What is the differential diagnosis (DDX) for 70% cerebrospinal fluid (CSF) monocytosis?

Differential Diagnosis of 70% CSF Monocytosis

A CSF profile showing 70% monocytes (lymphocytic/mononuclear predominance) most commonly indicates viral meningitis, but you must urgently exclude partially treated bacterial meningitis, tuberculous meningitis, fungal infections, and autoimmune encephalitis through CSF glucose, protein, and specific microbiological testing. 1

Primary Diagnostic Considerations

Viral Infections (Most Common)

• Herpes simplex virus (HSV), Varicella-zoster virus (VZV), Epstein-Barr virus (EBV), and cytomegalovirus (CMV) are the most frequent viral causes of lymphocytic pleocytosis 1
• HSV-2 meningitis specifically can present with marked monocytosis (84-100% monocytes) and may cause complications including hydrocephalus 2, 3
• Enterovirus infections, particularly EV-71, should be considered especially if lower cranial nerve involvement is present 4
• Normal CSF glucose with lymphocytic pleocytosis strongly suggests viral infection 1

Partially Treated Bacterial Meningitis (Critical to Exclude)

• This is a dangerous mimic: bacterial meningitis can present with lymphocytic predominance in 32% of cases when CSF WBC count is ≤1,000/mm³ 5
• Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae are the most common organisms in these cases 5
• Research demonstrates that monocyte percentages overlap significantly between bacterial (median 5%, range 0-60%) and viral meningitis (median 8%, range 0-57%), making cell differential alone unreliable 6
• CSF glucose <20-30 mg/dL or CSF:plasma glucose ratio <0.5 indicates bacterial infection despite lymphocytic predominance 7

Tuberculous Meningitis

• Low CSF:plasma glucose ratio (<0.5) with lymphocytic pleocytosis is characteristic 1
• Elevated protein (typically 100-200 mg/dL or higher) is common 1
• Consider in patients with subacute presentation, immunocompromised state, or endemic exposure 4

Fungal Infections

• Cryptococcosis, histoplasmosis, and coccidioidomycosis typically produce lymphocytic pleocytosis 1
• Low CSF glucose and markedly elevated protein are typical features 1
• Particularly important in immunocompromised patients, including those with HIV, cancer, or on immunosuppressive therapy 4

Listeria monocytogenes

• Accounts for 5% of bacterial meningitis overall but 20-40% in immunocompromised patients, elderly, diabetics, and those on immunosuppressive therapy 4
• Can present with lymphocytic predominance and is resistant to third-generation cephalosporins 4
• Consider in patients >50 years, pregnant women, or those with cellular immune defects 4

Autoimmune/Inflammatory Encephalitis

• Mild-to-moderate CSF abnormalities (50-70% of cases) with lymphocytic predominance occur in neuropsychiatric SLE 4
• Anti-NMDA receptor encephalitis and other autoimmune encephalitides should be considered when psychiatric symptoms, seizures, or movement disorders are prominent 4
• Neurosarcoidosis and Behçet's disease can present with lymphocytic meningitis 4

Neuroborreliosis (Lyme Disease)

• Presents with lymphocytic pleocytosis (median 5% monocytes, range 0-53%) 6
• Consider in endemic areas with appropriate exposure history 4

Critical Diagnostic Algorithm

Immediate CSF Analysis Required

1. CSF glucose and simultaneous serum glucose: CSF:plasma ratio <0.5 mandates treatment for bacterial/TB/fungal infection 1, 7
2. CSF lactate: <2 mmol/L effectively rules out bacterial disease 1
3. CSF protein: Markedly elevated (>200 mg/dL) suggests TB, fungal, or Listeria 1
4. Gram stain and bacterial culture: Essential despite lymphocytic predominance 7

Specific Microbiological Testing

• HSV-1/2, VZV, enterovirus PCR on CSF for viral etiologies 4, 1
• Mycobacterial culture and TB PCR if glucose is low or presentation is subacute 1
• Fungal culture and cryptococcal antigen in immunocompromised patients 1
• Listeria culture in elderly or immunocompromised patients 4

Imaging and Additional Studies

• Brain MRI with contrast to evaluate for parenchymal involvement, abscess, or autoimmune patterns 4
• Autoimmune encephalitis antibody panel (NMDA, LGI1, GFAP, etc.) if clinical features suggest autoimmune etiology 4
• Serum testing: HIV, ANA, ENA, ACE (for sarcoidosis), Lyme serology based on clinical context 4

Common Pitfalls to Avoid

Do Not Assume Viral Etiology Based on Cell Differential Alone

• Lymphocytic predominance occurs in 32% of bacterial meningitis cases with WBC ≤1,000/mm³ 5
• The overlap in monocyte percentages between bacterial and viral meningitis makes cell differential unreliable for discrimination 6

Do Not Delay Antibiotics While Awaiting Test Results

• If bacterial meningitis cannot be definitively excluded, start empiric antibiotics immediately (ceftriaxone + vancomycin + ampicillin if >50 years or immunocompromised) 4
• Treatment should begin within one hour of presentation when bacterial meningitis is suspected 4

Do Not Use Third-Generation Cephalosporins Alone in Risk Groups

• Listeria is resistant to cephalosporins; ampicillin must be added for patients >50 years, immunocompromised, or pregnant 4

Do Not Overlook Autoimmune Causes in Appropriate Clinical Context

• Psychiatric symptoms, seizures, movement disorders, or subacute cognitive decline warrant autoimmune encephalitis evaluation 4
• Normal MRI does not exclude autoimmune encephalitis; consider FDG-PET if clinical suspicion is high 4