Herpes 101


Herpes simplex encephalitis is associated with substantial morbidity and mortality and may be related to timely diagnosis and treatment. In severe cases of HSE, reduced carbon dioxide reactivity is usually present and these patients don’t respond to the usual treatment of brain edema and intracranial hypertension. Acyclovir induced neurotoxicity and herpes encephalitis have similar clinical feature but their treatments are completely different. Recognition has implications for all physicians given the prevalence of chronic kidney disease and acute kidney injury. However, there is an increasing knowledge that acyclovir may cause severe adverse effects, such as CNS-symptoms and thrombotic microangiopathy, especially in patients with decreased renal function. EEG abnormalities included generalized background slowing and periodic lateralizing epileptiform discharges (PLEDS) and neuroimaging abnormalities included localized edema, mass effect, high/low-density lesions, or infarction and hemorrhage, with localization to the limbic, parietal, frontal, occipital lobes or thalami [1]. It has not been possible to connect high concentrations of acyclovir with acyclovir-toxicity, even if several reporters have suspected this in their reports [2, 3].

To cite this article: Ng, HW and Pang, CT. A range of symptoms from tremor to coma have been described, with typical onset 24 to 72 hours after both oral and intravenous aciclovir. Acyclovir is metabolized probably by alcohol dehydrogenase and aldehyde dehydrogenase to 9-carboxy-methoxymethylguanine (CMMG) and to a smaller extent to 8-hydroxy-9- (2-hydroxyethoxymethyl) guanine (8-OH-acyclovir) [6]. At our institution, there is a high threshold for admitting patients with suspected encephalitis to the PICU, representing children with more severe neurologic symptoms and a higher pre-test probability of CNS infection, leading to different physician approaches to clinical decision making. The renal clearance for acyclovir is 100 – 300 mL/min indicating both glomerular filtration and tubular secretion [7]. Availability: ISSN: 1024-9079. Renal insufficiency increases the urinary concentration of CMMG [8].

In these earlier studies on acyclovir metabolism the main metabolite CMMG was studied, but inconsistently. At our institution, a complete course of acyclovir was considered 14 days prior to 1999 and 21 days after 1999 [1]. Acyclovir-induced neuropsychiatric symptoms in ESRD patients may develop within a few hours after the first dose [9]. Both intravenous administration and treatment with valaciclovir may yield high acyclovir concentrations, depending on the dose. Intravenous administration to previously healthy patients given too fast or without sufficient saline hydration may cause crystal precipitation in tubuli, resulting in acute renal failure [10] and decreased renal excretion of acyclovir. If acyclovir cannot be excreted, a greater part may be metabolized by hepatic metabolism to CMMG. DMK reviewed the pharmacy database and encephalitis registry to determine eligibility.

If so, a simple blood test could support the diagnosis. The study was based on blood samples from 93 patients sent to the Department of Clinical Pharmacology, Huddinge University Hospital, Stockholm, Sweden for analysis of serum concentrations of acyclovir from November 1991 until June 1999. The patient’s charts were reviewed to acquire information on e.g. age, sex and estimated creatinine clearance. They have been defined as clinical decision-making tools that quantify the relative importance of three or more variables from history, physical examination, or simple tests to provide the probability of an outcome or suggest a single diagnostic or therapeutic course of action for an individual patient [20,21]. Furthermore, the result from clinical investigations such as EEG and CPR was analyzed. The research ethics committee of Huddinge University Hospital approved the study.

Patients with encephalitis were also included, because they might have had symptoms both from their infection and acyclovir treatment. These patients were included in a mixed subgroup.