Valproate For Epilepsy Research Articles

Abstract- Poster

Introduction:Agenesis of Corpus callosum (ACC) is a rare disorder that presents at birth (congenital), it is characterized by partial or complete absence of an area of the brain that connects two cerebral hemispheres. It is linked with psychiatric disorders, cognitive deficits, learning disabilities and developmental delays.Case 1:A 13-year-old male was brought to OPD with c/o aggressive behaviour, school refusal and epilepsy of one week duration. History revealed delayed milestones, MRI showing partial ACC. He was treated with olanzapine and sodium valproate with significant improvement in aggression.Case 2:A 22-year-old male was brought to OPD with c/o irritability, decreased sleep, delayed milestones, epilepsy with left sided hemiparesis in the last 3 weeks. Was treated with phenytoin and valproate for epilepsy. Birth history revealed pre-term twin delivery with birth asphyxia. He was treated with risperidone with significant improvement in behavioural abnormalities.Conclusion:Early diagnosis and treatment of behavioural abnormalities and epilepsy can improve the outcome and improve quality of life.

Is the Medicines and Healthcare products Regulator Agency (MHRA) guidance on sodium valproate acceptable to women of childbearing age?

The UK Medicines and Healthcare products Regulatory Agency (MHRA) published guidelines restricting the use of sodium valproate in women of childbearing age unless they consented to the pregnancy prevention programme (PPP), receiving counselling by an epilepsy specialist, or meeting exclusion criteria. We contacted every woman of childbearing age on valproate for epilepsy in NHS Tayside (122). Seventeen out of 122 (13.9%) responded to the initial invitation to attend, and 25 out of 122 (20.4%) responded to a letter sent to their GP. Twenty-five attended, 21 completed a consent form, seven switched to another drug and three attended to express dissatisfaction with the MHRA guidance. There were 53 patients identified with learning difficulties. Consent was only taken from three patients, with carers declining to sign consent because the patient was not sexually active. Our study suggests that patients and carers do not wish to stop valproate or engage in PPP despite being made aware of MHRA guidance.

Evaluation of sodium valproate loaded nanoparticles in acute and chronic pentylenetetrazole induced seizure models

Background and purposeEfficacy of sodium valproate in epilepsy is limited by its poor blood brain barrier penetration and side effects. Nanoparticles may offer a better drug delivery system to overcome these limitations. This study evaluated the efficacy of sodium valproate encapsulated in nanoparticles in pentylenetetrazole (PTZ) induced acute and kindling models of seizures in male Wistar rats. MethodsPoly lactic-co-glycolic acid (PLGA) based, polysorbate 80 stabilized sodium valproate loaded nanoparticles (nano sodium valproate) and rhodamine loaded nanoparticles (RLN) were formulated by double emulsion- solvent evaporation method and characterized for their size, shape, zeta potential and drug loading percentage. RLN was used to demonstrate blood brain barrier (BBB) permeability of nanoparticles. Serum drug levels were estimated using high performance liquid chromatography. The efficacy of standard sodium valproate (300 mg/kg) and nano sodium valproate (∼300, ∼150 and ∼75 mg/kg of sodium valproate) were evaluated in experimental animal models of seizures along with their effects on behavioral and oxidative stress parameters. Drugs were administered 60 min before PTZ in acute model. In the kindling model, drugs were administered every day while PTZ was administered on alternate days 60 min after drug administration. All the study drugs/compounds were administered intraperitoneally. ResultsRLN were observed to be clustered in cortex which implied that the nanoparticles crossed BBB. Both standard sodium valproate and nano sodium valproate reached therapeutic serum level at 15 min and 1 h, but were undetectable in serum at 24 h. In acute PTZ (60 mg/kg) model, nano sodium valproate (∼300 mg/kg of sodium valproate) and standard sodium valproate showed protection against seizures till 6 h and 4 h, respectively. There were significant behavioral impairment and oxidative stress with standard sodium valproate in acute model as compared to nano sodium valproate at 6 h. In kindling model, induced with PTZ (30 mg/kg, every alternate day for 42 days), complete protection from seizures was observed with nano sodium valproate (∼150 mg/kg and ∼75 mg/kg of sodium valproate) and standard sodium valproate (300 mg/kg). Similarly, significant protection from behavioral impairment and oxidative stress was observed with standard sodium valproate and nano sodium valproate as compared to PTZ. ConclusionWhen compared to conventional therapy, nano sodium valproate showed protection from seizures at reduced doses and for a longer duration in animal models of epilepsy. This study suggests the potential of nano sodium valproate in the treatment of epilepsy.

