Different clinical manifestations of hyperammonemic encephalopathy

Valproate is an effective anticonvulsant. Although it is usually well tolerated, it has been associated with many neurological, hematopoietic, hepatic, and digestive system side effects. Among these side effects, hyperammonemia without clinical or laboratory evidence of hepatotoxicity is rare and is an important clinical consideration. The aim of this article was to evaluate the reasons for the unexpected symptoms observed in seven patients with epilepsy patients during valproate treatment. We evaluated seven adult patients with localization-related epilepsy who presented with different acute or subacute neurological symptoms related to valproate-induced hyperammonemic encephalopathy. Four of the seven patients had acute onset of confusion, decline in cognitive abilities, and ataxia. Two had subacute clinical symptoms, and the other patient had symptoms similar to those of acute toxicity. These unusual clinical symptoms and similar cases had not been reported in the literature before. Serum ammonia levels were elevated in all seven patients. After discontinuation of valproate, complete clinical improvement was observed within 5-10 days. On the basis of our work, we suggest that the ammonia levels of a patient who has new neurological symptoms and has been taking valproate must be checked. Clinicians should be aware that these clinical symptoms may be related to valproate-induced hyperammonemic encephalopathy. The symptoms have been observed to resolve dramatically after withdrawal of the drug.     

Effects of Valproate and Citrulline on Ammonium-Induced Encephalopathy

Summary: Hyperammonemia is a recognized side effect of treatment with the antiepileptic drug (AED) valproate (VPA). Encephalopathic complications have also been observed in some patients receiving VPA therapy. The relation between VPA-induced hyperammonemia and encephalopathy is not clear, however. A model of ammonium (NH₄,+)-induced coma was used to investigate the contribution of VPA and to assess the efficacy of citrulline (a urea cycle intermediate) on hyperammonemia and encephalopathy. In groups of 6–12 rats, administration of VPA (2.5 mmol/kg) was associated with (a) a decrease in the dose of NH₄+ that produces coma in 50% of the animals (CD₅₀) from 6.1 to 3.6 mmol/kg, and (b) significant increases in blood ammonia concentrations in NH₄,+ treated animals. In addition, clear evidence also showed that in the presence of VPA, a lesser concentration of ammonia produced coma. Citrulline treatment (5. 0 mmol/ kg) was associated with (a) an increase in the CD₅₀ value of NH₄,+treated animals from 6.1 to 8.6 mmolikg, (b) a statistically significant decrease in ammonia concentration at all doses examined, (c) complete protection from encephalopathic effects of NH, + at citrulline concentrations threeto tenfold greater than basal levels; and (d) a 24% increase in the CD, value and a statistically significant decrease in ammonia concentration of VPA/NH₄,+ treated animals. These findings indicate that VPA has a dual effect on encephalopathy and that citrulline should benefit those patients treated with VPA who experience adverse encephalopathic effects.     

Valproate induced hyperammonemic encephalopathy successfully treated with levocarnitine

Valproate-induced hyperammonemic encephalopathy is an unusual but serious adverse effect that is usually characterized by the acute onset of impaired consciousness, focal neurological symptoms and increased seizure frequency. It has been reported to occur at therapeutic valproate levels. We report a patient who developed valproate-induced hyperammonemic encephalopathy after a short treatment with valproate and was successfully treated with levocarnitine. We discuss this patient and review the literature regarding the use of levocarnitine in similar patients.     

Valproate-induced encephalopathy: assessment with MR imaging and 1H MR spectroscopy

The anticonvulsant agent valproate (VPA) may cause hyperammonemic encephalopathy. Magnetic resonance imaging (MRI) and proton MR spectroscopic (MRS) findings in a patient with VPA-induced hyperammonemic encephalopathy are described. MRI showed a metabolic-toxic lesion pattern with bilateral T2-hyperintense lesions in the cerebellar white matter and in the globus pallidus. MR spectroscopic findings were indistinguishable from hepatic encephalopathy with severe depletion of myoinositol and choline and with glutamine excess. N-Acetylaspartate levels were moderately decreased. Quantitative MRS gave detailed insight into alterations of brain metabolism in VPA-induced encephalopathy.     

