topiramate and Hyperammonemia

Hyperammonemia can occur after acute overdose or chronic use of valproic acid (VPA). Although VPA-related hyperammonemic encephalopathy (VHE) is a rare complication of VPA therapy, early recognition of VHE and identifying its risk factors are important because VHE can lead to loss of consciousness and increased seizure frequency.. The purpose of our study is to evaluate the risk factors of hyperammonemia in epilepsy patients during treatment with VPA therapy.. We reviewed the medical records of 1084 adult patients with epilepsy and enrolled 116 patients with VPA therapy who had results of blood levels of ammonia over a 3-year period. Hyperammonemia was defined as a blood ammonia level exceeding 80 µg/dL. Correlations of blood levels of ammonia with dosages and blood levels of VPA were evaluated. We further performed univariate and multivariate linear regression analyses to identify risk factors for hyperammonemia in epilepsy patients treated with VPA therapy.. Blood levels of ammonia were well correlated with dosages of VPA (p = 0.036), but not with blood levels of VPA (p = 0.463). Hyperammonemia was more common in patients with higher VPA dosage and higher total drug loads of concurrent antiseizure medications (ASMs). Hyperammonemia was also associated with the use of topiramate and phenobarbital. In multivariate analysis, we identified total drug load of ASMs (p = 0.003) and use of topiramate (p = 0.007) as independent predictors of hyperammonemia. Four patients (4/116, 3.4 %) had clinical symptoms of VHE. Three of them had hyperammonemia while the other patient had normal blood level of ammonia with a high blood level of VPA.. Our study shows that higher total drug loads of concurrent ASMs and use of topiramate were independent risk factors of hyperammonemia in epilepsy patients with VPA therapy. Although the incidence of VHE was not high in our study, clinicians should be aware of this potential adverse effect of VPA therapy, especially in patients with polytherapy of ASMs including topiramate.

Topics: Adult; Ammonia; Anticonvulsants; Epilepsy; Humans; Hyperammonemia; Risk Factors; Topiramate; Valproic Acid

Topics: Anticonvulsants; Blood Coagulation Disorders; Cerebral Palsy; Chemical and Drug Induced Liver Injury; Child; Combined Modality Therapy; Drug Monitoring; Epilepsy; Fructose; Humans; Hyperammonemia; Intellectual Disability; Liver; Liver Failure, Acute; Male; Topiramate; Treatment Outcome

Topics: Anticonvulsants; Brain Diseases; Carbamazepine; Child; Electroencephalography; Fructose; Humans; Hyperammonemia; Hypnotics and Sedatives; Male; Oxcarbazepine; Phenobarbital; Topiramate

To identify risk factors for hyperammonemia in pediatric patients with epilepsy.. A total of 2,944 pediatric patients (ages 0-15 years) were classified into the following three groups: a group without drug treatment (n = 445, group I), a group receiving antiepileptic drugs other than valproic acid (VPA) (n = 673, group II), and a VPA-treated group (n = 1,826, group III). Hyperammonemia was defined as a plasma ammonia level exceeding 100 μg/dl with reference to the standard range and previous reports.. The mean ammonia level of groups I, II, and III was 36.0, 56.0, and 86.8 μg/dl, respectively, and the incidence of hyperammonemia was 1.6%, 7.7%, and 31.7%, respectively. In each group, the mean ammonia level of patients aged 3 years or younger was significantly higher than that of patients aged 4-15 years. In group II, concomitant use of topiramate and zonisamide were risk factors for hyperammonemia (adjusted odds ratio [OR] 3.9, 95% confidence interval [CI] 1.7-9.2, and OR 3.5, 95% CI 1.9-6.5, respectively). In group III, the ammonia level increased in a VPA dose-dependent manner. At a VPA dose of 30 mg/kg, there was 4.3-fold increase in the incidence of hyperammonemia. The other significant risk factors identified were female gender (OR 1.3, 95% CI 1.0-1.6), symptomatic generalized epilepsy (OR 1.4, 95% CI 1.1-1.8), and the concomitant use of phenytoin (OR 4.7, 95% CI 3.3-6.9), phenobarbital (OR 2.2. 95% CI 1.6-3.2), acetazolamide (OR 6.6, 95% CI 2.5-17.2), topiramate, or zonisamide.. A young age and concomitant use of carbonic anhydrase inhibitors are associated with an increased risk of hyperammonemia regardless of whether the patient is taking VPA. In patients receiving VPA, concomitant use of phenytoin and/or phenobarbital enhances the risk of hyperammonemia. An increase in ammonia can be caused by multiple factors. Our results may help clinicians to avoid problems of hyperammonemia.

Topics: Acetazolamide; Adolescent; Age Factors; Anticonvulsants; Child; Child, Preschool; Dose-Response Relationship, Drug; Epilepsy; Female; Fructose; Humans; Hyperammonemia; Infant; Isoxazoles; Male; Phenobarbital; Phenytoin; Retrospective Studies; Risk Factors; Sex Factors; Topiramate; Valproic Acid; Zonisamide

We present a woman with epilepsy secondary to a lesion in the left frontal lobe. She developed episodes of disorientation and behavioral changes. She was taking valproic acid (1500 mg/day), topiramate (200 mg/day), and phenobarbital (100 mg/day). During an episode, the EEG revealed moderate encephalopathy and ammonia levels were increased (195 μg/dL, reference range: 11-60 μg/dL). Episodes ceased after withdrawal of valproic acid.

