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.     

Valproate-induced hyperammonemia in juvenile ceroid lipofuscinosis (Batten disease)

PurposeValproate-induced hyperammonemia (VHA) and hyperammonemic encephalopathy (VHE) are well-known complications of valproate (VPA) treatment. Currently recognised risk factors for VHE include a high VPA dosage, the need for polytherapy and long duration of treatment. Despite the severe nature of the epilepsy, presence of concomitant psychiatric manifestations, and frequent need for poly-pharmacy associated with juvenile ceroid lipofuscinosis (JNCL, Batten disease) neither this disorder nor other subtypes of neuronal ceroid lipofuscinosis have previously been identified as risk factors for VHA/VHE. The aim of the present publication is to describe four cases with VHE in a well-defined Danish population of JNCL.MethodAn examination of medical records of all 35 patients with JNCL in Denmark was conducted and revealed fourteen patients treated with VPA.ResultsFour patients treated with VPA developed VHE. All patients were prescribed VPA in standard dosages, had normal plasma concentrations of VPA and received antiepileptic drug (AED) polytherapy. Symptoms occurred shortly after commencement or increase in dose of VPA, and were quickly reversible upon discontinuation of VPA. Carnitine supplement was administrated in two patients, which resulted in resolution of symptoms and normalized ammonium levels.ConclusionPatients with JNCL are in great risk of developing VHA and VHE due to a high rate of polytherapy. Furthermore, studies have shown that carnitine level can be depressed in JNCL, which may increase the risk of VHA and VHE. We recommend that increased attention should be given to these patients.     

Valproate-induced panhypogammaglobulinemia

Valproate is one of the most used anti-epileptic drugs. Its common side effects are nausea, vomiting, weight gain, hair loss, tremor, changes in behavior, slowed thinking and impaired liver function. Blood dyscrasias are also relatively frequent and a few studies reported changes in serum immunoglobulin concentrations with valproate treatment. We describe a case of panhypogammaglobulinemia with transient pancytopenia due to valproate. Pancytopenia was recovered after discontinuation of valproate but panhypogammaglobulinemia has been persisting. Intravenous immunoglobulin is being administrated monthly. Previous reports describe that other sodium channel blockers, such as phenytoin and carbamazepine, have been associated with hypogammaglobulinemia. This report also suggests that immunodeficiencies can be caused by valproate.     

Valproate-induced hyperammonemic encephalopathy

Valproate-induced hyperammonemic encephalopathy (VHE) is an unusual complication characterized by a decreasing level of consciousness, focal neurological deficits, cognitive slowing, vomiting, drowsiness, and lethargy. We have thoroughly reviewed the predisposing factors and their screening, the biochemical and physiopathological mechanisms involved, the different treatments described, and those that are being investigated. Etiopathogenesis is not completely understood, although hyperammonemia has been postulated as the main cause of the clinical syndrome. The increase in serum ammonium level is due to several mechanisms, the most important one appearing to be the inhibition of carbamoylphosphate synthetase-I, the enzyme that begins the urea cycle. Polytherapy with several drugs, such as phenobarbital and topiramate, seems to contribute to hyperammonemia. Hyperammonemia leads to an increase in the glutamine level in the brain, which produces astrocyte swelling and cerebral edema. There are several studies that suggest that treatment with supplements of carnitine can lead to an early favorable clinical response due to the probable carnitine deficiency induced by a valproate (VPA) treatment. Development of the progressive confusional syndrome, associated with an increase in seizure frequency after VPA treatment onset, obliges us to rule out VHE by screening for blood ammonium levels and the existence of urea cycle enzyme deficiency, such as ornithine carbamoyltransferase deficiency. Electroencephalography (EEG) is characterized by signs of severe encephalopathy with continuous generalized slowing, a predominance of theta and delta activity, occasional bursts of frontal intermittent rhythmic delta activity, and triphasic waves. These EEG findings, as well as clinical manifestations and hyperammonemia, tend to normalize after VPA withdrawal.     

