A 32-year-old woman presents to the emergency department with a 3-day history of severe headache, high fever (39.8°C), and neck stiffness. She has a vesicular rash on the genitals and a history of recurrent genital herpes. CSF analysis shows lymphocytic pleocytosis (180 cells/μL, 85% lymphocytes), protein 65 mg/dL, and glucose 42 mg/dL (serum glucose 98 mg/dL). PCR for HSV-2 in CSF is positive. She is started on intravenous acyclovir 10 mg/kg every 8 hours. After 48 hours of therapy, her fever persists, and she develops confusion and tremors. Serum creatinine rises from 0.9 to 2.1 mg/dL. What is the most likely cause of her neurological deterioration?

Explanation

## Clinical Context This patient has confirmed HSV-2 meningitis (positive CSF PCR) and is receiving appropriate antiviral therapy. However, she develops neurological deterioration (confusion, tremors) concurrent with acute kidney injury (AKI)—a classic presentation of acyclovir toxicity. ## Mechanism of Acyclovir Nephrotoxicity **Key Point:** Acyclovir causes dose-dependent nephrotoxicity via crystal-induced acute tubular necrosis (ATN). Acyclovir crystals precipitate in renal tubules, especially in the setting of dehydration, high-dose IV therapy, or pre-existing renal impairment. **High-Yield:** The standard dose of 10 mg/kg IV every 8 hours is appropriate for HSV meningitis, but rapid infusion, inadequate hydration, and electrolyte abnormalities increase risk. ## Neurotoxicity of Acyclovir Acyclovir crosses the blood–brain barrier and accumulates in CSF. At high concentrations, it causes: - Confusion and altered mental status - Tremors and myoclonus - Hallucinations - Seizures (in severe cases) - Encephalopathy This neurotoxicity is often **secondary to renal failure** (uremia) and electrolyte derangements (hyponatraemia, hypocalcaemia), but can also occur from direct CNS toxicity. ## Differential Exclusion | Finding | Why Not This Option | |---------|---------------------| | **Inadequate dosing** | 10 mg/kg Q8H is the standard meningitis dose; fever at 48 hrs is common in viral meningitis and does not mandate dose escalation | | **Bacterial superinfection** | CSF glucose would be lower (<40 mg/dL is typical for bacterial meningitis); lymphocytic pleocytosis is more consistent with viral disease | | **IRIS** | Patient is immunocompetent (no mention of HIV/AIDS); IRIS occurs in immunosuppressed patients after immune recovery | ## Management of Acyclovir Nephrotoxicity 1. **Discontinue or reduce acyclovir** dose 2. **Aggressive IV hydration** (0.9% saline) to maintain urine output >200 mL/hr 3. **Slow infusion rate** (infuse over ≥1 hour, not bolus) 4. **Monitor renal function** and electrolytes closely 5. **Consider hemodialysis** if severe AKI or persistent neurotoxicity **Clinical Pearl:** The combination of AKI + encephalopathy in a patient on acyclovir is acyclovir toxicity until proven otherwise. Renal function must be monitored every 24–48 hours during high-dose IV acyclovir therapy. **Warning:** Do NOT increase the acyclovir dose in response to persistent fever—this will worsen nephrotoxicity and encephalopathy.