Clinical Presentation

Mrs. V, age 89, was brought to the hospital for generalized weakness and confusion. She lived alone in her own home and functioned independently. On the day she arrived, however, her son found her in bed, soiled in urine and feces, and too weak to get up. On arrival, she had a 102.0°F temperature with otherwise normal vital signs. She has medical history of atrial fibrillation, hypothyroidism, and stage 3 chronic kidney disease. She responded to questions slowly but appropriately and was oriented to person and place but not the year. The remainder of her physical and neurologic examinations, including head and neck CT, were unremarkable. She was admitted for observation and diagnostic studies.

Diagnostic Testing

The next morning, Mrs. V was minimally responsive and nonverbal, although she opened her eyes on command and withdrew from a painful stimulus. Lumbar puncture was performed for cerebrospinal fluid (CSF) analysis and findings were positive for varicella zoster virus (VZV) DNA. Blood was drawn and of 2 cultures, 1 was positive for staphylococcus.


Acyclovir (10 mg/kg every 8 hours) using ideal body-weight dosing and broad-spectrum antibiotics were each initiated after the results of CSF analysis and blood culture were each available. By day 4 of her hospital stay, Mrs. V’s mental status returned to baseline. Antibiotics were discontinued after blood cultures demonstrated coagulase-negative staphylococcus, and acyclovir was continued with a plan to complete a 14-day course. On day 5, however, Mrs. V had a progressive decline in mental status, becoming responsive only to pain.

Further Workup

Urinalysis showed Mrs. V had developed an acute kidney injury with a creatinine level of 2.99 mg/dL and creatinine clearance of 13.3 mL/min (at admission creatinine was 1.05 mg/dL and creatinine clearance was 47.2 mL/min). Repeat head CT without contrast and MRI were both unremarkable. Repeat lumbar puncture and CSF analysis are shown in the Table. VideoEEG showed mild generalized slowing without ictal foci or discharges. Arterial blood gasses and ammonia levels were within the normal ranges.

Challenge Questions

1. What comorbidity is associated with acyclovir neurotoxicity?

A. Renal dysfunction

B. Hypertension

C. Cirrhosis

D. History of stroke

Click here for the answer

A, Acyclovir neurotoxicity is associated with renal dysfunction, likely caused by acyclovir metabolites 9‑carboxymethyl methylguanine (CMMG) or 8‑hydroxy‑acyclovir (8‑OH‑A)

2. What is the safest alternative to acyclovir treatment?

A. Ganciclovir

B. Valacyclovir

C. Discontinuing all antivirals

D. Valganciclovir

Click here for the answer

C, All antivirals should be discontinued. Although the exact toxicity rates are unknown, kidney dysfunction has been seen with other antiviral agents

3. What symptoms can be seen with acyclovir neurotoxicity?

A. Coma

B. Ataxia

C. Dysarthria

D. All of the above

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D, Acyclovir neurotoxicity can present with varied symptoms, including coma, ataxia, and dysarthria

4. What is the treatment for acyclovir neurotoxicity?

A. Steroids

B. Rifaximin

C. Stop acyclovir treatment

D. Decrease dose of acyclovir

Click here for the answer

C, Discontinuing the medication and allowing natural clearance is effective; if more rapid clearance is needed, dialysis may be started

1. Asahi T, Tsutsui M, Wakasugi M, et al. Valacyclovir neurotoxicity: clinical experience and review of the literature. Eur J Neurol. 2009;16(4):457-460.  

2. Helldén A, Lycke J, Vander T, Svensson JO, Odar-Cederlöf I, Ståhle L.. The aciclovir metabolite CMMG is detectable in the CSF of subjects with neuropsychiatric symptoms during acyclovir and valacyclovir treatment. J Antimicrob Chemother. 2006;57(5):945-999.  

3. Smith JP, Weller S, Johnson B, Nicotera J, Luther JM, Haas DW. 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. Antimicrob Agents Chemother. 2010;54(3):1146-1151.  

4. Berry L, Venkatesan P. Acyclovir-induced neurotoxicity: utility of CSF and serum CMMG levels in diagnosis. J Clin Virol. 2014;61(4):608-610.  

5. Kambhampati G, Pakkivenkata U, Kazory A. Valacyclovir neurotoxicity can be effectively managed by hemodialysis. Eur J Neurol. 2011;18(3):e33.  

6. Sakamoto H, Hirano M, Nose K, et al. A case of severe ganciclovir-induced encephalopathy. Case Rep Neurol. 2013;5(3):183-186.  

7. Prasad B, McIsaac M, Toppings J. Valacyclovir-associated neurotoxicity treated with intensification of peritoneal dialysis. BMJ Case Rep. 2017;2017.pii:bcr-2017-220678.  

8. Peyriere H, Jeziorsky E, Jalabert A, et al. Neurotoxicity related to valganciclovir in a child with impaired renal function: usefulness of therapeutic drug monitoring. Ann Pharmacother. 2006;40(1):143-146.

DH, JL, and GC report no disclosures.
The views expressed in this article are those of the author and do not reflect the official policy of the Department of Defense or the US Government.