Insulin-related metabolic changes during treatment with valproate in patients with epilepsy

Weight gain is a known side effect of valproate (VPA) therapy, which is associated with hyperinsulinemia and polycystic ovary-like syndrome and unfavorable lipid changes in women. Hyperinsulinemia has also been observed in male and lean subjects as well. Hyperinsulinemia is associated with several health risks, such as cardiovascular diseases and the metabolic syndrome. The purpose of this study was to evaluate whether VPA-related hyperinsulinemia is associated with other metabolic changes and whether there is any association between weight gain, other adverse effects related to VPA, and the metabolic syndrome. Fifty-one patients under VPA monotherapy and 45 healthy control subjects participated in the study. They were interviewed and clinically examined, and, after an overnight fast, blood samples were taken to evaluate fasting serum insulin, lipid, free fatty acid, and uric acid levels. Incidence of the metabolic syndrome was determined as well. Compared with control subjects, VPA-treated patients had higher circulating insulin concentrations relative to body mass index, higher uric acid and triglyceride levels, and lower high-density lipoprotein cholesterol concentrations. There was no significant difference in the frequency of the metabolic syndrome between the VPA-treated patient group and the control group. In conclusion, valproate therapy, especially if started at a young age, is associated with increased circulating insulin concentrations relative to body mass index, indicating that the high insulin levels are not a consequence of obesity. Although the frequency of the metabolic syndrome did not differ between VPA-treated patients and control subjects, VPA-treated patients had higher concentrations of triglycerides and uric acid and lower levels of high-density lipoprotein cholesterol than control subjects.     

Effect of valproic acid treatment on body composition, leptin and the soluble leptin receptor in epileptic children

PURPOSE: The aim of the study was to determine the influence of valproic acid (VPA) treatment on leptin, the soluble leptin receptor (sOB-R), the sOB-R/leptin ratio, body composition and insulin resistance in epileptic children. METHODS: A cross-sectional cohort study was conducted at the Medical University Innsbruck, Austria. Children >6 years with idiopathic epilepsy and antiepileptic drug therapy since at least six months were eligible. Leptin concentration, the sOB-R, the sOB-R/leptin ratio, body composition and glucose homeostasis were determined. RESULTS: 87 children (median [range] age 12.8 years [6.0-18.6]) were on treatment with VPA, 55 (12.3 years [6.4-18.3]) on other AEDs, comprising the non-VPA group. VPA-treated children had higher leptin concentrations, body-mass-index standard-deviation score (SDS), body fat (each p<0.001), serum insulin concentrations (p=0.014) and homeostasis model assessment (HOMA) index (p=0.009), as well as a lower sOB-R/leptin ratio (p<0.001) when compared to the non-VPA group. Overweight VPA-treated children showed lower sOB-R concentrations and a lower sOB-R/leptin ratio (each p<0.001) as well as higher body fat and leptin levels (each p<0.001) compared to lean VPA-treated children. CONCLUSION: VPA monotherapy was associated with higher body weight, body fat and serum leptin concentrations as well as impaired glucose homeostasis. Low sOB-R concentrations and a low sOB-R/leptin ratio in overweight VPA-treated patients might contribute to disturbances in glucose homeostasis and to the development of the metabolic syndrome in these children later in life.     

Hormone profiles in young adults with epilepsy treated with sodium valproate or lamotrigine monotherapy

