A case of valproate-induced hyperammonemic encephalopathy: look beyond the liver

Saleh Alqahtani; Paolo Federico; Robert P. Myers

doi:10.1503/cmaj.061272

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Carnitene in the treatment of valproic acid hyperammonemia
Adriano M Pellicelli

Posted on: 28 November 2007
Possible new clinical sign of hyperammonemia
Harold A Pupko

Posted on: 17 September 2007

Posted on: (28 November 2007)
Page navigation anchor for Carnitene in the treatment of valproic acid hyperammonemia
Carnitene in the treatment of valproic acid hyperammonemia
Adriano M Pellicelli
The article of Alqahtani et al. describes a case of hyperammonemia due to valproic acid (VPA). Although the majority of patients who had an hyperammonaemia related to VPA are asymptomatic, we have observed patients with hyperammoniemic encephalopathy associated to stupor and coma. Valproic acid can induce alteration of metabolism of ammonia through an alteration of urea cycle. In particular VPA inhibits enzyme carbam...
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The article of Alqahtani et al. describes a case of hyperammonemia due to valproic acid (VPA). Although the majority of patients who had an hyperammonaemia related to VPA are asymptomatic, we have observed patients with hyperammoniemic encephalopathy associated to stupor and coma. Valproic acid can induce alteration of metabolism of ammonia through an alteration of urea cycle. In particular VPA inhibits enzyme carbamyl phosphate synthetase which is the first enzyme involved in the urea cycle. Inhibition of this enzyme prevents the incorporation of ammonia in the urea. Hyperammoniemia results from greater renal production along with reduced hepatic production of urea. Furthermore VPA reduces, with a not so well elucidated mechanism, levels of carnitine especially during long term or high dose therapy. Hyperammonemia is directly associated to a considerable reduction in free serum carnitine concentration. L Carnitine depletion can further impair urea cycle resulting in accumulation of ammonia, and can cause an intracellular accumulation of toxic acyl-coa resulting in impairment in several enzymatic processes. In the case herein described, besides the suspension of VPA, it could has been usefull, for the pathogenetic mechamism at the basis of hyperammoniaemia, the administration of L carnitine. Several reports have demonstrated as L carnitine supplementation has been shown to improve and reduce the duration of symptoms due to VPA related toxicities and remove the inhibition of VPA on carbamyl phosphate synthetase and urea synthesis (1,2,3). Furthermore preventive administration of Carnitine can allow to continue receiving VPA, a medication for which there are currently few substitutes.
References 1.Lheureux ER, Penaloza A., Zahir S., Gris M. Science review : carnitine in the treatment of valproic acid-induced toxicity-what is the evidence?. Critical Care. 2005; 9:431-440 2. Wadzinski J., Franks R., Roane D., Bayard M. Valproate-associated hyperammonemic encephalopathy. J Am Board Fam Med. 2007; 20:499-502 3. Raby W.N Carnitine for valproic acide induced hyperammonemia. Am J Psychiatry.1997; 154:8
Conflict of Interest:
None declared
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Competing Interests: None declared.
Posted on: (17 September 2007)
Page navigation anchor for Possible new clinical sign of hyperammonemia
Possible new clinical sign of hyperammonemia
Harold A Pupko
The article by Alqahtani et al is a welcome reminder that hyperammonemia is a common side effect of valproate therapy. I am not, however, convinced that hyperammonemia is a benign asymptomatic condition. I wonder whether the sedation often accepted as a side effect of valproate is indeed a symptom of low-grade encephalopathy. I have had two patients with bipolar disorder taking valproate in the past year complain of foul sm...
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The article by Alqahtani et al is a welcome reminder that hyperammonemia is a common side effect of valproate therapy. I am not, however, convinced that hyperammonemia is a benign asymptomatic condition. I wonder whether the sedation often accepted as a side effect of valproate is indeed a symptom of low-grade encephalopathy. I have had two patients with bipolar disorder taking valproate in the past year complain of foul smelling urine. The odour was described by both as “strong,” and, on smelling it myself, I was at loss to come up with a better descriptor. Blood ammonia levels were elevated in both patients, and, since mood stabilization was sub optimal on an already optimal dose, I decided to discontinue the valproate. Both patients noted that the smell disappeared upon discontinuation of the medication and has since not returned. As well, mental clarity was subjectively felt to be improved as well. Of note, both patients were placed on oxcarbazepine instead of valproate with significant improvement in mood stability. If strong smelling urine is indeed a sign of valproate related hyperammonemia, it is simple enough to question patients as to whether they are experiencing this side effect. If they are, I would then suggest that a blood ammonia level be drawn and, if elevated, the need for this medication be reassessed. In family practice, this odour may be mistaken for a urinary tract infection. Should a negative culture come back in the absence of other clinical signs such as urgency and dysuria in a patient taking valproate, I would suspect the medication as the culprit. The authors recommendations for managing valproate related hyperammonemic encephalopathy are prudent, but I wonder if they are missing half the picture. Does valproate unmask underlying conditions such as urea cycle disorders or fatty acid oxidation defects? Were these disorders looked for in this patient, and, if not, why not? More importantly, how does the average family doctor begin investigating for these problems? What tests should the physician in the trenches be ordering to screen for these conditions once suspicions are raised? Perhaps the CMAJ could more thoroughly address this issue in a future edition. Harold Pupko M.D. Private practice Toronto
Conflict of Interest:
None declared
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Competing Interests: None declared.