An unexpectedly high occurrence of aciclovir-induced neuropsychiatric symptoms in patients treated for herpesvirus CNS infection: a prospective observational study

Abstract

Background: Aciclovir is effective in herpesvirus infections of the CNS. Aciclovir-induced neuropsychiatric symptoms (AINS) have been reported and are associated with high CSF concentrations of aciclovir metabolite 9-carboxymethoxymethylguanine (CMMG). Risk factors except for renal failure have not been explored, and disruption of the blood-brain barrier (BBB) in acute CNS infection may be of interest.

Objectives: To investigate the impact of risk factors on aciclovir and CMMG concentrations, and to relate the results to AINS.

Methods: We investigated 21 consecutively included, consenting patients treated with aciclovir or valaciclovir for herpesvirus CNS infection. Regression models were constructed to study the impact of risk factors including BBB disruption, as measured with CSF:serum albumin ratio, on CSF aciclovir and CMMG concentrations. Medical records were assessed retrospectively to identify patients with AINS.

Results: Increased CSF:serum albumin ratio, as well as decreased renal function and high aciclovir doses, was associated with increased aciclovir and CMMG concentrations in the CSF. We identified five patients with new neuropsychiatric symptoms; four of those were considered to have AINS and had increased CSF CMMG concentrations. Only one patient without suspicion of AINS had an increased CSF CMMG concentration.

Conclusions: In patients with herpesvirus CNS infections, BBB disruption is associated with increasing aciclovir and CMMG CSF concentrations. We also found an unexpectedly high number of patients with AINS. Evaluation of CSF:serum albumin ratios, renal function and CSF concentrations of aciclovir and CMMG may all contribute to the optimization of aciclovir dosing and avoidance of AINS.

Figure 1.

Distribution of aciclovir (left of divider) and CMMG (right of divider) in serum (n=32) and CSF (n=34) samples from patients (n=21) treated with aciclovir for herpesvirus CNS infection. Limit of detection is 0.15; values <0.15 are set to 0.08 for visualization purposes. Bar is set at median.

Figure 2.

Aciclovir concentrations in serum (n=32) and CSF (n=34) samples from patients (n=21) treated with aciclovir for herpesvirus CNS infection. (a) Increased CSF:serum albumin ratio, interpreted as an indication of BBB damage, is associated with increased aciclovir CSF concentrations. The dotted vertical line represents the upper normal reference for CSF:serum albumin ratio (10.2). (b) Decreased creatinine clearance, calculated using the Cockcroft–Gault formula, is associated with increased aciclovir serum and CSF concentrations. (c) Increasing dose of aciclovir is associated with increased aciclovir serum and CSF concentrations.

Figure 3.

CMMG concentrations in serum (n=32) and CSF (n=34) samples from patients (n=21) treated with aciclovir for herpesvirus CNS infection. (a) Increased CSF:serum albumin ratio, interpreted as an indication of BBB damage, is associated with increased CMMG CSF concentrations. The dotted vertical line represents the upper normal reference for CSF:serum albumin ratio (10.2). The dotted horizontal line represents a CMMG CSF concentration of 0.5 μmol/L, previously associated with AINS. (b) Decreased creatinine clearance, calculated using the Cockcroft–Gault formula, is associated with increased CMMG serum and CSF concentrations. The dotted horizontal line represents a CMMG CSF concentration of 0.5 μmol/L, previously associated with AINS. (c) Increased dosing of aciclovir is associated with increased CMMG serum and CSF concentrations. The upper dotted horizontal line represents a CMMG serum concentration of 10 μmol/L, previously associated with AINS, and the lower dotted horizontal line represents a CMMG CSF concentration of 0.5 μmol/L, previously associated with AINS.

Figure 4.

Comparison of peak CMMG concentrations in CSF samples from patients (n=21) treated with aciclovir for herpesvirus CNS infection. Comparison is made between patients with (n=4) and without (n=17) suspected AINS, previously associated with CMMG >0.5 μmol/L (upper dotted horizontal line). Bar is set at the median. The lower dotted horizontal line represents the CMMG analysis limit of quantification (LOQ) of 0.15 μmol/L.