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.

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.

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.

Familial encephalopathy with neuroserpin inclusion bodies.

We report on a new familial neurodegenerative disease with associated dementia that has presented clinically in the fifth decade, in both genders, and in each of several generations of a large family from New York State-a pattern of inheritance consistent with an autosomal dominant mode of transmission. A key pathological finding is the presence of neuronal inclusion bodies distributed throughout the gray matter of the cerebral cortex and in certain subcortical nuclei. These inclusions are distinct from any described previously and henceforth are identified as Collins bodies. The Collins bodies can be isolated by simple biochemical procedures and have a surprisingly simple composition; neuroserpin (a serine protease inhibitor) is their predominant component. An affinity-purified antibody against neuroserpin specifically labels the Collins bodies, confirming their chemical composition. Therefore, we propose a new disease entity-familial encephalopathy with neuroserpin inclusion bodies (FENIB). The conclusion that FENIB is a previously unrecognized neurodegenerative disease is supported by finding Collins bodies in a small kindred from Oregon with familial dementia who are unrelated to the New York family. The autosomal dominant inheritance strongly suggests that FENIB is caused by mutations in the neuroserpin gene, resulting in intracellular accumulation of the mutant protein.

Familial dementia caused by polymerization of mutant neuroserpin.

Aberrant protein processing with tissue deposition is associated with many common neurodegenerative disorders; however, the complex interplay of genetic and environmental factors has made it difficult to decipher the sequence of events linking protein aggregation with clinical disease. Substantial progress has been made toward understanding the pathophysiology of prototypical conformational diseases and protein polymerization in the superfamily of serine proteinase inhibitors (serpins). Here we describe a new disease, familial encephalopathy with neuroserpin inclusion bodies, characterized clinically as an autosomal dominantly inherited dementia, histologically by unique neuronal inclusion bodies and biochemically by polymers of the neuron-specific serpin, neuroserpin. We report the cosegregation of point mutations in the neuroserpin gene (PI12) with the disease in two families. The significance of one mutation, S49P, is evident from its homology to a previously described serpin mutations, whereas that of the other, S52R, is predicted by modelling of the serpin template. Our findings provide a molecular mechanism for a familial dementia and imply that inhibitors of protein polymerization may be effective therapies for this disorder and perhaps for other more common neurodegenerative diseases.

Male infertility: possible association with valproate exposure.

PURPOSE: To describe a potential association between male infertility and valproate (VPA) exposure. VPA has been implicated in the development of polycystic ovarian disease and subsequent menstrual and infertility problems in women with epilepsy. Infertility has been well described in population-based studies of persons with epilepsy. The low marital rates for men with epilepsy have previously been thought to play a major contributing role. METHODS: We report a case of a 32-year-old man whose wife and he were able to bear a child before the development of his epilepsy. With VPA monotherapy, the family were unable to conceive despite 4 years of unprotected intercourse. An infertility evaluation of the man revealed a very low sperm count of < 50,000/ml, no motile sperm, < 10% viability, and 100% with abnormal structure. Follicle-stimulating hormone, luteinizing hormone, and testosterone levels were normal. RESULTS: Felbamate (FBM) was initiated and VPA discontinued for improved seizure control. Within 4 months, the couple conceived their second child. A seminal analysis revealed a sperm count of > 16 million, 50% motility, 78% viability, and 72% with abnormal structure. CONCLUSIONS: One must be cautious in extrapolating from a case report, but these findings strongly suggest a direct effect of VPA on spermatic structure and function.

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.

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.

Contraception, pregnancy and lactation in women with epilepsy.

