Valproate-induced hyperammonemia as a cause of altered mental status.

The authors describe valproate-induced hyperammonemia and mental status changes in an 88-year-old man, the first known reported case in an elderly patient. They discuss this underrecognized complication of valproate use and the implications for treating elderly patients, in whom valproate use is increasing.     

Morphological changes in the testis after long-term valproate treatment in male Wistar rats

Uncertainty exists about the effect of antiepileptic drugs on gonadal function. In females, long-term valproate treatment has been shown to induce endocrine disturbances and an increased number of ovarian cysts. The aim of the present study was to investigate whether valproate can also induce morphological changes in the testis of male animals. In addition, possible morphological changes in the liver, heart, lungs, lymphatic nodes, pancreas, kidney or brain were studied. The carcinogenic implications were evaluated by the measurement of p53. Male Wistar rats were fed perorally with valproate mixture 200 mg kg(-1)(n= 15) or 400 mg kg(-1)(n= 20), or control solution (n= 15) twice daily for 90 days. Serum concentrations measured 4-6 hours after the last dose were 105 and 404 micromol l(-1)in low- and high-dose valproate treated animals respectively. There was a highly significant, 51% decrease (P< 0.001) in testicular weight in the high-dose treated valproate rats with no changes in the other groups. There was widespread testicular atrophy with histologically verified spermatogenic arrest in 15/20 of the high-dose valproate treated animals. No changes in the testis were seen in the low-dose valproate treated rats, nor in the control rats. There were no morphological changes in the other investigated organs. None of the groups showed over-expression of p53. In conclusion, a dose-dependent effect of chronic valproate treatment was found on testicular morphology in rats. Caution must be taken before these results can be applied to humans.     

Role of valproate across the ages. Treatment of epilepsy in children

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.     

Metopic suture craniosynostosis: sodium valproate teratogenic effect. Case report]

OBJECTIVE: the aim of this report is to warn that sodium valproate used during pregnancy can produce craniosynostosis in the newborn, particularly trigonocephaly. METHOD: we describe a case of trigonocephaly in a six month-old girl, daughter of a young non-smoker couple, whose mother had used phenobarbital 100 mg daily and sodium valproate 500 mg twice daily during the whole pregnancy. We also review current literature about this topic. RESULT: bone sclerosis over the metopic suture was confirmed during surgery. Bibliographical review yields previous reports on valproate teratogenicity, mainly determining metopic suture craniosynostosis. CONCLUSION: sodium valproate used during pregnancy can produce craniosynostosis by teratogenic effect, specially trigonocephaly (premature fusion of metopic suture).     

Variability in Level-Dose Ratio of Valproate: Monotherapy Versus Polytherapy

One of the most useful pharmacokinetic parameters of a drug is the level-dose ratio. This ratio originates from a relationship between the dosing rate (i.e., the daily dose) and the corresponding steady-state plasma level. For most drugs that relationship is linear, indicating that changes in doses are associated with proportional changes in plasma levels. This proportionality between plasma level and dose is an expression of the fact that the clearance of the drug is constant. Valproic acid has been available in a number of countries for over a decade, and in spite of the large number of pharmacokinetic studies available in the literature, it is not possible, at the present time, to define a characteristic level-dose ratio. This situation is a result of the fact that the clearance of valproate exhibits large interpatient variability. This article presents an analysis of the causes for the variability in valproate clearance. It is shown that when the determinants of valproate clearance are understood and taken into consideration, only a few factors are found to have a profound influence on it. Most important among these are age and polytherapy.     

Weight gain associated with valproate in childhood

Weight gain is a common side effect of valproate treatment. Several mechanisms have been suggested for its pathophysiology; of these, impairment of beta-oxidation of fatty acids and increased insulin secretion have been supported by clinical studies. To investigate whether changes in carnitine and insulin levels had a role in the weight gain occurring with valproate treatment in children, 20 patients with epilepsy were randomly assigned to receive either carnitine or placebo supplementation in addition to valproate. After a follow-up period of 3 months, weight gain was observed in both groups. The mean insulin concentration and insulin/glucose ratios increased. Weight gain did not correlate with carnitine levels. These results suggest that weight gain during valproate treatment is not related to a decrease in carnitine levels. However, an increase in insulin levels together with a decrease in glucose levels may cause weight gain, possibly by stimulating appetite.     

Valproate hepatotoxicity in an adult patient taking Simvastatin

Hepatotoxicity is an exceedingly rare complication of sodium valproate monotherapy. Valproate is metabolized by a number of different pathways and interaction with other anticonvulsants, in particular cytochrome P₄₅₀ inducers such as phenobarbital, are thought to be major contributing factors to hepatotoxicity. Simvastatin is also known to cause an elevation of hepatic transaminases but there have been no previously documented reports of a hepatic enzyme pathway interaction with valproate. We report a case of symptomatic valproate hepatotoxicity in an adult patient also taking simvastatin.     