Adverse Effects of Valproate

Any review on adverse effects alone without due reference to the therapeutic benefits of a valuable drug is in danger of exaggerating the side effects. Nevertheless, it is reasonable to expect that some of the signs and symptoms seen in patients with epilepsy may not be due to the epilepsy but rather to the adverse effects of antiepileptic drugs (Schmidt and Seldon, 1982). Awareness of the common and the less well-known adverse effects will increase the safety of a drug, such as valproate, that is taken chronically by many patients worldwide. From a clinical perspective, any unwanted reaction may be seen as an adverse effect. Adverse effects can usually be classified in a small number of rather rare but sometimes fatal and mostly unpredictable drug-induced diseases or in more frequent, mostly mild, dose-related, and reversible side effects (Schmidt, 1983). The adverse effects of valproate are difficult to classify in that scheme, because dose dependency is rare and the mechanisms of most adverse reactions are not well understood. It may therefore be useful to start with an overview of the common adverse effects observed in therapeutic trials, followed by a review of the individual organ systems involved in the adverse effects of valproate, including rather rare drug-induced diseases. The purpose of this review is to provide an overview of the adverse effects of valproate, except for its hepatotoxic and teratogenic actions, which will be covered by Prof. Jeavons (S50–55).     

Valproate reduces spontaneous generalized spikes and waves but not photoparoxysmal reactions in patients with idiopathic generalized epilepsies

Purpose: Patients with idiopathic generalized epilepsies (IGEs) often present with interictal spike‐wave discharges (SWDs) at rest (spontaneous SWDs), during hyperventilation, and in response to photic stimulation (photoparoxysmal response or PPR). Valproic acid (VPA) is a first‐line antiepileptic drug for therapy of patients with IGE. Herein we investigated the effect of VPA on all three types of SWDs in children and adolescents with IGE. Methods: Routine electroencephalography (EEG) during wakefulness, which was recorded before VPA monotherapy and up to four times during the first year of the VPA treatment, was analyzed retrospectively. For the analysis of the VPA effect on spontaneous SWDs and SWDs under hyperventilation, the number and duration of SWDs were counted. SWDs under intermittent photo stimulation (IPS) were classified according to the extent of propagation (grading). Response to VPA treatment (rest/hyperventilation) was defined as a disappearance of SWDs within the year after VPA introduction. Key Findings: Eighty‐four patients (37 male and 47 female, mean age 9.5 ± 4.1 years) exhibited spontaneous SWDs or SWDs under hyperventilation. From this sample, 34 patients exhibited the PPR (7 male and 27 female, mean age 10.1 ± 3.9 years). A significant reduction in the number and duration of spontaneous SWDs and SWDs under hyperventilation was observed in the first 6 weeks of treatment (p ≤ 0.001, corrected, 87.3% responders). This effect remained stable over the 1 year observation period. Concerning PPR, only 4 (12.9%) of 31 patients were classified as responders. The difference between groups of patients with spontaneous/induced SWDs and PPR according to the number of responders was significant (p < 0.001). Significance: This study provides evidence that the effect of VPA on SWDs differs dependent on the types of SWDs. In the majority of patients, spontaneous SWDs and SWDs induced by hyperventilation disappeared, whereas the PPR mostly remained under VPA treatment. These results point to different pathogenetic mechanisms underlying the spontaneous and the evoked generalized epileptic activity in the EEG.     