Despite all of our advances women with epilepsy face obstacles when it comes to pregnancy and childbearing. Many of these obstacles are social, based on incorrect and inappropriate attitudes of the public towards persons with epilepsy. Unfortunately many of the uninformed public are health care providers. We must continue to educate not only our patients but our colleagues so that women with epilepsy will cease to face discriminatory behaviour. Most women with epilepsy can conceive and bear healthy children. They have higher probabilities of infertility but this is often amenable to treatment. Complications of pregnancy are higher and revolve primarily around the increased risk of maternal seizures. Careful monitoring of the clinical condition of the patient and her free anticonvulsant levels will obviate much of this difficulty. Maternal seizures themselves can pose hazards for women with epilepsy and their offspring and generalized convulsive seizures are clearly to be avoided. Adverse pregnancy outcomes tend to be seen more often in particular: congenital malformations 4-6%; dysmorphic features < 10%; neonatal haemorrhage < 7%; fetal death and neonatal and infant mortality a two to threefold increase over the general population; and an uncertain risk of developmental delay particularly in the area of language acquisition. Of the potential variables of interest: anticonvulsants, maternal seizures during gestation, and the genetics of maternal epilepsy, it is at present unclear which is the most important in determining a good pregnancy outcome. Current research suggests that anticonvulsant drugs are probably responsible for the increased risk of malformations. Malformations are, however, only one of the adverse outcomes of concern. Risks can be reduced by ensuring good seizure control; monotherapy: preconceptual use of multivitamins with folate. The plethora of new anticonvulsants offers us new opportunities for improving the function and control of persons with epilepsy. Unfortunately we are uncertain how hazardous the newer anticonvulsant drugs are in pregnancy. Felbamate, gabapentin, lamotrigine, vigabatrine, and topiramate have all been recently introduced. The number of exposed women is so small that no pattern or estimates of risk can be determined at this time. Careful monitoring as is being performed by the Lamotrigine and North American Epilepsy and Pregnancy Registries will hopefully provide the necessary safety information in the near future. All of the risks aside, the majority of women with epilepsy can and will have healthy children.

PIP: More effective anti-epileptic drugs, therapeutic plasma monitoring of drug effects, and better understanding of the risk factors for pregnancy have made it possible for women with epilepsy to have healthy, normal children. Nonetheless, women with epilepsy face special problems with regard to contraception, pregnancy, and lactation. Since enzyme-inducing anti-epileptic drugs lower estrogen concentrations by 40-50%, thereby compromising contraceptive effectiveness, hormonal contraceptives prescribed to women with epilepsy should contain at least 50 mcg of ethinyl estradiol. During pregnancy, up to one-third of women with epilepsy experience an increase in seizure frequency as drug plasma concentrations decline. Epileptic women are also at greater risk of obstetric complications during pregnancy and delivery, including anemia, vaginal bleeding, pre-eclampsia, abruptio placentae, premature labor, and stillbirth. The research literature suggests that the risk of congenital abnormalities, most notably neural tube defects, is 4-8% for infants exposed in utero to anti-epileptic drugs compared to 2-3% for the general population. To date, six clinical anti-epileptic-drug-related fetal syndromes have been identified. Since anticonvulsant drugs are secreted in breast milk, infants may become sleepy and stop feeding prior to satiation. Despite these potential complications, the likelihood of a positive pregnancy outcome can be enhanced by preconceptional use of folic acid supplements, monthly monitoring of treatment drug levels to prevent seizures, and ultrasound or amniocentesis at 16-18 weeks of gestation to detect neural tube defects.

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.

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.

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.

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).

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.

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.

Pregnancy and epilepsy.

Women with epilepsy account for approximately 0.5% of all pregnancies. Their pregnancies are high risk because of an increased frequency of maternal seizures, complications of pregnancy, and adverse pregnancy outcomes. The increase in seizure frequency is associated with a progressive decline in antiepileptic drug (AED) levels during pregnancy even with constant dosing. Fetal deaths after a generalized seizure, although rare, have been reported, and a marked decline in fetal heart rate has been demonstrated after such seizures during delivery. AEDs have been implicated in causing a twofold increase in the rate of congenital malformations, a variety of minor physical anomalies, mostly involving the midface, and a neonatal hemorrhagic disorder. The clinician caring for a pregnant woman with epilepsy is therefore faced with a dilemma and must carefully chart a middle ground providing effective seizure control while minimizing fetal exposure to AEDs.

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.