A 54-year-old man with a history of seizure disorder is brought to the emergency department with progressive lethargy over the last 2 days. He has not had any headache, fever, or flu-like symptoms. He had a severe allergic reaction to levetiracetam in the past and failed phenytoin therapy. He is currently maintained on valproic acid. His last generalized tonic-clonic seizure was 1 week ago and his neurologist doubled the dose of his valproic acid at that time. The patient's past medical history is also significant for type 2 diabetes mellitus, hypertension, and hyperlipidemia. Additional medications include metformin, lisinopril, and atorvastatin.
The patient's temperature is 36.7 C (98 F) , blood pressure is 140/90 mm Hg, pulse is 70/min, and respirations are 12/min. Pulse oximetry shows 96% on room air. His BMI is 29 kg/m². On examination he appears lethargic, but is arousable, oriented to person and place, and follows simple commands.
Laboratory values are as follows:

Urinalysis and urine drug screen are normal. Chest x-ray and non-contrast head CT are normal.
Which of the following is the best next step in management of this patient?

Question

A 54-year-old man with a history of seizure disorder is brought to the emergency department with progressive lethargy over the last 2 days. He has not had any headache, fever, or flu-like symptoms. He had a severe allergic reaction to levetiracetam in the past and failed phenytoin therapy. He is currently maintained on valproic acid. His last generalized tonic-clonic seizure was 1 week ago and his neurologist doubled the dose of his valproic acid at that time. The patient's past medical history is also significant for type 2 diabetes mellitus, hypertension, and hyperlipidemia. Additional medications include metformin, lisinopril, and atorvastatin.
The patient's temperature is 36.7 C (98 F) , blood pressure is 140/90 mm Hg, pulse is 70/min, and respirations are 12/min. Pulse oximetry shows 96% on room air. His BMI is 29 kg/m². On examination he appears lethargic, but is arousable, oriented to person and place, and follows simple commands.
Laboratory values are as follows:

Urinalysis and urine drug screen are normal. Chest x-ray and non-contrast head CT are normal.
Which of the following is the best next step in management of this patient?

Quizplus · Accepted Answer

This patient is likely presenting with valproic acid induced hyperammonemic encephalopathy related to the recent doubling of his valproic acid dose. Valproic acid can inhibit enzymes within the urea cycle and lead to elevated serum ammonia levels resulting in confusion, lethargy, coma, and rarely death. All patients on valproic acid who present with encephalopathy should have their serum ammonia and valproic acid levels checked as part of the workup. Valproic acid levels do not always correlate with the degree of encephalopathy and can be normal at times. Liver enzymes can also be normal despite elevations in ammonia levels. The mainstay of treatment is discontinuation of valproic acid. Synthetic disaccharides such as lactulose can be used to lower the serum ammonia levels, and L-carnitine has been shown to improve valproic acid metabolism and reduce ammonia levels as well. (Choice B) Creatine kinase (CK) can be elevated in rhabdomyolysis (eg, from prolonged convulsive seizure activity and/or statin toxicity) but is unlikely to be useful in this patient as he does not have muscle pain or weakness, has a normal basic metabolic panel, and his urinalysis does not show blood. (Choice C) Metformin toxicity typically occurs in patients with concomitant renal or liver disease or as a result of acute overdose. A major complication is lactic acidosis. Patients classically present with gastrointestinal symptoms, followed by altered mental status, dyspnea, and hypotension. This patient's lack of gastrointestinal symptoms and normal calculated anion gap (10 mEq/L) make this diagnosis unlikely. (Choices D and E) Lumbar puncture and brain MRI can be considered in patients with an unclear cause of acute altered mental status and a negative head CT, but this patient should have his serum ammonia level checked first. Educational objective: Valproic acid can lead to elevated serum ammonia levels resulting in encephalopathy. Patients presenting with encephalopathy on valproic acid should have their serum ammonia and valproate levels checked. Treatment includes discontinuing the drug and starting lactulose. L-carnitine can also be considered. __________ References: Valproate-associated hyperammonemic encephalopathy. (http://www.ncbi.nlm.nih.gov/pubmed/17823470) Valproic acid induced hyperammoneamic encephalopathy. (http://www.ncbi.nlm.nih.gov/pubmed/23865136)

A 54-Year-Old Man with a History of Seizure Disorder Is