Intensification of Peritoneal Dialysis Improves Valacyclovir Neurotoxicity

Abstract

Valacyclovir induced neurotoxicity is a life-threatening complication, usually starting 24–48 h after drug-peak serum concentrations. The elderly with impaired renal function seem to be the most susceptible group to valacyclovir neurotoxicity. Although hemodialysis is considered the best method for rapid drug removal, our case showed that intensive peritoneal dialysis regimen leads to the recovery of neurotoxicity after 3 days.

• peritoneal dialysis
• valacyclovir
• neurotoxicity
• intensification
• life-threatening

INTRODUCTION

Valacyclovir induced neurotoxicity is a life-threatening complication, usually starting 24–48 h after drug-peak serum concentrations. The elderly with impaired renal function seem to be the most susceptible group to valacyclovir neurotoxicity. Although hemodialysis (HD) is considered the best method for rapid drug removal, our case showed that intensive peritoneal dialysis (PD) regimen leads to the recovery of neurotoxicity after 3 days.

CASE REPORT

A 72-year-old woman on continuous ambulatory PD (CAPD) for 5 years was admitted to our Department with confusion and visual hallucinations. Her medical history was significant for end stage renal disease (ESRD) due to glomerulonephritis, arterial hypertension, and dyslipidemia. Also, she had been seen by a dermatologist for a vesicular herpes zoster eruption, located along her right femoral region, of 3-day duration; receiving valacyclovir tablets 3 g daily (dose unadjusted for ESRD) without nephrologists’ consultation. Generally, she had been well-controlled with the dialysis prescription of four, 2-L exchanges daily (three exchanges of 2 L 2.5% dextrose plus one exchange of 2 L icodextrin overnight), and the following medications: nifedipine, 5 mg daily; irbesartan, 150 mg daily; cinacalcet, 60 mg daily; atorvastatin, 10 mg daily; and alfacalcidol, 1 μcg daily (Kt/V = 1.6). She was anuric (urine volume lower than 100 mL/day).

On admission, she was afebrile with dysarthria, dysesthesia, impaired coordination, dysarthria, dysesthesia agitation, and dizziness. Her laboratory findings showed Hb, 11.4 g/dL; leucocytes, 6100/mm³ with normal differential count; CRP, 1.38 mg/L; urea, 199 mg/dL (24.8 mmol/L); creatinine, 12.9 mg/dL (806.25 μmol/L); glucose, 108 mg/dL (5.98 mmol/L); sodium, 132 meq/L (132 mmol/L); potassium, 5.8 meq/L (5.8 mmol/L); total protein, 5.8 g/dL (58 g/L); and albumin, 3.4 g/dL (34 g/L) with normal liver enzymes. Arterial blood gas analysis showed pH, 7.43; PCO_2, 35.9 mmHg; PO₂, 86 mmHg; and bicarbonate, 21.9 meq/L (21.9 mmol/L). Blood pressure was within normal ranges. Emergency brain magnetic resonance imaging revealed microangiopathy. Valacyclovir neurotoxicity was suspected and the drug was discontinued. However, drug-level evaluation in serum or dialysate was not available. During her hospital stay, she had fever up to 38°C, nightmares, and sense of death. Lumbar puncture excluded central nervous system infection. In the meanwhile, her PD schedule was increased to six, 2-L bag exchanges daily (five exchanges of 2 L 2.5% dextrose plus one exchange of 2 L icodextrin overnight). After 24 h of PD intensification dysarthria and dizziness resolved, and after 3 days, the patient was well-oriented without hallucinations. Patients’ 24-h improvement and her family reluctance prevented us for starting HD immediately. The vesicular rash showed signs of improvement and she was discharged 5 days after admission, in a good condition. At home, she continued her dialysis schedule as before hospitalization, and in the weekly follow-up, she remained without any sign of neurologic symptoms recurrence. The eruption resolved completely within 2 weeks, without receiving other antiviral medication.

DISCUSSION

Valacyclovir is an antiviral medicine used for the treatment of genital herpes and herpes zoster and for cytomegalovirus prophylaxis posttransplantation. It maintains the established efficacy and safety of acyclovir, offering a more convenient daily dosing regimen. In the management of herpes zoster, valacyclovir is superior to acyclovir, because it accelerates the resolution of herpes zoster-associated pain significantly.¹

The neurotoxicity of valacyclovir in patients undergoing CAPD has been documented at least in five reports.^2–6 In most cases, as in our patient, valacyclovir has been administered in a dosage above the recommended. However, valacyclovir neurotoxicity has occurred even when treatment was with adjusted dosage. The recommended dosage for patients on CAPD is 500 mg every 24 h, although two pharmacokinetic studies suggested the same dosage every 48 h.^3,4 In patients with normal renal function, valacyclovir is excreted primarily as acyclovir (89%) in urine, after 2.5–3.3 h. In patients on CAPD (4 × 2 L exchanges), the half-time elimination of the drug is prolonged to 14–20 h, while only 5.27 mL/min (0.355 L/h/1.73 m²) are removed by the peritoneum (1% drug reduction during a 24 h collection period).^4,5 That low acyclovir clearance makes physicians to put patients receiving CAPD on conventional HD in case of valacyclovir neurotoxicity.^2,7 Indeed, HD is at least 20 times more efficient than CAPD in removing acyclovir. Acyclovir HD clearance was 113 mL/min with a 61.55% reduction in plasma drug level after a 6-h session.⁸

Our experience with the present patient showed that neurologic symptoms improved by increasing the dose of CAPD (from four to six exchanges for 5 days, during hospital stay), offering a practical treatment option for valacyclovir neurotoxicity in CAPD patients. Similarly, Takayanagi et al.² continued CAPD in a patient with valacyclovir neurotoxicity. However, they did not intensify the dialysis dose and their patient had consumed 5 g of the drug over 5-day time. Furthermore, in Takayanagi et al. report,² continuation of CAPD, without intensification of dialysis dose, resulted in complete recovery of neurotoxic symptoms after 7 days, whereas intensification of dialysis dose in our case resulted in resolution of symptoms in 3 days. Our patient had received high dose of the drug—regarding her renal function—in a short period of time (3.5 g during 2.5-day time). Initial mild neurologic symptoms (disorientation and numbness) had appeared 1 day before hospitalization, after receiving 3 g of acyclovir.

The beneficial influence of intensification of dialysis prescription on acyclovir removal cannot be easily explained. The nondetermination of acyclovir levels on admission and after changing CAPD schedule limits further interpretation. Usually, the neurotoxicity occurs with serum acyclovir levels >15 μmol/L,⁴ although lower levels have also been reported.³ Nephrologists should remain aware about valacyclovir neurotoxicity on CAPD patients and this intensification of CAPD can lead to its amelioration. For severe neurotoxicity symptoms, HD offers the fastest and the most efficient removal of acyclovir and should be used over PD.

Declaration of interest: There are no conflicts of interest. All authors have read and approved the submitted manuscript. The study complies with ethical considerations.