What diagnosis is most likely in a patient whose cerebrospinal fluid shows 85 cells/µL white blood cells with 61% lymphocytes and a negative cryptococcal antigen?

Viral Meningoencephalitis (Most Likely HSV or VZV)

With CSF showing 85 WBC/µL with 61% lymphocytic predominance and negative cryptococcal antigen, viral meningoencephalitis—particularly HSV or VZV—is the most likely diagnosis and should prompt immediate empiric acyclovir therapy while awaiting PCR confirmation 1.

Diagnostic Reasoning

The CSF profile you describe is classic for viral CNS infection:

• Lymphocytic pleocytosis (61% lymphocytes) with moderate cell count (85 cells/µL) is the hallmark of viral meningoencephalitis 2, 1
• This falls within the typical range for HSV encephalitis, which usually shows "tens to hundreds of cells" with lymphocytic predominance 1
• The negative cryptococcal antigen effectively rules out cryptococcal meningitis in most cases, though rare false negatives can occur with acapsular strains 3, 4

Priority Pathogens to Test

HSV-1/2, VZV, and enteroviruses account for 90% of identified viral encephalitis cases 1. Your immediate workup should include:

• CSF PCR for HSV-1, HSV-2, and VZV (highest priority)
• Enterovirus PCR
• Consider additional testing based on clinical context (travel, exposures, season)

Critical Timing Note

In 5-10% of HSV encephalitis cases, the initial CSF may be completely normal with negative HSV PCR early in illness 1. If initial testing is negative but clinical suspicion remains high, repeat lumbar puncture at 24-48 hours is essential 1.

Important Differential Considerations

Bacterial Meningitis Cannot Be Excluded

Lymphocytic predominance occurs in 32% of bacterial meningitis cases when WBC count is ≤1,000/mm³ 5. This is a critical pitfall. You must also evaluate:

• CSF glucose (compare to simultaneous plasma glucose—bacterial causes typically show low CSF:plasma ratio)
• CSF protein (elevated in bacterial causes)
• CSF lactate if available (<2 mmol/L essentially rules out bacterial meningitis) 1
• Gram stain and bacterial culture

Partially treated bacterial meningitis, tuberculosis, listeriosis, and brucellosis can all present with lymphocytic CSF 1.

Cryptococcal Infection Caveat

While the negative CrAg makes cryptococcosis unlikely, be aware that:

• Rare acapsular strains can produce false-negative CrAg tests 3, 4
• Early infection or low fungal burden may yield negative results 6, 7
• If the patient is severely immunocompromised, send CSF fungal culture regardless 3, 4

Immediate Management Algorithm

1. Start empiric IV acyclovir immediately (10-15 mg/kg q8h) while awaiting PCR results—do not delay for test results 1

2. Send CSF for:

   • HSV-1/2, VZV, enterovirus PCR
   • Bacterial culture, Gram stain
   • Glucose (with simultaneous plasma), protein, lactate
   • Fungal culture if immunocompromised
   • TB testing if risk factors present

3. Obtain brain MRI (superior to CT for detecting encephalitis) 2—look for temporal lobe involvement suggesting HSV

4. If initial CSF PCR negative at 24-48 hours but clinical suspicion persists, repeat LP 1

5. Continue acyclovir for minimum 14-21 days if HSV confirmed; adjust based on PCR results and clinical response

The lymphocytic CSF profile with negative CrAg strongly points toward viral etiology, but the overlapping presentations of various CNS infections demand comprehensive testing to avoid missing treatable bacterial or fungal causes.