What is the appropriate management for a patient with nucleated cells in their cerebrospinal fluid (CSF)?

Management of Nucleated Cells in Cerebrospinal Fluid

The immediate priority when nucleated cells are detected in CSF is to determine the cell differential and initiate empiric antibiotics within one hour if bacterial meningitis cannot be definitively excluded, as delayed treatment significantly worsens morbidity and mortality. 1, 2

Immediate Actions and Risk Stratification

Cell Differential Analysis is Critical

• Obtain a manual cell differential immediately to distinguish neutrophilic from lymphocytic predominance, as this fundamentally changes management 1, 2
• Neutrophilic predominance (>50% neutrophils) suggests bacterial meningitis and requires immediate empiric antibiotics 1
• Lymphocytic predominance suggests viral, tuberculous, fungal, or autoimmune etiologies, but 10% of bacterial meningitis cases present with lymphocytic predominance, particularly Listeria monocytogenes 2
• Early viral meningitis may show neutrophilic predominance initially, though total CSF white cell count is unlikely to exceed 2000 cells/mm³ 2

Empiric Antibiotic Coverage

Start antibiotics immediately (within one hour) if bacterial meningitis cannot be excluded: 2

• For patients >50 years, immunocompromised, pregnant, or diabetic: Ceftriaxone + Vancomycin + Ampicillin (Listeria is resistant to cephalosporins and accounts for 20-40% of bacterial meningitis in these populations) 2
• For patients <50 years without risk factors: Ceftriaxone + Vancomycin 2
• Do not delay antibiotics for imaging or additional testing when bacterial meningitis is suspected 2

Diagnostic Algorithm Based on CSF Profile

Lymphocytic Pleocytosis with Normal Glucose

This pattern suggests viral encephalitis or autoimmune etiology: 1, 2

Immediate testing:

• HSV-1/2, VZV, enterovirus PCR (sensitivity 96-98% for HSV in adults, 75-100% in neonates; remains positive during first week of therapy) 1
• West Nile virus, EBV, CMV serology if clinically indicated 1, 2
• Brain MRI with contrast to evaluate for temporal lobe involvement (HSV), parenchymal lesions, or autoimmune patterns 1, 3

If viral PCR negative and clinical features suggest autoimmune encephalitis:

• Autoimmune antibody panel in both serum and CSF (anti-NMDAR, anti-LGI1, anti-VGKC, anti-CASPR2, anti-MOG) - testing both fluids is essential as sensitivity varies by antibody type 3, 4
• Do not delay antibody testing if CSF shows normal cell counts, as autoimmune encephalitis can present with normal routine CSF studies 3
• Initiate high-dose IV methylprednisolone (1000 mg/day for 3-5 days) immediately if autoimmune encephalitis is suspected clinically, without waiting for antibody confirmation 3, 4

Lymphocytic Pleocytosis with Low CSF:Plasma Glucose Ratio (<0.5)

This pattern suggests tuberculous meningitis, fungal infection, or partially treated bacterial meningitis: 2

Essential testing:

• AFB smear and culture, TB PCR 2
• Fungal culture and cryptococcal antigen (particularly in immunocompromised patients) 2
• Bacterial culture even if partially treated 2
• Consider Listeria in appropriate populations (may show lymphocytic predominance despite being bacterial) 2

Elevated Protein (100-200 mg/dL) with Lymphocytic Pleocytosis

Measure CSF lactate: <2 mmol/L effectively rules out bacterial disease 2

Consider additional etiologies:

• Neurosarcoidosis (check serum ACE) 2
• Neuroborreliosis (Lyme serology in endemic areas) 2
• Neuropsychiatric SLE (occurs in 50-70% of cases; check ANA, ENA, anti-dsDNA) 2
• Behçet's disease 2

Special Populations and Pitfalls

Neonates and Infants

• HSV PCR sensitivity is more variable (75-100%) compared to adults 1
• Immature hematopoietic elements may contaminate CSF from vertebral bone marrow during lumbar puncture in children - these are benign contaminants, not indicative of infection or leukemia 5
• Pathologist review of all pediatric CSF cytocentrifuge preparations is essential to distinguish contaminants from pathologic cells 5

Immunocompromised Patients

• Listeria monocytogenes accounts for 20-40% of bacterial meningitis (vs 5% in general population) 2
• Fungal infections (histoplasmosis, coccidioidomycosis, cryptococcosis) typically produce lymphocytic pleocytosis 2
• HIV-1 provirus detection in CSF nucleated cells by PCR provides early evidence of neurologic involvement 6

Malignancy Considerations

• Leptomeningeal metastases require cytologic analysis of CSF with adequate volume - cytology may be negative on first sample, requiring repeat sampling from both lumbar and ventricular sites 1
• Neoplastic meningitis presents with multifocal neurologic deficits; median survival untreated is 4-6 weeks 1
• Flow cytometry improves detection of malignant cells beyond routine cytology 1

Critical Pitfalls to Avoid

• Never assume lymphocytic predominance excludes bacterial meningitis - Listeria and partially treated bacterial meningitis can present this way 2
• Never delay empiric antibiotics for imaging or additional testing when bacterial meningitis is in the differential 2
• Never skip ampicillin in patients >50 years or immunocompromised - Listeria is resistant to cephalosporins 2
• Never rely solely on initial negative HSV PCR in neonates - sensitivity is lower and repeat testing may be needed 1
• Never assume normal CSF cell counts exclude autoimmune encephalitis - proceed with antibody testing if clinically suspected 3
• Never use MS therapies (interferon-beta, natalizumab, fingolimod) if MOG antibodies are positive - these worsen MOG-positive disease 4

Monitoring and Follow-up

• EEG is sensitive for cerebral dysfunction and essential for detecting nonconvulsive seizures in confused or obtunded patients 1
• Rapidly improving EEG findings indicate good prognosis 1
• Repeat lumbar puncture at 48-72 hours if diagnosis remains unclear and patient not improving 1
• For autoimmune encephalitis, retest antibodies at 6-12 months to assess for monophasic vs relapsing disease 4