PURPOSE: Treatment with sodium valproate (VPA) may be associated with polycystic ovarian syndrome (PCOS) in some women with epilepsy. By comparing hormone profiles in young adults taking VPA or lamotrigine (LTG) as monotherapy, this study aimed to explore whether a pharmacologic effect of VPA could be responsible for this observation. METHODS: Hormone profiles in men and women taking VPA (n = 40) or LTG (n = 36) monotherapy for epilepsy were compared. None of the women were receiving hormonal contraception or replacement. Patients gave details of seizure type and frequency, menstrual cycle, and medical and drug history. Body mass index was calculated, and fasting insulin, glucose, cholesterol, triglycerides (TG), high- and low-density lipoproteins, testosterone, dihydroepiandosterone (DHEA), androstenedione, sex hormone-binding globulin (SHBG), free androgen index (FAI), luteinising hormone (LH), follicle-stimulating hormone (FSH), and antiepileptic drug (AED) concentrations were measured. RESULTS: There were no differences between treatment groups for both sexes in age and seizure control. Only four obese VPA-treated women were hyperinsulinaemic (p = 0.05); three with abnormal menstrual cycles; one with raised testosterone. Testosterone (p = 0.02), FAI (p = 0.03), and TG (p = 0.02) levels were higher, however, in women taking the drug. Obese patients of both sexes (p = 0.01) and VPA-treated men (p = 0.03) had higher insulin concentrations. CONCLUSIONS: VPA therapy may be associated with subclinical elevation in fasting insulin levels. Testosterone and TG levels were higher in VPA-treated women compared with the levels in those taking LTG. However, only a minority of obese females exhibited biochemical characteristics suggestive of PCOS. Biochemical screening may allow women at risk of developing PCOS to avoid VPA.     

Serum androgen levels and testicular structure during pubertal maturation in male subjects with epilepsy

Summary:  Purpose: To evaluate reproductive endocrine function in boys and young men with epilepsy taking an antiepileptic drug in a population-based, controlled study.
Methods: Seventy patients and 70 controls matched for age and pubertal stage participated in this study. Twenty-eight patients were taking carbamazepine (CBZ); five, lamotrigine (LTG); 12, oxcarbazepine (OXC); and 25, valproate (VPA) as monotherapy for epilepsy. All subjects were examined clinically, and their medical histories were obtained. Serum reproductive hormone and sex hormone–binding globulin concentrations were measured, and testicular ultrasonography was performed.
Results: Serum testosterone levels were within the normal range in young male patients with epilepsy. However, the patients taking VPA had high serum androstenedione levels at all pubertal stages. In prepuberty, their serum androstenedione values were already approximately fivefold compared with the values of the controls (8.7 n M ; SD, 4.0 vs. 1.8 n M , SD, 1.0; p < 0.0003), and they were elevated in 64% of the VPA-treated patients compared with none of the other patients, p = 0.0006. Serum sex hormone–binding globulin levels were increased, and serum dehydroepiandrosterone sulfate concentrations decreased in the pubertal patients taking CBZ. The mean testicular volumes did not differ between the patients and the controls.
Conclusions: CBZ and VPA, but not LTG and OXC, are associated with changes in serum sex-hormone levels in boys and young men with epilepsy. However, the long-term health consequences of these reproductive endocrine changes during pubertal development remain to be established.     

Physical growth and endocrinal disorders during pubertal maturation in girls with epilepsy

PURPOSE: This study investigated the effect of epilepsy and/or antiepileptic drugs (AEDs) on the physical growth, pubertal development, and androgenic status of girls with epilepsy between ages 8 and 18 years. METHODS: Sixty-six female patients with epilepsy, their mean ages 13.47 +/- 3.5 years, were included. Anthropometric measurements, staging of pubertal maturation, and clinical manifestations of hyperandrogenism were assessed, as well as measurement of serum levels of testosterone, dehydroepiandrosterone sulfate (DHEAS), sex hormone-binding globulin (SHBG), and free androgen index (FAI). Of the included patients, 44 had transabdominal ultrasonic examination of the ovaries and fasting serum insulin levels were measured. Forty healthy age-matched females served as a control group. RESULTS: Patients showed reduced mean height percentile compared with controls (z = 2.07; p = 0.04), which was negatively correlated with the duration of their epilepsy. Patients showed increased frequency of obesity, especially postpubertal girls taking valproate (VPA; 67%), who also showed higher insulin levels (t = 8.01; p = 0.0003). Patients showed increased frequency of clinical hyperandrogenemia in the different stages of puberty. High levels of testosterone and DHEAS were found in female patients with epilepsy, especially pubertal and postpubertal girls. Hyperandrogenism (clinical and/or laboratory) was most affected by the types of AEDs, with higher incidence in patients taking VPA compared with those taking enzyme-inducing AEDs (chi2= 9.16; p = 0.01). Eighteen percent of the patients were diagnosed as having polycystic ovary syndrome (PCOS). No difference was found in the types of seizures, degree of seizure control, type of AEDs, or insulin levels between patients with and those without PCOS. CONCLUSIONS: Longer duration of the disease has a negative impact on the stature of female patients with epilepsy. Postpubertal girls taking VPA are more liable to obesity, which is associated with increased incidence of hyperinsulinemia. Clinical and/or laboratory evidence of hyperandrogenism is seen at a high frequency in patients, especially with the use of VPA. Furthermore, female patients with epilepsy especially in the postpubertal stage of sexual maturation, have a high prevalence of PCOS, independent of the type of AED or the characteristics of the epilepsy disorder.     

