Figure 2 - uploaded by T. Do
Content may be subject to copyright.
Synthesis and Degradation Pathways of Glutamate. Ammonia (NH 4 ) concentrations may increase due to VPA increasing the activity of glutaminase while TPM and the metabolite 4-en-VPA decrease the activity of glutamine synthetase.
Source publication
A 17-year-old female developed hyperammonemic encephalopathy 2 weeks after valproic acid (VPA), 500 mg twice a day, was added to her regimen of topiramate (TPM), 200 mg twice a day. She presented to the emergency department (ED) with altered mental status, hypotension, bradycardia, and lethargy. Laboratory analysis showed mild non-anion gap hyperch...
Contexts in source publication
Context 1
... Alternative sources of ammonia could explain why this may be the case. Ammonia is produced when glutamine is converted to glutamate via glutaminase (Figure 2), while glutamine synthetase converts glutamate and ammonia to glutamine. VPA's metabolite 4-en-VPA increases glutaminase activity in the renal cortex, 1 while VPA and TPM appear to decrease activity of glutamine synthetase in the kidneys and brain. ...
Context 2
... metabolite 4-en-VPA increases glutaminase activity in the renal cortex, 1 while VPA and TPM appear to decrease activity of glutamine synthetase in the kidneys and brain. 11 Both of the effects on the conversion of glutamate to glutamine could contribute to the increase in serum ammonia (Figure 2). ...
Context 3
... Alternative sources of ammonia could explain why this may be the case. Ammonia is produced when glutamine is converted to glutamate via glutaminase (Figure 2), while glutamine syn- thetase converts glutamate and ammonia to glutamine. VPA's metabolite 4-en-VPA increases glutaminase activity in the renal cortex, 1 while VPA and TPM appear to decrease activity of glutamine synthetase in the kidneys and brain. ...
Context 4
... metabolite 4-en-VPA increases glutaminase activity in the renal cortex, 1 while VPA and TPM appear to decrease activity of glutamine synthetase in the kidneys and brain. 11 Both of the effects on the conversion of glutamate to glutamine could contribute to the increase in serum ammonia (Figure 2). ...
Similar publications
Hyperinsulinism-hyperammonemia syndrome (HI/HA) is the second most common form of persistent hyperinsulinemic hypoglycemia of infancy (PHHI). The main clinical characteristics of HI/HA syndrome are repeated episodes of symptomatic hypoglycemia, but not usually severe. Consequently, children with HI/HA syndrome are frequently not recognized in the f...
Valproic acid (VA) induced encephalopathy is an unusual complication characterized by decreasing level of consciousness, focal neurological defi cits, cognitive slowing, vomiting, drowsiness, and lethargy, with or without hyperammonemia. Electroencephalography (EEG) is characterized by continuous generalized slowing. The EEG fi ndings, as well as c...
Methylmalonic acidemias (MMAs) are inborn errors of metabolism due to the deficient activity of methylmalonyl-CoA mutase (MUT). MUT catalyzes the formation of succinyl-CoA from methylmalonyl-CoA, produced from propionyl-CoA catabolism and derived from odd chain fatty acids β-oxidation, cholesterol, and branched-chain amino acids degradation. Increa...
Citations
... 4,6,12,15,16 One recognized predictor is the concomitant administration of hepatic cytochrome P450 (CYP) enzymeinducing AEDs, namely phenytoin, phenobarbital, carbamazepine, and newer-generation drugs such as topiramate. 4,[16][17][18] It has been hypothesized that the subsequent accelerated metabolism of VPA to 2-en-propyl-4-pentenoate (4-en-VPA) and propionate by such concomitant AEDs could result in VAH ( Figure 1). 4 This prospective observational cohort study was performed to determine the incidence and clinical presentation of VAH among neurosurgical patients. ...