Topics: Drug Synergism; Drug Therapy, Combination; Epilepsy; Female; Fructose; Humans; Hyperammonemia; Middle Aged; Neurotoxicity Syndromes; Phenobarbital; Topiramate; Valproic Acid

To describe the dose-concentration relationship of a continuous intravenous infusion of valproic acid (VPA) in pediatric patients when a dosing protocol is used.. Retrospective and concurrent chart review.. Tertiary care, 473-bed, academic medical center with a 120-bed, dedicated children's hospital.. Twenty-six pediatric patients (< 18 yrs old) who received VPA according to the protocol for continuous intravenous infusions between January 1, 2004, and March 31, 2006, identified by using a pharmacy order-entry system.. Patient demographics, VPA treatment regimens, clinical responses, and safety data were recorded and analyzed. Median patient age was 8.5 years (range 1.4-16 yrs). Approximately two thirds received VPA for seizures, and one third for migraines. Patients were given a mean +/- SD VPA loading dose of 28.5 +/- 5.2 mg/kg followed by a continuous infusion rate of 1 +/- 0.2 mg/kg/hour. Mean +/- SD serum concentration measured 4.5 +/- 1.6 hours after the loading dose was 83.3 +/- 22.8 microg/ml. Steady-state concentration at 23.3 +/- 3.0 hours after the start of the continuous infusion was 80.0 +/- 26.0 microg/ml. Postload and steady-state serum concentrations were within the target concentration of 50-100 microg/ml in 77% and 69% of patients, respectively. On further analysis, when the target range was expanded to 50-125 microg/ml (125 microg/ml was deemed acceptable if no adverse effects were noted), 89% and 92% of patients, respectively, had postload and steady-state VPA serum concentrations within this range. The response rate was excellent, with nearly 85% of patients achieving a complete or partial response to therapy. Adverse effects were generally mild and uncommon.. The continuous-infusion protocol permitted rapid intravenous loading of VPA in pediatric patients while minimizing adverse events and achieving concentrations in the upper region of the therapeutic range.

Topics: Administration, Oral; Adolescent; Anticonvulsants; Child; Child, Preschool; Drug Therapy, Combination; Drug Utilization Review; Female; Fructose; Hallucinations; Humans; Hyperammonemia; Infusions, Intravenous; Male; Medical Records; Metabolic Clearance Rate; Migraine Disorders; Phenobarbital; Phenytoin; Retrospective Studies; Seizures; Topiramate; Treatment Outcome; Valproic Acid

A 15-year-old boy with inverted duplication of chromosome 15 was admitted for acute onset of irritability, increasing sleepiness, and worsening of seizures. He had been on valproate and other anti-convulsants. However, he was found to have hyperammonemia within 2 weeks after the addition of low-dose topiramate to valproate. He recovered within 7 days after discontinuation of valproate. Topiramate was tailed off. The reintroduction of valproate monotherapy caused hyperammonemia again without clinical features of encephalopathy. He also developed anticonvulsant hypersensitivity syndrome following the use of phenytoin. We propose the term topiramate-valproate-induced hyperammonemic encephalopathy syndrome to include the following features: excessive sleepiness or somnolence, aggravation of seizures, hyperammonemia, and absence of triphasic waves on electroencephalography in any individual on simultaneous topiramate-valproate therapy. The ammonia level ranged from 1.5 to 2 times normal. The serum valproate level might be within the therapeutic range. The possible mechanism is topiramate-induced aggravation of all the known complications of valproate monotherapy. This condition is reversible with cessation of either valproate or topiramate.

Topics: Adolescent; Anticonvulsants; Brain Diseases; Chromosome Inversion; Chromosomes, Human, Pair 15; Drug Therapy, Combination; Epilepsy; Fructose; Humans; Hyperammonemia; Male; Syndrome; Topiramate; Valproic Acid

We report two children with localization related epilepsies, who presented with somnolence, seizure exacerbation, behavioral alteration, decline in speech and cognitive abilities, and ataxia while being treated with a combination of valproate and topiramate, but had previously tolerated valproate with other antiepileptic drugs. These children had elevated serum ammonia, normal transaminase levels, and generalized slowing of EEG background activity during encephalopathy, which promptly reverted back to normal along with clinical improvement following withdrawal of valproate. To our knowledge, this is the first documentation of valproate-induced hyperammonemic encephalopathy enhanced by topiramate from India. We intend to alert internists, pediatricians, psychiatrists and neurologists about this underrecognized adverse effect of antiepileptic drug polytherapy.

Topics: Ammonia; Anticonvulsants; Child; Child, Preschool; Drug Therapy, Combination; Female; Fructose; Humans; Hyperammonemia; Male; Neurotoxicity Syndromes; Seizures; Topiramate; Valproic Acid

We present three children with severe therapy-refractory epilepsy who tolerated valproate (VPA) well in various combinations with other antiepileptic drugs (AEDs) but developed typical VPA side effects in combination with topiramate (TPM).. The clinical symptoms began with apathy in all three children; two of them also had hypothermia. Furthermore all children had elevated blood ammonia levels, one child in combination with increased liver transaminases and one with thrombocytopenia.. All children recovered completely after discontinuation of VPA or TPM.. TPM seems likely to enhance the risk of side effects usually attributed to VPA and not described in TPM monotherapy. Our case reports suggest that possible adverse effects of VPA should be given particular attention when VPA is combined with TPM.

Topics: Affective Symptoms; Anticonvulsants; Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Epilepsy; Female; Fructose; Humans; Hyperammonemia; Hypothermia; Infant; Liver; Liver Diseases; Male; Risk Factors; Thrombocytopenia; Topiramate; Transaminases; Valproic Acid