What is the recommended treatment for herpes simplex meningitis with a negative cerebrospinal fluid (CSF) polymerase chain reaction (PCR)?

Treatment of Herpes Simplex Meningitis with Negative CSF PCR

Despite a negative CSF PCR result, acyclovir should be continued for 14-21 days in patients with clinically suspected herpes simplex meningitis, as false-negative PCR results can occur, particularly early in the disease course. 1

Diagnostic Considerations with Negative PCR

• Initial CSF PCR can be negative in HSV encephalitis/meningitis, especially if performed early in the illness (<72 hours after symptom onset) or late after viral clearance has begun 1
• False-negative PCR results have been documented in confirmed cases of HSV encephalitis, including cases with two consecutive negative PCR results 2, 3
• MRI findings consistent with HSV infection (particularly temporal lobe involvement) should prompt continued treatment despite negative PCR results 3, 4
• CSF pleocytosis, elevated protein, and reduced glucose in the appropriate clinical context should maintain suspicion for HSV meningitis even with negative PCR 5

Treatment Algorithm

Initial Management

• Intravenous acyclovir (10 mg/kg three times daily) should be started immediately when HSV meningitis/encephalitis is suspected, without waiting for confirmatory test results 1
• Dose adjustment is required in patients with renal impairment 1

When to Continue Treatment Despite Negative PCR

Continue acyclovir if ANY of the following apply:

• Clinical suspicion remains high despite negative PCR 1, 2
• CSF was sampled <72 hours after symptom onset 1
• MRI shows findings consistent with HSV infection (particularly temporal lobe involvement) 3, 4
• CSF shows pleocytosis or other abnormalities consistent with viral meningitis 1
• Patient has altered consciousness or other neurological symptoms 1

When Treatment Can Be Safely Discontinued

Acyclovir can be stopped in immunocompetent patients if:

• An alternative diagnosis has been established 1
• HSV PCR in CSF is negative on two occasions 24-48 hours apart, AND MRI is not characteristic for HSV infection 1
• HSV PCR in CSF is negative once >72 hours after symptom onset, WITH normal level of consciousness, normal MRI (performed >72 hours after symptom onset), AND CSF white cell count <5×10^6/L 1

Duration of Treatment

• For confirmed HSV meningitis/encephalitis: 14-21 days of intravenous acyclovir 1
• Consider repeating CSF examination at the end of treatment to confirm clearance of virus by PCR 1
• If CSF remains positive for HSV by PCR at the end of treatment, continue intravenous acyclovir with weekly PCR until negative 1

Adjunctive Therapy

• Corticosteroids are not routinely recommended for HSV meningitis/encephalitis while awaiting results of ongoing clinical trials 1
• Corticosteroids may be considered in cases with significant cerebral edema, brain shift, or raised intracranial pressure under specialist supervision 1

Special Considerations

• Negative PCR should be interpreted with caution, especially when clinical suspicion is high 2, 3
• Early treatment with acyclovir significantly reduces mortality and morbidity (mortality decreases to 8% if therapy is initiated <4 days after symptom onset) 1
• Relapse of HSV encephalitis has been reported after completion of acyclovir therapy, with rates as high as 5% in adults 1
• Valaciclovir is not recommended as initial therapy due to inadequate CSF penetration, but may have a role in ongoing treatment after initial IV acyclovir, particularly in patients with HSV still detectable in CSF after 2-3 weeks 1