Epilepsy and bone health in adults

Adults taking antiepileptic drugs (AEDs) have an augmented risk for osteopenia and osteoporosis because of abnormalities of bone metabolism associated with AEDs. The increased fracture rates that have been described among patients with epilepsy may be related both to seizures and to AEDs. The hepatic enzyme-inducing AEDs phenytoin, phenobarbital, and primidone have the clearest association with decreased bone mineral density (BMD). Carbamazepine, also an enzyme-inducing drug, and valproate, an enzyme inhibitor, may also adversely affect bone, but further study is needed. Little information is available about specific effects of newer AEDs on bone. Physicians are insufficiently aware of the association between AEDs and bone disease; a survey found that fewer than one-third of neurologists routinely evaluated AED-treated patients for bone disease, and fewer than 10% prescribed prophylactic calcium and vitamin D. Physicians should counsel patients taking AEDs about good bone health practices, and evaluation of bone health by measuring BMD is warranted after 5 years of AED treatment or before treatment in postmenopausal women.     

The association between CYP 2C9 polymorphism and bone health

PurposeThere is a strong scientific rationale to support the view that cytochrome P450 (CYP P450) enzyme-inducing AEDs induce bone loss in patients with epilepsy. However, no study has investigated the association between CYP 2C9 polymorphism and bone mineral density (BMD), 25-hydroxyvitamin D or parathyroid hormone levels in patients with epilepsy. This study sought to determine the association between BMD and CYP 2C9 polymorphism.MethodsNinety-three patients taking phenytoin as monotherapy were examined for CYP 2C9 polymorphism, vitamin D level and parathyroid hormone level and underwent basic chemistry testing. The bone mineral density of the lumbar spine and left femur were measured using dual-energy X-ray absorptiometry.ResultsThe results indicated that about 18.3% of the patients with epilepsy were positive for CYP2C9*3. Furthermore, bone mineral density was associated with CYP 2C9 polymorphism epileptic patients. Specifically, patients with 2C9 polymorphism had higher T-scores and Z-scores of the femoral neck (p = 0.02 and 0.04, respectively), but not of the lumbar spine (p = 0.27 and 0.06, respectively). There was also a trend of having higher serum PTH levels and statistically significantly lower 25-hydroxyvitamin D levels in patients with wild type than in those compared with CYP 2C9 polymorphism (p = 0.05 and 0.03, respectively). Additionally, the patients with CYP 2C9 polymorphism had higher plasma levels of phenytoin, particularly when compared with those with wild type (p = 0.01). However, there was no association between serum levels of phenytoin and low BMD at femoral neck or lumbar spine.ConclusionCYP 2C9 polymorphism is associated with higher BMD, independent of plasma levels of phenytoin.     

A 6-month longitudinal study of bone mineral density with antiepileptic drug monotherapy

Antiepileptic drugs (AEDs) can affect bone metabolism, but the exact mechanisms or differences in individual drugs are still unknown. The purpose of this study was to prospectively investigate the alterations in bone mineral density (BMD) and markers of bone metabolism induced by different AEDs in Koreans with epilepsy. Subjects included 33 drug-naïve, newly diagnosed patients with epilepsy aged between 18 and 50. BMD at right calcaneus and various markers for bone metabolism were measured before and after 6 months of AED monotherapy including carbamazepine, valproic acid, and lamotrigine. Carbamazepine caused a significant decrease in BMD, which was accompanied by a decrease in the level of vitamin D (25-OHD₃). BMD and vitamin D were not affected by 6 months of valproic acid or lamotrigine therapy. Interestingly, valproic acid and lamotrigine, but not carbamazepine, significantly increased osteocalcin, a marker of bone formation. All AEDs almost doubled the parathyroid hormone level, whereas urinary Pyrilinks, a marker of bone resorption, was not affected by those AEDs. These findings suggest that carbamazepine, a hepatic enzyme-inducing drug, decreases BMD.     

