Antiepileptic drugs, particularly cytochrome P450 enzyme inducers, are associated with disorders of bone metabolism. We studied premenopausal women with epilepsy receiving antiepileptic drug monotherapy (phenytoin, carbamazepine, valproate, and lamotrigine). Subjects completed exercise and nutrition questionnaires and bone mineral density studies. Serum was analyzed for indices of bone metabolism including calcium, 25‐hydroxyvitamin D, parathyroid hormone, insulin growth factor I, insulin binding protein III, and bone formation markers, bone‐specific alkaline phosphatase, and osteocalcin. Urine was analyzed for cross‐linked N‐telopeptide of type I collagen, a bone resorption marker. Calcium concentrations were significantly less in subjects receiving carbamazepine, phenytoin, and valproate than in those receiving lamotrigine ( p = 0.008). Insulin growth factor‐I was significantly reduced in subjects receiving phenytoin compared with those receiving lamotrigine ( p = 0.017). Subjects receiving phenytoin had significantly greater levels of bone‐specific alkaline phosphatase ( p = 0.007). Our results demonstrate that phenytoin is associated with changes in bone metabolism and increased bone turnover. The lower calcium concentrations in subjects taking carbamazepine or valproate compared with those taking other antiepileptic drugs suggest that these antiepileptic drugs may have long‐term effects. Subjects receiving lamotrigine had no significant reductions in calcium or increases in markers of bone turnover, suggesting this agent is less likely to have long‐term adverse effects on bone. Ann Neurol 2005;57:252–257

Women with epilepsy are believed to be at risk for sexual dysfunction. Disorders of sexual desire and sexual arousal, including dyspareunia, vaginismus, and lack of lubrication, affect an estimated 30 to 60% of women with epilepsy. In this study, 57 reproductive-aged women with either localization related (LRE) or primary generalized epilepsy (PGE) on antiepileptic drug (AED) monotherapy and 17 nonepileptic controls completed questionnaires examining sexual experience, arousability, anxiety, and symptoms, as well as an inventory of depression. An endocrine assessment was performed during the early follicular phase of the menstrual cycle. Sexual dysfunction was more common in women with LRE, in women receiving phenytoin, in women with low levels of estradiol and dehydroepiandrosterone sulfate, and in women with self-reported symptoms of mild depression. The mechanisms of sexual dysfunction in women with epilepsy are multifactorial, but AED choice appears to be one cause that is modifiable.

This epidemiologic study of Paget's disease of bone used data from 788 cases and 387 spouse controls to investigate the following: (1) the extent to which this disorder aggregates in families; (2) the cumulative incidence of the disease in first-degree relatives of patients throughout life; and (3) the influence of age at diagnosis (< 55 versus 55+ years) and presence of bone deformity in the case on risk of Paget's disease in relatives.A positive family history in parents or siblings was reported by 12.3% of cases and 2.1% of controls. The rate of Paget's disease was approximately seven times as high in relatives of cases as in relatives of controls, and this increased rate did not differ according to gender of case or control or gender of relatives. Cumulative incidence of Paget's disease to age 90 was much higher in relatives of cases (8.9 + 1.0% SEM) than in relatives of controls (1.8 +/- 0.9% SEM). Among relatives of cases, cumulative risk was highest when the case had both early age at diagnosis and bone deformity (20.7 +/- 3.6% SEM) compared with risk when the case had early age at diagnosis but not bone deformity (10.8 +/- 3.2% SEM), bone deformity but not early age at diagnosis (5.8 +/- 1.3% SEM), or neither bone deformity nor early age at diagnosis (3.6 +/- 0.8% SEM). Risk in siblings of cases was higher when a parent was affected (22.1 +/- 8.0% SEM) than when both parents were unaffected (6.7 +/- 1.1% SEM).These findings suggest that first-degree relatives of patients with Paget's disease have increased risk of developing the disorder, especially if the affected relatives have early age at diagnosis or deforming bone disease.

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.