Effects of enalapril and losartan alone and in combination with sodium valproate on seizures, memory, and cardiac changes in rats

PurposeCardiac changes accompanying seizures may be responsible for sudden unexpected death in epilepsy (SUDEP), and drugs with antiseizure and favorable cardiovascular profile could be beneficial. The effect of losartan and enalapril alone and in combination with sodium valproate on seizures, cognition, cardiac histopathology, and serum brain-derived neurotropic factor (BDNF) levels were determined. MethodsMale “Wistar” rats (200–250 g) were administered enalapril (20 mg/kg, intraperitoneally (i.p.)) and losartan (10 mg/kg, i.p.) daily and simultaneously subjected to pentylenetetrazole (PTZ)-kindling (PTZ 30 mg/kg, i.p., every alternate day). Enalapril and losartan were injected 45 & 120 min before seizure stimuli. In another set of experiments, sodium valproate (150 mg/kg, i.p.) alone or in combination with enalapril (20 mg/kg, i.p.) and losartan (10 mg/kg, i.p.) were administered daily during induction of kindling. The effect on seizures and behavior were noted; rats were sacrificed, and blood and hearts were collected for further analysis, i.e., BDNF levels, heart weight–body weight (HWBW) ratio, and cardiac histopathology. ResultsLosartan, but not enalapril, suppressed the seizure score in PTZ kindling. Sodium valproate alone or in combination with losartan or enalapril prevented kindled seizures. Sodium valproate per se caused cognitive impairment, which was prevented on combining with losartan or enalapril. A decrease in HWBW ratio was observed only in enalapril group (p value = 0.02). Kindling led to cardiac ischemic changes, which could be prevented by losartan and sodium valproate. Serum BDNF level was decreased in PTZ (p value = 0.02) and sodium valproate per se group (p value = 0.04), but sodium valproate could reverse the PTZ-induced decrease in serum BDNF level. ConclusionThe use of losartan with sodium valproate in epilepsy may prevent the cognitive and cardiac sequelae of seizures. The BDNF levels as a marker for cardiovascular risk in persons with epilepsy (PWE) needs to be explored further.

Study of anticonvulsant activity of acetazolamide on albino rats and its influence on anticonvulsant activity of sodium valproate

Background: Epilepsy is a common neurological disorder. 30-40% of patients will continue to have seizures despite the use of antiepileptic drugs either alone or in combination. The present study is undertaken to evaluate the anticonvulsant activity of Acetazolamide (ACZ) in albino rats and its influence on anticonvulsant activity of sodium valproate.Methods: Albino rats (150-200gms) of male sex were randomly selected, from central animal facility, MMCRI, Mysore. They were divided into 6groups (per model) of 6 rats each, control group-normal saline 0.5ml, standard group-sodium valproate (300mg/kg), dose 1-ACZ (8.75mg/kg), dose 2-ACZ (17.5mg/kg) and dose 3-ACZ (35mg/kg), dose 4-ACZ (8.75mg/kg) with sodium valproate (150mg/kg). The anti-convulsant activity was screened using MES model and PTZ model.Results: Results were analysed by ANOVA followed by post hoc Fisher’s LSD test. The ACZ has shown anticonvulsant activity at the dose of 17.5mg/kg and 35mg/kg body weight and combination of ACZ 8.75mg/kg with sodium valproate 150mg/kg both in MES model and PTZ model. The anticonvulsant activity of ACZ was less when compared to Sodium Valproate in both MES model and PTZ model. The anticonvulsant activity of combination, ACZ 8.75mg/kg with Sodium valproate 150mg/kg was comparable and more significant when compared to standard drug alone in MES model and PTZ model.Conclusions: The ACZ has shown anticonvulsant activity in MES model and PTZ induced seizure model of epilepsy. This study has shown that ACZ potentiated the effect of sodium valproate and can be used as add on drug with sodium valproate in epilepsy.

