Neurotoxicity from acyclovir and valacyclovir in patients undergoing peritoneal dialysis: Still rare,but still present

Introduction

Acyclovir has been used for more than 45 years to treat herpes virus infections, with the kidneys serving as the primary route of excretion. ¹ Valacyclovir, the L-valyl ester of acyclovir, is an oral prodrug that is rapidly converted into acyclovir in vivo. Both drugs are efficiently removed by hemodialysis.^1,2 When administered orally, the incidence of neurotoxicity is low; however, it can occur in elderly patients and those with chronic kidney disease (CKD).^3,4 Neurotoxicity associated with acyclovir or valacyclovir has been reported in patients undergoing either hemodialysis^3,5–8 or peritoneal dialysis (PD).^4,5,9–13 Clinical manifestations often include cerebellar involvement, but may also present as mental confusion, autonomic instability, hemiparesthesia, disorientation, psychomotor agitation, visual hallucinations, and coma.^3,12,14

Here, we describe three cases of patients on automated peritoneal dialysis (APD) who developed neurotoxicity following treatment with acyclovir or valacyclovir for herpes zoster.

Case reports

All patients were treated at home and referred to the monitoring center upon the onset of neurological symptoms. In all cases, the herpes zoster lesions resolved completely (Table 1).

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Table 1.

Described cases.

Case	Age	sex	Dose administered acyclovir (A), valacyclovir (V)	Dose recommended by the manufacturer	Start symptoms (days)	Symptoms	Treatment	Outcome
1	83	M	A: 400 mg q8 h	200 mg q12 h or 400 mg q12 h in severe cases	03	Mental confusion, psychomotor agitation	Restarted APD. Did not stop the drug	Improved 3 days after starting APD + maintained acyclovir treatment for 10 days
2	74	F	A: 400 mg q12 h	200 mg q12 h or 400 mg q12 h in severe cases	02	Limb paresis, hallucinations, dysarthria, dysgeusia, dysphagia	Discontinued drug 6 days after starting treatment and maintained APD	Symptoms improved after 4 days of discontinuing the medication
3	80	M	V:500 mg q8h	500 mg every 24 h	04	Mental confusion, dysarthria, difficult gait, involuntary lower limb movements	Discontinued drug after 4 days and maintained APD	He improved after 7 days of discontinuing the medication, but he continued to have no appetite and weight loss. Complete recovery in 30 days

APD: automated peritoneal dialysis.

Discussion

Acyclovir is primarily eliminated by the kidneys, with clearance approximately three times higher than creatinine clearance, indicating the contribution of both tubular secretion and glomerular filtration. ¹⁵ In individuals with normal renal function, its half-life is 2 to 3 hours, whereas in patients with end-stage CKD it increases to ∼20 hours.^1,15 Accordingly, dose adjustment is mandatory in patients with CKD, particularly those on dialysis, to prevent neurotoxicity.^12,16 In the present cases, neurological symptoms emerged 2 to 4 days after the initiation of treatment. The temporal relationship with drug administration, absence of focal neurological deficits suggestive of stroke, and lack of findings compatible with viral encephalitis supported the diagnosis of drug-induced neurotoxicity. Viral encephalitis typically manifests later, often more than 7 days after rash onset, and includes fever, headache, meningeal signs, and cerebrospinal fluid pleocytosis. ¹⁷ Resolution of symptoms following drug discontinuation further supports the diagnosis of acyclovir/valacyclovir neurotoxicity. In our series, two patients received doses exceeding manufacturer recommendations, while one received a dose at the higher end of the recommended range. Many previous reports also describe overdosing relative to renal function.^5,6,11,14,18 Acyclovir's small molecular weight (225 Da), high water solubility, and low protein binding (9–22%) account for its high clearance by hemodialysis (82 mL/min). ¹⁴ Hemodialysis can therefore be both therapeutic, shortening the duration of neurotoxicity, and diagnostic when toxicity is suspected.^14,17 In contrast, clearance via PD is approximately 22-fold lower than hemodialysis, removing <10% of the administered dose.^15,19 Consequently, PD is less effective but still capable of gradual drug removal, as observed in our patients and in previous reports.^{4,11,13,18,20} Faster recovery is often reported with hemodialysis,^4,12,13 although intensification of PD may also provide benefit.^11,20 Conversely, maintaining a standard PD schedule has been associated with delayed recovery or death.^4,16 Our three cases demonstrate that PD alone can be sufficient for recovery, though the process may be slower, particularly in elderly patients. Manufacturer recommendations for patients with CrCl <10 mL/min are as follows: Acyclovir (Zovirax^®): 800 mg every 12 hours. However, due to multiple reports of neurotoxicity, many experts recommend lower doses of 200 mg every 12 hours, up to 400 mg every 12 hours according to the severity of the case.^4,14 For intravenous administration, the recommended doses are 2.5 to 5.0 mg/kg/dose, calculated based on ideal weight rather than current weight, administered every 24 hours. ²¹ Valacyclovir (Valtrex^®): 500 mg every 24 hours; in some cases, even 500 mg every 48 hours may be preferable.^10,11,18,22 Importantly, neurotoxicity has been reported even with doses consistent with manufacturer guidelines,^8,22 underscoring the need for careful monitoring in dialysis patients. This report has limitations, including its retrospective design, absence of formal neurological evaluation in all patients, and lack of additional laboratory investigations for differential diagnosis. Despite decades of clinical use and multiple published cases, acyclovir- and valacyclovir-induced neurotoxicity continue to occur in patients with CKD, particularly elderly individuals on peritoneal dialysis. These reports serve as a reminder that, although rare, neurotoxicity can occur even at apparently safe doses in patients with severe renal impairment.