Editor – We read with interest the article by Bell and colleagues (Clin Med June 2009 pp 231–5). They describe aciclovir therapy as essentially safe, highlighting the potential risk of crystal nephropathy. This potentially life-threatening complication is well recognised in nephrology, but not widely publicised, as it is often only evident in the presence of renal impairment. Recognition has implications for all physicians given the prevalence of chronic kidney disease and acute kidney injury. Such concerns might explain five patients not receiving full dose aciclovir in their study.
Aciclovir and latterly valaciclovir are established antiviral agents versus herpes simplex (HSV) and varicella zoster (VZV). Neurotoxic side effects have been described since the early 1980s.1–3 Such cases often resulted from recommended aciclovir dosing for HSV encephalitis in the context of renal impairment. As approximately 90% of the drug is renally excreted; half-life and serum levels of aciclovir are markedly elevated in renal disease.
A range of symptoms from tremor to coma have been described, with typical onset 24 to 72 hours after both oral and intravenous aciclovir. Visual hallucinations and death delusion are striking features in patients prescribed aciclovir with previously normal brain function (usually for treatment of shingles or as anticytomegalovirus prophylaxis).3 In patients with presumed encephalitis, failure to consider aciclovir neurotoxicity may lead to misinterpretation of neuropsychiatric symptoms as worsening encephalitis; precipitating inappropriate dose increases, rather than reduction or withdrawal.
The exact mechanism is unknown. 9-carboxymethoxymethylguanine (CMMG) is an aciclovir metabolite, present in serum and cerebral spinal fluid. In patients with neuropsychiatric side effects, significantly higher serum CMMG levels have been demonstrated; with stronger symptom correlation than aciclovir.5 Most affected patients had renal impairment.5
To improve the therapeutic regimen aciclovir dosing should always be adjusted for renal function6 and patients adequately hydrated prior to oral or intravenous administration. Possible aciclovir neurotoxicity should be considered with new neurological symptoms after 24 hours, particularly in the presence of renal impairment. Serum aciclovir measurements require 24 hours in most UK centres and often lag behind clinical signs. Levels might be useful for diagnostic confirmation. Early recognition with appropriate dose changes is crucial. If distinguishing worsening encephalitis from neurotoxicity proves difficult, a trial of haemodialysis might be appropriate.7
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