Bone mineral density in an outpatient population receiving enzyme-inducing antiepileptic drugs

Antiepileptic drug (AED) use is identified as being associated with increased fracture risk. AEDs commonly associated with osteopathies are inducers of the hepatic cytochrome p450 enzyme system (EIAEDs). We performed a retrospective cross-sectional study assessing bone mineral density (BMD) in an adult outpatient population receiving EIAEDs. Patients were routinely referred for dual-energy X-ray absorptiometry to evaluate BMD. BMD was measured at the femoral neck of hip and lumbar spine. Results were presented as absolute BMD (g/cm(2)), T score, and Z score. T and Z scores were used in this analysis. As a group, those with BMD measurements represent people with intractable epilepsy. There were no statistically significant differences found in the T or Z scores by gender; therefore all analyses combined both men and women. Significant reductions in both T and Z scores were present in men and women <50 and >or=50.     

Bone density and antiepileptic drugs: a case-controlled study.

This case-controlled study explored the relationship between bone mineral density (BMD) and long-term treatment with antiepileptic drugs (AEDs) in older adults with epilepsy. Seventy-eight patients (47 post-menopausal females, 31 males, aged 47-76 years) with epilepsy participated in the study. Each had only ever received treatment with either enzyme-inducing (n = 52) or non-inducing (n = 26) AEDs. Individuals were matched for age, sex, height and weight with a drug-naive control. All patients underwent bone densitometry at the lumbar spine and femoral neck and had blood sampling and urine collected for a range of bone markers. Male patients had lower BMD than controls at the lumbar spine (P < 0.01) and neck of the femur (P < 0.005). Female patients had significantly reduced bone density at the femoral neck (P < 0.05) only. AED usage was independently associated with an overall reduction in bone density at femoral sites and contributed to just over 5% of the variance at the femoral neck. Duration of treatment and type of AED were not independent factors for reduction in BMD. This case-controlled study supports the hypothesis that long-term AED therapy is an independent risk factor for reduced BMD in epileptic patients. Adults receiving treatment for epilepsy are at higher risk of osteoporosis and should be offered bone densitometry.     

Normal vitamin D and low free estradiol levels in women on enzyme-inducing antiepileptic drugs

Relationships between reproductive hormone levels, bone turnover marker levels, bone mineral density, and rates of bone loss were evaluated in premenopausal women with epilepsy taking enzyme-inducing antiepileptic drugs (EIAEDs: phenytoin or carbamazepine) or lamotrigine. Calciotropic and reproductive hormone levels, bone turnover marker levels, and bone mineral density were measured at baseline and 1 year. Bone mineral density did not differ between groups. Serum calcium (P<0.001) and estrone (P<0.001) levels were lower in the EIAED group. Sex hormone-binding globulin levels were higher (P<0.001) and percentage free estradiol levels were lower (P<0.001) in the EIAED group. We detected no relationship between bone mineral density change and calciotropic hormone or bone turnover marker levels. Women with higher sex hormone-binding globulin and lower free estradiol levels sustained more bone loss at the total hip (P=0.04 and P=0.02) and a trend toward more bone loss at the lumbar spine (P=0.07 and P=0.08). These findings suggest that lower estrogen levels may contribute to bone loss in premenopausal women with epilepsy.     

Disease- and treatment-related effects on the pituitary–gonadal functional axis: a study in men with epilepsy

The consideration of the patient’s gender has become an established practice in the choice of antiepileptic drugs (AEDs) for the treatment of epilepsy. This study was undertaken to confirm that temporal lobe epilepsy and the use of hepatic enzyme-inducing AEDs, have a negative effect on sex hormones in men. We calculated the testosterone (T)/luteinizing hormone (LH) ratio to reflect the effects of epilepsy or its treatment on the most important androgen and its pituitary control hormone. Of 324 men with focal epilepsy identified (untreated or on AED monotherapy), 201 were eligible for inclusion (mean age 37.5 years¸ mean duration of epilepsy 14.7 years). A total of 105 men served as healthy controls (mean age 33.9 years). Patients with temporal lobe epilepsy were more likely to show abnormal T/LH ratios than patients with extratemporal epilepsy (p < 0.01). Patients receiving AEDs with marked hepatic enzyme-inducing effects were more likely to have low T/LH ratios than patients taking nonenzyme-inducing AEDs or healthy controls (p < 0.01). Focus localization and AED choice affect male sex hormones. Findings raise some concerns about the effect of enzyme-inducing AEDs on sexual endocrine functions.     

