Initiation Of Valproate Therapy Research Articles

Influence of sodium valproate treatment on body mass and insulin resistance parameters in children with epilepsy

Introduction/Objective. One of the main side effects in patients undergoing valproic acid treatment is weight gain, which might be the reason for drug discontinuation, especially in adolescent girls, and it also has to be considered before introducing the drug. The main goal of our study is to investigate a possible influence of antiepileptic therapy with sodium valproate on weight and glucose homeostasis in pediatric patients with epilepsy. Methods. The investigation included 49 healthy children with recently diagnosed epilepsy. We measured height, weight, and serum 12-hour overnight fasting glucose and insulin level before initiation and after six- and 12-month valproic acid treatment periods. The body mass index and homeostasis model assessment indexes were calculated for each patient and correlated after the initiation of therapy and after six and 12 months of therapy. Results. We found that children significantly gained weight with statistical significance (p < 0.01) even after six months of therapy with a significant glucose metabolism change and statistical difference in average serum glucose and insulin levels (p < 0.05). Conclusion. Our results show that a 12-month treatment with valproic acid in children with epilepsy has a great impact on weight gain and glucose homeostasis and metabolism. We strongly recommend that all children with recently diagnosed epilepsy at the initiation of valproate therapy should be closely monitored on a six-month basis. Consultations with a nutritionist is advised especially in children with a preexisting body weight problem.

Polymorphisms of peroxisome proliferator-activated receptor γ (PPARγ) and cluster of differentiation 36 (CD36) associated with valproate-induced obesity in epileptic patients.

Valproate (VPA) is a choice for the treatment of primary generalized epilepsies and partial epilepsies. Unfortunately, weight gain or obesity is one of the most frequent adverse effects of VPA treatment. Genetic factors were shown to be involved in the effect. The aim of this study was to investigate the association of selected single nucleotide polymorphisms (SNPs) of cluster of differentiation 36 (CD36) and peroxisome proliferator-activated receptor γ (PPARγ) with VPA-induced weight gain and obesity in epileptic patients. A total of 225 Chinese Han epilepsy patients receiving VPA treatment were recruited in the study. Height and weight for the calculation of body mass index (BMI) were measured at the initiation of VPA therapy and in the follow-up examination. A BMI of 25kg/m2 or higher was defined as obesity on the basis of the World Health Organization (WHO) criteria for Asian populations. Four SNPs in CD36 (rs1194197, rs7807607) and PPARγ (rs10865710, rs2920502) were genotyped using the Sequenom® MassArray iPlex platform. About 19.6% of epileptic patients receiving VPA therapy were found to become obese. After covariate analysis of age, gender, sex, height, initial BMI, and VPA dosage, the CD36 rs1194197 C allele and rs7807607 T allele (OR, 0.31; 95%CI, 0.13-0.72; P = 0.009 and OR, 0.38; 95%CI; 0.18-0.83; P = 0.02, respectively) were identified as protective factors for VPA-induced obesity. The PPARγ rs10865710 C allele carriers were found to be less likely to suffer from VPA-induced obesity compared with GG genotype carriers (OR, 0.04; 95%CI, 0.01-0.12; P < 0.001). After a Bonferroni correction for multiple comparisons, the genotypic associations of CD36 rs1194197 and PPARγ rs10865710 and the allelic association of CD36 rs7807607 with obesity remained statistically significant. Our data first indicated that CD36 and PPARγ polymorphisms may be associated with VPA-induced obesity and weight gain, suggesting that CD36 and PPARγ may have potential value in predicting VPA-induced obesity in Chinese Han epileptic patients.

Valproate-induced hyperammonaemic encephalopathy: review of 14 cases in the psychiatric setting

To review signs and symptoms of valproate-induced hyperammonaemic encephalopathy without hepatotoxicity in the psychiatric setting, explore its mechanisms, and give recommendations for prevention and treatment. Medline search with keywords valproate, ammonia, hyperammonaemia, encephalopathy, and then cross-references to articles obtained through this search. Only cases with indication of valproate for psychiatric condition were included. Fourteen cases published in the psychiatric setting are reviewed. Valproate-induced hyperammonaemic encephalopathy is a rare adverse event, occurring almost equally in men and women, with a large age range, and reported in two patients with mental retardation. Symptoms appeared either a few days after initiation of valproate therapy, or after several months or years. The main symptoms were fluctuations in consciousness and disorientation. Clinical severity was not related to blood ammonia levels. All patients recovered after valproate-induced hyperammonaemic encephalopathy diagnosis and treatment, usually involving discontinuation of valproate. Valproate-induced hyperammonaemic encephalopathy is rare and usually reversible in patients without urea cycle disorders when valproate is discontinued. Therapy with carnitine is recommended. Special caution should be used in patients with mental retardation. Psychiatrists should suspect valproate-induced hyperammonaemic encephalopathy when consciousness deteriorates.