Sodium valproate use is associated with reduced parietal lobe thickness and brain volume

We hypothesized that total brain volume, white matter volume, and lobar cortical thickness would be different in epilepsy patients. We studied valproate relative to nonvalproate by using patients with epilepsy and healthy controls. Patients with focal intractable epilepsy from a tertiary epilepsy center were the primary group for analysis. A confirmatory analysis was carried out in an independent group of subjects imaged as part of a community-based study of childhood-onset epilepsy. Total brain volume; white matter volume; and frontal, parietal, occipital, and temporal lobe thickness were measured by processing whole-brain T1-weighted MRI using FreeSurfer 5.1. Total brain volume, white matter volume, and parietal thickness were reduced in the valproate group relative to controls and nonvalproate users (valproate, n = 9; nonvalproate, n = 27; controls, n = 45; all male). These findings were confirmed in an independent group (valproate, n = 7; nonvalproate, n = 70; controls, n = 20; all male). Sodium valproate use in epilepsy is associated with parietal lobe thinning, reduced total brain volume, and reduced white matter volume. This study provides Class IV evidence that use of valproate in epilepsy is associated with reduced parietal lobe thickness, total brain volume, and white matter volume.

Unusual drug reaction between valproate sodium and meropenem

We describe here a rare case in which valproic acid (VPA) levels were affected by ertapenem but not by meropenem even though ertapenem and meropenem are in the same carbapenem class. A 68-year-old Filipino male treated with valproate for epilepsy and ertapenem for an infectious disease had decreased VPA levels during the first day of ertapenem therapy. His VPA level increased soon after terminating ertapenem therapy. Two types of carbapenems had different drug reactions with concomitant use of VPA in this patient. Closer monitoring of VPA concentrations are necessitated using carbapenems for treating infection in patients being administered VPA. Another option is the use of anti-epileptic drugs other than VPA if concomitant use with a carbapenem is warranted.

A meta-analysis of polycystic ovary syndrome in women taking valproate for epilepsy

To conduct a meta-analysis to quantify whether valproate (VPA) is associated with an increased risk of polycystic ovary syndrome (PCOS) in women with epilepsy. A comprehensive literature search for all published studies of MEDLINE and EMBASE was performed for English language studies published from 1st January 1990 to 4th February 2011. The studies included should be prospective and controlled. We then performed a meta-analysis to identify polycystic ovary syndrome in women with epilepsy treated with VPA. The meta-analysis included 11 studies that met inclusion/exclusion criteria, involving 556 women with epilepsy treated with VPA, 593 women treated with other antiepileptic drugs (AEDs), 120 women with untreated epilepsy and 329 healthy controls. The calculated incidence of PCOS in women treated with VPA was higher than that in women treated without VPA (10 studies included, P<0.05, OR 3.04, 95% CI 2.09-4.43). According to different definitions or diagnostic criteria of PCOS, the results were different. VPA's treatment was associated with higher incidence of PCOS in the criteria of hyperandrogenism and/or hyperandrogenemia, oligoovulation (4 studies included, P<0.05, OR 3.22, 95% CI 1.79-5.80), and in the criteria of two of the three following fulfilled: appearance of polycystic ovary (PCO) on the ultrasonogram, elevated serum testosterone levels and irregular (oligo-/amenorrhea) menstrual cycles (1 post hoc reanalysis study included, P<0.05, OR 5.01, 95% CI 2.40-10.49. Another prospective and crosssectional included, P<0.05, OR 3.50, 95% CI 1.30-9.40). However, in the criteria of PCO with ovulatory dysfunction (polymenorrhea, amenorrhea, or oligomenorrhea), clinical and/or biochemical evidence of hyperandrogenism according to National Institutes of Child Health and Human Development (NICHHD) and The National Institutes of Health (NIH) Consensus Conference, VPA did not increase the PCOS incidence compared with other AEDs (4 studies included, P>0.05, OR 1.37, 95% CI 0.59-3.19). Data on PCOS's components were pooled. PCO was higher in women treated with VPA than in those without VPA (6 studies included, P<0.05, OR 1.94, 95% CI 1.28-2.95) or in healthy controls (4 studies included, P<0.05, OR 4.99, 95% CI 2.97-8.37). VPA treated women were more subject to hyperandrogenism than non-VPA treated women (5 studies included, P<0.05, OR 2.35, 95% CI 1.57-3.53). There is significant difference of menstrual disorders between VPA treated women and non-VPA treated women (7 studies included, P<0.05, OR 1.64, 95% CI 1.19-2.25). Results of this meta-analysis suggest that the raw incidence of PCOS in VPA treated women with epilepsy is approximately 1.95 folds that in other AEDs treated women. PCOS and its components may be associated with VPA treated women with epilepsy. We recommend monitoring PCOS and its components in women with VPA mono-/polytherapy. In light of limitations and heterogenicity, there is surely the need for more prospective studies to identify VPA and PCOS.