... 12 This review supports the conclusions of previous epilepsy patient studies that the concomitant prescription of CYP enzymeinducing AEDs is an important risk factor for VAH and may exacerbate VHE. 3,4,16,18,34 Enzyme-inducer pharmacokinetic drug interactions are known to decrease serum VPA concentrations, requiring the administration of greater doses to maintain its narrow therapeutic index, which could have contributed to VAH. 35 To illustrate, a retrospective study of patients with epilepsy revealed mean VPA concentrations were reduced by 76%, 50%, and 66% in those co-medicated with phenobarbital, phenytoin, and carbamazepine, respectively. 36 Our results also revealed that phenobarbital posed a greater risk for VAH than phenytoin. ...
Objective:
Sodium valproate (VPA) is a commonly prescribed antiepileptic drug (AED) in daily neurosurgical practice. However, the incidence of VPA-associated hyperammonemia (VAH) and its life-threatening consequence, VPA-induced hyperammonemic encephalopathy (VHE), in neurosurgical patients is unknown. We determined the incidence, clinical presentation, and risk factors for VAH.
Methods:
This prospective cohort study was performed on adult neurosurgical patients prescribed VPA for at least a week over a 22-month period. Blood tests for ammonia, VPA, and liver function were performed at the time of recruitment. The primary end point was VAH. Secondary end points were VHE and liver dysfunction.
Results:
In total, 252 patients were recruited. The commonest disease etiology was brain tumors (27%, 69), followed by aneurysmal subarachnoid hemorrhage (SAH; 26%, 65). VPA was prescribed for primary seizure prophylaxis in 110 patients (44%). The mean daily dose was 1148 mg for a mean duration of 48 months. The mean serum VPA level was 417 μmol/L. In total, 92 patients (37%) were prescribed an additional AED, the most common being phenytoin (65%, 60/92). The mean serum ammonia level was 47 μmol/L. In total, 28% (71/252) of patients had VAH and only 0.7% had VHE. Independent factors were aneurysmal SAH (adjusted odds ratio [aOR] 2.1; 95% confidence interval [CI] 1.1-4.2), concomitant phenytoin (aOR 1.9; 95% CI 1.0-3.5), and phenobarbital (aOR 4.6; 95% CI 1.1-20.0). No associations with VPA dose, duration, serum levels, and liver function were observed.
Conclusions:
Although VAH is common among neurosurgical patients, VHE is rare. Patients with aneurysmal SAH or on concomitant enzyme-inducing AEDs are at risk. Clinicians should be vigilant for VHE symptoms in these patients.
... Whereas reports of hyperammonemia in the setting of VPA and TPM co-administration are frequent [7], ZON and VPA co-administration causing hyperammonemia is rarely reported [8]. Both ZON and TPM are carbonic anhydrase inhibitors, however, there are pharmacokinetic differences. ...
Hyperammonemia can often appear in the presence of supratherapeutic serum concentrations of valproic acid (VPA) or, less frequently, as a result of drug-drug interactions. Zonisamide (ZON), much like topiramate (TPM), is a carbonic anhydrase inhibitor which may provoke hyperammonemia when co-administered with VPA. We present a rare case of hyperammonemia with minimal dosage increase of valproic acid (VPA) in the setting of stable doses of the anticonvulsants (ZON) and levetiracetam (LEV). Brain MRI findings of cytotoxic edema were found alongside severely elevated ammonia levels warranting the discontinuation of VPA. As a result, gradual improvement occurred.
... Cases of VHE developing with simultaneous use of VPA and drugs like topiramate, quetiapine, or risperidone have been reported (10)(11)(12). It is known that the concomitantly used drug competes with VPA and thus may cause an increase in the free drug level (11). ...
... L-carnitine deficiency in hepatocytes cases impaired urea synthesis and development of hyperammonemia. (12) Some authors (13,14) showed that the development of ADRs on the background of VPA use was associated with the development of hyperammonemia in patients with no liver diseases. L-carnitine is successfully used to eliminate the ADRs caused by hyperammonemia, including in the treatment of acute valproate overdose. ...
