What is the diagnosis and treatment for pleocytosis?

Pleocytosis: Diagnosis and Management

What is Pleocytosis?

Pleocytosis is an abnormal elevation of white blood cells in the cerebrospinal fluid (CSF), defined as more than 5 cells per microliter, and requires systematic evaluation to identify the underlying cause—which ranges from viral infections to autoimmune diseases to malignancies—followed by targeted treatment of the specific etiology. 1

Differential Diagnosis by Cell Type and Count

Lymphocytic Pleocytosis (Lymphocyte-Predominant)

• Viral infections are the most common cause, including HSV, VZV, EBV, CMV, and enteroviruses 1
• Tuberculosis meningitis characteristically produces lymphocytic pleocytosis with low CSF glucose (<0.5 CSF:plasma ratio) and elevated protein 1
• Fungal infections (histoplasmosis, coccidioidomycosis, cryptococcosis) typically cause lymphocytic pleocytosis 1
• Partially treated bacterial meningitis can present with lymphocytic predominance rather than neutrophilic 1
• Autoimmune encephalitis commonly shows mild to moderate lymphocytic pleocytosis (20-200 cells, occasionally up to 900) with elevated protein and oligoclonal bands 2
• Guillain-Barré syndrome classically shows albumino-cytological dissociation (elevated protein with normal cell count), though mild pleocytosis (10-50 cells/μL) is compatible with the diagnosis 2

Neutrophilic Pleocytosis (Neutrophil-Predominant)

• Bacterial meningitis is the primary concern with neutrophilic pleocytosis, very low glucose (<20-30 mg/dL), and gram-negative diplococci on Gram stain 2
• Tickborne rickettsial diseases (RMSF, ehrlichiosis) can cause either neutrophilic or lymphocytic pleocytosis, typically <100 cells/μL 2
• Early viral infections may initially present with neutrophilic predominance before transitioning to lymphocytic; enterovirus causes 64% of neutrophil-predominant CSF in viral CNS infections 3
• E. ewingii infection characteristically shows neutrophilic pleocytosis 2

Magnitude of Pleocytosis

• Cell counts >100/μL are mainly caused by CNS infections, particularly bacterial meningitis 4
• Cell counts <50/μL have a broader differential including non-infectious neurological diseases, autoimmune conditions, malignancy, and seizures 4
• Viral meningitis rarely exceeds 2000 cells/mm³, with enteroviral disease typically showing lower counts 5

Critical Diagnostic Workup

CSF Analysis (Essential First Step)

• Cell count with differential to determine lymphocytic vs. neutrophilic predominance 1
• Protein level: mildly elevated (100-200 mg/dL) in viral/rickettsial infections; markedly elevated in bacterial meningitis and TB 2, 1, 5
• Glucose and CSF:plasma glucose ratio: normal in viral infections; <0.5 suggests TB, fungal, or bacterial meningitis 1, 5
• CSF lactate <2 mmol/L effectively rules out bacterial disease 1
• Gram stain and cultures for bacterial/fungal pathogens 2
• Viral PCR panel including HSV1/2, VZV, enteroviruses 2
• IgG index, synthesis rate, and oligoclonal bands for autoimmune etiologies 2
• Cytology and flow cytometry when malignancy is suspected 2

Blood Tests

• Complete blood count: leukopenia and thrombocytopenia suggest tickborne rickettsial diseases 2
• Metabolic panel: hyponatremia is common in LGI-1 antibody encephalitis 2
• Inflammatory markers (CRP, ESR): CRP >5 mg/dL increases likelihood of bacterial meningitis 6
• Autoimmune panels: antinuclear antibodies, extractable nuclear antigens, antithyroid antibodies when autoimmune encephalitis suspected 2
• Neural autoantibody testing in serum and CSF (NMDAR, LGI1, GFAP, etc.) 2

Neuroimaging

• Brain MRI should be performed before lumbar puncture when possible to assess for mass effect and identify anatomical patterns suggesting specific etiologies 2
• CT head is acceptable if MRI unavailable or patient too agitated, primarily to rule out contraindications to lumbar puncture 2
• Neuroimaging changes are present in only 44% of CNS infections, so normal imaging does not exclude infection 7

The CHANCE Score for Bacterial Meningitis

When bacterial meningitis must be distinguished from other causes of pleocytosis, use the CHANCE score (sensitivity 92.1%, specificity 90.9%): 6

• CSF cell count >100 cells/μL
• CSF protein >100 mg/dL
• CRP >5 mg/dL
• Elevated white blood cell count (peripheral)
• Abnormal mental status
• Nuchal rigidity

Treatment Approach

Empiric Treatment When Diagnosis Uncertain

• For ill-appearing patients with fever, rash, and pleocytosis where neither tickborne rickettsial disease nor meningococcal infection can be ruled out: treat empirically for BOTH conditions 2

  • Doxycycline for tickborne rickettsial diseases
  • Ceftriaxone for meningococcal disease
  • Do not delay treatment while awaiting culture results 2

• For suspected autoimmune encephalitis with inflammatory CSF after excluding infection: initiate empiric immunotherapy 2

  • First-line: IV methylprednisolone, IVIG, or plasmapheresis
  • Do not wait for antibody results before starting treatment 2

Specific Etiologies

• Bacterial meningitis: immediate IV antibiotics (ceftriaxone + vancomycin, add ampicillin if >50 years or immunocompromised) 6
• Viral meningitis: supportive care; acyclovir if HSV/VZV suspected 7
• Tickborne rickettsial diseases: doxycycline is the treatment of choice for all ages 2
• Tuberculous meningitis: four-drug anti-TB therapy (rifampin, isoniazid, pyrazinamide, ethambutol) plus corticosteroids 1
• Autoimmune encephalitis: immunotherapy (corticosteroids, IVIG, plasmapheresis) with tumor screening 2

Critical Pitfalls to Avoid

• Marked pleocytosis (>50 cells/μL) should prompt consideration of alternative diagnoses beyond GBS, including leptomeningeal malignancy or infectious/inflammatory polyradiculitis 2
• Normal CSF protein does not rule out GBS: 30-50% have normal protein in the first week, 10-30% in the second week 2
• Seizures alone can cause transient CSF pleocytosis (mean 72 cells/mm³, range 3-464), with 57% showing PMN predominance; this diagnosis requires excluding all other treatable causes first 8
• Approximately 50% of enterovirus-positive infants will have CSF pleocytosis, which does not indicate bacterial meningitis 2, 5
• Time to diagnosis averages 16 days for confirmed CNS infections but varies widely by pathogen; 53% of patients with pleocytosis never receive a definitive diagnosis 7
• CSF neutrophilic pleocytosis in viral infections (24.7% of cases) is not associated with worse outcomes and is more common with enterovirus, younger age, and respiratory symptoms 3