The mechanisms of action of valproate in neuropsychiatric disorders: can we see the forest for the trees?

After more than 40 years of clinical use, the mechanisms of action of valproate in epilepsy, bipolar disorder and migraine are still not fully understood. However, recent findings reviewed here shed new light on the cellular effects of valproate. Beyond the enhancement of gamma-aminobutyric acid-mediated neurotransmission, valproate has been found to affect signalling systems like the Wnt/beta-catenin and ERK pathways and to interfere with inositol and arachidonate metabolism. Nevertheless, the clinical relevance of these effects is not always clear. Valproate treatment also produces marked alterations in the expression of multiple genes, many of which are involved in transcription regulation, cell survival, ion homeostasis, cytoskeletal modifications and signal transduction. These alterations may well be relevant to the therapeutic effects of valproate, and result from its enhancement of activator protein-1 DNA binding and direct inhibition of histone deacetylases, and possibly additional, yet unknown, mechanism(s). Most likely, both immediate biochemical and longer-term genomic influences underlie the effects of valproate in all three indications.

Multiple mechanisms induce transcriptional silencing of a subset of genes, including oestrogen receptor α, in response to deacetylase inhibition by valproic acid and trichostatin A

Valproate (VPA) and trichostatin A (TSA), inhibitors of zinc-dependent deacetylase activity, induce reduction in the levels of mRNA encoding oestrogen receptor-alpha (ERalpha), resulting in subsequent clearance of ERalpha protein from breast and ovarian cell lines. Inhibition of oestrogen signalling may account for the endocrine disorders, menstrual abnormalities, osteoporosis and weight gain that occur in a proportion of women treated with VPA for epilepsy or for bipolar mood disorder. Transcriptome profiling revealed that VPA and TSA also modulate the expression of, among others, key regulatory components of the cell cycle. Meta-analysis of genes directly responsive to oestrogen indicates that VPA and TSA have a generally antioestrogenic profile in ERalpha positive cells. Concomitant treatment with cycloheximide prevented most of these changes in gene expression, including downregulation of ERalpha mRNA, indicating that a limited number of genes signal a hyperacetylated state within cells. Three members of the NAD-dependent deacetylases, the sirtuins, are upregulated by VPA and by TSA and sirtuin activity contributes to loss of ERalpha expression. However, prolonged inhibition of the sirtuins by sirtinol also induces loss of ERalpha from cells. Mechanistically, we show that VPA invokes reversible promoter shutoff of the ERalpha, pS2 and cyclin D1 promoters, by inducing recruitment of methyl cytosine binding protein 2 (MeCP2) with concomitant exclusion of the maintenance methylase DNMT1. Furthermore, we demonstrate that, in the presence of VPA, local DNA methylation, deacetylation and demethylation of activated histones and recruitment of inhibitory complexes occurs on the pS2 promoter.