The purpose of this study was to develop a sequential process of personalized valproic acid (VPA) prescription in patients with epilepsy.
Materials and Methods: We randomly selected 167 patients with epilepsy receiving VPA, based on carriage of CYP2C9*2 and/or CYP2C9*3 and therapeutic drug monitoring. The patients’ CYP2C9 status was determined by CYP2C9 genotyping before the beginning of anticonvulsant therapy.
Results: The sequence of personalized valproic acid prescription has been developed.
Conclusion: Using the sequential process of personalized VPA prescription will allow neurologists, psychiatrists and general practitioners to select starting and maintenance dosages of VPA with respect to the individual patient’s pharmacogenetic profile and thereby, significantly improve the safety of pharmacotherapy in epilepsy patients.
... And Blackford et al. found normal carnitine levels in a patient who developed hyperammonemic encephalopathy with VPA. They emphasized the discrepancies between serum and tissue/ muscle concentrations of carnitine (11). Gomceli et al. evaluated seven adult patients who were diagnosed as VHE. ...
Valproate induced hyperammonemic encephalopathy (VHE) is a severe adverse effect of medicine. An epileptic patient with an acute hyperammonemia after the addition of valproic acid to his treatment presented with acute mental status changes consistent with encephalopathy. Notably, plasma ammonia level was 2 times of the upper limit, despite normal liver function tests. Plasma valproic acid level was in the therapeutic range. His symptoms resolved with the discontinuation of valproic acid and Lcarnitine administration. We discuss this case and review the possible mechanisms of valproic acid-associated encephalopathy and the efficacy of L-carnitine.
... As a group, antiepileptic drugs are a relatively common cause of encephalopathy, either by direct CNS effect, or, in some cases, by inducing hyperammonemia. This is a well-established complication of valproic acid and has now been reported to occur in patients previously treated with valproic acid to which TPM was added [1][2][3][4][5][6][7][8]. Topiramate is a broad-spectrum anticonvulsant that is also extensively used for migraine prophylaxis, as a mood stabilizer, and for alcohol dependency. ...
... Although the use of TPM can be associated with cognitive symptoms, this side effect appears to be due to a direct effect of the drug in the CNS and is not secondary to any metabolic abnormality. Hyperammonemia secondary to the combined use of TPM and other antiepileptic drugs, particularly VPA, has been reported but is probably not common, with only a few cases reported in the literature [1][2][3][4][5][6][7][8]. ...
Hyperammonemia is an uncommon side effect of topiramate (TPM) that has only been reported when it is used as an adjunct to valproate. We report a patient with mental retardation who developed reversible encephalopathy from TPM. Ammonia level was monitored during the course of TPM treatment. This patient had recurring, reversible elevations in serum ammonia levels that coincided with the administration of TPM. To our knowledge, symptomatic hyperammonemia has not been reported to occur with TPM monotherapy.
... T he combination of valproic acid and topiramate has been shown to increase the risk of encephalopathy. [1][2][3][4][5] Certain authors have proposed that this combination evokes a synergistic mechanism that produces hyperammonemia, which in turn results in encephalopathy. 2,6 Described here is a case of encephalopathy potentially induced by the combination of valproic acid and topiramate, in which serial serum ammonia measurements suggested that encephalopathy may occur before hyperammonemia. ...
... Monotherapy with either valproic acid or topiramate or combination therapy with the 2 drugs has frequently been reported to cause encephalopathy. [2][3][4][5][7][8][9] In a recent retrospective chart analysis, the odds ratio for development of encephalopathy was 10 for patients receiving valproic acid -topiramate combination therapy relative to patients receiving valproic acid alone. 1 In the case reported here, the patient's improved neurologic status after withdrawal of valproic acid suggested that this drug had a role in the development of encephalopathy. ...