Increased oxidative stress in epileptic children treated with valproic acid

PURPOSE: To determine influence of Valproic Acid (VPA) treatment on oxidative status in non-obese and overweight epileptic children. METHODS: A prospective study was conducted at the Departments of Pediatrics, University of Chieti and Bologna. Thirty-one epileptic children were studied before and after 1 year of therapy with VPA. Also 31 sex-, age- and BMI-matched healthy controls were evaluated. Insulin and glucose serum levels and plasma Vitamin E, Lag phase and Malondialdehyde (MDA) levels were determined. RESULTS: Before the beginning of VPA therapy, insulin and glucose serum values and plasma Vitamin E, Lag phase and MDA levels were normal in all subjects. At the end of follow-up, 11 (35.5%) epileptic patients developed obesity. In obese VPA treated patients, we found lower serum levels of antioxidant (Vitamin E, p<0.001) and higher levels of oxidant markers (MDA, p<0.001; Lag phase, p<0.001) compared to VPA-treated non-obese patients and controls. CONCLUSION: After 1 year of VPA therapy oxidative stress occurs only in overweight children. This increase in the levels of oxidant markers, probably caused by obesity, might contribute to the development of endothelial dysfunction and atherosclerosis later in life.     

Brief Clinical Report DOES LONG-TERM USE OF VALPROATE CAUSE WEIGHT GAIN IN PREPUBERTAL EPILEPTIC CHILDREN?

In this experiment, we studied the effect of valproate (VPA) on weight gain, and serum leptin levels in prepubertal epileptic children receiving VPA. Our purpose was to determine whether or not long-term use of VPA causes weight gain in childhood, and to evaluate serum leptin levels in a group of prepubertal children receiving VPA. Our study included 15 patients (9 males, 6 females) with new diagnosed epilepsy and 16 healthy age-matched controls (9 males, 7 females). The subjects ages ranged from 9 months to 12 years. Weight gain was noted in 9 (60%) of 15 patients in the study group, and 8 (50%) of 16 subjects in the control group (p >. 05). There was no difference between the groups for body mass index (BMI) and serum leptin levels. Although higher serum leptin levels were found in the patients treated with VPA weight gaining (5.65 &#45 3.06 ng/ml vs. 3.28 &#45 1.69 ng/ml), we did not find a difference between the patients weight gaining and nonweight gaining (p >. 05). While a significant correlation between BMI and serum leptin levels was found in the study group (r =. 704; p =. 003), it was not significant in the control group (r =. 330; p =. 211). In conclusion, our findings showed that long-term use of VPA did not cause weight gain in a group of prepubertal children receiving VPA and, parallel to this, serum leptin levels were similar in both the control and study group.     

