http://www.theannals.com/content/43/1/45.

abstract Body Mass Index and Serum Lipid Changes During Treatment with Valproic Acid in Children with Epilepsy Abstract BACKGROUND: Valproic acid is the drug of choice for a wide variety of epileptic seizures and syndromes because of its broad spectrum of activity and because, in most patients, it is well tolerated. Although weight gain is a well-known adverse effect of valproic acid therapy, only a few studies have addressed weight gain associated with it in children aged 28 years. OBJECTIVE: To evaluate valproic acidassociated changes in the body mass index (BMI) z-scores and to assess changes in serum triglyceride, cholesterol, and fasting glucose levels in young children receiving valproic acid treatment. METHODS: Eighty-seven patients (39 females, 48 males) receiving valproic acid therapy for at least 3 months were included in the retrospective longitudinal study. Mean SD age at initiation of therapy was 4.8 0.8 years. Changes in BMI z-scores as well as serum triglyceride, total cholesterol, and fasting glucose levels were evaluated as continuous variables and analyzed by longitudinal methods for all patients. RESULTS: The average change from baseline in BMI z-scores was 0.80 (p = 0.001) at 3.1 years of follow-up. No significant change in triglyceride, cholesterol, and serum fasting glucose levels was observed over the same period. The percentage of overweight children at baseline was 6.9% and rose to 16% by the final visit (p = 0.081). CONCLUSIONS: Valproic acidassociated weight gain may occur in young children. However, only 16% of patients were categorized as overweight at the end of the study; this percentage overlaps the percentage of overweight healthy young Italian children. The BMI z-scores significantly increased during the first 16 months of therapy, then appeared to level off. These observations may influence clinical practice and decision-making regarding suspending the drug due to weight gain in children in whom seizure control has been achieved. http://content.karger.com/ProdukteDB/produkte.asp?Aktion=ShowFulltext&ArtikelNr=321664&Ausgabe=255072&Produ ktNr=223855 Original Paper Circulating Levels of Allopregnanolone, a Neuroactive Steroid, and Leptin during Treatment with Valproic Acid in Children with Epilepsy a, Stefano Luisib, Rosa Mostardinia, Mariarosaria Materac, Enzo Gabriele Barloccoc, Elena Casarosad, Salvatore Grosso Paolo Balestria, Felice Petragliab Neuroendocrinology 2011;93:159-164 (DOI: 10.1159/000321664) Abstract: Weight gain is a well-known unwanted effect of valproic acid (VPA) therapy. Studies on VPA-associated changes of homeostatic hormones remain limited and controversial. Allopregnanolone (AP) is a circulating neuroactive steroid involved in modulation of behavioral activities whose serum levels are increased in obese children. The aim of the present study was to determine whether VPA therapy affects leptin and AP circulating levels in prepubertal girls with epilepsy. One-hundred and one patients were divided into four groups: epileptic patients with VPA-associated obesity (n = 21); lean epileptic patients under VPA therapy (n = 35); healthy obese children (n = 23), and healthy lean children (n = 22). Patients with VPA-associated obesity had significantly enhanced blood concentrations of AP (p = 0.001) and leptin (p = 0.007) than lean subjects. There were no differences in leptin and AP plasma levels between patients with VPAassociated obesity and obese controls (p = 0.45 and p = 0.10, respectively), as there were no differences between lean patients under VPA therapy and lean healthy controls (p = 0.06). In patients under VPA therapy, both plasma leptin and

AP levels were significantly correlated with BMI (r = 0.074, p = 0.02, and r = 0.084, p = 0.01, respectively). Plasma leptin concentrations were not correlated with AP levels (r = 0.023, p = 0.13). In conclusion, a correlation between obesity and neuroactive steroids was shown. It remains to be established whether the increased circulating level of AP is a secondary effect of anxiolytic-sedative processes occurring in subjects with obesity-related emotional and behavioral anomalies, or plays a central role in determining abnormal eating behaviors. Copyright 2010 S. Karger AG, Basel http://jcn.sagepub.com/content/17/4/265.abstract Insulin Resistance in Epileptic Girls Who Gain Weight After Therapy With Valproic Acid Abstract : Valproic acid is effective for treatment of many types of epilepsy, but its use in epileptic patients can be associated with an increase in body weight that could interfere with treatment compliance. The weight gain may result from different mechanisms, but the exact pathogenesis is still unknown. To evaluate insulin sensitivity in adolescents who gained weight during treatment with valproic acid, we studied 20 girls with different types of epilepsy: 15 patients had primary generalized seizures, including absence seizures (3 cases), and 5 patients had partial seizures. After 1 year of valproic acid treatment, the obese patients had serum insulin levels significantly higher than patients who did not gain weight (51.4 25.3 versus 28.2 12.9). Moreover, we observed that epileptic patients who gained weight were also insulin resistant in comparison with nonobese epileptic subjects. At the end of treatment, all patients showed normal levels of serum testosterone, androstenedione, dehydroepiandrosterone sulfate, follicle-stimulating hormone (FSH), and luteinizing hormone. We found no significant correlation between insulinemia and serum valproic acid concentrations in obese and nonobese patients treated with valproic acid. Our study demonstrates that basal hyperinsulinemia and insulin resistance can be present in patients who develop obesity during valproic acid treatment. Therefore, these obese patients could be exposed to the risks related to these metabolic abnormalities; if these data are confirmed in longer studies, these side effects may raise some concerns about the safety of valproic acid. (J Child Neurol 2002;17:265-268). http://www.ncbi.nlm.nih.gov/pubmed/10456757 J Child Neurol. 1999 Aug;14(8):490-5. Risk of excessive weight gain in epileptic children treated with valproate. Novak GP, Maytal J, Alshansky A, Eviatar L, Sy-Kho R, Siddique Q. Abstract ; We sought to identify factors associated with excessive weight gain in children treated with valproate, excluding patients fed by gastrostomy or treated with medications known to affect appetite (eg, stimulants). Weight and height were recorded before treatment and at the time of follow-up; a measure of adiposity, body mass index, was computed and expressed in kg/m2, and weight and height for age were converted to Z-score. Putative risk factors included sex, age at start of treatment, monotherapy at start of treatment, duration of follow-up, mental retardation, seizure type (generalized or partial), etiology (idiopathic or cryptogenic versus remote symptomatic), and dose of valproate. Fifty-five children (30 girls, 25 boys), ranging in age at the start of therapy from 1.8 to 16.9 years were followed for 8.6 to 33.8 months. Fortythree patients had primarily generalized seizures, 34 had idiopathic or cryptogenic epilepsy (including 30 with generalized idiopathic epilepsy), and 18 had mental retardation. Valproate was the first antiepileptic drug for 21 patients, and 43 were on monotherapy at the time of follow-up. Height Z-score decreased significantly in girls but was stable in boys. There was a significant increase in body mass index and in weight Z-score. Body mass index was greater than the 90th percentile for age in 14 patients at the start of treatment and in 20 patients at follow-up. Decrease in height Z-