Effect of antiepileptic drugs on bone density in ambulatory patients

BACKGROUND: Long-term antiepileptic drug (AED) use causes multiple abnormalities in calcium and bone metabolism that have been most extensively described in institutionalized patients. The objective is to determine the effect of AED on vitamin D levels and bone density in ambulatory patients and to compare the effects of enzyme-inducing and -noninducing AED and of single vs multiple therapy on bone density. METHODS: A cross-sectional evaluation was conducted of 71 patients (42 adults and 29 children/adolescents) on anticonvulsant therapy for at least 6 months who presented to neurologists at a tertiary referral center. Bone mineral density (BMD) as well as serum 25 hydroxy-vitamin D (25-OHD) levels were measured. A detailed questionnaire assessing calcium intake as well as previous and current intake of antiepileptic medications was administered to all patients. RESULTS: Over 50% of adults and children/adolescents had low 25-OHD levels, but this finding did not correlate with BMD. Antiepileptic therapy decreased BMD in adults. Generalized seizures, duration of epilepsy, and polypharmacy were significant determinants of BMD, more so at skeletal sites enriched in cortical bone. Subjects on enzyme-inducing drugs such as phenytoin, phenobarbital, carbamazepine, and primidone tended to have lower BMD than those on noninducers such as valproic acid, lamotrigine, clonazepam, gabapentin, topamirate, and ethosuximide. CONCLUSION: Epilepsy and its therapy, including the newer drugs, are risk factors for low bone density, irrespective of vitamin D levels. Skeletal monitoring with the institution of appropriate therapy is indicated in patients on chronic antiepileptic therapy.     

BsmI vitamin D receptor’s polymorphism and bone mineral density in men and premenopausal women on long‐term antiepileptic therapy

Background: Utilization of antiepileptic drugs (AEDs) has long been associated with bone deleterious effects. Furthermore, the BsmI restriction fragment polymorphism of the vitamin D receptor (VDR) has been associated with reduced bone mineral density (BMD), mostly in postmenopausal women. This study evaluates the association between bone metabolism of patients with epilepsy and the BsmI VDR’s polymorphism in chronic users of AEDs. Methods: This study evaluated 73 long‐term users of antiepileptic drug monotherapy, in a cross‐sectional design. Fasting blood samples were obtained to estimate the circulating serum levels of calcium, magnesium, phosphorus, parathormone, 25hydroxyvitamin D as well as the VDR’s genotype. Bone mineral density at the lumbar spine was measured with Dual Energy X‐Ray Absorptiometry. Results: Bone mineral density was significantly associated with the genotype of VDR (mean BMD: Bb genotype 1.056 ± 0.126 g/cm²; BB genotype 1.059 ± 0.113 g/cm²; bb genotype 1.179 ± 0.120 g/cm²; P < 0.05). Additionally, the presence of at least one B allele was significantly associated with lower bone mineral density (B allele present: BMD = 1.057 ± 0.12 g/cm², B allele absent: BMD = 1.179 ± 0.119 g/cm²; P < 0.01). Patients with at least one B allele had lower serum levels of 25hydroxyvitamin D when compared with bb patients (22.61 ng/ml vs. 33.27 ng/ml, P < 0.05), whilst they tended to have higher levels of parathyroid hormone. Discussion: Vitamin D receptor polymorphism is associated with lower bone mass in patients with epilepsy. This effect might be mediated through the vitamin D‐parathormone pathway.     

