How should suspected herpes simplex virus encephalitis be managed, including initial intravenous acyclovir dosing, diagnostic work‑up, intensive‑care monitoring, and second‑line therapy for acyclovir‑resistant cases?

Management of Herpes Simplex Virus Encephalitis

Start intravenous acyclovir 10 mg/kg every 8 hours immediately upon clinical suspicion of HSV encephalitis—within 6 hours of admission—without waiting for confirmatory testing, because delays beyond 48 hours increase mortality from 8% to 28%. 1, 2

Immediate Empiric Treatment

When to Start Acyclovir

• Initiate acyclovir within 6 hours of admission if initial CSF or imaging findings suggest viral encephalitis, or if these results are awaited. 1
• Continue acyclovir even if initial CSF microscopy and imaging are normal when clinical suspicion of HSV or VZV encephalitis remains high. 1
• Do not delay treatment for lumbar puncture in deteriorating patients—CSF PCR remains positive for 7–10 days after starting acyclovir, so delayed LP can still confirm diagnosis. 1, 2

Dosing Regimen

Adults and children >12 years:

• 10 mg/kg IV every 8 hours 1, 2

Children 3 months–12 years:

• 500 mg/m² IV every 8 hours 1

Neonates with HSV CNS disease:

• 20 mg/kg IV every 8 hours for 21 days (higher dose due to worse outcomes in this age group) 2

Renal Dose Adjustment

• Reduce dose based on creatinine clearance because acyclovir is 62–91% renally excreted. 2, 3
• Monitor renal function throughout treatment—nephrotoxicity manifests after approximately 4 days of IV therapy in up to 20% of patients. 1, 2
• Maintain adequate hydration to prevent crystalluria and obstructive nephropathy. 1, 2

Diagnostic Work-Up

Lumbar Puncture

• Perform LP immediately unless contraindications exist—do not delay for CT scan unless focal neurological signs, papilledema, or immunocompromise are present. 1
• CT scan is often normal in encephalitis and should not be relied upon to make or refute the diagnosis. 1
• A pragmatic approach: perform CT first only if LP will be significantly delayed, then obtain MRI as soon as possible. 1

CSF Analysis

• Send CSF for HSV-1, HSV-2, and VZV PCR (mandatory). 2
• Include protein, glucose, cell count with differential, and bacterial culture. 4
• CSF typically shows lymphocytic pleocytosis, mildly elevated protein, and normal glucose in HSV encephalitis. 2

Neuroimaging

• MRI is the investigation of choice—shows characteristic temporal lobe involvement in HSV encephalitis. 1, 4
• T2/FLAIR hyperintensity in medial temporal lobes, insular cortex, and inferior frontal lobes is typical. 1
• Obtain MRI as soon as feasible, even if initial CT was performed. 1

Treatment Duration and Monitoring

Standard Treatment Course

Confirmed HSV encephalitis:

• Continue IV acyclovir for 14–21 days (minimum 21 days in children 3 months–12 years due to relapse rates of 26–29% with shorter courses). 1, 2

Repeat lumbar puncture:

• Perform repeat LP with HSV PCR at 14–21 days to confirm viral clearance. 1, 2
• If CSF PCR remains positive, continue IV acyclovir with weekly CSF PCR until negative. 1, 2

Common Pitfall to Avoid

Never use oral acyclovir for acute HSV encephalitis—oral formulations do not achieve adequate CSF concentrations; IV therapy is mandatory. 2

Intensive Care Monitoring

ICU Indications

• Falling level of consciousness requires urgent ICU assessment for airway protection, ventilatory support, and management of raised intracranial pressure. 1
• Monitor for seizures—occur in 38% of HSV encephalitis cases. 1, 5
• Optimize cerebral perfusion pressure and correct electrolyte imbalances. 1

Seizure Management

• Treat seizures with antiepileptic drugs (levetiracetam is commonly used). 6
• Use EEG monitoring to identify non-convulsive seizures in confused or comatose patients. 6

Second-Line Therapy for Acyclovir-Resistant Cases

When to Suspect Resistance

• Persistent or worsening symptoms despite 7–10 days of appropriate acyclovir therapy. 2
• Persistent HSV-positive CSF PCR after 21 days of treatment. 1, 2
• Most relevant in immunocompromised patients (HIV, transplant recipients, prolonged corticosteroid use). 2

Alternative Treatment

Foscarnet:

• 40 mg/kg IV every 8 hours (or every 12 hours) for 2–3 weeks or until clinical improvement. 2, 7
• Requires dose adjustment for renal function—consult dosing nomograms. 7
• Must use infusion pump to control rate; establish diuresis before and during treatment. 7

Immunocompromised Patients

• May require prolonged courses beyond 21 days if CSF PCR remains positive. 2
• Consider combination therapy or higher acyclovir doses (15 mg/kg every 8 hours) if renal function permits, though most clinicians use standard 10 mg/kg dosing. 1

Adjunctive Therapies

Corticosteroids

• Role remains controversial—may reduce cerebral edema but could theoretically facilitate viral replication. 1
• Consider in patients with marked cerebral edema, brain shift, or raised intracranial pressure. 1
• A prospective randomized controlled trial is ongoing to establish efficacy. 1

Prognosis

• Even with acyclovir, mortality remains 20–30% (versus 70% untreated). 1
• Outcome is worse with advanced age, reduced Glasgow Coma Score on admission, and treatment delays >48 hours. 1
• Early treatment within 4 days of symptom onset reduces mortality to 8%. 2

Monitoring for Adverse Effects

Nephrotoxicity

• Reversible nephropathy develops after approximately 4 days in up to 20% of patients. 1, 2
• Monitor creatinine and maintain adequate hydration throughout treatment. 1, 2, 3

Rare Adverse Events

• Hepatitis, bone marrow failure, and acyclovir-induced encephalopathy can occur. 1
• These are mitigated by appropriate dosing and vigilant monitoring. 2

Intracranial Hemorrhage

• Very rare complication (2.7% of cases) but requires close neurological monitoring. 5
• Obtain repeat imaging if neurological status fails to improve or deteriorates despite appropriate treatment. 5