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

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.

Valaciclovir therapy for herpes encephalitis: caution advised.

Recently some authors have suggested that oral valaciclovir 1 g q8h is a valid alternative to intravenous aciclovir for herpes encephalitis. We are concerned about numerous caveats that we think have not been sufficiently addressed to allow such use outside of a controlled research setting.

Valacyclovir for herpes simplex encephalitis.

The recommended treatment for herpes simplex encephalitis (HSE) remains intravenous acyclovir. In resource-poor countries, however, intravenous formulations are usually unavailable or unaffordable. We report the penetration of acyclovir into the cerebrospinal fluid (CSF) in patients with HSE, treated with the oral prodrug valacyclovir at 1,000 mg three times daily. The oral therapy achieved adequate acyclovir concentrations in the CSF and may be an acceptable early treatment for suspected HSE in resource-limited settings.

Acyclovir resistance in herpes simplex encephalitis.

Herpes simplex virus type 1 is a common cause of severe sporadic encephalitis. Treatment with acyclovir is highly effective in this disease. We report the case of a 27-year-old, immunocompetent woman with acyclovir-resistant herpes simplex encephalitis. Although she had not been treated before, herpes simplex virus type 1 DNA from the cerebrospinal fluid showed a non-synonymous mutation in the thymidine kinase gene, which is likely to have caused resistance to acyclovir. Herpes simplex encephalitis resolved after treatment with foscarnet. To our knowledge, this is the first report of acyclovir-resistant herpes simplex virus encephalitis in an immunocompetent, previously therapy-naive adult.

Pharmacokinetics of acyclovir and its metabolites in cerebrospinal fluid and systemic circulation after administration of high-dose valacyclovir in subjects with normal and impaired renal function.

Valacyclovir, the L-valyl ester prodrug of acyclovir (ACV), is widely prescribed to treat infections caused by varicella-zoster virus or herpes simplex virus. Rarely, treatment is complicated by reversible neuropsychiatric symptoms. By mechanisms not fully understood, this occurs more frequently in the setting of renal impairment. We characterized the steady-state pharmacokinetics of ACV and its metabolites 9-[(carboxymethoxy)methyl]guanine (CMMG) and 8-hydroxy-acyclovir (8-OH-ACV) in cerebrospinal fluid (CSF) and the systemic circulation. We administered multiple doses of high-dose valacyclovir to 6 subjects with normal renal function and 3 subjects with chronic renal impairment (creatinine clearance [CrCl], approximately 15 to 30 ml/min). Dosages were 2,000 mg every 6 h and 1,500 mg every 12 h, respectively. Indwelling intrathecal catheters allowed serial CSF sampling throughout the dosing interval. The average steady-state concentrations of acyclovir, CMMG, and 8-OH-ACV were greater in both the systemic circulation and the CSF among subjects with impaired renal function than among subjects with normal renal function. However, the CSF penetration of each analyte, reflected by the CSF-to-plasma area under the concentration-time curve over the 6- or 12-h dosing interval (AUC(tau)) ratio, did not differ based on renal function. Renal impairment does not alter the propensity for ACV or its metabolites to distribute to the CSF, but the higher concentrations in the systemic circulation, as a result of reduced elimination, are associated with proportionally higher concentrations in CSF.

Multiple oral dosing of valacyclovir in horses and ponies.

The aim of the current study was to investigate whether multiple oral dosing of valacyclovir could result in plasma concentrations exceeding the EC(50)-value of acyclovir against equine herpesvirus 1 (EHV1) during the majority of the treatment period. Additionally, we wanted to determine the concentration of acyclovir in nasal mucus and cerebrospinal fluid (CSF). Valacyclovir was administered to four horses and two ponies, three times daily, at a dosage of 40 mg/kg, for four consecutive days. Blood was collected prior to each administration and 1 h after dosing. Nasal mucus samples and CSF were collected once during treatment; 1 h after the last administration. This dosage regimen resulted in plasma concentrations that were higher than the EC(50)-value of 1.7 microg/mL, i.e. EC(50) of an isolate highly susceptible to acyclovir, for 80% of the treatment period; and higher than the EC(50)-value of 3.0 microg/mL, i.e. EC(50) of an isolate less susceptible to acyclovir, for 60% of the treatment period. Concentration in nasal mucus samples and CSF was 0.36-1.17 microg/mL and 0.11-0.23 microg/mL, respectively. This study illustrates that multiple dosing of valacyclovir may result in a therapeutic benefit as plasma concentrations could be maintained above the EC(50)-value of acyclovir against EHV1 for more than 50% of the treatment period. Acyclovir could be detected in both nasal mucus samples and CSF. However, these concentrations were lower than the EC(50).

Rapid determination of acyclovir in plasma and cerebrospinal fluid by micellar electrokinetic chromatography with direct sample injection and its clinical application.

A simple MEKC with UV detection at 254 nm for analysis of acyclovir in plasma and in cerebrospinal fluid (CSF) by direct injection without any sample pretreatment is described. The separation of acyclovir from biological matrix was performed at 25 degrees C using a BGE consisting of Tris buffer with SDS as the electrolyte solution. Several parameters affecting the separation of the drug from biological matrix were studied, including the pH and concentrations of the Tris buffer and SDS. Using dyphylline as an internal standard, the linear ranges of the method for the determination of acyclovir in plasma and in CSF all exceeded the range of 2-50 microg/mL; the detection limit of the drug in plasma and in CSF (S/N = 3; injection 3.45 kPa, 5 s) was 1.0 microg/mL. The applicability of the proposed method for determination of acyclovir in plasma and CSF collected at 8 h after intravenous administration of 500 mg acyclovir (Zovirax) in two patients with herpes simplex encephalitis was demonstrated.