score was significantly correlated with female sex and duration of follow-up. Changes in weight Z-score and body mass index were significantly correlated with initial weight Z-score and initial body mass index, respectively, but not with age at start of therapy, duration of follow-up, sex, seizure type, etiology, dose of valproate, or monotherapy. http://www.ncbi.nlm.nih.gov/pubmed/12724077 An Pediatr (Barc). 2003 May;58(5):443-8. [Effects of valproate on sexual development]. Abstract INTRODUCTION: Valproate use in young girls has been associated with the adverse endocrinological effects of weight gain and hyperandrogenism. Furthermore, polycystic ovaries and hyperinsulinism have been described in adult women. In men and young boys, however, the possible adverse endocrinological effects of valproate have scarcely been analyzed. OBJECTIVES: The aim of this study was to evaluate the effects of valproate treatment on pubertal development, especially the possible hyperandrogenic effects, in girls and boys with epilepsy. MATERIAL AND METHODS: Twenty-three girls and 15 boys (aged 8-16 years old) who were undergoing valproate treatment for epilepsy were compared with 15 control girls and 10 control boys of the same age range. Anthropometric indexes, sexual maturation, and hirsutism scores were evaluated. Serum concentrations of follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone, androstenedione, dehydroepiandrosterone, estradiol, and insulin were measured. Ultrasound examination of ovaries and estimation of bone age through X-ray of the left hand were also performed. RESULTS: Valproate did not affect pubertal development in the study group. No hirsutism or polycystic ovaries were found. Increases in weight, relative weight, and body mass index were observed in the group undergoing valproate treatment, but no statistically significant differences compared with the control group were found. Plasma testosterone was higher in valproate-treated girls (0.71 0.51 ng/ml) than in control girls (0.35 0.15) (p 0.001). This finding was independent of valproate dose and treatment duration. Hyperandrogenism was not found in valproate-treated boys. CONCLUSIONS: Valproate may induce hyperandrogenism in epileptic girls but not in boys. This is an early adverse effect and is independent of the dose used. No changes in normal pubertal development or physical repercussions were found in epileptic patients. http://www.ncbi.nlm.nih.gov/pubmed/15921170 J Pediatr Endocrinol Metab. 2005 May;18(5):423-30. Endocrine and metabolic changes in epileptic patients receiving valproic acid.

Verrotti A, Greco R, Latini G, Chiarelli F. Abstract It has been well known for many years that valproic acid (VPA) therapy can induce obesity and important endocrine dysfunctions; among these dysfunctions, the most common are hyperandrogenism, menstrual disorders, polycystic ovary syndrome, hyperinsulinism, and changes in LH, FSH, and sexual and thyroid hormones. Moreover, abnormalities in pubertal development and impaired skeletal growth have been reported. The aim of this review is to analyze the main effects of VPA on endocrinological functions in patients with epilepsy in order to understand in depth the pathophysiological mechanisms and, consequently, to improve the care of these patients. http://www.ncbi.nlm.nih.gov/pubmed/16776492 Acta Neurol Scand Suppl. 2006;184:1-13. Role of valproate across the ages. Treatment of epilepsy in children. Aldenkamp A, Vigevano F, Arzimanoglou A, Covanis A. Abstract In June 2005 a team of experts participated in a workshop with the objective of reaching agreement on the place of valproate use in the treatment of paediatric epilepsy patients. A general "consensus of the meeting" was that the initiation of antiepileptic drug (AED) treatment should be based on a seizure-syndromic approach in children. Participants of the meeting also agreed that valproate is currently the AED with the broadest spectrum across all types of seizures and syndromes. Its superiority has been shown over almost 40 years of clinical experience. The best results are seen in idiopathic generalized epilepsy with or without photosensitivity, idiopathic focal and symptomatic generalized tonic-clonic seizures (GTCS). Evidence supports the use of valproate, ethosuximide and lamotrigine in absence epilepsies and the use of carbamazepine, lamotrigine, oxcarbazepine, phenytoin, topiramate, valproate and phenobarbital for primary GTCS. For new AEDs trials have been undertaken to define their therapeutic role but studies comparing their role to 'old' broad-spectrum drugs in specific syndromes are missing. Experts concluded that intravenous (i.v.) valproate is a useful agent in the treatment of non-convulsive status epilepticus (SE). There is an easy transition to oral treatment following i.v. valproate use. The discussion also concluded that, despite the lack of studies, valproate is an interesting, underutilized alternative in convulsive SE but more controlled studies are needed. The side effects of valproate use are well documented. Its effect on cognition and behaviour is more favourable than many of the other AEDs which is an important consideration in children. Overall, the clinical consensus of the meeting was that valproate's well established therapeutic properties far outweigh the negative side effects. Contraindication or withdrawal should be assessed individually. http://www.ncbi.nlm.nih.gov/pubmed/12269862 CNS Drugs. 2002;16(10):695-714. Pharmacological and therapeutic properties of valproate: a summary after 35 years of clinical experience. Perucca E. Abstract Thirty-five years since its introduction into clinical use, valproate (valproic acid) has become the most widely prescribed antiepileptic drug (AED) worldwide. Its pharmacological effects involve a variety of mechanisms, including increased

