Encephalopathy Due to Hyperammonemia from Chronic Valproic Acid Treatment
A 51-year-old white male with mental disability and known seizure disorder presented to his neurologist with a new onset of headache, dizziness, confusion, weakness, lethargy, and hand tremors.
History. He has been taking valproic acid (VPA) 4 g/d, levetiracetam 4.5 g/d, and dilantin 300 mg/d, all on divided doses, for several years. He experiences a few 10-second seizures each day on this regimen.
Physical examination. The patient had a blood pressure of 132/91 mm Hg, temperature of 97.3°F, body mass index of 48.9 kg/m2, and a Glasgow coma scale measurement of 15. He appeared cognitively slow but able to answer questions appropriately, and had significant asterixis.
Laboratory tests. A CT scan of the brain showed 1.3 cm increased density on the parietal lobe, which has been stable for the past 4 years. The patient had an elevated ammonia level of 150 mmol/L (11-35 mmol/L). VPA level was 78 mcg/mL (normal: 50-100 mcg/mL). Liver enzymes, albumin, prothrombin time, and international normalized ratio measurements were all within normal range. Viral hepatitis panel was negative. An antismooth muscle antibody test was done to rule out autoimmune hepatitis and it came back negative as well. Ultrasound of the abdomen showed fatty liver.
Treatment. The patient was admitted due to metabolic encephalopathy secondary to hyperammonemia. He was initially given a loading dose of L-carnitine, VPA was decreased to 3 g/d, and his other antiseizure medications were continued. His symptoms and ammonia levels improved with L-carnitine administration and lactulose.
The carnitine level was drawn while on replacement. It was elevated at
131 nmol/mL (34-78 nmol/ml) with a free carnithine level of 103 nmol/L (25-54 nmol/L) and a normal acylated carnitine to free carnitine ratio of 0.3 (0.1-0.8) indicative of carnitine replacement. The patient was discharged home on VPA 2 g/d, levetiracetam 4.5 g/d, dilantin 400 mg/d, lactulose, rifaximin, and L-carnitine.
During follow-up, all his antiseizure medications were continued at the same dose. Rifaximin, carnitine, and lactulose were stopped. When his ammonia level started to increase again, lactulose was restarted at a small dose to maintain 1 to 2 bowel movements a day. He remained completely asymptomatic on this maintenance dose of lactulose despite the moderately-elevated ammonia level.
The carnitine level was repeated 2 months after stopping the replacement and was 59 nmol/mL (normal: 34-78 nmol/ml).
Discussion. VPA is an antiepileptic drug that is a branched-chain carboxylic acid. The therapeutic daily doses range from 500 mg to 2 g in adults.1 Literature has documented hyperammonemia as an adverse effect of VPA toxicity but some studies found hyperammonemia on therapeutic levels as well.
A 2007 meta-analysis showed a significant increase in VPA with other medications, especially concomitant use of other anticonvulsive therapies, such as phenytoin and phenobarbital.2 There is also a case report of hyperammonemia on a patient taking VPA, dilantin, and levetiracetam—with documented improvement of the ammonia level and symptoms on stopping the VPA.3 Most of these studies reported symptomatic encephalopathy, elevated ammonia level with normal VPA level, and liver function test just like our patient.
Hyperammonemia can be due to non-dose related toxicity due to chronic VPA therapy. There is no single explanation for the mechanism of hyperammonemic encephalopathy due to VPA. The inhibition of carbamoyl synthase I activity by propionic acid, which plays an important role in the regulation of the synthesis of urea,1,4 as well as depletion of carnitine used for ammonia metabolism, are both thought to be related mechanisms. There is no specific test available to document this abnormality. Either of these 2 pathways can lead to accumulation of ammonia causing encephalopathy. In our case, the carnitine level was normal 2 months after stopping the replacement.
Symptoms. Valproate-related hyperammonemic encephalopathy (VHE) can include symptoms of confusion, lethargy, vomiting, and increased seizure frequency—which can lead to stupor, coma, and even death. Symptoms can be immediate after a loading dose or slowly on patients on chronic treatment.5
Risk factors noted for VHE include mental retardation, carnitine deficiency, and urea cycle disorder. Dosage and length of treatment has no significant impact on the ammonia level and severity of the VHE.5
Treatment. Recommended medication includes lactulose, L-carnitine, and rifaximin. Lactulose is metabolized in the colon by bacterial flora to short chain fatty acids and effectively reducing plasma NH3 concentrations. Rifaximin, an antibiotic that targets the colonic bacterial flora that produces ammonia, is FDA-
approved for reducing overt hepatic encephalopathy recurrence.6,7
In chronically-treated patients, oral L-carnithine was also found to decrease the ammonia level and has been shown to be generally safe.7-9 Some data has showed that early intravenous supplementation with L-carnitine could potentially improve survival in severe VPA-induced hepatotoxicity and has been shown to speed the decrease of ammonemia in patients with VPA-induced encephalopathy.10
Outcome of the case. This patient’s seizure disorder was previously poorly controlled with other antiepileptic drugs. The potentially dangerous consequences of stopping VPA on this patient led the neurologist to keep him on VPA despite the hyperammonemia. Hepatic and renal causes of the hyperammonemia, other than the VPA, were ruled out. His symptoms subsided with L-carnitine, lactulose, and rifaximin. His ammonia level dropped but remained elevated despite the treatment. Later, both L-carnitine and rifaximin were stopped. Maintainenance therapy on lactulose alone was sufficient to keep his ammonia level low enough to keep him asymptomatic.
References:
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