Valproate-induced coma with ketosis and carnitine insufficiency

We observed two patients who developed coma following administration of valproate in dosages of 32 to 40 mg/kg per day. Valproate levels were within the therapeutic range, and results of liver function studies were normal. Both patients had ketosis and adipic aciduria. Plasma free carnitine levels were decreased during coma and after recovery. One patient excreted ethylmalonic acid, butyrylcarnitine, and glutarylcarnitine during and after resolution of coma, suggesting a multiple acyl coenzyme A dehydrogenation defect. Low serum carnitine levels may predispose patients to development of altered consciousness when treated with valproate.     

Valproate-induced Parkinsonism in epilepsy patients.

We systematically examined 226 epilepsy patients in a tertiary-referral center and found 6 (5.04%) to have valproate-induced Parkinsonism. There was a significantly higher prevalence of patients with Parkinsonism in the group of patients treated with valproate compared to those who were on other antiepileptic drugs (6 [5.04%] of 119 vs. 0 [0%] of 107; chi2 = 5.54; P = 0.025). These six patients had been on valproate for more than 3 years (mean, 75.67 +/- 25.32 months) at an average dose of 750 +/- 273.86 mg/day. The valproate doses were decreased or discontinued with supplementation from another antiepileptic medication. The mean UPDRS motor score significantly improved from 10.67 +/- 5.1 to 4.75 +/- 2.75 (P < 0.05). There was no relapse of seizures. Clinicians working in tertiary-referral centers should have a high index of suspicion for valproate-induced Parkinsonism. Early recognition and switching into another antiepileptic medication may help reduce unnecessary suffering in these patients.     

Valproate-induced hyperammonemic encephalopathy with normal liver function

Hyperammonemic encephalopathy with normal liver function is an uncommon serious adverse effect of valproate therapy. We retrospectively analyzed the case records of 5 patients of epilepsy on valproate with hyperammonemic encephalopathy. Of the 5 patients, 3 were on monotherapy. The mean valproate dose was 1250 mg/day and the duration of therapy ranged between 4 and 90 days. Alteration in the sensorium was the presenting clinical feature. The risk factors included high initial dose (2), long-term valproate therapy (1), and long-term valproate therapy with concomitant topiramate (1). There was good correlation between the fall in serum ammonia levels and clinical improvement. Hyperammonemic encephalopathy should be suspected in patients on valproate with altered sensorium. Response to treatment is rewarding.     

Valproate-induced thrombocytopenia: a prospective monotherapy study

PURPOSE: The frequency of valproate (VPA)-induced thrombocytopenia varied widely in previous studies, due to methodological differences. Our objective was to evaluate the relationship between trough VPA plasma levels and platelet counts and assess risk factors for the development of thrombocytopenia. METHODS: Patients with refractory partial epilepsy were enrolled in this double-blind, multicenter, concentration-response trial that evaluated the efficacy and safety of high versus low trough plasma VPA concentrations following administration of divalproex sodium as monotherapy. Trough VPA concentrations and concomitant platelet counts were drawn at baseline and intermittently throughout the 24-week trial. Bivariate correlations and multivariate stepwise regression analysis were performed between platelet counts and multiple variables. A logistic regression analysis was done to determine the probability of developing thrombocytopenia at various VPA levels. RESULTS: A total of 851 VPA levels and concomitant platelet counts were analyzed in 265 patients. Of these, 17.7% of patients experienced at least one episode of thrombocytopenia (platelet count < or = 100,000/microl) after exposure to divalproex sodium. A significant negative correlation was found between VPA levels and platelet counts. Women were significantly more likely to develop thrombocytopenia. The probability of developing thrombocytopenia substantially increased at trough VPA levels above 100 microg/ml in women and above 130 microg/ml in men. DISCUSSION: Our data strongly support a causal relationship between rising plasma VPA levels and reduced platelet counts, with additional risk factors including female gender and lower baseline platelet counts.     

Valproate-induced chorea and encephalopathy in atypical nonketotic hyperglycinemia

Nonketotic hyperglycinemia is a disorder of amino acid metabolism in which a defect in the glycine cleavage system leads to an accumulation of glycine in the brain and other body compartments. In the classical form it presents as neonatal apnea, intractable seizures, and hypotonia, followed by significant psychomotor retardation. An important subset of children with nonketotic hyperglycinemia are atypical variants who present in a heterogeneous manner. This report describes a patient with mild language delay and mental retardation, who was found to have nonketotic hyperglycinemia following her presentation with acute encephalopathy and chorea shortly after initiation of valproate therapy.