Prospective analysis of weight gain and endocrinologic-metabolic alterations in children who undergo antiepileptic therapy (valproic acid)

Objective: Epilepsy is an important chronic disease in childhood that necessitates long-term therapy. The existence of long-term therapy lays the groundwork for the side effects of the used drugs. In this study, we aimed to the evaluate the etiologic factors considered to play role in weight gain and obesity during valproic acid (VPA) therapy.Materials and methods: Thirty-four patients who were diagnosed for epilepsy and taken under VPA treatment between January 2006 and December 2007 in Pediatric Neurology Department of Dokuz Eylul University Medical School were included in the study. Patients with pathologic cranial imaging findings, chromosomal anomaly, having another coexisting illness, under a drug administration which could cause weight gain (tricyclic antidepressants, anti-physcotic drugs, eg), using more than one antiepileptic drug, with physicomotor retardation, endocrinologic disease, obesity and anormal neurological examination findings were excluded. The ages of the patients ranged from 7 months to 17 years. Initial oksologic parameters (weight, length, BMI, weight SDS), liver function tests (AST, ALT, GGT), in addition to these fasting insulin and glucose, HDL (high density lipoprotein) LDL (low density lipoprotein), triglycerid (TG), total cholesterol (TC) were compared with the samples taken in 6th and 12th months of the threapy; initial sex hormon binding proteins (SHBG) and adrenal androgen levels {17-OH progesteron, androstenodion, dihidroepiandrostenodion sulfat (DHEA-S), free testosteron (FTE), total testosteron(TTE)}were compared with the levels obtained at 12th month.Results: Thirty-four children with a medium age of 7.76±4.75 (0.75-17.0) years, 21 male (%61.8) and 13 female (%38.2), were included in the study. Twenty-four of these were prepubertal and 10 of them were in the several stages of the pubertal period. When the weight gains during the course of the therapy were evaluted, weight percentiles (p=0.049), BMI percentiles, BMI SDS (p=0.009) in the sixth month of the therapy were found to display a statistically significant increase when compared with the initial values. However, this significant increase could not be demonstrated in the comparison of the initial and 12th month results, likewise in 6th and 12th month results. When the possible causes of the significant weight gain in the first sixth month of the therapy showing a contrast with the 12th month results were investigated, abscence of the arrengements of the drug doses in spite of the weight gain resulting for lower doses of valproic acid administrations per new body weight was found to be the etiologic factor (p=0.002). Higher serum VPA levels in the 12th month than 6th month levels supported this finding (p=0.014). The number of overweight patients in respect of BMI was 8 in the beginning and the sixth month of the therapy, in the 12th month of the therapy it was 6. Although there was no patient with obesity (body weight > 95p) initially, 4 patients developed obesity in the 6th and 12th months.When serum glucose and insulin levels and insulin resistance (fasting glucose/insulin ratio and HOMA index) were evaluated, fasting serum glucose leves in the 6th month and fasting glucose/insulin ratio in the 12th month displayed statistically significant increases in comparasion with the initial levels (p=0.02 and p=0.05 respectively). In contrast, by comparasion of the serum glucose levels in the 6th and the 12th months with them of the initial and the 12th month?s; by comparasion of the fasting glucose/insulin ratios in the beginning of the study with them of the 6th month and in the sixth month with them of the 12 th month we could not find significant differences. Likewise, fasting insulin levels and HOMA indexes did not demonstrate significant differences during the course of the study. The evaluation of the serum androgen (TTE, FTE, DHEAS, 17 OH progesteron, androstenodion) and SHBG levels in whole number patients or by seperating them in pubertal and prepubertal periods did not denote a significant change in the course of one year treatment period.When the alterations in lipid profiles were invastigated in the course of the VPA therapy the increase in TC levels in both 6th (p=0.001) and 12th (p=0.001) months compared with the initial levels; increase in LDLc levels in 12th month when compared with initial levels (p=0.003) and 6th month levels (p=0.02) were found statistically significant. TG and HDLc levels did not display any significant changes.Conclusion: In this prospective study evaluating patients taking VPA therapy, the weight gain that we determined during the first 6 months in a limited number of patients having normal initial body weights, to a large extend turned into normal values at the end of the first year. Hyperinsulinemia and hyperandrogenism could not be confirmed. In the analysis of serum lipids, the increase in TC and LDLc levels betrays the necessity the of screening their lipid profiles periodically and paying attention for atherosclerosis and coronary artery diseases. The pathogenesis of the weight gain and obesity, appearing to arise by adverse effects of VPA, has not be exactly understood yet. Further studies taking multifactorial interactions in account such as inheritance, socioeconomical, nutritional, environmental factors, education of the family are necessary.Key words: Valproic acid, epilepsy, obesity, lipid profile, insulin resistance