In a patient with CSF showing 85 cells/µL with 61% lymphocytes, negative cryptococcal antigen, negative VDRL (Venereal Disease Research Laboratory test), and presumed negative HSV (herpes simplex virus), what is the most likely diagnosis and recommended management?

Lymphocytic Meningitis with Negative Cryptococcal Antigen and VDRL

Despite negative HSV PCR and VDRL, this patient's CSF profile (85 cells/µL with 61% lymphocytes) is consistent with viral meningitis/encephalitis, and empiric acyclovir should be continued until HSV encephalitis is definitively excluded through repeat testing or alternative diagnosis is confirmed.

Clinical Context and Diagnostic Approach

The CSF findings show:

• Moderate pleocytosis (85 cells/µL) with lymphocytic predominance (61%)
• Negative cryptococcal antigen (effectively excludes cryptococcal meningitis 1, 2)
• Negative VDRL (makes neurosyphilis unlikely, though CSF-VDRL has limited sensitivity of 30-71% 3, 4)
• Presumed negative HSV PCR

Critical Management Decision: When to Stop Acyclovir

Acyclovir can be safely discontinued ONLY if ALL of the following criteria are met 5:

1. HSV PCR negative on TWO occasions 24-48 hours apart, AND MRI not characteristic for HSV encephalitis

   OR

2. Single negative HSV PCR obtained >72 hours after symptom onset with ALL of the following:

   • Unaltered consciousness
   • Normal MRI (performed >72 hours after symptom onset)
   • CSF <5 white cells/µL

This patient does NOT meet stopping criteria because:

• CSF shows 85 cells/µL (far exceeds the <5 cells/µL threshold)
• Only presumed single negative HSV test mentioned
• Clinical status regarding consciousness and imaging not specified

Why HSV Cannot Be Excluded Yet

Initial HSV PCR can be falsely negative in several scenarios 6, 5:

• Early sampling (<72 hours after symptom onset) - virus may not yet be detectable
• Late sampling - after viral clearance has begun
• Presence of PCR inhibitors (hemoglobin) in CSF
• Neonates/infants have more variable test sensitivity (75-100% vs 96-98% in adults)

The CSF pleocytosis of 85 cells/µL with lymphocytic predominance is entirely consistent with HSV encephalitis, which typically presents with 10-500 WBCs/µL 6.

Recommended Management Algorithm

Immediate Actions:

1. Continue IV acyclovir 10 mg/kg every 8 hours (adults with normal renal function) 6, 5
2. Repeat lumbar puncture in 24-48 hours for second HSV PCR 5
3. Obtain or review MRI brain - look specifically for temporal lobe involvement characteristic of HSV encephalitis 5

If Second HSV PCR is Negative:

• With normal MRI and improving consciousness: Consider stopping acyclovir 5
• With temporal lobe abnormalities OR altered consciousness OR CSF pleocytosis persists: Continue acyclovir and consider third CSF sample at 3-7 days 6, 5

If HSV is Confirmed:

• Continue IV acyclovir for 14-21 days total 5
• Repeat LP at 14-21 days to confirm CSF HSV PCR negativity 5
• If still positive, continue IV acyclovir with weekly PCR until negative 5

Alternative Diagnoses to Consider

Given negative cryptococcal antigen and VDRL, pursue:

Other viral etiologies:

• Varicella zoster virus (VZV) - CSF PCR
• Enteroviruses - CSF PCR
• West Nile virus - CSF IgM (>60% sensitivity) 6
• Epstein-Barr virus - though positive PCR may reflect latent infection 6

Non-infectious causes:

• Autoimmune/paraneoplastic encephalitis
• Drug-induced aseptic meningitis

Neurosyphilis caveat: While CSF-VDRL is highly specific (89-96%), its sensitivity is poor (12-48%) 7. If clinical suspicion remains high (especially with serum RPR ≥1:32 4), consider:

• CSF FTA-ABS (more sensitive)
• CSF CXCL13 (78-83% sensitivity, 76-81% specificity) 7
• Serum treponemal testing if not already done

Common Pitfalls to Avoid

1. Stopping acyclovir based on single negative HSV PCR when CSF shows significant pleocytosis - this is the most dangerous error given HSV encephalitis mortality without treatment 6, 5

2. Over-relying on CSF-VDRL to exclude neurosyphilis - sensitivity is only 30-71% 3, 4, 8

3. Assuming negative cryptococcal antigen is definitive - while highly sensitive, false negatives can occur, particularly early in infection 2

4. Failing to obtain neuroimaging - temporal lobe involvement strongly suggests HSV even with negative initial PCR 5

The stakes are too high to prematurely discontinue acyclovir - untreated HSV encephalitis carries significant mortality and devastating neurological sequelae, while the risks of continuing empiric acyclovir for several more days are minimal 6, 5.