This case1 of an elderly patient with end-stage renal disease (ESRD) highlights challenges that can arise in diagnosing and managing comorbidities in such vulnerable patients.
An African-American man, age 80, presents to the emergency department with painful swelling and skin lesions along the left side of his face. His left eye and cheek are affected by the edema. He describes the pain as radiating down to his jaw. He has been experiencing generalized weakness and feverish episodes recently as well.
His medical history includes pulmonary arterial hypertension and congestive heart failure. For the past 6 years, he has been receiving cyclic peritoneal dialysis for ESRD. He is diagnosed with impetigo and prescribed oral clindamycin and mupirocin cream to treat the skin lesions.
When he presents subsequently to the peritoneal dialysis clinic, the lesions have not improved. While there are no obvious skin vesicles, he has left-side facial edema affecting the periorbital area. He is found to be alert and oriented to his surroundings. He describes feeling very weak and having no appetite.
The patient is referred to Infectious Disease and Dermatology for investigation, and is found to have herpes zoster. He is admitted to the hospital, and placed in isolation due to infectious disease concerns, and because of suspected encephalitis and potential eye involvement.
To treat the herpes zoster infection and prevent complications such as encephalitis and potentially sight-threatening eye involvement, he is started on intravenous acyclovir 5 mg/kg, as advised in the product monograph. His peritoneal dialysis regimen is continued without further interruption. Two days later, his treatment is changed from IV to oral acyclovir at a renally adjusted dose of 200 mg bid, and he is discharged from the hospital.
The patient returns within 24 hours, presenting with altered mental status — he is confused, delusional, disoriented, and restless, and experiencing visual hallucinations.
Laboratory tests to confirm suspected acyclovir neurotoxicity vs herpes encephalopathy include a spinal tap, which shows clear cerebrospinal fluid (CSF) with elevated white blood cell count, primarily lymphocytes, a glucose level of 50, and a protein level of 37 mg/dL.
Treatment and Outcome
Acyclovir is discontinued. To facilitate clearance of the drug, the patient is switched from peritoneal dialysis to hemodialysis, which he receives on 2 consecutive days for 4 hours. Dialyzers include hollow fiber, high flux, with polysulfone membranes dialyzers. Blood flow rate is 350 mL/minute, and dialysate flow rate is 600 mL/minute. His mental status improves quickly in response to treatment.
Blood cultures, computed tomographic scan of the head, and analysis of CSF for bacteria and viruses are all negative.
After resumption of intravenous treatment with acyclovir, the patient’s serum levels of acyclovir are elevated at 2.1 and 6.3 mcg/mL as compared with normal peak level of 0.4 to 2 mcg/mL.
Subsequently, while still in the hospital, the patient has a seizure episode and suffers a subdural hematoma due to a fall from his chair. Following surgical evacuation of the hematoma and a relatively short period of hospitalization and physical rehabilitation, he recovers and is discharged on hemodialysis treatment.
Herpes zoster (also known as shingles) occurs secondary to infection with the herpes zoster-varicella virus, a common infection that usually presents during childhood as varicella. The vaccine-preventable disease often emerges after years of dormancy in the cranial nerves or posterior root ganglia. Risk factors implicated in its development include old age, hard work, steroid use, malignancy, human immunodeficiency syndromes, and organ transplantation.2,3
Herpes virus infections are generally treated with the antiviral agent acyclovir, an acyclic guanosine nucleoside analogue. Alternatively, its prodrugs, valacyclovir, ganciclovir, or valganciclovir may be used — all have been linked with neurotoxic and nephrotoxic effects.4
When acyclovir is administrated intravenously, the total dose enters the circulation where it is picked up by herpes-infected cells; converted to an active form, acyclovir triphosphate; and incorporated into cell nuclei where it inhibits DNA polymerases.4
In contrast, oral acyclovir is poorly absorbed (15-30% absorption) and widely distributed in body fluids. Excretion of the remaining 60-90% of acyclovir and its congeners occurs through glomerular filtration and tubular secretion. This can be reduced in people with kidney disease,4,5 including those on any type of dialysis. While the half-life of acyclovir is 2-3 hours in patients with normal kidney function, it can reach 20 hours in patients with ESRD.5 These patients are particularly at risk of drug toxicity that can cause alteration of mental status and encephalopathy.
Clinicians reporting a similar case in which Bayesian-informed clearance estimates supported a therapeutic intervention for acyclovir-associated neurotoxicity noted that population estimates of renal function are both likely to be inaccurate and potentially dangerous to the patient.6
Declining renal function results in a larger proportion of the parent drug being converted into the 9-carboxymethoxymethylguanine (CMMG) metabolite. Elevated plasma concentrations of acyclovir have been linked with increased exposure to both CMMG and the parent drug in the central nervous system.7
High serum or CSF levels of CMMG are highly predictive of acyclovir neurotoxicity8 — with serum levels showing a sensitivity of 91% and specificity of 93% for the development of neuropsychiatric symptoms.9 Furthermore, acyclovir is a good candidate for removal by hemodialysis due to its low molecular weight and several other factors.10
Factors favoring acyclovir removal by hemodialysis include the following10:
- Molecular weight 225 Daltons
- Protein binding 9-33%
- Volume of distribution 0.6 L/kg
- High water solubility
- Extraction ratio by dialysis 0.45±12
The authors reporting this case of acyclovir neurotoxicity advised caution and careful dose modification when using acyclovir and all its prodrugs in patients with reduced kidney function, and particularly in oliguric and dialysis-dependent patients.
Specifically, the authors advised using 2.5 mg/kg/day of intravenous acyclovir — half the current recommended dose — and noted that where possible, dosing should be based on ideal and not actual body weight. In addition, the team said, acyclovir neurotoxicity can be addressed much more quickly with hemodialysis than peritoneal dialysis.
1. Sadjadi SA, et al “Acyclovir neurotoxicity in a peritoneal dialysis patient: Report of a case and review of the pharmacokinetics of acyclovir” Am J Case Rep 2018; 19:1459-1462.
2. Cohen JI “Herpes zoster” N Eng J Med 2013; 369(3):255-263.
3. Kawai K, et al “Risk factors for herpes zoster: A systematic review and meta-analysis” Open Forum Infect Dis 2017; 4(Suppl 1):S313-S314.
4. Rogers HJ, Fowle ASE “The clinical pharmacology of acyclovir” J Clin Hosp Pharm 1983; 8:89-102.
5. Laskin OL “Clinical pharmacokinetics of acyclovir” Clin Pharmacokinet 1983; 8:187-201.
6. Watson WA, et al “Resolution of acyclovir-associated neurotoxicity with the aid of improved clearance estimates using a Bayesian approach: A case report and review of the literature” J Clin Pharm Ther 2017; 42(3):350-355.
7. Hellden A, et al “The aciclovir metabolite CMMG is detectable in the CSF of subjects with neuropsychiatric symptoms during aciclovir and valaciclovir treatment” J Antimicrob Chemother 2006; 57(5):945-949.
8. Gentry JL III, Peterson C “Death delusions and myoclonus: Acyclovir toxicity” Am J Med 2015; 128(7):692-694.
9. Hellden A, et al “High serum concentrations of the acyclovir main metabolite 9-carboxymethoxymethylguanine in renal failure patients with acyclovir related neuropsychiatric side effects: An observational study” Nephro Dial Transplant 2003; 18(6):1135-1141.
10. Almond MK, et al “Avoiding acyclovir neurotoxicity in patients with chronic renal failure undergoing hemodialysis” Nephron 1995; 69:428-432.
No disclosures were reported.