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Assistant Professor of Clinical Pharmacy Practice Department of Pharmacy Practice Arnold and Marie Schwartz College of Pharmacy and Health Sciences Long Island University 75 DeKalb Avenue Brooklyn, New York 11201-5497 FAX 212/523-5703 arivkina{at}liu.edu
Published Online, October 15, 2003. www.theannals.com, DOI 10.1345/aph.1D175
Case Report. A 68-year-old Hispanic man presented to the emergency department with altered mental status, agitation, confusion, tremulousness, and irrational behavior. Prior to presentation, he had been started on valacyclovir 1000 mg 3 times a day for varicella zoster. The patient had received 3000 mg before developing any symptoms. His past medical history was significant for atrial flutter, type 2 diabetes mellitus, hypothyroidism, coronary artery bypass graft, and end-stage renal disease (ESRD). He was receiving hemodialysis 3 times weekly, with the last dialysis session 2 days prior to admission.
He was noted to have abnormal movements in his right arm at short intervals with internal rotation and spasm. A computed tomography (CT) scan of the head was performed. The patient emerged from the scanner with severe tongue laceration, possibly secondary to an unwitnessed seizure. A loading dose of intravenous phenytoin was given, the patient was intubated, and hemodialysis was begun. Despite documentation of therapeutic phenytoin concentrations, the patient developed another seizure episode and received an additional phenytoin loading dose. The only new medication the patient was receiving before admission was valacyclovir; maintenance medications included erythropoietin, glipizide, nephrovite, sildenafil, amlodipine, calcium acetate, levothyroxine, metoprolol, and paricalcitol.
Laboratory findings were significant for blood urea nitrogen 101 mg/dL, serum creatinine 15.6 mg/dL, potassium 5.8 mEq/dL, and glucose 146 mg/dL. The patient had anemia of chronic renal failure, but otherwise normal laboratory evaluation. Multiple brain CTs performed during the hospitalization demonstrated no gross abnormalities. Lumbar puncture was not performed due to herpes zoster lesions on the back. An initial electroencephalogram (EEG) showed no focal epileptiform abnormalities, triphasic waves suggesting metabolic disturbances. Repeat EEG confirmed the prior report.
An acyclovir concentration obtained prior to hemodialysis on the day of admission was 11.2 µg/mL. It was concluded that the patient's seizures were secondary to acyclovir accumulation. Valacyclovir was discontinued, and the patient slowly recovered his mental function over 2 weeks. Use of the Naranjo probability scale indicated a probable relationship between seizure activity and valacyclovir administration.1
Discussion. There are 7 case reports (MEDLINE search, October 7, 2003) of valacyclovir-induced neurotoxicity in ESRD patients in the literature (3 in English, 4 in other languages).2-4 Since 99% of the absorbed dose is converted to acyclovir, only acyclovir plasma concentrations are evaluable. Pharmacokinetic parameters are summarized in Table 1. Serum half-life is significantly prolonged in patients with ESRD (14 h). The half-life of valacyclovir during hemodialysis is 4 hours, and one-third of the drug is removed over a 4-hour hemodialysis session. The recommended valacyclovir dose in patients with ESRD is 500 mg/d.
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Our patient's acyclovir concentration was high according to our
institutional reference range (0.83–9.8 µg/mL). The reference range
is derived from the peak concentrations after a 200-mg oral acyclovir dose and
5-mg/kg intravenous acyclovir dose. However, acyclovir concentrations achieved
with 10 mg/kg far exceed these levels (mean 22.9 µg/mL, range
14.1–44.1). In a pooled analysis of 45 cases of acyclovir neurotoxicity,
plasma concentrations ranged from about 0.3 to 66 µg/mL (average 
18),
providing doubtful correlation between serum concentrations and
neurotoxicity.5
The neurotoxicity in our patient was probably due to elevated concentrations
of acyclovir. Patients with renal dysfunction may be more prone to
neurotoxicity in the presence of increased acyclovir concentrations combined
with other metabolic abnormalities.
References
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