Women with epilepsy (WWE) are at increased risk for reproductive disorders. This study was designed to evaluate whether WWE are more likely to have anovulatory cycles and to assess the relative association of the epilepsy syndrome category and antiepileptic drugs (AEDs) to ovulatory dysfunction. Subjects included women aged 18 to 40 years not receiving hormones. Women without epilepsy (23 controls) and women with localization-related epilepsy (LRE, n = 59) or idiopathic (primary) generalized epilepsy (IGE, n = 35) receiving either a cytochrome P450 enzyme (cP450) inducing AED (carbamazepine, phenytoin, and phenobarbital), a cP450 inhibiting AED (valproate), or an AED that does not alter cP450 enzymes (lamotrigine and gabapentin) in monotherapy for 6 months or more were followed for three menstrual cycles. A transvaginal ovarian ultrasound was obtained. Endocrine and metabolic variables were measured and luteinizing hormone sampled over 8 hours on days 2 to 5 of one cycle. Anovulatory cycles occurred in 10.9% of cycles in controls, 14.3% of cycles with LRE, and 27.1% of cycles with IGE. Of women using valproate currently or within the preceding 3 years, 38.1% had at least one anovulatory cycle in contrast with 10.7% of women not using valproate within the preceding 3 years. Predictors of ovulatory failure included IGE syndrome, use of valproate currently or within 3 years, high free testosterone, and fewer numbers of luteinizing hormone pulses, but not polycystic-appearing ovaries. WWE are more likely to experience anovulatory menstrual cycles and the effects of epilepsy syndrome, and AED therapy may be additive. Women with IGE receiving valproate were at highest risk for anovulatory cycles, polycystic-appearing ovaries, elevated body mass index, and hyperandrogynism. WWE with anovulatory cycles may have no other signs of reproductive dysfunction. Therefore, clinicians must be alert to this potential complication of epilepsy.

Background/Aims: Studies comparing quality of life (QOL) between peritoneal and hemodialysis patients have yielded inconsistent results. Physical (PCS) and mental component summary (MCS) scales of Short Form 36 (SF-36) health survey are highly validated measures of self-assessed QOL. We sought to evaluate these indices in PD patients: (1) as measures of QOL, (2) predictors of QOL, (3) to study change in QOL over time, and (4) to compare QOL in PD vs. hemodialysis patients. Methods: SF-36 questionnaires were administered every 3 months to patients over a 2-year period and PCS and MCS were calculated. Mean follow-up was 15.3 ± 6.6 months for PD and 14.5 ± 5.7 months for HD. Results: Average PCS in PD (31.8 ± 7.8) was lower than HD (36.9 ± 9.8) (p < 0.02), while MCS was similar in the groups (p = NS). The prevalence of depression was 26.1% in PD and 25.4% in HD patients (p = NS). Serum albumin was the only significant predictor of PCS among PD patients and explained much of the decrease in PCS in them. The number of hospitalizations and in-hospital days were significantly lower for PD compared to HD patients (p < 0.05). PCS as well as MCS remained stable in both groups throughout the observation period. Conclusion: Self-assessed physical function is diminished, while mental function is similar in PD compared to HD patients. When corrected for serum albumin, this difference is eliminated. Over time, QOL in patients treated with PD remained stable.

Background. Physical (PCS) and mental (MCS) component summary scales of the Short Form 36 (SF-36) health survey are validated measures of quality of life (QOL) and functional status. We sought to evaluate the PCS and MCS in haemodialyis patients as compared to the general population and other chronic diseases.Methods, A cohort of 134 haemodialysis patients (mean age 60.9 +/- 14.3 years, males 63.4%, Caucasians 66.4%) was followed from January 1996 to December 1998 (mean follow up 14.5 +/-5.7 months). SF-36 questionnaires were administered every 3 months and PCS and MCS were calculated.Results were compared to the general population and other chronic diseases. Correlators of PCS and MCS, change in QOL over time, and the correlators of this change were determined. Results. Mean PCS was 36.9 +/-8.8 and mean MCS was 47 +/- 10.7. Compared to the general US population, these represent a decline of 8.7 +/-0.8 for PCS (P<0.0001) and 2.70.8 for MCS (P<0.001). PCS and MCS in end-stage renal disease (ESRD) were lower than in most other chronic diseases studied. Univariate correlators of PCS in haemodialysis patients included age, male sex, haematocrit, serum albumin, and severity of comorbid cardiac and pulmonary illnesses. Multivariate analysis demonstrated independent correlators of PCS to be male sex, serum albumin and severity of comorbid cardiac and pulmonary diseases. Univariate as well as multivariate correlators of MCS included: serum albumin, KT/V-urea, and status living alone. A trend analysis revealed that both PCS and MCS tended to decline in the initial months of dialysis but stabilized over time. Status living alone was a significant predictor of improvement in MCS by univariate as well as multivariate analysis.Conclusions. Self assessed physical and mental health of haemodialysis patients is markedly diminished compared to the general population and other chronic diseases.