Acyclovir levels in serum and cerebrospinal fluid after oral administration of valacyclovir.

The possible involvement of herpesviruses in the pathogenesis of multiple sclerosis (MS) was recently investigated in a clinical trial of valacyclovir in patients with MS. As an important part of that survey we performed an independent pharmacokinetic study in order to determine the concentration of acyclovir in cerebrospinal fluid (CSF). The concentrations of acyclovir in serum and CSF were measured at steady state after 6 days of oral treatment with 1,000 mg of valacyclovir three times a day. Samples were obtained from 10 patients with MS. All patients had normal renal function, and none had signs of a damaged blood-CSF barrier. The maximum concentration of acyclovir in serum was reached after 1 to 3 h (mean +/- standard deviation [SD], 27.1 +/- 5.6 micro M), and the minimum concentration in serum was 3.1 +/- 1.1 micro M (mean +/- SD). The acyclovir concentrations in CSF at 2 and 8 h were essentially stable, with the mean +/- SD levels being 2.5 +/- 0.9 and 2.3 +/- 0.7 micro M, respectively. Similar levels were recorded in serum and CSF samples from five other MS patients after 6 months of oral treatment with valacyclovir at identical dosages. The area under the concentration-time curve (AUC) for acyclovir in CSF to the AUC for acyclovir in serum (CSF/serum AUC ratio) was approximately 20%. We conclude that the improved bioavailability previously reported for valacyclovir in plasma results in higher concentrations in CSF, while the CSF/serum AUC ratio remains constant.

Cerebrospinal fluid retrieval in the conscious dog: a methods development study.

A chronic cerebrospinal fluid access system is described for use in the conscious sling-restrained dog. In a pilot study of ten dogs, a fenestrated barium-impregnated silastic catheter was surgically implanted in the subarachnoid space of the second cervical vertebra through a dorsal laminectomy. This fenestrated catheter was coupled to a subcutaneous access port. Following surgery, cerebrospinal fluid was sampled weekly and evaluated for protein content and cytology. The cerebrospinal fluid albumin to serum albumin ratio was calculated for each sample to evaluate blood-brain barrier integrity. The instrumentation was successfully implanted in five of the first eight dogs using a midbody dorsal laminectomy. Cerebrospinal fluid access was maintained in these dogs for 21 +/- 10 days. Using a slight modification of the original technique, the final two dogs were instrumented through a caudodorsal laminectomy of the second cervical vertebra. The cerebrospinal fluid access system remains patent after 444 days of study in these two dogs. Necropsy evaluation suggested that catheter failure in the immediate postoperative period was due to gross malposition of the catheter. Chronic catheter failure occurred secondary to obstruction by local fibrous tissue reaction. Using this instrumentation, a pharmacokinetic evaluation of the plasma and cerebrospinal fluid deposition of an intravenous bolus of acyclovir was successfully performed twice in a single dog without complications. This instrumentation could provide chronic cerebrospinal fluid access for multiple pharmacokinetic studies in the conscious dog.

[Neurotoxicity of acyclovir in peritoneal dialysis apropos of 1 case]. / Neurotoxicité de l'aciclovir chez le dialysé péritonéal à propos d'un cas.

We report a case of reversible myoclonic encephalopathy which appeared after intravenous acyclovir treatment in a patient in CAPD for which pharmacological dosages have been made in serum, peritoneal dialysate and cerebrospinal fluid (CSF). Encephalopathy appeared after two intravenous doses of 7.33 mg/kg (doses higher than recommended), administered on admission and 16 hours later. Pharmacological dosages indicated that acyclovir peritoneal clearance was negligible, and that acyclovir persisted a long time in plasma and CSF. Neurological symptoms persisted although serum concentrations returned to normal value. The diagnostic value of pharmacological dosages in serum and CSF is discussed. In addition, neurological symptoms disappeared following two consecutive hemodialysis procedures. Hence we suggest that hemodialysis could be used for drug removal in case of acyclovir overdose in CAPD patients.

Acyclovir concentrations in serum and cerebrospinal fluid at steady state.

A long-term clinical trial of acyclovir, 800 mg tid, as a therapeutic agent in multiple sclerosis (MS) is in progress. In three patients paired serum and cerebrospinal fluid (CSF) specimens were sampled after one, four, eight and twelve months of continuous treatment. These samples were collected 1.5 h before or 1.5 h after an oral dose. Acyclovir concentrations were assessed by radioimmunoassay. In the CSF, the acyclovir concentration was relatively stable, with a mean of 0.83 microM, while the serum acyclovir concentration was variable with mean peak and trough concentrations of 4.08 and 2.47 microM, respectively. In two other MS patients the acyclovir concentration time profile in serum and CSF was studied at steady state during the 8 h dose interval. In this study the acyclovir concentration in the CSF was only slightly affected by the fluctuations in serum and the acyclovir CSF/acyclovir serum ratio was apparently not influenced by the blood-brain barrier function. We found no indication of an accumulation of acyclovir in cerebrospinal fluid after one to twelve months of oral treatment.

A case of herpes zoster associated encephalitis with rapid response to acyclovir.

A case of herpes zoster encephalitis which responded very rapidly to acyclovir is presented. The differential serum: cerebrospinal fluid antibody response was followed and its value in making the diagnosis is discussed. The penetration of acyclovir into the cerebrospinal fluid was measured, and found to be in agreement with predicted values.