gamma-aminobutyric acid (GABA)-ergic transmission, reduced release and/or effects of excitatory amino acids, blockade of voltage-gated sodium channels and modulation of dopaminergic and serotoninergic transmission. Valproate is available in different dosage forms for parenteral and oral use. All available oral formulations are almost completely bioavailable, but they differ in dissolution characteristics and absorption rates. In particular, sustained-release formulations are available that minimise fluctuations in serum drug concentrations during a dosing interval and can therefore be given once or twice daily. Valproic acid is about 90% bound to plasma proteins, and the degree of binding decreases with increasing drug concentration within the clinically occurring range. Valproic acid is extensively metabolised by microsomal glucuronide conjugation, mitochondrial beta-oxidation and cytochrome P450-dependent omega-, (omega-1)- and (omega-2)-oxidation. The elimination half-life is in the order of 9 to 18 hours, but shorter values (5 to 12 hours) are observed in patients comedicated with enzyme-inducing agents such as phenytoin, carbamazepine and barbiturates. Valproate itself is devoid of enzyme-inducing properties, but it has the potential of inhibiting drug metabolism and can increase by this mechanism the plasma concentrations of certain coadministered drugs, including phenobarbital (phenobarbitone), lamotrigine and zidovudine. Valproate is a broad spectrum AED, being effective against all seizure types. In patients with newly diagnosed partial seizures (with or without secondary generalisation) and/or primarily generalised tonic-clonic seizures, the efficacy of valproate is comparable to that of phenytoin, carbamazepine and phenobarbital, although in most comparative trials the tolerability of phenobarbital was inferior to that of the other drugs. Valproate is generally regarded as a first-choice agent for most forms of idiopathic and symptomatic generalised epilepsies. Many of these syndromes are associated with multiple seizure types, including tonic-clonic, myoclonic and absence seizures, and prescription of a broad-spectrum drug such as valproate has clear advantages in this situation. A number of reports have also suggested that intravenous valproate could be of value in the treatment of convulsive and nonconvulsive status epilepticus, but further studies are required to establish in more detail the role of the drug in this indication. The most commonly reported adverse effects of valproate include gastrointestinal disturbances, tremor and bodyweight gain. Other notable adverse effects include encephalopathy symptoms (at times associated with hyperammonaemia), platelet disorders, pancreatitis, liver toxicity (with an overall incidence of 1 in 20,000, but a frequency as high as 1 in 600 or 1 in 800 in high-risk groups such as infants below 2 years of age receiving anticonvulsant polytherapy) and teratogenicity, including a 1 to 3% risk of neural tube defects. Some studies have also suggested that menstrual disorders and certain clinical, ultrasound or endocrine manifestations of reproductive system disorders, including polycystic ovary syndrome, may be more common in women treated with valproate than in those treated with other AEDs. However, the precise relevance of the latter findings remains to be evaluated in large, prospective, randomised studies. http://www.ncbi.nlm.nih.gov/pubmed/7512905 Drugs. 1994 Feb;47(2):332-72. Valproic acid. A reappraisal of its pharmacological properties and clinical efficacy in epilepsy. Davis R, Peters DH, McTavish D. Abstract Valproic acid is a branched-chained fatty acid, structurally unrelated to any other antiepileptic drug. Since publication of the original review in the Journal in 1977, several clinical trials have documented its efficacy and safety in adults and children for the treatment of generalised seizures (absence, tonic-clonic, myoclonic), partial seizures (simple, complex, secondarily generalised) and compound/combination seizures (including those refractory to treatment with other antiepileptic drugs). Valproic acid monotherapy has demonstrated efficacy equivalent to that of carbamazepine, phenytoin, and phenobarbital in the treatment of both generalised and partial seizures and ethosuximide in the treatment of absence seizures. Adverse effects associated with the drug are primarily gastrointestinal (nausea, vomiting, dyspepsia) in nature, although the use of enteric-coated formulations has reduced the incidence of abdominal

discomfort. Weight gain, tremor and transient hair loss are commonly reported. Importantly, valproic acid has minimal neurological adverse effects (sedation, ataxia, impairment of cognitive function) compared with other antiepileptic drugs, a finding that may be of particular relevance in many patients with epilepsy. The incidence of rare, fatal liver failure has been greatly reduced by identifying and avoiding administration of valproic acid to high risk patient populations. An estimated risk of 1 to 2% for neural tube defects, predominantly spina bifida aperta, with maternal use of valproic acid therapy has been reported. Valproic acid inhibits hepatic drug metabolism and displaces other highly bound drugs from their plasma protein binding sites. Therefore, coadministered drugs which are highly protein bound or hepatically metabolised may require dosage adjustment. Enzyme-inducing antiepileptic drugs may increase valproic acid metabolism and necessitate increasing its dosage. Thus, comparative trials and extensive clinical experience have demonstrated the efficacy and tolerability of valproic acid and support its role as a valuable and well established first-line treatment for patients with a broad range of seizure types. http://www.ncbi.nlm.nih.gov/pubmed/8784210 Epilepsia. 1995;36 Suppl 2:S2-12. Antiepileptic drug mechanisms of action. Abstract Established antiepileptic drugs (AEDs) decrease membrane excitability by interacting with neurotransmitter receptors or ion channels. AEDs developed before 1980 appear to act on sodium channels, gamma-aminobutyric acid type A (GABAA) receptors, or calcium channels. Benzodiazepines and barbiturates enhance GABAA receptor-mediated inhibition. Phenytoin (PHT), carbamazepine (CBZ), and possibly valproate (VPA) decrease high-frequency repetitive firing of action potentials by enhancing sodium-channel inactivation. Ethosuximide (ESM) and VPA reduce a low threshold (T-type) calcium-channel current. The mechanisms of action of the new AEDs are not fully established. Gabapentin (GBP) binds to a high-affinity site on neuronal membranes in a restricted regional distribution of the central nervous system. This binding site may be related to a possible active transport process of GBP into neurons; however, this has not been proven, and the mechanism of action of GBP remains uncertain. Lamotrigine (LTG) decreases sustained high-frequency repetitive firing of voltage-dependent sodium action potentials that may result in a preferential decreased release of presynaptic glutamate. The mechanism of action of oxcarbazepine (OCBZ) is not known; however, its similarity in structure and clinical efficacy to CBZ suggests that its mechanism of action may involve inhibition of sustained high-frequency repetitive firing of voltage-dependent sodium action potentials. Vigabatrin (VGB) irreversibly inhibits GABA transaminase, the enzyme that degrades GABA, thereby producing greater available pools of presynaptic GABA for release in central synapses. Increased activity of GABA at postsynaptic receptors may underline the clinical efficacy of VGB. http://www.ncbi.nlm.nih.gov/pubmed/8848979 Adv Neurol. 1995;67:329-60. Mechanism of action of antiepileptic and antimyoclonic drugs. Pranzatelli MR, Nadi NS. Abstract Most drugs used to treat myoclonus are also antiepileptic. The main drugs are the benzodiazepines, valproate, and barbituates. Advances in the understanding of antiepileptic drug mechanisms of action have revealed two main patterns: increasing inhibition either through GABA or glycine, or decreasing excitation due to glutamate. Anticonvulsants such as

