Case Presentation: A 55-year-old woman with a history of Trisomy 21, dementia and seizure disorder previously on Levetiracetam presented with acute altered mental status that began 24-48 hours prior. Patient initially presented to her neurologist 4 days prior to admission for concern of behavioral changes by her caretakers and was started on valproic acid (VPA). In the ED, patient was lethargic with waxing and waning level of consciousness, but had no seizure activity. She had mildly elevated aminotransferases (AST 48, ALT 47). She was ultimately admitted for altered mental status secondary to community acquired pneumonia and started on antibiotics. The patient exhibited seizure activity early in admission. By day 2, elevated aminotransferases had resolved. She was given a loading dose of VPA on day 2 and continued on maintenance dosing. Despite therapeutic VPA levels, she continued to have worsening mental status and seizure-like activity. Video EEG revealed diffuse slowing with no focal findings during seizure like activity. Ammonia levels drawn revealed patient was hyperammonemic with non-toxic levels of VPA. Patient’s VPA dose was then decreased and supplemented with lacosamide, and she was started on lactulose. However, there was no improvement in mental status in the next 24 hours. The following day, the patient was started on L-carnitine with her hyperammonemia resolving and patient approaching baseline mental status within the next three days. She was discharged with a reduced dose of valproate, lacosamide and a maintenance dose of L-carnitine to prevent future episodes of encephalopathy.
Discussion: Valproic Acid is a medication widely used for both neurological and psychiatric diseases. VPA induced hyperammonemic encephalopathy (VHE) is not an uncommon side effect of VPA therapy. Studies demonstrate high ammonia levels in up to 50% of patients on VPA. Although it should be noted that in most cases VPA had been prescribed chronically or the patient was found to have a supratherapeutic level of VPA, unlike our patient. The mechanism for VHE is not completely understood. However, it is known that VPA both decreases ammonia excretion and increases nitrogenous waste.Clinically, a case of acute VHE with a therapeutic VPA level presents a diagnostic challenge.. This is particularly true in the geriatric population in which dementia and delirium are common. Episodes of confusion can also be mistaken with partial seizures which further complicates diagnosis as it may be difficult to recognize that behavioral changes may be an adverse effect of VPA rather than a disease process itself. Hyperammonemic encephalopathy without liver failure is potentially reversible, making early identification critical to avoiding complications. Currently, there is no formal protocol for treating VHE. Recommendations in the literature include discontinuation of VPA followed by lactulose or rifaximin and/or L-carnitine. Cessation of VPA is not always necessary as parallel administration of L-carnitine can resolve hyperammonemia and allow for long term use of VPA for a patient who has limited options for anti-epileptics.
Conclusions: This case illustrates the potential for hyperammonemia induced encephalopathy acutely after initiating VPA in the absence of VPA toxicity. Recognition of this side effect and its reversal via L-carnitine supplementation early is essential in preventing potentially serious complications. This is especially important in patients with an underlying neurocognitive disorder.