Folate status in women of childbearing age with epilepsy

Treatment with cytochrome P450 enzyme-inducing antiepileptic drugs (P450-inducing AEDs) is known to interfere with folate metabolism. Low folate status is of special concern in women with epilepsy who might become pregnant. Therefore, folate status was assessed in women age 16-42 treated for epilepsy. Staple food is not folic acid fortified in Norway. Only 1/94 women was folate-deficient by the laboratory reference value for serum folate of > 4 nM. Fourteen (15%) patients with serum folate values from 5 to 9 nM may be considered folate-insufficient. Plasma homocysteine was elevated > 13 microM in 2/65 women. These findings compare favorably with previous reports. A questionnaire addressing factors interfering with folate metabolism was answered by 58 of the women. In women who did not use a supplement containing > or =0.2 mg of folic acid regularly (n=33), the median serum folate value was lower in those using P450-inducing AEDs than in those using other AEDs (p=0.023). The interaction between P450-inducing AEDs and folate metabolism may be clinically relevant and can be balanced by supplementation of small doses of folic acid. The results of this survey support the recommendation that women of childbearing age treated with AEDs receive folic acid supplementation, particularly those taking P450-inducing AEDs.     

Bone health in people with epilepsy: is it impaired and what are the risk factors?

Diseases of the bone are becoming increasingly prevalent. Persons with epilepsy treated with antiepileptic drugs (AEDs) are at greater risk as evidenced by changes in bone turnover, osteoporosis, alterations in bone quality, and fracture. Biochemical indices of bone and mineral metabolism including calcium, vitamin D, parathyroid hormone, and bone turnover markers can be affected. AED exposure is a cause of secondary osteoporosis with decreased bone mineral density (BMD) secondary to poor bone accrual in children or accelerated bone loss in adults. Early reports described osteomalacia, a change in bone quality with increased unmineralized bone. Recent studies do not reveal osteomalacia, but there may be more subtle changes in bone quality. Multiple studies have found an increased risk of fractures in association with epilepsy and AED exposure. Cytochrome P450 enzyme inducing AEDs are most commonly associated with a negative impact on bone, but studies also suggest an effect of valproate. There is limited data regarding the newer AEDs. No single mechanism has emerged to explain all the changes in bone in association with epilepsy and AEDs. Although multiple therapies are available for the treatment of bone disease, there is limited study in persons with epilepsy. It is recommended that all persons obtain adequate amounts of calcium and vitamin D. In addition BMD screening is warranted for persons with long-term AED exposure particularly if they have other risk factors for bone disease.     

Antiepileptic drugs as independent predictors of plasma total homocysteine levels.

Low folate levels have consistently been reported in patients with epilepsy on phenytoin (PHT), phenobarbital (PB) and primidone (PRD), while data on valproate (VPA) are conflicting. Furthermore, antiepileptic drugs (AEDs) may be associated with high levels of plasma total homocysteine (p-tHcy). Therefore, we have investigated the levels of p-tHcy, serum folate (S-FA) and erythrocyte folate (E-FA) in patients on PHT, PB and PRD (Group 1, n=21) and VPA (Group 2, n=24). Both groups had their own matched controls. Blood samples were drawn fasting and 6 h post methionine loading (6 h-PML). The Group 1 patients had fasting and 6 h-PML p-tHcy levels significantly higher than their controls (P=0.05 and <0.0001, respectively), and patients without dietary multivitamin supplementation (n=14), had lower fasting S-FA and E-FA levels than their controls (P=0.02 and 0.0003, respectively). The Group 2 patients had fasting and 6 h-PML levels of p-tHcy, S-FA and E-FA not different from their controls. In a multiple stepwise regression model comprising all subjects (n=90), the AEDs of Group 1 and the S-FA levels were independent predictors of p-tHcy levels. Thus, PHT, PB and PRD are associated with high p-tHcy and low folate levels, whereas VPA does not influence S-FA, E-FA and p-tHcy levels in adult patients.     