the benzodiazepines, barbiturates, vigabatrin, tiagabine, or progabide act through GABA. New prototype anticonvulsants such as dizocilpine and remacemide target glutamate receptors or associated ion channels. For some antimyoclonic drugs such as piracetam, many effects are reported but no mechanism of action has been established. Many newer anticonvulsants have not been tested in human myoclonic disorders but efficacy against PTZ-induced seizures suggests antimyoclonic activity. Our ability to improve the treatment of myoclonus requires greater knowledge of the molecular mechanisms of myoclonus and more exact delineation of its relation to epilepsy. Better drugs also will result from refinements from prototype drugs and new concepts about brain function. Most of the discussion has been focused on the use of drugs as symptomatic treatment, but drugs such as glutamate blockers are already having a role in the treatment of degenerative neurological disorders, an important cause of some myoclonic disorders. It also may be possible to improve treatment by focusing on selective regional effects of drugs or drug delivery. The CNS penetration of drugs is often no uniform. For many antimyoclonic and antiepileptic drugs, regional studies have not been performed, especially in humans. Lack of efficacy could therefore be due to lack of drug delivery to myoclonic generators or suppression structures. It is conceivable that drug effects in different brain regions also may be opposing, such as in forebrain and hindbrain structures. Stimulation of the same receptor subtype may have different implications for myoclonus if the sites are pre- or postsynaptically located (as in 5-HTIA sites), or predominantly cerebellar versus hippocampal (as in BDZ I vs II sites). Molecular genetic abnormalities in neurological disease may affect neurotransmission and the action of drug either directly at the receptor site or in other ways such as transduction, translation, or expression. Further insights into these abnormalities may provide new targets for pharmacotherapy. Most antiepileptic and antimyoclonic drugs developed to date have aimed at broad-spectrum treatment of the symptoms, rather than treatment of regional problems such as in the forebrain or the hindbrain. Because of this, the currently available drugs have broad side effects such as cognitive impairment, tremors, teratogenicity, etc. To develop more region-specific and more efficacious drugs, we need to develop a better understanding of local central nervous system problems in myoclonus and epilepsy. The development and application of molecular biological techniques have increased our knowledge of receptors and transporters immensely. It is conceivable that in the near future we will be able to determine whether small mutations affect the structure and function of these molecules. In addition, the glimpses into the process of cell death and sprouting by remaining neurons in the epileptic brain, and perhaps the myoclonic brain, raise the possibility of designing regionally oriented drugs with greater efficacy and fewer side effects. The current developments in the understanding of the central neurons should allow for the development of exciting new pharmacotherapies in the future. http://www.ncbi.nlm.nih.gov/pubmed/8097295 Neurochem Res. 1993 Apr;18(4):485-502. Effects of the antiepileptic drug valproate on metabolism and function of inhibitory and excitatory amino acids in the brain. Abstract Valproate is currently one of the major antiepileptic drugs in clinical use. Because of its wide spectrum of anticonvulsant activity against different seizure types, it has repeatedly been suggested that valproate acts through a combination of several mechanisms. As shown in this review, there is substantial evidence that valproate increases GABA turnover and thereby potentiates GABAergic functions in some specific brain regions, such as substantia nigra, thought to be involved in the control of seizure generation and propagation. Furthermore, valproate seems to reduce the release of the epileptogenic amino acid gamma-hydroxybutyric acid and to block cell firing induced by NMDA-type glutamate receptors. In addition to effects on amino acidergic neurotransmission, valproate presumably exerts a direct action on ion channels, thereby limiting sustained repetitive neuronal firing. Recent microdialysis data suggest that valproate also alters dopaminergic and serotonergic functions. These diverse effects of valproate might explain why the drug not only

exerts anticonvulsant activity but also other pharmacodynamic and pharmacotherapeutic actions, such as antipsychotic and antidystonic efficacy. http://www.ncbi.nlm.nih.gov/pubmed/10321796 Prog Neurobiol. 1999 May;58(1):31-59. Valproate: a reappraisal of its pharmacodynamic properties and mechanisms of action. Lscher W. Abstract Valproate is currently one of the major antiepileptic drugs with efficacy for the treatment of both generalized and partial seizures in adults and children. Furthermore, the drug is increasingly used for therapy of bipolar and schizoaffective disorders, neuropathic pain and for prophylactic treatment of migraine. These various therapeutic effects are reflected in preclinical models, including a variety of animal models of seizures or epilepsy. The incidence of toxicity associated with the clinical use of valproate is low, but two rare toxic effects, idiosyncratic fatal hepatotoxicity and teratogenicity, necessitate precautions in risk patient populations. Studies from animal models on structure-relationships indicate that the mechanisms leading to hepatotoxicity and teratogenicity are distinct and also differ from the mechanisms of anticonvulsant action of valproate. Because of its wide spectrum of anticonvulsant activity against different seizure types, it has repeatedly been suggested that valproate acts through a combination of several mechanisms. As shown in this review, there is substantial evidence that valproate increases GABA synthesis and release and thereby potentiates GABAergic functions in some specific brain regions, such as substantia nigra, thought to be involved in the control of seizure generation and propagation. Furthermore, valproate seems to reduce the release of the epileptogenic amino acid gamma-hydroxybutyric acid and to attenuate neuronal excitation induced by NMDA-type glutamate receptors. In addition to effects on amino acidergic neurotransmission, valproate exerts direct effects on excitable membranes, although the importance of this action is equivocal. Microdialysis data suggest that valproate alters dopaminergic and serotonergic functions. Valproate is metabolized to several pharmacologically active metabolites, but because of the low plasma and brain concentrations of these compounds it is not likely that they contribute significantly to the anticonvulsant and toxic effects of treatment with the parent drug. By the experimental observations summarized in this review, most clinical effects of valproate can be explained, although much remains to be learned at a number of different levels of valproate's mechanisms of action. http://www.ncbi.nlm.nih.gov/pubmed/12269861 CNS Drugs. 2002;16(10):669-94. Basic pharmacology of valproate: a review after 35 years of clinical use for the treatment of epilepsy. Lscher W. Abstract Since its first marketing as an antiepileptic drug (AED) 35 years ago in France, valproate has become established worldwide as one of the most widely used AEDs in the treatment of both generalised and partial seizures in adults and children. The broad spectrum of antiepileptic efficacy of valproate is reflected in preclinical in vivo and in vitro models, including a variety of animal models of seizures or epilepsy. There is no single mechanism of action of valproate that can completely account for the numerous effects of the drug on neuronal tissue and its broad clinical activity in epilepsy and other brain diseases. In view of the diverse molecular and cellular events that underlie different seizure types, the combination of several neurochemical and neurophysiological mechanisms in a single drug molecule might explain the