Associations Between Risk Factors for Valproate Hepatotoxicity and Altered Valproate Metabolism

The effects of three risk factors for valproate (VPA) hepatotoxicity (i.e., young age, polypharmacy, and high VPA serum level) on the metabolism of VPA to its monounsaturated metabolites [2-en-VPA (2-en), 3-en-VPA (3-en) and 4-en-VPA (4-en)] were investigated in 106 patients treated with VPA (56 cases of monotherapy and 50 cases of polytherapy). In the monotherapy group, there was a significant negative correlation between age and 4-en/VPA ratio. In the same group, the 4-en/VPA ratio showed a significant positive correlation with serum VPA level, while 3-en/VPA and 2-en/VPA ratios showed significant negative correlations. In patients greater than 10 years, the 4-en/VPA ratio was significantly higher, while the 2-en/VPA ratio was significantly lower in the polytherapy group than in the monotherapy group. Our results indicate that all three risk factors clearly increase the metabolic conversion of VPA to 4-en, the most toxic VPA metabolite, and that polytherapy and high VPA serum level result in the inhibited beta-oxidative metabolism of VPA to 2-en. These altered VPA metabolic profiles are strikingly similar to the abnormal VPA metabolism previously reported in cases with fatal hepatic failure. Although VPA-induced fatal hepatotoxicity has been regarded as an idiosyncratic reaction, it is possible that these three factors enhance susceptibility to VPA hepatotoxicity by altering the metabolism of VPA.     

Valproate augmentation in a subgroup of patients with treatment-resistant unipolar depression

Objectives: About 50% of patients with unipolar depression suffer from treatment-resistant depression (TRD). Animal studies have suggested potential antidepressant properties of valproate (VPA) possibly due to its implication in epigenetic programming. Methods: Fourteen TRD patients (seven males and seven females; age 19–59) received VPA (375–1000?mg/day) in addition to their treatment regimen after previously failing to respond to two or more antidepressant trials and/or different combinations. Clinical response to VPA was investigated prior the treatment (T-0) and after 1 (T-1), 4 (T-4) and 7 (T-7) months of therapy using the Montgomery–Asberg Depression Rating Scale (MADRS) and the Clinical Global Impression (CGI). Results: Compared to T-0, VPA significantly decreased MADRS score at T-1 (P?<?0.001), T-4 (P?<?0.001) and T-7 (P?<?0.001) (partial η²=0.86). Importantly, MADRS score at T-7 (13.6?±?1.6, mean?±?SEM) was closer to the reported value of remission (MADRS?<10), and none of the patients relapsed during the observational period. Compared to T-0, VPA also decreased CGI-Severity of illness score at T-1 (p?=?0.03), T-4 (p?<?0.001) and T-7 (p?<?0.001) (partial η²?=?0.74). Conclusions: Antidepressant augmentation with VPA provided substantial clinical improvement and maintenance over a relatively long-term period in a subgroup of patients with severe TRD. VPA thus deserves further exploration in large double-blind clinical trials.     

Valproate Metabolites in High-Dose Valproate Plus Phenytoin Therapy

Summary: Purpose: We wished to determine the relation between liver function, β-, and ω-, and ω-1-oxidation metabolites and 4-en-valproate (VPA).
Methods: We measured the serum levels of VPA and its metabolites in children and adolescent receiving high-dose VPA plus phenytoin (PHT) therapy using gas chromatography-mass spectrometry with selected ion monitoring (GC/MS/SIM).
Results: In high-dose VPA plus PHT polytherapy, the total VPA serum concentration was distinctly low, the concentrations of total β -oxidation metabolites were decreased, the percentage values of VPA (percent of VPA) of total β -oxidation metabolites were increased, and the E-2-en-VPM3-keto-VPA ratios were decreased, as compared with those in high-dose VPA monotherapy. In high-dose VPA plus PHT polytherapy, 4-en-VPA (μ M ) was decreased and the concentrations of (ω+ (ω - 1)]-oxidation metabolites (μ M) were decreased as compared with those in high-dose VPA monotherapy. In high-dose VPA plus PHT, serum glutamic-oxaloacetic transarninase (GOT), glutarnic-pyruvic transaminase (GPT) and lactic dehy-drogenase (LDH) did not correlate significantly with the (β/ω+ (ω - 1) metabolites ratio and 4-en-VPA levels, but serum GOT, GPT, and LDH were increased as compared with those in high-dose VPA therapy. We were not able to establish a significant relation between the formation of metabolites of VPA metabolites and liver dysfunction in patients receiving high-dose VPA and PHT concurrently.
Conclusions: Metabolic levels do not appear to be a reliable predictor of hepatotoxicity in children receiving pharrnacological antiepileptic drug (AED) therapy.     

