JAC Advance Access originally published online on March 15, 2006
Journal of Antimicrobial Chemotherapy 2006 57(5):945-949; doi:10.1093/jac/dkl067
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The aciclovir metabolite CMMG is detectable in the CSF of subjects with neuropsychiatric symptoms during aciclovir and valaciclovir treatment
1 Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital, Huddinge, SE-141 86 Stockholm, Sweden; 2 Department of Neurology, Institute of Clinical Neuroscience, Göteborg University, Sahlgrenska University Hospital, Göteborg, Sweden; 3 Department of Internal Medicine, Soroka Medical Center, Beer-Sheva, Israel
Received 31 August 2005; returned 12 November 2005; revised 10 January 2006; accepted 14 February 2006
* Corresponding author. Tel: +46-8-58581054; Fax: +46-8-58581070; E-mail: anders.hellden{at}labmed.ki.se
Objectives: Neuropsychiatric symptoms related to aciclovir or valaciclovir treatment have been a problem since aciclovir was introduced in the early 1980s. We have previously found that subjects with aciclovir-related neuropsychiatric symptoms have increased serum concentrations of aciclovir's main metabolite, 9-carboxymethoxymethylguanine (CMMG). The aim of this study was to investigate whether CMMG was present in the CSF of aciclovir- or valaciclovir-treated subjects with or without neuropsychiatric side effects that appeared during therapy.
Methods: We investigated retrospectively CSF collected from 21 aciclovir- or valaciclovir-treated subjects. Of these, 9 were subjects with neuropsychiatric signs and symptoms and 12 were asymptomatic subjects, including 10 subjects from a valaciclovir multiple sclerosis trial and 2 subjects with recurrent herpes encephalitis.
Results: CMMG could only be detected in the CSF of subjects with neuropsychiatric symptoms and signs (median CMMG concentration 1.0 µmol/L, range 0.6–7.0). The concentration of CMMG was below the limit of quantification (<0.5 µmol/L) in asymptomatic subjects (P < 0.001). All patients with neuropsychiatric signs and symptoms, except one, had acute renal function impairment or chronic renal failure.
Conclusions: These results are consistent with the hypothesis that CMMG is involved in the development of neuropsychiatric side effects in aciclovir- or valaciclovir-treated patients. Measurement of CMMG in CSF and/or serum is a promising tool in the diagnostic procedure for aciclovir- or valaciclovir-treated patients with neuropsychiatric symptoms and may help to differentiate between side effects and herpes encephalitis.
Keywords: serious adverse reactions , 9-carboxymethoxymethylguanine , neurotoxicity , renal failure