Higher androgens and weight gain with valproate compared with lamotrigine for epilepsy

Background: Valproate is used widely for the treatment of epilepsy but has been associated with hyperandrogenism, hyperinsulinemia, and dyslipidemia. The mechanism for these associations is unknown, but they have been hypothesized to be secondary to valproate-associated weight gain. This study was conducted to test the hypothesis that the antiepileptic drug lamotrigine, which also has a broad spectrum of anti-seizure efficacy, would not be associated with endocrine abnormalities and would not cause weight gain. Objective and Methods: This open-label, cross-sectional study compared (1) endocrine and lipid measures during the early follicular phase of the menstrual cycle; (2) prevalence of menstrual disorders (from patient diaries recorded over three cycles); and (3) body weight of women with epilepsy on lamotrigine monotherapy ( n=119) with those on valproate monotherapy ( n=103) for <5 years. Results: Mean total serum testosterone and androstenedione levels were higher ( P<0.02) in the valproate group compared with the lamotrigine group. More lamotrigine patients (87%) than valproate patients (77%) reported regular menstrual cycles at the Screening Visit. The prevalence of anovulation did not differ between lamotrigine and valproate. Mean HDL cholesterol levels were higher ( P<0.01) with lamotrigine compared with valproate as were LDL and total cholesterol levels ( P<0.05). Mean total insulin levels did not significantly differ between the groups. Whereas mean body weight in lamotrigine patients did not differ between the time lamotrigine treatment was initiated and the Study Visit, mean weight in valproate patients increased by 3.7 kg. Conclusions: Compared with lamotrigine monotherapy, valproate monotherapy was associated with weight gain and higher androgen levels in women with epilepsy. These data suggest that the hyperandrogenism observed in some women using valproate for epilepsy may be secondary to drug therapy. Lamotrigine monotherapy may be more appropriate than valproate for women in whom reproductive endocrine or metabolic abnormalities are potential concerns, i.e. women with concerns about weight gain, diabetes, hirsutism, polycystic ovary syndrome, menstrual dysfunction or infertility.

Valproic acid-associated weight gain in older children and teens with epilepsy

This research was undertaken to determine the incidence and predictors of weight gain in older children and teens treated with valproate for epilepsy. Subjects who were 10 to 17 years of age, who began valproate treatment between January 1, 1996, and December 31, 2000, and who had documented weight and height measurements at medication initiation and at least one follow-up visit were retrospectively identified. Exclusion criteria were follow-up <2 months, discontinuation of valproate within 2 months, concurrent therapy with medication known to affect weight, or gastrostomy feeding. Body mass index was calculated at initiation and either discontinuation of valproate or last follow-up and stratified into four categories: underweight, (<fifth percentile), appropriate (fifth to eighty-fifth percentile), potentially overweight (≥eighty-fifth to ninety-fifth percentile) and overweight (ninety-fifth percentile or higher). Potential predictors of change in body mass index were examined. Mild-to-moderate weight gain was observed in 58% of the 43 subjects treated with valproate (median increase, 2; twenty-fifth to seventy-fifth percentile, 1-6.4). Seventy-nine percent remained in the same body mass index category, and 14% moved up to a potentially overweight or overweight category. The only predictor of an overweight category at follow-up was a potentially overweight or overweight category at initiation ( P <0.0002). Two factors tended to predict an increase in body mass index: normal neurocognitive status ( P = 0.06) and primary generalized seizure type ( P = 0.07).

Altered ovarian function and cardiovascular risk factors in valproate-treated women