Open Trials with Valproate in Epilepsy

Valproic acid (VPA) was first synthesized in the United States (Burton, 1882) and was used worldwide for 80 years as an organic solvent. Its unexpected antiepileptic activity was discovered 20 years ago in Grenoble, France (Meunier et al., 1963; Carraz et al., 1964). The aim of this work is to report the progressive evolution of ideas and the clinical approach to the treatment of epilepsy with sodium valproate (Na VPA) and VPA, according to published open trials and to our own unpublished data.     

Valproate modulates glucose metabolism in patients with epilepsy after first exposure

Valproate (VPA) treatment has been reported to be associated with weight gain and metabolic changes, such as hyperinsulinemia. The question of whether hyperinsulinemia and other metabolic changes are consequences of increased weight, or are instead direct results of VPA treatment, remains a matter of debate. The aim of the current study was to explore the influence of VPA treatment on glucose and insulin levels during the oral glucose tolerance test (OGTT) directly following the first intravenous (IV) administration. Sixteen patients (18–46 years old) with newly diagnosed epilepsy underwent an OGTT with 75 g glucose prior to the start of VPA treatment, as well as directly following the first IV VPA administration. We observed that plasma glucose levels during the 120 min of OGTT session following infusion of VPA were significantly lower than those measured during OGTT without VPA treatment (mean ± standard deviation [SD] 4.28 ± 0.94 mmol/l vs. 4.75 ± 1.09 mmol/l respectively, p = 0.038). However, blood concentrations of insulin and C‐peptide did not differ significantly between the two measurements. This is the first study to show a potential acute glucose‐lowering effect of VPA during OGTT in patients with newly diagnosed epilepsy.     

Risperidone,a risk factor for valproate-induced encephalopathy?

Valproate-induced encephalopathy (ViE) has been increasingly reported and several risk factors have been proposed. We report a case whereby a patient became encephalopathic while treated with valproate and upon initiation of risperidone. The underlying mechanism could be risperidone's interference with valproate's binding to albumin, raising free valproate levels, which would impair the urea cycle and reduce ammonia conversion, leading to a hyperammonemic encephalopathy. The present case suggests a causal link, although further studies will be necessary to establish this. Nevertheless, clinicians should be aware of this possible interaction and consider carefully before concomitant administration of valproate and risperidone, mainly in patients with other risk factors for ViE, so this complication can be avoid or promptly diagnosed and treated.     

Non-Dose-Related Side Effects of Valproate

The clinical and histological findings in 88 patients in whom hepatotoxicity with valproate has been reported were reviewed. The characteristic lesion is microvesicular steatosis. Hepatotoxicity appears to be an idiosyncratic reaction and is most likely to appear within 6 months from the start of therapy, especially in young patients on comedication. The condition may be reversible if the drug is immediately withdrawn in patients who show acute gastrointestinal symptoms, drowsiness or lethargy, jaundice, or change in seizure pattern. Clinical monitoring is more important than laboratory monitoring. The outcome of pregnancies in 344 women who received valproate in the first trimester was reviewed. There were 225 normal babies and 68 abnormal babies. The role of valproate in the aetiology of neural tube defects remains uncertain, but mothers treated with valproate should receive prenatal counselling.     

