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JAC Advance Access first published online on March 15, 2006
This version published online on March 22, 2006
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkl067
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© The Author 2006. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org
Received August 31, 2005
Revised January 10, 2006
Accepted February 14, 2006

Original article

The aciclovir metabolite CMMG is detectable in the CSF of subjects with neuropsychiatric symptoms during aciclovir and valaciclovir treatment

Anders Helldén 1 *, Jan Lycke 2, Tatiana Vander 3, Jan-Olof Svensson 1, Ingegerd Odar-Cederlöf 1, and Lars Ståhle 1

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

* To whom correspondence should be addressed.
Anders Helldén, E-mail: anders.hellden{at}labmed.ki.se


  Abstract

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.
The originally published version of this article was incorrect. The limit of quantification of CMMG concentration was incorrect in the abstract. The Journal apologizes for this error.
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