broad antiepileptic efficacy of valproate. Furthermore, by acting on diverse regional targets thought to be involved in the generation and propagation of seizures, valproate may antagonise epileptic activity at several steps of its organisation. There is now ample experimental evidence that valproate increases turnover of gamma-aminobutyric acid (GABA) and thereby potentiates GABAergic functions in some specific brain regions thought to be involved in the control of seizure generation and propagation. Furthermore, the effect of valproate on neuronal excitation mediated by the N-methyl-Daspartate (NMDA) subtype of glutamate receptors might be important for its anticonvulsant effects. Acting to alter the balance of inhibition and excitation through multiple mechanisms is clearly an advantage for valproate and probably contributes to its broad spectrum of clinical effects. Although the GABAergic potentiation and glutamate/NMDA inhibition could be a likely explanation for the anticonvulsant action on focal and generalised convulsive seizures, they do not explain the effect of valproate on nonconvulsive seizures, such as absences. In this respect, the reduction of gammahydroxybutyrate (GHB) release reported for valproate could be of interest, because GHB has been suggested to play a critical role in the modulation of absence seizures. Although it is often proposed that blockade of voltage-dependent sodium currents is an important mechanism of antiepileptic action of valproate, the exact role played by this mechanism of action at therapeutically relevant concentrations in the mammalian brain is not clearly elucidated. By the experimental observations summarised in this review, most clinical effects of valproate can be explained, although much remains to be learned at a number of different levels about the mechanisms of action of valproate. In view of the advances in molecular neurobiology and neuroscience, future studies will undoubtedly further our understanding of the mechanisms of action of valproate. http://www.ncbi.nlm.nih.gov/pubmed/11687121 Cochrane Database Syst Rev. 2001;(4):CD001769. Phenytoin versus valproate monotherapy for partial onset seizures and generalized onset tonic-clonic seizures. Tudur Smith C, Marson AG, Williamson PR. Abstract BACKGROUND: Phenytoin and valproate are commonly used antiepileptic drugs. It is generally believed that phenytoin is more effective for partial onset (simple partial, complex partial and secondary generalized tonic-clonic seizures) seizures whilst valproate is more effective in generalized onset seizures (generalized tonic-clonic seizures, absence, myoclonus) although there is no evidence from randomized controlled trials to support this belief. The use of individual patient data meta-analysis enabled us to examine time to event outcomes which are important in epilepsy monotherapy trials, and also to examine treatment-covariate interactions. OBJECTIVES: To review the best evidence comparing phenytoin and valproate when used as monotherapy in subjects with partial onset seizures, or generalized onset tonic-clonic seizures with or without other generalized seizure types. SEARCH STRATEGY: Our search strategy included: (i) the Cochrane Epilepsy Group trial register, (ii) MEDLINE 1966-2000, (iii) handsearching relevant journals, (iv) the pharmaceutical industry, and (v) researchers in the field.

SELECTION CRITERIA: Randomized controlled trials in children or adults with partial onset seizures or generalized onset tonic-clonic seizures. Trials must have included a comparison of phenytoin monotherapy with valproate monotherapy. DATA COLLECTION AND ANALYSIS: This was an individual patient data review. Outcomes were time to (i) withdrawal of allocated treatment, (ii) 12 month remission, (iii) six month remission, and (iv) first seizure post randomization. Data were analysed using stratified logrank analysis with results expressed as hazard ratios (HR) and 95% confidence intervals (95% CI), where a HR>1 indicates an event is more likely on phenytoin. A test for interaction between treatment and seizure type (partial onset versus generalized onset) was also undertaken for each outcome. MAIN RESULTS: Data were available for 669 subjects from five trials, representing 60% of the subjects recruited into the eleven trials that met our inclusion criteria. One important limitation of these data is that in four of the five trials, for patients classified as having generalized onset seizures, tonic-clonic seizures were the only seizure types recorded at follow up, despite the fact that some patients will have been experiencing other generalized seizure types such as absence or myoclonus. Their results for the generalized seizures therefore relate only to generalized onset tonic-clonic seizures. The main overall results were as follows (HR(95% CI), HR>1 indicates a clinical advantage for phenytoin for both remission outcomes and a clinical advantage for valproate for the outcomes time to withdrawal and time to first seizure) (i) time to withdrawal of allocated treatment 1.10(0.79-1.54), (ii) time to 12 month remission 1.04(0.78-1.38), (iii) time to six month remission 0.89(0.71-1.11), and (iv) time to first seizure 0.92(0.74-1.14). The results suggest no overall difference between drugs for these outcomes. The test for an interaction between treatment and seizure type (generalized versus partial onset) was non significant for all outcomes. REVIEWER'S CONCLUSIONS: We have not found evidence that a significant difference exists between phenytoin and valproate for the outcomes examined in this review. As generalized seizures such as absence and myoclonus were counted in only one trial, results do not address the treatment of these seizure types. We found no unequivocal evidence to overthrow or support the policy of using valproate in generalized onset tonic-clonic seizures and phenytoin in partial onset seizures. http://www.ncbi.nlm.nih.gov/pubmed/18077226 Epileptic Disord. 2007 Dec;9(4):353-412. Treatment of pediatric epilepsy: European expert opinion, 2007. Wheless JW, Clarke DF, Arzimanoglou A, Carpenter D. Abstract BACKGROUND: Childhood epilepsies are a heterogeneous group of conditions that differ in diagnostic criteria and management and have dramatically different outcomes. Despite increasing data on treatment of epilepsy, research findings on childhood epilepsy are more limited and many clinical questions remain unanswered, so that clinicians must often rely on clinical judgment. In such clinical situations, expert opinion can be especially helpful.

