Measurement of total anticonvulsant concentrations in newborns may be misleading, because of altered protein binding in the neonate. For the medications tested, neonatal and maternal exposures to unbound drug appear to be equivalent.

Pharmacokinetics of anticonvulsants in pregnancy: alterations in plasma protein binding.

Anticonvulsant levels decline as pregnancy progresses, even in the face of constant and, in some cases, increased dosages of medications. It has been suggested that this decline is responsible for the increase in seizure frequency seen in approximately one-third of the women with epilepsy who become pregnant. Changes in plasma protein binding may explain the declines in anticonvulsant concentrations during pregnancy. A prospective cohort study was designed to test this hypothesis. Carbamazepine, phenytoin and phenobarbital were studied. The mean total concentrations of all 3 drugs declined as pregnancy progressed, rising in the postpartum period. Free concentrations also declined, but did so significantly only for phenobarbital. The free fraction for all anticonvulsants studied rose significantly throughout pregnancy. Protein binding is significantly altered during pregnancy for all 3 drugs studied and appears to account for much of the decline in anticonvulsant concentrations seen in this condition. It is suggested that free rather than total drug concentrations be monitored in pregnant women with epilepsy.

Epilepsy and pregnancy. New issues for an old disorder.

Clinicians and their women patients with epilepsy face difficult decisions. There is evidence to suggest that antiepileptic drugs increase the risk of major malformations, minor anomalies, neonatal hemorrhage, and delayed fetal growth and development. Maternal seizures also appear to be disadvantageous to the fetus, increasing the risk of miscarriage, premature labor, intracranial hemorrhage, and perhaps, developmental or learning difficulties. Both medications and seizures have the potential to cause difficulties. This article discusses change in antiepileptic drug metabolism, changes in seizure frequency, adverse pregnancy outcomes, and principles of management.

Pregnancy, teratogenesis, and epilepsy.

Women with epilepsy who are of childbearing age need to understand what the risks of pregnancy are. These women have a 33% risk of increased seizures, a twofold increase in risk of hemorrhage, eclampsia, premature labor, and an increased need for cesarean sections. Babies born to women with epilepsy face a higher risk of miscarriage, stillbirth, prematurity, developmental delay, and major malformations. Seizure control should be obtained without clinical toxicity. Monotherapy reduces the risk of adverse outcomes.

Women with epilepsy. Reproduction and effects of pregnancy on epilepsy.

Conventional wisdom and prevailing medical practice strongly support the belief that medication should be avoided during pregnancy. For the nearly one million women of childbearing age with epilepsy in the United States this is often difficult, if not impossible, and for many of these women becoming pregnant raises many conflicting issues. Women with epilepsy may face a possible increase in the frequency and severity of seizures, and in generalized tonic-clonic seizures there is a small but increased risk of miscarriage.

Management of epilepsy: pharmacologic therapy and quality-of-life issues.

Treatment of epilepsy extends far beyond the administration and monitoring of antiepileptic drug therapy. Persons with epilepsy have cognitive, vocational, and psychosocial needs that may exceed the scope of the primary care physician's clinical responsibilities. In such cases, the physician can assemble and manage a team of medical and social service professionals to address these needs. By establishing this support system and maintaining effective communication with the patient and the management team, the primary care physician offers patients with epilepsy the opportunity to improve and maintain their quality of life and receive safe and effective pharmacologic treatment.

Risks of pregnancy in women with epilepsy.

Pregnant women with epilepsy are at increased risk of seizures and complications. An increase in seizure frequency is seen in 25-30% of pregnant women with epilepsy; the offspring of mothers who experienced seizures during pregnancy are at a 2.5 times higher risk for seizures later in life. One of the main reasons for the increase in seizures during pregnancy is a decline in plasma concentrations of antiepileptic drug (AED) that occurs as pregnancy progresses, largely as a result of marked alterations in plasma protein binding. It is well known that epilepsy represents a risk for a variety of adverse pregnancy outcomes or malformations, especially in polytherapy. The adverse outcomes range from dysmorphic features to hemorrhagic disorders resulting from a deficiency of vitamin K-dependent clotting factors or to spina bifida. Folic acid supplements appear to reduce the risk of spina bifida. A strong genetic link seems to exist for many of the malformations that occur, and more research is required in this field. In the meantime, there are interventions that clinicians can already make to reduce the risk of adverse outcomes, such as seizure control without toxicity, monotherapy, and preconceptual use of vitamins with folate.

Problems and management of the pregnant woman with epilepsy.

Pregnancies occurring in women who are epileptic are considered to be high risk. These women are at increased risk of seizures during pregnancy, labor, and delivery and of pregnancy complications and adverse pregnancy outcomes. Pregnancy alters the pharmacokinetics of anticonvulsant drugs, the levels of which decline as pregnancy advances. Not all drugs are altered in a similar manner, however. The rate of congenital malformations in infants of epileptic mothers is 2.4 times higher than in the general population. Malformations occur with all of the commonly used anticonvulsant drugs. The possible mechanisms of teratogenicity include folic acid antagonism, fetal tissue binding, and toxic effects of metabolic intermediates. Therapy with more than one drug increases the risk of congenital malformations. A unique hemorrhagic phenomenon in the infants of epileptic mothers has been reported and appears to be the result of a deficiency of vitamin K-dependent clotting factors. When taken by a pregnant woman, all antiepileptic drugs except valproic acid manifest themselves in breast milk, but only if the infant exhibits evidence of sedation should breastfeeding be discontinued. The dilemma for the physician treating the pregnant epileptic woman is to protect the mother from seizures and the fetus from unnecessary exposure to anticonvulsant medications.