Diagnosis of Nonketotic Hyperglycinemia in Patients Treated with Valproic Acid

Morrison et al. [ [1] Morrison P.F. Sankar R. Shields W.D. Valproate-induced chorea and encephalopathy in atypical non ketotic hyperglycinemia. Pediatr Neurol. 2006; 35: 356-358 Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar ] report an instructive case involving the diagnosis of nonketotic hyperglycinemia in an 11-year-old girl with developmental delay who developed acute encephalopathy and chorea shortly after initiation of valproate therapy. Valproate-Induced Chorea and Encephalopathy in Atypical Nonketotic HyperglycinemiaPediatric NeurologyVol. 35Issue 5PreviewNonketotic hyperglycinemia is a disorder of amino acid metabolism in which a defect in the glycine cleavage system leads to an accumulation of glycine in the brain and other body compartments. In the classical form it presents as neonatal apnea, intractable seizures, and hypotonia, followed by significant psychomotor retardation. An important subset of children with nonketotic hyperglycinemia are atypical variants who present in a heterogeneous manner. This report describes a patient with mild language delay and mental retardation, who was found to have nonketotic hyperglycinemia following her presentation with acute encephalopathy and chorea shortly after initiation of valproate therapy. Full-Text PDF

Valproate-Induced Chorea and Encephalopathy in Atypical Nonketotic Hyperglycinemia

Nonketotic hyperglycinemia is a disorder of amino acid metabolism in which a defect in the glycine cleavage system leads to an accumulation of glycine in the brain and other body compartments. In the classical form it presents as neonatal apnea, intractable seizures, and hypotonia, followed by significant psychomotor retardation. An important subset of children with nonketotic hyperglycinemia are atypical variants who present in a heterogeneous manner. This report describes a patient with mild language delay and mental retardation, who was found to have nonketotic hyperglycinemia following her presentation with acute encephalopathy and chorea shortly after initiation of valproate therapy.

Valproate-Induced Tinnitus Misinterpreted as Psychotic Symptoms

Valproate sodium is an anticonvulsant medication, which has also been shown to be effective in the treatment of bipolar disorder. We report a case of valproate-induced tinnitus that was initially misinterpreted as increasing psychotic symptoms, which began approximately 2 days after initiation of valproate therapy. Tinnitus worsened during the next 6 days of treatment until it was recognized that this symptom was related to valproate. After discontinuance of the medication, the tinnitus gradually resolved over a period of 10 days with no residual effects. Although it is a rare adverse effect, valproate-induced tinnitus should be included in the differential diagnosis for tinnitus in patients receiving this medication. Tinnitus may be difficult to recognize in patients with active psychosis or mania.

Parkinsonian Syndrome in Childhood After Sodium Valproate Administration

Among the side effects attributed to sodium valproate administration, the production of a parkinsonian syndrome is very uncommon, particularly in children. We report a 12-year-old girl with secondary epilepsy; 7 days after the initiation of valproate therapy she developed parkinsonism that disappeared completely when valproate was replaced by carbamazepine. We discuss the possible role of alterations in GABAergic neurotransmission in the extrapyramidal syndrome that developed.

Valproate (VPA) metabolites in various clinical conditions of probable VPA-associated hepatotoxicity.

Of a cohort of 470 epileptic patients in whom valproate (VPA) serum metabolites had been measured, 170 subjects without symptoms or signs of hepatic side effects were chosen as a reference group to establish the usual metabolic pattern. A wide interindividual variation of VPA metabolite concentrations was noted. Infants receiving VPA monotherapy and comedication with other antiepileptic drugs (AEDs) showed lower concentrations of the potential hepatotoxin 4-ene-VPA than did older children. In 11 patients with early symptoms and signs of possible fatal VPA-associated hepatotoxicity, the following spectrum of benign clinical conditions was observed: unusually severe side effect during initiation of VPA therapy (1 patient), high VPA dosage (2 patients), reversible impairment of coagulation with bleeding manifestations in association with a slight increase in transaminase levels (1 child), and reversible liver dysfunction associated with febrile illness (7 patients). Reversible or irreversible fulminant liver failure had occurred in 5 children. Three of the 4 children with a fatal outcome had massive lactic acidosis. In all patients with probable VPA-associated hepatotoxicity, some aspects of VPA metabolism differed distinctly from that of the reference group, but the inter-individual profile of metabolites varied considerably, even in the subgroup of 4 children who died. Impairment of VPA beta-oxidation and increase of metabolites of alternative metabolic pathways (omega- and omega 1-hydroxylation, dehydrogenation reactions) were the most frequent findings. Increased values of 2-n-propyl-4-pentenoic acid metabolite of VPA (4-ene-VPA), could be detected only in 1 of the 5 patients with fulminant liver failure and in one other child with a slight hepatic dysfunction, indicating that this VPA metabolite is not the decisive hepatotoxin or indicator of hepatotoxicity. Because we cannot distinguish between benign and life-threatening hepatic adverse reactions on the basis of VPA metabolites, all identified changes are considered secondary to an as-yet-unknown primary metabolic event. The most toxic compound could be VPA itself, which may unmask an inborn or an acquired metabolic defect in the processing of fatty acids.

Valproic acid in epilepsy: Clinical and pharmacological effects

The antiepileptic drug valproic acid was studied in an open clinical trial as adjunct medication for 23 patients with uncontrolled seizures of a generalized or partial type. Two-thirds of the patients experienced reduction in seizure frequency ranging from 25 to 100%. Extensive testing revealed no evidence of serious systemic toxicity due to the drug. Minor side effects (e.g., nausea, vomiting, or sedation) were usually transient. Sodium valproate syrup and valproic acid in capsules gave equivalent mean low (23.3 microgram/ml) and maximum (42.5 microgram/ml) serum concentrations. The drug had a relatively short half-life of 8.7 hours, necessitating administration in divided daily doses. During initiation of valproate therapy there was evidence of a decline in total serum phenytoin concentration (16.5 to 10.2 microgram/ml; p less than 0.001) while the percentage of free phenytoin increased (10.9 to 20%). The quantity of unbound phenytoin was relatively stable throughout. This observation was interpreted as a drug interaction: valproic acid competed with phenytoin for access to plasma protein binding sites.