Last updated: Lesson of the Month - January 2019…
on 01 Jan 2019

Addendum to Lesson of the Month July 2012

We thank Dr Anders Helldén for his feedback on our Lesson of the Month article (July 2012) on acyclovir toxicity. He points out that this typical case demonstrates the difficulty in distinguishing viral encephalitis from acyclovir neurotoxicity. Although our article does mention that serum measurement of the acyclovir metabolite 9-carboxymethoxymethylguanine (CMMG) is possible, we did not offer any guidance on how results are interpretted. This was largely because the CMMG assay is not available in UK laboratories, and we have very little experience in interpretting the results. Below is a summary of his comments and suggestions for how these results might be interpretted.

Dr Helldén's group have been measuring acyclovir (and especially CMMG) in Sweden as a routine test for nearly 15 years, including 1700 samples from 700 patients. They have more than 150 cases of acyclovir neurotoxicity that have been diagnosed by their method, resulting in stopped acyclovir treatment and acute haemodialysis in many cases.

A CMMG level above 10 µmol/L indicates acyclovir neurotoxicity and has shown to be a much better predictor than serum acyclovir concentration (1).

Their method is well known among colleagues in Sweden from the Departments of Nephrology, Infection, and Neurology and has received poster and oral presentation awards. The method has also gained increasing interest from many countries such as Japan, Taiwan, Canada, UK, US and Netherlands, in some cases resulting in case reports (2, 3).


  1. Helldén A, Odar-Cederlöf I, Diener P, Barkholt L, Medin C, Svensson JO, Säwe J, Ståhle L. High serum concentrations of the acyclovir main metabolite 9-carboxymethoxymethylguanine in renal failure patients with acyclovir-related neuropsychiatric side effects: an observational study. Nephrol Dial Transplant. 2003 Jun;18(6):1135-41. PubMed PMID: 12748346.
  2. van Berlo-van de Laar IR, Goet ER, Helldén A, Sluiter HE. [Adverse effect of valaciclovir in disturbed kidney function]. Ned Tijdschr Geneeskd. 2009 Apr 11;153(15):706-9. Dutch. PubMed PMID: 19452773.
  3. Mahad DJ, Helldén A, Jarvis J, Mitra D, Gholkar A, Chinnery PF. Aciclovir induced posterior leucoencephalopathy. J Neurol Neurosurg Psychiatry. 2005 Sep;76(9):1308-9. Erratum in: J Neurol Neurosurg Psychiatry. 2005 Dec;76(12):1747. Mahad, D [corrected to Mahad, DJ]. PubMed PMID: 16107379; PubMed Central PMCID: PMC1739775.Dr


Dr Anders Helldén MD, PhD is assistant consultant in Clinical Pharmacology,
Specialist in Nephrology and Clinical pharmacology
Dept. of Laboratory Medicine,
Div. of Clinical Pharmacology
Karolinska University Hospital, Huddinge, Stockholm


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