METHODS: A survey on pediatric epilepsy and seizures (33 questions and approximately 650 treatment options) was sent to 57 European physicians specializing in pediatric epilepsy, 42 (74%) of whom completed it. In some questions, the experts were asked to recommend overall treatment approaches for specific syndromes (the order in which they would use certain strategies). Most of the questions asked the experts to rate options using a modified version of the RAND 9-point scale for medical appropriateness. Consensus was defined as a non-random distribution of scores by chi-square test, with ratings used to assign a categorical rank (first line/usually appropriate, second line/equivocal, and third line/usually not appropriate) to each option. RESULTS: Valproate was treatment of choice for symptomatic myoclonic and generalized tonic-clonic seizures. For initial monotherapy for complex partial seizures, carbamazepine and oxcarbazepine were treatments of choice, with valproate also first line. As initial therapy for infantile spasms caused by tuberous sclerosis, viagabatrin was treatment of choice. As initial therapy for infantile spasms that are symptomatic in etiology, vigabatrin was also treatment of choice, with adrenocorticotropic hormone (ACTH) and prednisone other first-line options. As initial therapy for Lennox-Gastaut syndrome, valproate was treatment of choice. For acute treatment of a prolonged febrile seizure or cluster of seizures, rectal diazepam was treatment of choice. Valproate was treatment of choice as preventive therapy for febrile seizures. For benign childhood epilepsy with centro-temporal spikes, valproate was treatment of choice. For childhood and juvenile absence epilepsy, valproate was treatment of choice, with lamotrigine another first-line option (ethosuximide was another first-line option for childhood absence epilepsy). For juvenile myoclonic epilepsy in adolescent males, valproate was treatment of choice, with lamotrigine another first-line option; for juvenile myoclonic epilepsy in adolescent females, lamotrigine was treatment of choice, with valproate another firstline option. As initial therapy for neonatal status epilepticus, intravenous (IV) phenobarbital was treatment of choice. As initial therapy for all types of pediatric status epilepticus, IV diazepam was treatment of choice. For generalized tonic-clonic status epilepticus, rectal diazepam and IV lorazepam were also treatments of choice; for complex partial status epilepticus, IV lorazepam was another first-line option. CONCLUSION: The expert panel reached consensus on many treatment options. Within the limits of expert opinion and with the understanding that new research data may take precedence, the experts' recommendations provide helpful guidance in situations where the medical literature is scant or lacking. The information in this report should be evaluated in conjunction with evidence-based findings. http://www.ncbi.nlm.nih.gov/pubmed/12534314 Drugs Aging. 2003;20(2):141-52. Drug treatment of epilepsy in elderly people: focus on valproic Acid. Stephen LJ. Abstract Despite old age being the commonest time of life to develop epilepsy, relatively little is known about the condition in later years. Antiepileptic drugs (AEDs) are the mainstay of treatment and valproic acid (VPA) has been prescribed for older patients with seizures for over 35 years. VPA is available in a variety of formulations. The drug is generally rapidly absorbed, although there are no data on the extent of oral absorption in the elderly. The volume of distribution (Vd) and

elimination half-life have been compared in older and younger patients. One study reported no change in either parameter between elderly and younger patients (Vd: 0.16 vs 0.14 L/kg; elimination half-life: 15.3 vs 13.0h), the other found an increase in both for older patients (Vd: 0.19 vs 0.13 L/kg; elimination half-life 14.9 vs 7.2h). Total VPA clearance is similar in young and elderly subjects. The drug does not induce the metabolism of hepatic enzymes, but can act as a metabolic inhibitor, raising plasma concentrations of lamotrigine, phenobarbital (phenobarbitone), carbamazepine-10-11-epoxide, lorazepam, nimodipine and zidovudine. Concomitant use of VPA may also lead to an elevation in phenytoin, diazepam, warfarin, amitriptyline and chlorpromazine concentrations. A number of enzymeinducing AEDs such as phenytoin, phenobarbital, primidone and carbamazepine can increase the clearance of VPA. Plasma concentrations of VPA may also rise when the drug is administered with felbamate, stiripentol, aspirin (acetylsalicylic acid), naproxen, phenylbutazone, isoniazid, fluoxetine and chlorpromazine. The majority of elderly patients present with partial and/or secondary generalised seizures, although a few have long-standing primary generalised seizures. Results from meta-analyses and randomised studies of patients comparing VPA with other AED monotherapies suggest that the drug is as effective as carbamazepine, phenytoin and phenobarbital in treating these seizure types. Although some of these studies recruited older patients, there have been no randomised double-blind trials examining the efficacy of VPA with other AEDs in an exclusively elderly cohort. There is no direct correlation between efficacy and plasma VPA concentrations. The majority of older patients require lower doses of AEDs than younger adults. Higher VPA doses may be needed in patients taking drugs which induce hepatic microsomal enzymes. Once-daily dosing of the controlled-release preparation can help to improve compliance and may render some frail elderly people seizure free. There is a perception that the elderly are generally more susceptible to the adverse effects of AEDs than younger adults, although there are few data to validate this claim. Dose-dependent and idiosyncratic reactions may be more frequent. Common adverse effects of VPA include gastrointestinal symptoms and tremor. Slowdose escalation and controlled-release preparations may minimise these. In summary, VPA is a long established AED. Its broad spectrum of action and dosing schedule are favourable properties for its use in older people. To accurately establish the place of this and other AEDs in treating elderly patients with epilepsy, well designed clinical trials are urgently required in this vulnerable population. http://www.ncbi.nlm.nih.gov/pubmed/12269862 CNS Drugs. 2002;16(10):695-714. Pharmacological and therapeutic properties of valproate: a summary after 35 years of clinical experience. Perucca E. Abstract Thirty-five years since its introduction into clinical use, valproate (valproic acid) has become the most widely prescribed antiepileptic drug (AED) worldwide. Its pharmacological effects involve a variety of mechanisms, including increased gamma-aminobutyric acid (GABA)-ergic transmission, reduced release and/or effects of excitatory amino acids, blockade of voltage-gated sodium channels and modulation of dopaminergic and serotoninergic transmission. Valproate is available in different dosage forms for parenteral and oral use. All available oral formulations are almost completely bioavailable, but they differ in dissolution characteristics and absorption rates. In particular, sustained-release formulations are available that minimise fluctuations in serum drug concentrations during a dosing interval and can therefore be given once or twice daily. Valproic acid is about 90% bound to plasma proteins, and the degree of binding decreases with increasing drug concentration within the clinically occurring range. Valproic acid is extensively metabolised by microsomal glucuronide conjugation, mitochondrial beta-oxidation and cytochrome P450-dependent omega-, (omega-1)- and (omega-2)-oxidation. The elimination half-life is in the order of 9 to 18 hours, but shorter values (5 to 12 hours) are observed in patients comedicated with enzyme-inducing agents such as phenytoin, carbamazepine and barbiturates. Valproate itself is devoid of enzyme-inducing properties, but it has the potential of inhibiting drug