Metabolic and hormonal disturbances in women with epilepsy on antiepileptic drug monotherapy

PURPOSE: Women with epilepsy (WWE) tend to have hormonal and metabolic abnormalities, raising concerns about an increased risk of cardiovascular disorders. This study was performed to determine whether epilepsy itself and/or antiepileptic drug (AED) medication cause metabolic abnormalities. METHODS: WWE in premenopausal state aged 18 to 45 years old, currently on AED monotherapy for more than six months, were recruited for this study. The subjects checked their oral temperature each morning, and tested serum levels for lipid profiles, insulin, glucose, and leptin. A HOMA-index was used as a marker for insulin resistance. RESULTS: Of the 54 total patients, 18 women were diagnosed with primary generalized epilepsy (PGE) and the other 36 were diagnosed with localization-related epilepsy (LRE). Among the subjects, 19 women were on carbamazepine (CBZ), 12 on valproate (VPA), 12 on lamotrigine (LTG), and 11 on topiramate (TPM). Body mass index increased and HDL-cholesterol decreased in patients on VPA monotherapy compared with CBZ, LTG, or TPM (p=0.046 and 0.002). Metabolic syndrome was more frequently associated with VPA-treated patients (41.7%) than CBZ (5.3%), LTG (0%), or TPM group (0%) (p=0.005). There were no differences in hormonal and metabolic indices between PGE and LRE groups. CONCLUSIONS: WWE on VPA monotherapy are more obese and more frequently suffer from metabolic syndrome. LTG or TPM may be safer when prescribed to the patients with high risk of cardiovascular disease.     

Does long-term use of valproate cause weight gain in prepubertal epileptic children?

In this experiment, we studied the effect of valproate (VPA) on weight gain, and serum leptin levels in prepubertal epileptic children receiving VPA. Our purpose was to determine whether or not long-term use of VPA causes weight gain in childhood, and to evaluate serum leptin levels in a group of prepubertal children receiving VPA. Our study included 15 patients (9 males, 6 females) with new diagnosed epilepsy and 16 healthy age-matched controls (9 males, 7 females). The subjects' ages ranged from 9 months to 12 years. Weight gain was noted in 9 (60%) of 15 patients in the study group, and 8 (50%) of 16 subjects in the control group (p > .05). There was no difference between the groups for body mass index (BMI) and serum leptin levels. Although higher serum leptin levels were found in the patients treated with VPA weight gaining (5.65 +/- 3.06 ng/ml vs. 3.28 +/- 1.69 ng/ml), we did not find a difference between the patients weight gaining and nonweight gaining (p > .05). While a significant correlation between BMI and serum leptin levels was found in the study group (r = .704; p = .003), it was not significant in the control group (r = .330; p = .211). In conclusion, our findings showed that long-term use of VPA did not cause weight gain in a group of prepubertal children receiving VPA and, parallel to this, serum leptin levels were similar in both the control and study group.     

Plasma leptin, neuropeptide Y, ghrelin, and adiponectin levels and carotid artery intima media thickness in epileptic children treated with valproate

Background

Weight gain is a common side effect of valproate (VPA) treatment, although the mechanism is not clear. Abnormal weight gain and obesity are associated with dyslipidemia, hypertension, and atherosclerosis. Measurement of the common carotid artery intima media thickness (CAIMT) gives a picture of early arterial wall alterations and, currently, is considered a noninvasive marker of premature atherosclerosis. The aim of the present study was to evaluate plasma insulin, leptin, neuropeptide Y (NPY), ghrelin, and adiponectin levels in children with epilepsy treated with VPA and to evaluate these parameters for early atherosclerosis.

Material and methods

Twenty prepubertal children with idiopathic epilepsy treated with VPA were enrolled in this study. Body mass index (BMI) and fasting insulin glucose ratio (FIGR) were calculated, and the plasma insulin, leptin, NPY, ghrelin, and adiponectin levels; the lipid profiles; and CAIMT were measured for all subjects before the treatment and after a follow-up period of 6 and 12?months.

Results

When pretreatment values were compared with those at the end of 6 and 12?months, the mean BMI values, plasma insulin, leptin, NPY levels, and FIGR were increased, whereas the plasma ghrelin and adiponectin levels, lipid profiles, and CAIMT did not change significantly at the end of 6 and 12?months.

Conclusion

These results suggest that weight gain during VPA treatment may be related to increases in insulin, leptin, and NPY levels. Additionally, in this study, no increase in the risk for early atherosclerosis was determined by CAIMT in children with epilepsy treated with VPA.