Challenge Case Report: Aseptic Meningitis Worsening With Treatment

Case Resolution

Acyclovir was discontinued and Mrs. V started dialysis. Based on the acuity of her kidney dysfunction and normal urea level, kidney dysfunction was not considered the primary cause of encephalopathy relapse. On her first day of dialysis, Mrs. V began to arouse and follow some commands with limited language production. By day 4, she became more alert and conversant and followed commands. Treatment with ganciclovir at 2.5 mg/ kg was initiated 6 days after acyclovir discontinuation because of Mrs. V’s ongoing encephalopathy and concern for varicella zoster (VZV). Mrs. V’s mental status continued to improve, and at discharge 3 weeks later, she was much improved with persistent mild deficits in attention, and memory.

Discussion

Acyclovir neurotoxicity has variable presentations, although confusion and visual hallucinations are most common. Dysarthria, ataxia, myoclonus, and coma have also been reported.¹ Acyclovir neurotoxicity is typically associated with renal dysfunction, either chronic or acute, and is seen in patients receiving higher doses of acyclovir. A higher prevalence has been reported in Japan, where higher doses are typically used.¹

The mechanism of neurotoxicity is not entirely known and is suggested to be a result of accumulation of 9-carboxymethyl methylguanine (CMMG) or 8-hydroxy-acyclovir (8-OH-A), 2 metabolites of acyclovir.² Acyclovir neurotoxicity is less likely in individuals with normal renal function, and these metabolites are present in higher levels in the CSF and serum of individuals with impaired kidney function taking acyclovir.³ This suggests that 9-CMMG and/or 8-OH-A are directly neurotoxic, although the mechanism for this is not known. It has been suggested that 9-CMMG inhibits transport proteins at the blood-brain barrier and increases the risk for uremic encephalopathy.^3,4

Obesity also appears to be a risk factor for acyclovir neurotoxicity. This may occur, at least in some cases, because actual body weight (instead of ideal body weight) doses of acyclovir are used.¹ In the case presented, Mrs. V received ideal body weight dosing.

Dehydration caused by decreased oral intake in an encephalopathic state may contribute to acyclovir neurotoxicity because of acute kidney injury or, possibly, because of increased serum concentrations from a given dose of acyclovir. Acyclovir neurotoxicity is reported to occur more commonly during drip infusions, which is thought to be related to high peak serum levels of acyclovir.¹

The primary treatment for acyclovir neurotoxicity is discontinuation of the medication. Many cases improve simply with time and natural clearance of the medication. However, because the drug is easily dialyzable, a faster resolution with dialysis can be a relatively safe option.⁵

Although neurotoxicity associated with ganciclovir is reported,⁶ in this case, Mrs. V tolerated ganciclovir without any evident adverse side effects.

The risk of ganciclovir neurotoxicity after acyclovir neurotoxicity is not known, although it appears to be rare. Toxicity has been reported with other acyclovir derivatives, including oral agents.^7,8 The biggest risk factor for neurotoxicity from acyclovir derivatives, regardless of agent, appears to be decreased renal function, and acyclovir neurotoxicity improves with a renal clearance of acyclovir.^2,5-8

Summary

This case illustrates a rare but known side effect of a commonly used medication that may be difficult to distinguish in a patient with an already existing central nervous system pathology. It also highlights the need to continually re-evaluate a diagnosis when a clinical situation changes or new information is presented.