BACKGROUND:Accurate information on prevalence and status of blood pressure (BP) control in hemodialysis patients is lacking. Our Hemodialysis Quality Improvement Program, sought to determine: 1) The extent and control of hypertension (HTN), 2) whether Erythropoietin (EPO) dose or intradialytic fluid loss had any effect on BP and 3) a means to follow the severity of HTN.PATIENTS AND METHODS:The pre/post mid-week dialysis BP readings of 190 patients (64+/-14.1 years, 53% males, 77% whites) were evaluated over a 3 month period. HTN was defined as BP >150/90. Hypertension was further characterized according to whether the patients had normal or elevated pre-dialysis systolic, pre-dialysis diastolic, post-dialysis systolic or post-diastolic BP readings on more than 6 of the possible 13 recordings. The average EPO dose and weight loss during dialysis was correlated with BP. To better understand the extent of HTN, systolic and diastolic pressures were separately graded from 0 to 3 and a number designated as hypertension sensitivity index (HSI) was assigned to each patient.RESULTS:Of the 190 patients, 146 (76.8%) were hypertensive. 117 out of 146 hypertensive patients (80.1%) had persistent elevation of BP despite being on one or more antihypertensive medications. Most patients were on calcium channel blockers (39%) with 27% being on beta-blockers and 14% on Angiotensin converting enzyme inhibitors. There was no correlation between the number of medications used and the control of HTN. The dose of EPO also had no effect on the degree of HTN. 69.8% of all HTN was systolic. Of this, 64.7% was pre-dialysis and 35.3% post-dialysis. Multiple regression analysis demonstrated a significant correlation with loss of weight during dialysis and lowering of systolic BP (r = 0.33, p = 0.0001). The mean HSI for this population was 2.3+/-1.8.CONCLUSION:HTN was a frequent finding in our hemodialysis population and it was controlled in only 19.9% of hypertensive patients. Most of this HTN was pre-dialysis systolic. There was a significant correlation between fluid loss during dialysis and lowering of blood pressure. The use of the HSI has proven to be helpful in differentiating type and severity of HTN.

We measured the ultrasound parameters of the heels of 49 women with vertebral fractures and 87 age-matched controls using an Achilles ultrasound device. Average broadband ultrasound attenuation (BUA), speed of sound (SOS) and Stiffness were significantly lower in fracture patients (p < 0.0001). We also estimated the ultrasound parameters of patients compared with age-matched non-fracture controls and found the mean BUA to be -1.02 SD below control values. The mean SOS was -0.97 SD and the mean Stiffness was -1.12 SD below control values. Femoral bone mineral density (BMD) at the neck, Ward's triangle and the trochanter, the total-body BMD and L2-4 BMD were measured with dual-energy X-ray absorptiometry (DXA) and found to be significantly lower in fracture patients (p < 0.0001). All correlation coefficients between ultrasound parameters and DXA measurements were > 0.5 and statistically significant (p < 0.0001). A stepwise logistic regression with presence or absence of vertebral fracture as the response variable and all ultrasound--DXA parameters as the explanatory variables indicated that the best predictor of fracture was Stiffness, with additional predictive ability provided by spine BMD. Sensitivity and specificity of all measures were determined by the areas under the receiver operating characteristic (ROC) curve, which were 0.76 +/- 0.04 for BUA, 0.77 +/- 0.04 for SOS, 0.78 +/- 0.04 for Stiffness and 0.78 +/- 0.03 for spine BMD. The areas under the ROC curves of BUA, SOS, Stiffness and spine BMD were compared and it was found that Stiffness and spine BMD were significantly better predictors of fracture than BUA and SOS. These results support many recent studies showing that ultrasound measurements of the os-calcis have diagnostic sensitivity comparable to DXA, and also demonstrated that Stiffness was a better predictor of fracture than spine BMD.