metabolism and can increase by this mechanism the plasma concentrations of certain coadministered drugs, including phenobarbital (phenobarbitone), lamotrigine and zidovudine. Valproate is a broad spectrum AED, being effective against all seizure types. In patients with newly diagnosed partial seizures (with or without secondary generalisation) and/or primarily generalised tonic-clonic seizures, the efficacy of valproate is comparable to that of phenytoin, carbamazepine and phenobarbital, although in most comparative trials the tolerability of phenobarbital was inferior to that of the other drugs. Valproate is generally regarded as a first-choice agent for most forms of idiopathic and symptomatic generalised epilepsies. Many of these syndromes are associated with multiple seizure types, including tonic-clonic, myoclonic and absence seizures, and prescription of a broad-spectrum drug such as valproate has clear advantages in this situation. A number of reports have also suggested that intravenous valproate could be of value in the treatment of convulsive and nonconvulsive status epilepticus, but further studies are required to establish in more detail the role of the drug in this indication. The most commonly reported adverse effects of valproate include gastrointestinal disturbances, tremor and bodyweight gain. Other notable adverse effects include encephalopathy symptoms (at times associated with hyperammonaemia), platelet disorders, pancreatitis, liver toxicity (with an overall incidence of 1 in 20,000, but a frequency as high as 1 in 600 or 1 in 800 in high-risk groups such as infants below 2 years of age receiving anticonvulsant polytherapy) and teratogenicity, including a 1 to 3% risk of neural tube defects. Some studies have also suggested that menstrual disorders and certain clinical, ultrasound or endocrine manifestations of reproductive system disorders, including polycystic ovary syndrome, may be more common in women treated with valproate than in those treated with other AEDs. However, the precise relevance of the latter findings remains to be evaluated in large, prospective, randomised studies. http://www.ncbi.nlm.nih.gov/pubmed/16608372 Paediatr Drugs. 2006;8(2):113-29. Valproate as a mainstay of therapy for pediatric epilepsy. Guerrini R. Abstract This article reviews relevant pharmacologic and clinical information gathered for valproate since it was introduced into clinical practice 37 years ago and the application of this information for the treatment of childhood epilepsy. Valproate is available for oral and parenteral use. Oral forms are almost completely bioavailable but the rate of absorption varies between formulations. The Chrono tablet formulation has not been adapted for children aged <6 years, in whom the oral solution or syrup, requiring two or three daily administrations, has been used until recently. A new formulation specifically adapted for children, Chronosphere, administrated once or twice daily, is a modified-release formulation of valproate that minimizes fluctuations in serum drug concentrations during a dosage interval. Plasma protein binding is 80-94% and tends to decrease with increasing drug concentration. Valproate elimination is markedly decreased in newborns compared with older children and adults. Elimination by glucuronidation only becomes fully effective by the age of 3-4 years. In children aged 2-10 years receiving valproate, plasma clearances are 50% higher than those in adults. Over the age of 10 years, pharmacokinetic parameters approximate those of adults. Valproate can increase plasma concentrations of concomitant drugs, such as phenobarbital and lamotrigine, by inhibiting their metabolism. As a result of its broad spectrum of efficacy in a wide range of seizure types and epilepsy syndromes, valproate is a drug of choice for children with newly diagnosed epilepsy (focal or generalized), idiopathic generalized epilepsy, epilepsies with prominent myoclonic seizures or with multiple seizure types, and photosensitive epilepsies. In the group of cognitive epilepsies, in which severe spike and wave discharges are accompanied by cognitive deterioration, valproate, ethosuximide, or both should be tested before using corticosteroids. In comparative trials with carbamazepine, phenytoin, and phenobarbital in focal epilepsy and with ethosuximide in absence epilepsy, valproate was as effective and showed a favorable tolerability profile, with minimal adverse cognitive and CNS effects. The low potential for

paradoxical seizure aggravation and the long-term efficacy of the drug are additional important factors that contribute to its excellent profile. Intravenous valproate may be effective for the treatment of convulsive and non-convulsive status epilepticus that is refractory to conventional drugs. In infants, potential benefits should be carefully weighed against the risk of liver toxicity. Gastrointestinal intolerance is a relatively frequent, dose-related adverse effect of the drug in children. Bodyweight increase and tremor may be observed in older children and adolescents. Despite the challenge of newer drugs, valproate remains a gold standard antiepileptic drug for the treatment of children. http://www.ncbi.nlm.nih.gov/pubmed/8619542 Ann Neurol. 1996 May;39(5):579-84. Obesity and endocrine disorders in women taking valproate for epilepsy. Isojrvi JI, Laatikainen TJ, Knip M, Pakarinen AJ, Juntunen KT, Myllyl VV. Abstract 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. http://www.ncbi.nlm.nih.gov/pubmed/15179681 Zhejiang Da Xue Xue Bao Yi Xue Ban. 2004 May;33(3):216-8. [Insulin resistance in epileptic patients during treatment of valproic acid]. [Article in Chinese] Ding MP, Bao YY, Chen Z, Liu ZR, Xu LL. Abstract OBJECTIVE: To investigate the possible role of valproic acid therapy in the development of the weight gain and hyperinsulinemia of epileptic patients.

METHODS: The weight and fasting insulin levels were measured in 43 epileptic patients treated with valproic acid (VPA) alone and 39 patients with carbamazepine (CBZ) alone for at last 2 years. The body mass index (BMI) and homeostasis model assessment (HOMA) index were studied in the two groups. RESULT: BMI was higher in the VPA-treated group (23.47+/-1.45) than that in the CBZ-treated group (22.27+/-2.10, P<0.05). Fasting insulin level and HOMA index in the VPA group were also higher [(6.64+/-0.79)mU/L and 1.33+/-0.21] than those in the CBZ group [(5.52+/- 0.52)mU/L, P<0.01; 1.15+/-0.12, P<0.01]. While BMI in the VPA group showed no significant correlation with plasma concentration and dose of valproate. CONCLUSION: VPA therapy is associated with significantly greater weight gain and hyperinsulinemia, suggesting development of insulin resistance. http://www.ncbi.nlm.nih.gov/pubmed/20880119 Obes Rev. 2011 May;12(5):e32-43. doi: 10.1111/j.1467-789X.2010.00800.x. Epub 2010 Sep 6. Weight gain following treatment with valproic acid: pathogenetic mechanisms and clinical implications. Verrotti A, D'Egidio C, Mohn A, Coppola G, Chiarelli F. Abstract In the last years, a growing body of literature indicates an association between valproic acid therapy and weight gain. Weight gain during valproate treatment can be observed within the first 3 months of therapy and women seem to be more susceptible than men. The mechanism through which valproic acid may induce a weight gain is still controversial. The scope of this paper is to investigate the possible causal link between treatment and weight gain in epileptic patients. Systematic review of published epidemiological studies has been done in order to evaluate the real extent of this side effect of valproic acid and its clinical implications, such as an increased risk of insulin resistance and other secondary metabolic abnormalities. The knowledge of the potential of valproic acid to cause significant changes in body weight will help in appropriate selection and modification of antiepileptic therapy to minimize the risk for weight abnormalities. Measurements of body weight before initiation of valproic acid therapy should be done as part of the monitoring of patients with epilepsy to detect changes before there are serious adverse consequences; an increase of 2 kg of body weight after 1 month of treatment should imply considerations to change antiepileptic drug therapy. http://www.ncbi.nlm.nih.gov/pubmed/12370846 Metabolism. 2002 Oct;51(10):1274-8. Increase in postprandial serum insulin levels in epileptic patients with valproic acid therapy. Luef G, Abraham I, Hoppichler F, Trinka E, Unterberger I, Bauer G, Lechleitner M.