Effects of long-term antiepileptic drug monotherapy on vascular risk factors and atherosclerosis

Purpose: Long‐term therapy with antiepileptic drugs (AEDs) has been associated with metabolic consequences that lead to an increase in risk of atherosclerosis in patients with epilepsy. We compared the long‐term effects of monotherapy using different categories of AEDs on markers of vascular risk and the atherosclerotic process. Methods: One hundred sixty adult patients who were receiving AED monotherapy, including two enzyme‐inducers (carbamazepine, CBZ; and phenytoin, PHT), an enzyme‐inhibitor (valproic acid, VPA), and a noninducer (lamotrigine, LTG) for more than 2 years, and 60 controls were enrolled in this study. All study participants received measurement of common carotid artery (CCA) intima media thickness (IMT) by B‐mode ultrasonography to assess the extent of atherosclerosis. Other measurements included body mass index, and serum lipid profile or levels of total homocysteine (tHcy), folate, uric acid, fasting blood sugar, high sensitivity C‐reactive protein (hs‐CRP), or thiobarbituric acid reactive substances (TBARS). Key Findings: Long‐term monotherapy with older‐generation AEDs, including CBZ, PHT, and VPA, caused significantly increased CCA IMT in patients with epilepsy. After adjustment for the confounding effects of age and gender, the CCA IMT was found to be positively correlated with the duration of AED therapy. Patients with epilepsy who were taking enzyme‐inducing AED monotherapy (CBZ, PHT) manifested disturbances of cholesterol, tHcy or folate metabolism, and elevation of the inflammation marker, hs‐CRP. On the other hand, patients on enzyme‐inhibiting AED monotherapy (VPA) exhibited an increase in the levels of uric acid and tHcy, and elevation of the oxidative marker, TBARS. However, no significant alterations in the markers of vascular risk or CCA IMT were observed in patients who received long‐term LTG monotherapy. Significance: Patients with epilepsy who were receiving long‐term monotherapy with CBZ, PHT, or VPA exhibited altered circulatory markers of vascular risk that may contribute to the acceleration of the atherosclerotic process, which is significantly associated the duration of AED monotherapy. This information offers a guide for the choice of drug in patients with epilepsy who require long‐term AED therapy, particularly in aged and high‐risk individuals.     

Bone disease in epilepsy

Recent literature demonstrates an association between antiepileptic drugs (AEDs) and bone disease. Decreased bone mineral density (BMD) has been found in adults and children receiving both enzyme-inducing AEDs and valproate, which is an enzyme-inhibiting AED. Biochemical abnormalities include hypocalcemia, elevated parathyroid hormone, and elevated markers of bone formation and resorption. Although patients in earlier studies had evidence of decreased vitamin D, low BMD has been found to be independent of abnormal vitamin D chemistries in more recently published studies. Multiple mechanisms have been postulated to explain AED-associated bone disease, but no single mechanism fully explains all the abnormalities seen. Therapies are available for bone disease. However, few studies have evaluated the effects of treatment in bone disease associated with AEDs.     

Epilepsy, osteoporosis and fracture risk - a meta-analysis

This meta-analysis assesses the effects of epilepsy on fracture risk and changes in bone mineral density (BMD) in patients with epilepsy. A search of PubMed was conducted using the key words epilepsy, fracture, and bone mineral. A weighted estimate of relative risk of fractures and changes in BMD (Z-score) was calculated. From the changes in BMD, expected increase in relative fracture risk was calculated. A total of 11 studies on fracture risk and 12 studies on BMD were retrieved. The relative risk of any fracture was increased (2.2, 95% CI: 1.9-2.5, five studies), as was the risk of hip (5.3, 3.2-8.8, six studies), forearm (1.7, 1.2-2.3, six studies), and spine fractures (6.2, 2.5-15.5, three studies). A large proportion of fractures (35%) seemed related to seizures. Spine (mean +/- SEM: -0.38 +/- 0.06) and hip (-0.56 +/- 0.06) BMD Z-scores were significantly decreased, hip more than spine (2P < 0.05). The expected increases in relative risk of any fracture from BMD Z-scores were 1.2-1.3, and significantly lower than observed (2P < 0.05). The deficit in BMD in patients with epilepsy is too small to explain the observed increase in fracture risk. The remainder of the increase in fracture risk may be linked to seizures.     