The bone mineral density (BMD) of the spine was measured in the posteroanterior (PA) and lateral projections as well as the total body BMD in 447 black and white women. The lateral projection is comprised predominantly of cancellous bone whereas the total body BMD is predominantly cortical bone, and the PA spine is intermediate in composition. Black women had a higher BMD than white women for each measurement, but the difference was greatest in the lateral spine. Similarly, black women showed less decline in cancellous bone density with aging. The development of a high peak cancellous bone mass with reduced involutional loss may provide a major contribution towards protection against osteoporotic fractures in black women. Metabolic and pharmacologic studies in black and white women should consider the possibility of the influence of a larger cancellous bone mass.

Black women have 40% of the incidence rate for hip fracture and have a higher bone mineral density (BMD) than white women. The possibility was raised that bone quality may be disproportionately greater than the advantage in bone density in protection against osteoporotic fractures in black versus white women. Ultrasound (US) of the calcaneus is believed to measure properties of bone in addition to its density. We performed bone density measurements and US of the calcaneus in 108 black and 177 healthy white women, aged 20–70 years. The highest correlation was seen between total body bone density and speed of sound (r = 0.75). The interracial differences in BMD were all statistically significant and varied from 3.4 to 7.6%. The US measurements had lesser interracial differences than the bone density measurements, with velocity barely different between races. These findings suggest that US of the calcaneus measures properties of bone different from density. Fracture prediction data using US from prospective data in white women should not be extrapolated to black women because of the discordance between bone density and US measurements. Prospective studies are needed comparing US measurements in black women to the occurrence of osteoporotic fractures.

Water compartments were studied in 72 black and 128 white women, aged 20 to 70 years. Total body water (TBW) was measured by tritiated water dilution, and extracellular water (ECW) was measured by using delayed gamma neutron activation for the determination of total body chloride. Intracellular water (ICW) was assessed as the difference between TBW and ECW. Fat-free mass (FFM) was estimated by the measurement of total body potassium (TBK) and total body fat (TBF) by measurement of total body carbon (TBC). Total body protein was calculated from total body nitrogen (TBN). TBW was found to decline with age and to also be significantly influenced by body size. The extracellular water space was 41.5% of TBW. The decline of TBW with age is due primarily to a decline in ICW. The hydration of the FFM increased with age for the overall population because of a decline in TBK and TBN and an increase in ECW. Body composition models that have assumed constancy of hydration should be adjusted not only for gender but for age and body size.

Delayed gamma neutron activation analysis (DGNA) was performed on 99 black and 168 healthy white women, aged 20-80 years, to examine sodium distribution in the two ethnic groups. Elements measured included total body levels of sodium (TBNa) and chlorine (TBCl). The black women were heavier, and consequently had a higher body surface area. Sodium excess (Naes) was calculated from TBNa and TBCl. Total body water was measured by tritiated water dilution. TBNa was higher in black than white women, and this difference persisted when the values were corrected for body surface area. TBNa and Naes declined significantly with age in white women, whereas extracellular fluid sodium (ECFNa) remained constant. The change with age was not statistically significant in black women for TBNa, Naes or ECFNa. Our sample of healthy black women had a higher TBNa and Naes than healthy white women. This difference persisted after adjustment for body surface area, so that values for sodium distribution need to be adjusted for race. The change in TBNa with age in white women appears to be due to their decline of skeletal tissue mass with a consequent decline in nonexchangeable sodium.