Valproate, hyperandrogenism, and polycystic ovaries: a report of 3 cases

BACKGROUND: Reproductive endocrine disorders characterized by menstrual disorders, polycystic ovaries, and hyperandrogenism seem to be common among women treated with sodium valproate for epilepsy. OBJECTIVE: To describe the development of valproate-related reproductive endocrine disorders in women with epilepsy. DESIGN: Case report. PATIENTS: Three patients developed a reproductive endocrine disorder during treatment with valproate. It was characterized by hyperandrogenism and polycystic ovaries in all cases, and it was associated with weight gain and menstrual disorders in 2 of the 3 women. RESULTS: Replacing valproate with lamotrigine resulted in a decrease in serum testosterone concentrations in all 3 women. The polycystic changes disappeared from the ovaries in 2 of the women after valproate therapy was discontinued, and the 2 women who had gained weight and developed amenorrhea while being treated with valproate lost weight and resumed menstruating after the change in medication. CONCLUSIONS: The 3 cases presented here illustrate the development of reproductive endocrine disorders after the initiation of valproate therapy in women with epilepsy. The disorders were characterized by hyperandrogenism and polycystic ovaries in all cases, and were associated with weight gain and menstrual disorders in 2 of the 3 women. An evaluation of ovarian structure and function should be considered in women of reproductive age being treated with valproate for epilepsy, especially if they develop menstrual cycle disturbances during treatment.     

Hepatic Dysfunction as a Complication of Combined Valproate and Ketogenic Diet

BackgroundThe ketogenic diet has long been shown to be an effective therapy for children with medication-refractory seizures. Most complications of the ketogenic diet include short-lived gastrointestinal disturbances, acidosis, and dyslipidemia. Hepatic dysfunction and pancreatitis are among the less common but more serious complications of the ketogenic diet. Many patients on the ketogenic diet receive adjunct treatment with an anticonvulsant drug, and valproate is frequently used.Methods and ResultsWe describe a child who developed hepatic dysfunction in association with the combined use of valproate and the ketogenic diet. After stopping the valproate and then restarting the ketogenic diet, her liver enzymes normalized, and she was able to achieve markedly improved seizure control and quality of life.ConclusionsAlthough caution should be advised when using both treatments simultaneously, the development of hepatic dysfunction should not preclude continuation of the ketogenic diet, as the hepatotoxic effects may be completely reversed once the valproate is stopped.     

Idiopathic generalized epilepsy presenting with hemiconvulsive seizures

PURPOSE: Unilateral seizures, or hemiconvulsive attacks, are motor seizures with tonic and/or clonic phenomena that involve only one side of the body. METHODS: We describe three adolescents who presented with hemiconvulsive seizures and were found to have 3-cps generalized spike-and-wave discharges on ictal and/or interictal EEG. All had normal neuroimaging studies. Two patients had been previously treated with carbamazepine, which led to a partial response in one patient. RESULTS: All three patients, however, are now seizure free on either sodium valproate or a combination of sodium valproate and lamotrigine. We believe the electroclinical diagnosis is that of idiopathic generalized epilepsy. CONCLUSIONS: Idiopathic generalized epilepsy presenting with hemiconvulsive seizures has not, to our knowledge, been previously described. However, the correct diagnosis of an idiopathic generalized seizure disorder, as opposed to a partial seizure disorder, has important treatment implications. The possible mechanism of hemiconvulsive seizures in idiopathic generalized epilepsy is discussed.     

Bipolar disorder and myo-inositol: a review of the magnetic resonance spectroscopy findings

OBJECTIVES: Myo-inositol is an important component of the phosphatidylinositol second messenger system (PI-cycle). Alterations in PI-cycle activity have been suggested to be involved in the pathophysiology and/or treatment of bipolar disorder. More specifically, lithium has been suggested to act primarily by lowering myo-inositol concentrations, the so-called inositol-depletion hypothesis. myo-Inositol concentrations can be measured in vivo with magnetic resonance spectroscopy (MRS). METHODS: The current review primarily examines animal and human MRS studies that evaluated the role of myo-inositol in bipolar illness and treatment. RESULTS: Studies have been carried out in patients who are manic, depressed, and euthymic, both on and off treatment. However, there are several limitations of these studies. CONCLUSIONS: The preclinical and clinical MRS findings were generally supportive of the involvement of myo-inositol in bipolar disorder and its treatment. Overall, in bipolar patients who are manic or depressed there are abnormalities in brain myo-inositol concentrations, with changes in frontal and temporal lobes, as well as the cingulate gyrus and basal ganglia. These abnormalities are not seen in either euthymic patients or healthy controls, possibly due to a normalizing effect of treatment with either lithium or sodium valproate. There is also increasing evidence that sodium valproate may also act upon the PI-cycle. Nonetheless, it remains uncertain if these changes in myo-inositol concentration are primary or secondary. Findings regarding the specific inositol-depletion hypothesis are also generally supportive in acutely ill patients, although it is not yet possible to definitively confirm or refute this hypothesis based on the current MRS evidence.     