Pregnancy in women who have epilepsy

Ideal, comprehensive care of women who have epilepsy during the reproductive years must include effective preconceptional counseling and preparation. The importance of planned pregnancies with effective birth control should be emphasized, with consideration of the effects of the enzyme-inducing AEDs on lowering efficacy of hormonal contraceptive medications and the need for back-up barrier methods. Before pregnancy occurs, the patient's diagnosis and treatment regimen should be reassessed. Once the diagnosis of epilepsy is confirmed, it is important to verify if the individual patient continues to need medications and if she is taking the most appropriate AED to balance control of her seizures with teratogenic risks. For most women who have epilepsy, withdrawal of all AEDs before pregnancy is not a realistic option. A decision to undergo a trial while not taking AEDs before a planned pregnancy should be based on the same principles used for AED withdrawal in any person who has epilepsy. The taper should be completed at least 6 months before planned conception to provide some reassurance that seizures are not going to recur. If a woman who has epilepsy is in the more prevalent category of needing AEDs for seizure control, then monotherapy at the lowest effective dosage should be used. If large daily doses are needed, then frequent smaller doses or extended-release formulations may be helpful to avoid high peak levels. Some of the newest information about differential risks between AEDs also should be considered. The woman's AED regimen should be optimized and folate supplementation should begin before pregnancy. Given that 50% of pregnancies are unplanned in the United States, folate supplementation should be encouraged in all women of childbearing age who are taking any AED for any indication. Dosing recommendations vary from 0.4 mg/d to 5 mg/d. It is not uncommon for a physician to consider changing AED regimens when the patient first reports that she is pregnant. In many cases, she already is in or past the critical period of organogenesis (Table 3). If a woman who has epilepsy presents after conception and is taking a single AED that is effective, her medication usually should not be changed. Exposing the fetus to a second agent during a crossover period of AEDs only increases the teratogenic risk, and seizures are more likely to occur with any abrupt medication changes. If a woman is on polytherapy, it may be possible to switch to monotherapy safely. Seizure control remains an important goal during pregnancy. In particular, convulsive seizures place the mother and fetus at risk. Nonconvulsive seizures also may be harmful, especially if they involve falling or other forms of trauma. Monitoring serum AED levels during pregnancy can be helpful in optimizing seizure control. Prenatal screening can detect major malformations in the first and second trimesters. Vitamin K1 is given 10 mg/d orally during the last month of pregnancy followed by 1 mg intramuscularly or intravenously to the new-born. Although women who have epilepsy and women who are taking AEDs for other indications do have increased risks for maternal and fetal complications, these risks can be reduced considerably with effective preconceptional planning and careful management during pregnancy and the postpartum period.     

The association between BsmI polymorphism and bone mineral density in young patients with epilepsy who are taking phenytoin

Purpose: This study sought to determine the association between BsmI polymorphism and bone mineral density, 25‐hydroxyvitamin D, and parathyroid hormone levels in patients with epilepsy. Methods: We recruited ambulatory young adults with epilepsy who were taking phenytoin. Data regarding demographics, basic laboratory studies, history of clinical epilepsy, parathyroid hormone, and vitamin D levels, as well as BsmI polymorphism of the vitamin D receptor (VDR) gene, were obtained. The bone mineral density (BMD) of the lumbar spine and left femur were measured using dual‐energy x‐ray absorptiometry. Key Findings: Ninety‐four patients were included in the study. BsmI polymorphism had a statistically significant lower T‐score of the lumbar spine and left femoral neck than patients with wild‐type VDR gene (p < 0.01 and p < 0.01, respectively). In addition, patients with BsmI polymorphism had a statistically significant lower z‐score of the lumbar spine and left femoral neck than patients with wild‐type VDR gene (p < 0.01 and p < 0.01, respectively). The 25‐hydroxyvitamin D level in patients with wild‐type genes was higher than in epileptic patients with BsmI polymorphism (p < 0.01 and p < 0.01, respectively). Parathyroid hormone level in patients with wild‐type VDR gene or patients having BsmI polymorphism was not correlated with BMD at either site. Significance: In patients with epilepsy taking phenytoin, having BsmI polymorphism was associated with lower BMD.     

