What is the recommended treatment for a suspected case of encephalitis, possibly caused by herpes simplex virus (HSV), in an immunocompromised patient with a history of neurological symptoms?

Treatment of Suspected HSV Encephalitis in Immunocompromised Patients

Start intravenous acyclovir 10 mg/kg every 8 hours immediately upon suspicion of encephalitis in an immunocompromised patient, without waiting for diagnostic confirmation, and continue for 14-21 days in confirmed cases. 1, 2, 3

Immediate Treatment Initiation

• Begin IV acyclovir within 6 hours of admission if initial CSF and/or imaging findings suggest viral encephalitis, or if these results will not be available within this timeframe 2
• Do not delay treatment while waiting for lumbar puncture, imaging, or laboratory confirmation, as delays beyond 48 hours are associated with significantly worse outcomes 1, 2
• Mortality decreases dramatically with early treatment: 8% when started within 4 days of symptom onset versus 28% when delayed beyond 4 days 2
• Even with optimal treatment, mortality at 18 months remains 25-28%, making early intervention critical 2

Special Considerations for Immunocompromised Patients

• Immunocompromised patients are at higher risk for atypical viral pathogens including VZV, CMV, HHV-6/7, and HSV-2 (which causes approximately 10% of HSV encephalitis cases) 1, 2
• Consider additional CSF PCR testing for CMV, HHV-6/7, and HIV in immunocompromised patients 2
• VZV can cause multi-focal leukoencephalopathy in immunocompromised hosts, which also responds to acyclovir 1

Treatment Duration and Monitoring

• Continue IV acyclovir for 14-21 days in confirmed HSV encephalitis cases 1, 2, 3
• Perform a repeat lumbar puncture at 14-21 days to confirm CSF is negative for HSV by PCR 1, 4
• If CSF remains PCR-positive, continue IV acyclovir with weekly PCR testing until negative 1, 4
• The CSF typically remains PCR-positive for several days after starting treatment, so delayed lumbar puncture can still confirm diagnosis 1

Renal Function Monitoring

• Acyclovir is predominantly excreted by the kidneys and can cause reversible nephropathy through crystalluria in up to 20% of patients after 4 days of IV therapy 1, 4
• Adjust dosing based on creatinine clearance: patients with severe renal impairment (anuric) have a half-life of 19.5 hours versus 2.5 hours in normal renal function 3
• Maintain adequate hydration to prevent crystal formation and obstructive nephropathy 2

When to Stop Empiric Acyclovir

Acyclovir can be discontinued in immunocompetent patients (but use extreme caution in immunocompromised patients) if: 1, 4

• An alternative diagnosis has been definitively established, OR
• HSV PCR in CSF is negative on two occasions 24-48 hours apart AND MRI is not characteristic for HSV encephalitis, OR
• HSV PCR in CSF is negative once >72 hours after neurological symptom onset, with unaltered consciousness, normal MRI (performed >72 hours after symptom onset), and CSF white cell count <5×10⁶/L

Critical Pitfalls to Avoid

• Never rely on a single negative CSF PCR to rule out HSV encephalitis, especially if obtained <72 hours after symptom onset or late in illness when virus may be cleared 1, 2
• Do not use oral acyclovir or valacyclovir for CNS infections—oral acyclovir does not achieve adequate CSF levels 1, 4
• Do not stop empiric acyclovir prematurely based solely on clinical improvement, as this can lead to relapse 1
• CT scanning has only 25% sensitivity for initial HSV encephalitis diagnosis; MRI with diffusion-weighted imaging is the preferred modality (90% sensitivity within 48 hours) 2

Diagnostic Approach While Treatment Continues

• CSF PCR for HSV DNA is the diagnostic gold standard with >95% sensitivity and specificity when performed between days 2-10 of disease 2, 5
• MRI typically shows characteristic changes in the medial temporal lobes, cingulate gyrus, and entorhinal cortex 2
• Intrathecal HSV-specific IgG antibody synthesis can support diagnosis in CSF samples taken 10-12 days after symptom onset if PCR is negative 2