PurposePolycystic ovaries and menstrual disturbances seem to be common among women taking valproate for epilepsy. The purpose of the present study was to assess the frequency of valproate-related metabolic and endocrine disorders in different groups of women with epilepsy. Subjects and methodsSeventy-two women with epilepsy and 52 control subjects from centers in three European countries (Finland, Norway, and the Netherlands) participated in the study. Thirty-seven of the women with epilepsy were taking valproate monotherapy and 35 carbamazepine monotherapy. ResultsThe frequency of polycystic ovaries or hyperandrogenism, or both, among valproate-treated women with epilepsy was 70% (26 of 37) compared with 19% (10 of 52) among control subjects (P <0.001). They were found in 79% (11 of 14) of obese and 65% (15 of 23) of lean women on valproate, and in 20% (7 of 35) of carbamazepine-treated women. The obese valproate-treated women with polycystic ovaries or hyperandrogenism, or both, had hyperinsulinemia and associated unfavorable changes in serum lipid levels consistent with insulin resistance. ConclusionsPolycystic ovaries and related hyperandrogenism are frequently encountered in both obese and lean women taking valproate for epilepsy. The use of valproate is associated with risk factors for cardiovascular disease in obese women.

Thyroid function in men taking carbamazepine, oxcarbazepine, or valproate for epilepsy.

Antiepileptic drugs (AEDs) may affect serum thyroid hormone concentrations. This study aimed to evaluate thyroid function in men taking carbamazepine (CBZ), oxcarbazepine (OCBZ), or valproate (VPA) for epilepsy. Ninety men with epilepsy (40 taking CBZ, 29 taking OCBZ, and 21 taking VPA monotherapy) and 25 control subjects participated in the study. After clinical examination, a blood sample for hormone, gamma-glutamyl-transferase (GGT) and antibody (ab) assays was obtained. Serum thyroxine (T4) and free thyroxine (FT4) concentrations were low in men taking CBZ or OCBZ. Forty-five percent of men taking CBZ and 24% of men taking OCBZ had serum T4 and/or FT4 levels below the reference range. However, no correlations were found between T4 or FT4 and GGT concentrations in men taking CBZ or OCBZ. Thirteen percent of men taking CBZ, 17% of men taking OCBZ, and 6% of control men had increased levels of thyroid peroxidase (TPO)-ab and/or thyroglobulin (TG)-ab, but these were not associated with altered serum thyroid hormone concentrations. Serum triiodothyronine and thyrotropin levels in men taking CBZ or OCBZ were normal. In men taking VPA, the concentrations of thyroid hormones, thyrotropin, and antithyroid ab were normal. Serum thyroid hormone concentrations are low in CBZ- or OCBZ-treated men. However, these low levels do not seem to be due to liver enzyme induction or activation of immunologic mechanisms. Therefore, interference with hypothalamic regulation of thyroid function by CBZ and OCBZ seems possible. VPA does not have any significant effects on thyroid function.

Valproate, Menstrual Disorder and Polycystic Ovaries

Three patients treated with valproate for epilepsy, beginning at 16, 17, and 31 years of age, developed a reproductive disorder and are reported from the University of Oulu, Finland.

Valproate-induced hyperandrogenism during pubertal maturation in girls with epilepsy.

Valproate is effective for treatment of a variety of seizure types both in adults and in children with epilepsy, but it induces obesity and polycystic ovaries in a considerable proportion of adult women, particularly when the medication is started before the age of 20. In the present study we evaluated reproductive endocrine function in 41 girls, 8 to 18 years old, taking valproate for epilepsy and in 54 healthy control girls. Among the girls taking valproate, 16 were prepubertal, 11 were pubertal, and 14 were postpubertal, and the corresponding numbers were 20, 13, and 21 in the control group. The mean serum testosterone concentrations of prepubertal, pubertal, and postpubertal girls taking valproate were significantly higher than those of the control girls at the same pubertal stage. Hyperandrogenism, defined as serum testosterone levels higher than the mean + 2SD in the control girls at the same pubertal stage, was seen in 38% of prepubertal, 36% of pubertal, and 57% of postpubertal girls taking valproate. In addition, postpubertal girls taking valproate were more obese than the controls and the mean serum insulin-like growth factor binding protein-1 concentration of pubertal and postpubertal hyperandrogenic girls taking valproate was lower than in valproate-treated girls without hyperandrogenism. Valproate may induce hyperandrogenism in girls with epilepsy during the sensitive period of pubertal maturation, and the frequency of hyperandrogenism increases with pubertal development. This emphasizes the importance of careful endocrine observation of girls taking valproate for epilepsy.