... Given the potentially serious or even fatal consequences of not abrogating seizure activity rapidly in SE, the ratio of benefit to risk seems clearly in favor of treatment. Pre-treatment with barbiturates, topiramate, or combinations of both may increase the risk of acute encephalopathy [94][95][96][97][98]. The mechanisms leading to acute encephalopathy are not well understood, but hitherto unrecognized mitochondrial dysfunction may play a crucial role [77,99]. ...
The effectiveness of valproate (VPA) in the treatment of focal and generalized epilepsies is well established. The drug has a wide spectrum of action, good tolerability, and has been available as an injectable formulation since 1993. Despite the lack of class A evidence, it has been used extensively in various forms of status epilepticus (SE).
Our aim was to present a systematic review of data from randomized and non-randomized controlled trials to evaluate the efficacy and safety of intravenous VPA for the treatment of SE.
Data sources included MEDLINE, back tracing of references in pertinent studies, and contact with the manufacturer of VPA (Sanofi-Aventis).
Overall, the search strategy yielded 433 results (425 MEDLINE, seven congress abstracts, one unpublished study); after excluding duplicate publications and case reports, 30 studies were identified (the earliest was published in 1993, the most recent in 2012); ten were controlled (six randomized controlled trials, four non-randomized controlled studies), and 20 uncontrolled trials (eight prospective observational studies, 12 retrospective case series). The cumulative literature describes the experiences of 860 patients with various forms of SE treated with intravenous VPA. The overall response rate to abrogate SE was 70.9 % (601/848; 95 % confidence interval [CI] 67.8-73.9). Response rates to intravenous VPA were better in children than in adults and did not differ between the SE types. The most commonly reported effective doses were between 15 and 45 mg/kg in bolus (6 mg/kg/min) followed by 1-3 mg/kg/h infusion. Safety studies of intravenous VPA administration in patients with SE showed a low incidence of adverse events overall (<10 %), mainly dizziness, thrombocytopenia, and mild hypotension, which was independent of infusion rates. Of note, good cardiovascular and respiratory tolerability was observed in these studies, even at high doses and fast infusion rates (up to 30 mg/kg at 10 mg/kg/min), despite multiple morbidities or other antiepileptic drugs. The most serious concern relates to the possibility of acute encephalopathy, sometimes related to hepatic abnormalities or hyperammonemia.
The published experience is consistent with VPA being a safe and effective therapeutic option for patients with established SE who have previously failed conventional first-line treatment with benzodiazepines, but high-quality randomized controlled trials are needed to inform clinicians on its comparative effectiveness in SE.
... Although usually well-tolerated, VPA is known to be associated with idiosyncratic side effects. [1] Valproate-induced hyperammonemia without evidence of hepatotoxicity is an important idiosyncratic side effect and 16-52% of patients receiving VPA treatment may have mild elevations in ammonia. [2] Hyperammonemia can occur in patients receiving usual VPA dosages for short-and long-term treatment and can be successfully treated by single dose of carglumic acid. ...
Valproic acid (VPA) is an antiepileptic drug which is used in the treatment of various seizure disorders including tonic-clonic, myoclonic, absence, partial seizures and psychiatric disorders. VPA is usually well tolerated, but severe adverse effects may occur. Hyperammonaemic encephalopathy (HE) is a rare and potentially fatal complication of VPA treatment. The mechanism by which valproate induces hyperammonemia remains incompletely understood but is likely to relate to the urea cycle. Herein we present two cases with valproate-induced hyperammonemia at therapeutic valproate levels without signs of liver failure and were successfully treated by a single dose of carglumic acid.
Valproate (VPA) is broad-spectrum antiepileptic drug. Several adverse reactions including hepatotoxicity, fetal risk and pancreatitis are well known and labelled as boxed warnings in the USA. One adverse reaction that is less well known but clinically significant for its severe morbidity is hyperammonemic encephalopathy. We present a case of woman with hyperammonemic encephalopathy following the initiation of VPA therapy; she had a favourable outcome with discontinuation of the drug and prompt treatment with lactulose and L-carnitine.