Evaluation and measurement of bone mass

Patients taking antiepileptic drugs (AEDs) have an increased risk for osteoporosis and osteoporotic fractures. Bone mineral density (BMD) is the best predictor of fracture risk. Measurement of BMD allows the identification of patients at risk before they suffer a fracture. The current "gold standard" for the measurement of BMD and diagnosis of osteopenia and osteoporosis is dual-energy X-ray absorptiometry. Clinicians should be familiar with the ways in which bone mass measurements are reported and should understand how to use BMD measurements in making treatment decisions and monitoring treatment. They should also be aware of current controversies, including the role of peripheral versus central BMD measurements and the use of different reference databases for different patient groups. Laboratory assessment to identify secondary causes of osteoporosis, such as low vitamin D status in patients taking AEDs, is useful, but the role of markers of bone turnover in clinical practice has not been well defined.     

Antiepileptic drug-induced bone loss in young male patients who have seizures

BACKGROUND: Long-term antiepileptic drug (AED) therapy is a known risk factor for bone loss and fractures. Vitamin D deficiency is frequently cited as a cause for bone loss in patients who have seizures. OBJECTIVE: To determine whether men who have seizures, but who are otherwise healthy, suffer substantial bone loss in the hip while taking AEDs. PATIENTS AND METHODS: We prospectively examined femoral neck bone mineral density (BMD) by dual-energy x-ray absorptiometry in 81 consecutive men, aged between 25 and 54 years old (mean age, 45 years), who were attending an outpatient seizure clinic. Low BMD values were analyzed for known risk factors for bone loss. Dual-energy x-ray absorptiometry scans were repeated in 54 patients, 12 to 29 months later (mean, 19 months), to assess the rate of change in BMD over time. RESULTS: Multivariate linear regression analysis revealed that age (P<.001) and time receiving AEDs (P<.003) were the 2 important risk factors associated with low femoral neck BMD. Neither vitamin D deficiency, hypogonadism, cigarette smoking, nor excess alcohol intake were associated with low BMD after correcting for age and time on AEDs. Longitudinal analysis of femoral neck BMD revealed that only those in the youngest age group (25-44 years) showed significant declines in femoral neck BMD (1.8% annualized loss; 95% confidence interval, -3.1 to -0.9; P<.003) while receiving AED therapy. There was no evidence that a specific type of AED was more causally related to bone loss in this group although most patients were taking phenytoin sodium or carbamazepine during the longitudinal assessment. CONCLUSIONS: Long-term AED therapy in young male patients who have seizures causes significant bone loss at the hip in the absence of vitamin D deficiency. Dual-energy x-ray absorptiometry scanning of the hip is useful in identifying patients who are particularly susceptible to rapid bone loss while taking AEDs.     

Human sexuality, sex hormones, and epilepsy

The function of the hypothalamic-pituitary axis (HPA), including the production of luteinizing hormone, follicle-stimulating hormone, gonadotropin-releasing hormone, and prolactin, and the concentrations and metabolism of its end products, such as estrogen, testosterone, and dehydroepiandrosterone, appear to be modified in many people with epilepsy. Effects of the disorder itself and effects of antiepileptic drugs (AEDs) both appear to contribute to these hormonal alterations, which may be associated with sexual dysfunction. Focal epileptic discharges from the temporal lobe may affect HPA function, as is suggested by the normalization of androgen levels seen in men with temporal lobe epilepsy who become seizure-free after surgery. Hepatic enzyme-inducing AEDs such as carbamazepine and phenytoin may be most clearly linked to altered metabolism of sex steroid hormones, but valproic acid, an enzyme inhibitor, has also been implicated in the causation of reproductive endocrine abnormalities. Polycystic ovaries and polycystic ovarian syndrome (PCOS) are widely believed to be common in women with epilepsy, but the actual prevalence and the pathogenesis of PCOS in this population are disputed. Hormonal changes and sexual dysfunction need to be addressed in any comprehensive approach to epilepsy management, as well as any comprehensive epilepsy research program. Avoidance of enzyme-inducing AEDs and achievement of freedom from seizures as the goal of treatment are strongly recommended.