Abstract A significant weight gain and increase in serum leptin levels in the course of antiepileptic treatment with valproic acid (VPA) has been described in several clinical studies. With respect to the long treatment period in antiepileptic therapy, these side effects might increase insulin resistance and metabolic risk factors. We have studied clinical and laboratory effects of VPA treatment in a cohort of female patients (n = 22) and in patients treated with carbamazepine (CBZ) or lamotrigine monotherapy (n = 21). All study participants underwent an oral glucose tolerance test (OGTT) with 75 g glucose. Body mass index (BMI) in the VPA group was higher (28.1 +/- 3.6 kg/m(2)) than in the control group (23.9 +/3.7 kg/m(2)) (P <.039). While plasma glucose, serum leptin, insulin, and C-peptide levels did not differ significantly between the study groups in the fasting state, postprandial (pp) insulin and proinsulin levels were found to be significantly higher in the VPA than in the control group. In the course of the OGTT, serum insulin levels reached their peak values 1 hour postprandially with 68.8 +/- 10.0 microU/mL in the VPA group and 49.8 +/- 11.2 microU/mL in the control group (P <.042). After 2 hours, the corresponding serum insulin levels were 48.5 +/- 25.2 microU/mL and 34.1 +/- 17.2 microU/mL (P <.048) and the proinsulin levels 52.5 +/- 30.2 pmol/L and 29.5 +/- 12.0 pmol/L (P <.017). While BMI values in the non-VPA group showed a significant correlation only with the fasting values of insulin, proinsulin, and C-peptide, the BMI values of the VPA-treated group were also positively related to the 2-hour pp levels of insulin (R =.690; P <.001), proinsulin (R =.667; P <.001) and C-peptide (R =.502; P <.017). VPA is a fatty acid derivative, competes with free fatty acids (FFA) for albumin binding, and acts as a gamma aminobutyric acid (GABA)-ergic agonist, mechanisms, which are known to be involved in pancreatic beta-cell regulation and insulin secretion. Therefore, it might be suspected that VPA therapy is associated with increased glucose stimulated pancreatic secretion and thus a higher body weight in the VPA group. http://www.ncbi.nlm.nih.gov/pubmed/18174556 J Child Neurol. 2007 Dec;22(12):1384-8. The role of ghrelin in weight gain and growth in epileptic children using valproate. Gungor S, Ycel G, Akinci A, Tabel Y, Ozerol IH, Yologlu S. Abstract Ghrelin is a major hormone, regulating the energy balance of the body. Weight gain is a significant side effect of valproic acid, which has not been clearly identified pathogenetically. The aim of this study was to investigate the effect of valproic acid on ghrelin and its potential effects on weight gain and growth. Each patient and control group consisted of 35 children aged 3 to 15 years. Fasting serum glucose, insulin, C-peptide, leptin, ghrelin, insulin-like growth factor-1, and insulin-like growth factor binding protein-3 levels were measured in patients treated with valproic acid before and at month 6 of treatment. A significant increase in body weight, body mass index, height, and height standard deviation scores was observed in all patients after 6 months of treatment. Significant increases in growth velocity and weight gain were observed in the patient group compared with controls at 6 months of therapy. A significant increase in serum ghrelin levels (P < .01) was detected at the same time in the study group. A negative correlation of ghrelin with insulinlike growth factor-1 and insulin-like growth factor binding protein-3 was detected. Serum ghrelin levels were significantly increased (P < .05), and insulin-like growth factor-1 and insulin-like growth factor binding protein-3 levels were significantly decreased (P < .01 and P < .05, respectively) in the prepubertal group at 6 months of treatment, but no significant change was observed in the pubertal group. Consequently, ghrelin levels significantly increase in the prepubertal children treated with valproic acid. The weight gain in using valproic acid may be associated with the increase in ghrelin level in the early treatment period. http://www.ncbi.nlm.nih.gov/pubmed/12088081

J Child Neurol. 2002 Apr;17(4):265-8. Insulin resistance in epileptic girls who gain weight after therapy with valproic acid. Verrotti A, Basciani F, De Simone M, Trotta D, Morgese G, Chiarelli F. Abstract Valproic acid is effective for treatment of many types of epilepsy, but its use in epileptic patients can be associated with an increase in body weight that could interfere with treatment compliance. The weight gain may result from different mechanisms, but the exact pathogenesis is still unknown. To evaluate insulin sensitivity in adolescents who gained weight during treatment with valproic acid, we studied 20 girls with different types of epilepsy: 15 patients had primary generalized seizures, including absence seizures (3 cases), and 5 patients had partial seizures. After 1 year of valproic acid treatment, the obese patients had serum insulin levels significantly higher than patients who did not gain weight (51.4 +/- 25.3 versus 28.2 +/- 12.9). Moreover, we observed that epileptic patients who gained weight were also insulin resistant in comparison with nonobese epileptic subjects. At the end of treatment, all patients showed normal levels of serum testosterone, androstenedione, dehydroepiandrosterone sulfate, follicle-stimulating hormone (FSH), and luteinizing hormone. We found no significant correlation between insulinemia and serum valproic acid concentrations in obese and nonobese patients treated with valproic acid. Our study demonstrates that basal hyperinsulinemia and insulin resistance can be present in patients who develop obesity during valproic acid treatment. Therefore, these obese patients could be exposed to the risks related to these metabolic abnormalities; if these data are confirmed in longer studies, these side effects may raise some concerns about the safety of valproic acid.