Epilepsy and polycystic ovary syndrome: where is the link?

Abstract Several reports in the literature describe an increased prevalence of polycystic ovary syndrome (PCOS) in women with epilepsy. The possible pathogenesis of the association between epilepsy and PCOS is not clear yet, and different hypotheses have been proposed: while some authors suggest that epilepsy may affect the hypothalamic control of reproductive function, others propose a pathogenic role of the antiepileptic drug valproate. In this article we review the literature on the subject, and propose a pathogenic theory in which both epilepsy and valproate play different and significant roles in inducing reproductive endocrine disturbances in women with seizures.     

Carbamazepine-induced hypogammaglobulinemia

Carbamazepine is used to control seizures. Its common side effects are sleep disorders, anorexia, nausea, vomiting, polydipsia, irritability, ataxia, and diplopia. Involvement of the immune system is rare, and few cases of decreased immunoglobulin levels have been reported. We describe a patient with low immunoglobulin levels due to carbamazepine use who presented with recurrent urinary tract infection. Intravenous immunoglobulin was administered, and immunoglobulin levels increased to safer levels after discontinuation of carbamazepine. Previous reports describe severe infection after carbamazepine-induced hypogammaglobulinemia. Therefore, in patients using antiepileptics, particularly carbamazepine, serum immunoglobulin levels should be checked in those with recurrent infections.     

Valproate-induced worsening of seizures: clue to underlying diagnosis

The use of valproate sodium as an antiepileptic is not advised in children with an undiagnosed metabolic condition because of the increased risk of hepatotoxicity and encephalopathy. Here the authors describe a 2.5-year-old girl with a history of developmental delay, failure to thrive, and a seizure disorder whose seizures worsened after the introduction of valproate sodium. This led to a search for an underlying metabolic disorder, and after extensive investigations, a diagnosis of nonketotic hyperglycinemia was made. In this report, the authors discuss the metabolic conditions that can be worsened by valproate sodium. Valproate sodium interferes with the glycine cleavage enzyme synthesis in the mitochondria, hence increasing glycine levels. The increased glycine levels are responsible for worsening of the underlying metabolic condition and increased seizure frequency.     

Chronic valproate administration produces hepatic dysfunction and may delay brain maturation in infant mice

Infant mice (2 to 4 days old) received valproate (100 or 200 mg per kilogram body weight) subcutaneously once daily for 5 days. Both dosages decreased plasma beta-hydroxybutyrate levels to about one-third of the control value, in the face of normal free fatty acid and glycerol levels. At 200 mg per kilogram of valproate, there were significant decreases in brain weight and brain K content. Both doses produced metabolite changes in brain compatible with a reduced metabolic flux through the glycolytic pathway and the citric acid cycle. Valproate reduced brain aspartate but did not increase brain GABA levels in infant mice. At 200 mg per kilogram of valproate, brain glutamate decreased and taurine levels increased. Two hundred milligrams per kilogram of valproate caused a profound reduction of liver glycogen stores. The apparent decrease in cerebral metabolic rate, reduced glutamate and aspartate, and increased levels of taurine in brain may relate to the anticonvulsant action of valproate. Together with the decreased brain weight and K content, the findings are also compatible with maturational delay. Decreased ketonemia and liver glycogen content may relate to the hepatic toxicity associated with valproate administration in infants and children.     

Valproate causes metabolic disturbance in normal man.

Valproate is an important anticonvulsant which is rarely associated with fatal hepatotoxicity. Previous experiments have shown that valproate inhibits several metabolic processes in isolated rat hepatocytes and when administered to starved rats causes a fall in the blood concentrations of glucose and ketone bodies. Since these changes may be related to the hepatotoxicity, the effect of valproate administration on intermediary metabolism in man was studied. One gram of valproate given orally to fasted normal humans caused a 78% fall in the concentration of 3-hydroxybutyrate and a 60% fall in total ketones. Also the concentrations of lactate, pyruvate, alanine and glycerol increased after valproate administration. Similar changes were observed after intravenous administration of 400 mg of valproate. Valproate clearly has a significant effect on intermediary metabolism in the liver and this is probably related to the mechanism of the hepatotoxicity.     

Valproate in the treatment of epilepsy in people with intellectual disability

Valproate is a major broad-spectrum antiepileptic drug effective against many different types of epileptic seizures. Valproate is a first-line drug in the treatment of primary generalized seizures and syndromes, but it is also effective in other seizure and epilepsy types. The possible mechanisms of action and the pharmacokinetics of valproate are outlined. A limited number of studies on the efficacy and safety of valproate treatment in patients with West syndrome and Lennox-Gastaut syndrome have shown that even therapy-resistant people with intellectual disability can benefit from add-on valproate medication. In status epilepticus, valproate can be effective either intravenously, by gastric drip or following rectal administration. Patient tolerance towards valproate is generally good. The most serious adverse effect of valproate include hepatotoxicity and teratogenicity.