Valproate-Induced Hyperandrogenism in Girls

The reproductive endocrine function in 41 girls, 8 to 18 years old, treated with valproate for epilepsy and in 54 healthy control girls was evaluated at the University of Oulu, Finland.

Valproate, lamotrigine, and insulin-mediated risks in women with epilepsy.

We recently reported the frequent occurrence of polycystic ovaries and hyperandrogenism associated with weight gain and hyperinsulinemia in women taking valproate for epilepsy. The purpose of this study was to evaluate the risks related to valproate-induced hyperinsulinemia and their reversibility after discontinuing the medication. Sixteen women with valproate-related polycystic ovaries or hyperandrogenism participated in the study. Vaginal ultrasonography was performed, and endocrine and lipid parameters were measured. Thereafter, lamotrigine was substituted for valproate and the patients were observed for 12 months. Twenty-four healthy age-matched women served as control subjects. Twelve women completed the 12-month follow-up. While still on valproate they had centripetal obesity with associated hyperinsulinemia and unfavorable serum lipid profiles. The body-mass index and fasting serum insulin and testosterone concentrations decreased during the first year after replacing valproate with lamotrigine whereas the HDL-cholesterol/total cholesterol ratios increased from 0.17 +/- 0.06 to 0.26 +/- 0.05. The total number of polycystic ovaries in these women decreased from 20 during valproate medication to 11 one year after replacing valproate with lamotrigine. Valproate induces a metabolic syndrome with centripetal obesity, hyperinsulinemia, lipid abnormalities, and polycystic ovaries/hyperandrogenism in women with epilepsy. These valproate-related risks can be reduced by substituting lamotrigine for valproate.

Preventive treatment of migraine: an overview.

The pharmacologic treatment of migraine may be acute (abortive, symptomatic) or preventive (prophylactic). Most migraine preventive medications were designed to treat other disorders (e.g., propranolol for hypertension, valproate for epilepsy, etc.). Preventive medication is usually given daily for months or years; however, treatment can be episodic, subacute, or chronic. The medications can be divided into two major categories: (i) Alternatives of high efficacy, which include beta-blockers, tricyclic antidepressants, and divalproex, and of lower efficacy, which include selective serotonin reuptake inhibitors, calcium channel antagonists, and non-steroidal antiinflammatory drugs, and (ii) second-line choices of high efficacy, which include methysergide and monoamine oxidase inhibitors. The choice of preventive treatment depends on the individual drug's efficacy and side effects, the patient's wants, needs, and response to prior treatment, and the presence of any comorbid or coexistent disease.

Obesity and endocrine disorders in women taking valproate for epilepsy

We recently reported the frequent occurrence of polycystic ovaries and hyperandrogenism in women taking valproate for epilepsy, especially when the medication was started before the age of 20 years. In the present study we evaluated the association of obesity and hyperinsulinemia with valproate-related polycystic ovaries and hyperandrogenism in women with epilepsy. Sixty-five women participated in the study. Twenty-two received valproate monotherapy and 43 received carbamazepine monotherapy. In addition to clinical examination, vaginal ultrasonography was performed to determine ovarian size, and the concentrations of serum sex hormones, insulin, insulin-like growth factor 1, and the insulin-like growth factor-binding proteins 1 and 3 (IGFBP-1 and IGFBP-3) were measured. Fifty-nine percent of the women on valproate were obese, and in a retrospective analysis an indisputable weight gain (mean, 21 kg; range, 8-49 kg) was found in 50% of the women taking valproate. Fourteen (64%) of the women on valproate had polycystic ovaries, hyperandrogenism, or both. These women were obese, and in addition to elevated serum androgen levels, they had high concentrations of fasting serum insulin and low levels of serum insulin-like growth factor-binding protein 1. Valproate therapy for epilepsy is associated with weight gain during treatment in approximately 50% of women patients. The weight gain can be progressive, and is associated with hyperinsulinemia and low serum levels of insulin-like growth factor-binding protein 1, which may lead to hyperandrogenism and polycystic ovaries.