What is the appropriate management for a patient with scattered lymphocytes in their cerebrospinal fluid (CSF) report?

Management of Scattered Lymphocytes in CSF

Scattered lymphocytes in CSF require immediate empiric treatment with both intravenous acyclovir and antibiotics (ceftriaxone plus vancomycin) until bacterial meningitis and HSV encephalitis are definitively excluded, as lymphocytic pleocytosis does not distinguish between viral, bacterial (including partially treated), tuberculous, or fungal meningitis. 1

Immediate Treatment Protocol

• Start IV acyclovir 500 mg/m² every 8 hours immediately along with empiric antibiotics (ceftriaxone and vancomycin), as delays beyond 48 hours in HSV encephalitis significantly worsen outcomes (mortality 70% untreated vs 20-30% with treatment) 1
• Continue this dual therapy until bacterial meningitis and HSV are excluded by culture, PCR, and clinical course 1
• Never assume lymphocytic CSF means "just viral" - tuberculous meningitis, partially treated bacterial meningitis, and listeriosis all present identically with lymphocytic pleocytosis 1, 2

Critical Diagnostic Workup

Essential CSF Studies

• Send CSF PCR for HSV-1, HSV-2, VZV, and enteroviruses immediately, as these account for 90% of viral CNS infections 3, 1
• Obtain CSF bacterial culture and Gram stain to exclude partially treated bacterial meningitis 1
• Measure CSF lactate - levels <2 mmol/L effectively rule out bacterial disease 3, 1
• Check CSF glucose (with paired serum glucose), protein, and cell count with differential 3
• Consider flow cytometry in addition to conventional cytology, as this increases detection of lymphoproliferative disorders by 50% compared to cytology alone 3, 4

Imaging

• Obtain brain MRI with and without contrast to identify temporal lobe enhancement (HSV encephalitis), basilar meningeal enhancement (TB or fungal meningitis), or mass lesions 3, 1
• CT scan is acceptable only if MRI is contraindicated, though it has lower sensitivity (36% vs 71% for MRI) 3

Differential Diagnosis Algorithm

Bacterial Meningitis Considerations

• Lymphocytic pleocytosis occurs in 32% of bacterial meningitis cases when CSF WBC is ≤1,000/mm³ 2
• This is particularly common in neonates and those without meningismus 2
• Low CSF glucose ratio and elevated protein suggest bacterial etiology despite lymphocytic predominance 3

Viral Meningitis/Encephalitis

• HSV encephalitis can present with normal or minimally abnormal CSF in 5-10% of cases 1
• Approximately 50% of HSV encephalitis cases show elevated CSF red cell count due to hemorrhagic pathophysiology 3
• Type-I atypical lymphocytes (multilobulated nuclei) in CSF have 69% positive predictive value for enteroviral meningitis 5

Tuberculous/Fungal Meningitis

• Lymphocytic pleocytosis with low glucose and high protein suggests TB or fungal etiology 3
• Consider in patients with immunocompromise, travel history, or subacute presentation 3

Lymphoproliferative Disorders

• Flow cytometry detects monotypic B cells and increases diagnostic sensitivity for CNS lymphoma 3
• CSF from PCNSL often shows increased leukocyte count and protein with normal glucose 3
• Combined assessment of MYD88 L265P mutation, IL-10 levels, and PCR for IgVH rearrangement in CSF efficiently discriminates PCNSL from inflammatory disorders 3

Autoimmune Encephalitis

• NMDA receptor encephalitis should be considered in young women with psychiatric symptoms, seizures, and movement disorders 6
• Send serum and CSF for anti-NMDA receptor antibodies 6
• CSF frequently shows lymphocytosis (up to 500 cells/μL) in the first phase 3

Follow-Up Strategy

• Repeat lumbar puncture in 24-48 hours if initial CSF HSV PCR is negative and clinical suspicion remains high, as HSV PCR can be negative early in disease course 1
• Continue acyclovir for 14-21 days if HSV is confirmed 1
• Discontinue antibiotics once bacterial meningitis is excluded by negative cultures at 48-72 hours and improving clinical course 1
• Monitor for acyclovir nephrotoxicity and ensure adequate hydration 1

Common Pitfalls to Avoid

• Never delay acyclovir waiting for HSV PCR results - decreased level of consciousness with seizure warrants immediate treatment 1
• Do not assume lymphocytic CSF excludes bacterial meningitis, especially in partially treated cases or neonates 2
• Do not rely on cytology alone for suspected lymphoma - flow cytometry is essential 3, 4
• Corticosteroids can cause false-negative CSF cytology and should be avoided before lumbar puncture if lymphoma is suspected 3
• Samples older than 3 days or with insufficient cell counts cannot be reliably analyzed by flow cytometry 4