β-Oxidation of Valproate

The effects of glucose infusion, fasting, and clofibrate pretreatment on valproate (VPA) disposition were investigated in rats to determine the role of endogenous fatty acid beta-oxidation in the metabolic formation of 2-en-VPA. Rats undergoing each treatment received a continuous steady-state infusion of VPA and a single intravenous (i.v.) bolus of 2-en-VPA. Elimination clearance of VPA was significantly higher (median 31%, p = 0.002) with glucose infusion as compared with fasting but was unchanged by clofibrate pretreatment as compared with control. Formation clearance of 2-en-VPA was significantly higher with glucose infusion as compared with fasting (median 147%, p = 0.001) and with clofibrate pretreatment as compared with control (median 73%, p = 0.041). Fractional metabolism of VPA by this route averaged 6% in fasted and control rats and 10% in glucose-infused and clofibrate-pretreated rats. Thus, VPA elimination clearance was not greatly influenced by effects on this route in rats. Elimination clearance of 2-en-VPA was also higher with glucose infusion as compared with fasting (median 149%, p = 0.002), and with clofibrate pretreatment as compared with control (median 167%, p less than 0.001). These observations are consistent with glucose-sparing release of endogenous fatty acids (FAs) to compete with VPA for beta-oxidation, and increased beta-oxidative activity after clofibrate treatment. The results of this study provide strong in vivo evidence for involvement of beta-oxidation in metabolism of VPA.     

癫痫治疗中丙戊酸钠与苯妥英钠或卡马西平的相互作用

丙戊酸钠与苯妥英钠或卡马西平合用治疗各型癫痫90例,丙戊酸钠使苯妥英钠和卡马西平血浓度下降;丙戊酸钠和卡马西平是强有力的肝酶诱导剂,使丙戊酸钠血浓度降低。抗痫药之间的相互作用错综复杂,临床上选择单一用药,尽量避免联合用药。     

Repeated Neural Tube Defects and Valproate Monotherapy Suggest a Pharmacogenetic Abnormality

Valproate (VPA) is an effective, widely used antiepileptic drug. Unfortunately its use in pregnant women is associated with neural tube defects in the offspring. Although the etiology of neural tube defects is multifactorial, there is evidence that underlying genetic susceptibility plays a part. We describe two women taking moderate doses of VPA who repeatedly bore children with neural tube defects, despite folate supplementation. This suggests a pharmacogenetic susceptibility to the teratogenic effects of VPA.     

Valproate Metabolites and Hepatotoxicity in an Epileptic Population

Idiosyncratic hepatotoxicity, although rare, is of major concern when one is treating patients with valproate (VPA). Several clinical criteria are associated with an increased risk of developing this complication, but more specific predictors are needed. It has been postulated that 4-en-VPA or one of its further metabolites may be responsible for the hepatic toxicity and that under certain conditions the metabolism of VPA is shifted to this product. We postulated that measurement of serum concentrations of 4-en-VPA or another metabolite might be a simple technique that would be predictive of risk for developing idiosyncratic hepatotoxicity. Because this complication is rare, we chose to analyze our data by a multiple linear regression model, exploring associations between VPA or three of its metabolites and clinical risk factors for hepatotoxicity. 4-en-VPA correlated with older age and absence of encephalopathy. 4-en-VPA was only seen in patients receiving polytherapy; all patients were also receiving CBZ. 2-en-VPA correlated with poor nutritional status. We conclude that routine measurement of serum 4-en-VPA is unlikely to be a useful predictor of risk for developing fatal hepatotoxicity. Serum concentrations of 4-en-VPA may not reflect presence or effects in the liver as it may be metabolized to further intermediates or be bound to tissue. Thus, serum levels of 4-en-VPA do not reflect its important role in the pathogenesis of hepatotoxicity. This metabolite was detected only in patients receiving polytherapy, a potent risk factor for developing this rare complication.