How to interpret cerebrospinal fluid (CSF) analysis results in a patient with suspected central nervous system infection or inflammation?

Cerebrospinal Fluid (CSF) Interpretation in Suspected CNS Infection or Inflammation

Obtain a comprehensive CSF analysis panel including cell count with differential, protein, glucose (with simultaneous serum glucose), Gram stain, bacterial culture, and opening pressure as the baseline workup for all patients with suspected CNS infection or inflammation. 1, 2

Essential Parameters and Normal Values

Every CSF sample requires measurement of these core parameters:

• Opening pressure: Normal range 12-20 cm CSF (or 6-25 cmH₂O, mean ~18 cmH₂O). Elevated in bacterial, tuberculous, and fungal meningitis; normal or mildly elevated in viral meningitis 2
• Cell count with differential: Normal <5 cells/μL. This is mandatory for every sample as it provides critical diagnostic information about the inflammatory process 1, 2
• Protein concentration: Normal <45 mg/dL (some sources use <220 mg/dL as upper limit). Elevations suggest infection or inflammation 1, 3
• Glucose with simultaneous serum glucose: Normal CSF glucose >35 mg/dL with CSF-to-blood ratio >0.23 (or >0.66 by some criteria). Calculate the ratio immediately 1, 2
• Gram stain and bacterial culture: Mandatory when infection is suspected 1

Characteristic CSF Patterns by Disease Category

Bacterial Meningitis

Bacterial meningitis presents with ≥2,000 total WBCs/μL (or >100 cells/μL with neutrophil predominance), CSF glucose <35 mg/dL with CSF-to-blood ratio <0.23 (or <0.36), and protein ≥220 mg/dL. 1, 2

• Raised opening pressure is typical 2
• CSF lactate ≥35 mg/dL (or ≥2 mmol/L) has 93% sensitivity and 96% specificity for bacterial vs. viral differentiation when measured before antibiotics 4, 2
• A CSF lactate <2 mmol/L effectively rules out bacterial disease 4, 3

Viral Meningitis/Encephalitis

Viral CNS infections show mild to moderate lymphocytic pleocytosis (5-1,000 cells/μL), normal or mildly elevated protein (typically 50-120 mg/dL), and normal glucose 1, 2, 3

• HSV encephalitis can be hemorrhagic with elevated CSF red cell count in approximately 50% of cases 4
• An acellular CSF is described for VZV, EBV, and CMV, occurring more frequently in immunocompromised patients 4
• Although lymphocytic pleocytosis is typical, early viral encephalitis can show neutrophil predominance 2

Partially Treated Bacterial Meningitis

This critical pitfall can mimic viral meningitis with lymphocytic pleocytosis and moderately elevated protein. 3

• Prior antibiotic exposure converts the typical neutrophilic pattern to lymphocytic 3
• CSF lactate measurement becomes crucial in this scenario 4

Tuberculosis and Listeriosis

Non-viral infections, particularly TB and listeriosis, can present with lymphocytic CSF pleocytosis similar to viral infections 4

• TB meningitis classically shows elevated protein (often >100 mg/dL), low glucose, and lymphocytic pleocytosis 3
• Clinical setting and other CSF parameters (low glucose ratio and higher protein) help distinguish these from viral causes 4

Autoimmune Encephalitis

Commonly demonstrates mild to moderate lymphocytic pleocytosis (20-200 cells), elevated protein, and elevated IgG index/synthesis rate with oligoclonal bands in some cases 1

Specialized Testing Based on Clinical Context

For Suspected Bacterial Meningitis

• Start empirical antibiotics immediately after blood cultures if lumbar puncture is delayed 1
• Gram stain, culture, and antimicrobial susceptibility testing are the cornerstone 1

For Suspected Viral Encephalitis

All patients with suspected encephalitis must have CSF PCR for HSV-1, HSV-2, VZV, and enteroviruses, as this identifies 90% of known viral cases. 4, 1

• Send PCR testing immediately and start acyclovir empirically without waiting for results 3
• Consider EBV/CMV PCR, especially if immunocompromised 4
• Further testing should be directed by clinical features such as travel history and animal/insect contact 4

For Immunocompromised Patients

Expanded testing is essential and should include:

• Cryptococcal antigen testing 1
• Fungal stains and cultures 1
• Acid-fast bacilli smears and cultures 1
• PCR for opportunistic pathogens 1

For Suspected Autoimmune Encephalitis

• CSF analysis is the most important test and should be performed regardless of MRI findings 1
• Send for oligoclonal bands with paired serum sample if ADEM is in the differential 4
• Neuronal antibody panels should be tested in both CSF and serum 1

Critical Timing and Contraindications

Proceed with lumbar puncture immediately in any febrile patient with altered consciousness or focal neurologic signs, and in suspected meningitis or encephalitis. 1

When to Delay LP and Obtain Imaging First

Obtain CT/MRI before LP in patients with:

• New focal neurologic findings 1
• Signs of increased intracranial pressure 1
• Coagulopathy (platelet count <100 × 10⁹/L, though some recommend ≥20 × 10⁹/L) 4
• Local skin infection at puncture site 4
• Clinical suspicion of spinal cord compression 4

If imaging delays LP and bacterial meningitis is suspected, start empirical antibiotics immediately after blood cultures. 1

Correcting for Traumatic Tap

When blood contaminates the CSF sample:

• Subtract 1 white cell for every 700 red blood cells 4
• Subtract 0.1 g/dL protein for every 100 red blood cells 3
• However, in HSV encephalitis, blood-stained CSF may reflect the hemorrhagic pathophysiology of the condition, especially if serial specimens are blood-stained 4

Special Considerations for CNS Infection Treatment Monitoring

In patients with CNS infections receiving beta-lactam antibiotics, concomitant blood and CSF sampling at 24-48 hours after treatment onset may be useful to ensure adequate antibiotic exposure, as CSF concentrations are highly variable and unpredictable 4

Critical Pitfalls to Avoid

• Do not rely on a single CSF parameter—interpretation requires integration of all findings with clinical context 4
• Normal opening pressure (<250 mm H₂O), fewer than 5 WBCs/μL, and normal protein essentially excludes meningitis in immunocompetent patients 1
• If initial workup is non-diagnostic and clinical suspicion remains high, repeat lumbar puncture in 24-48 hours, as HSV PCR can be negative early in disease 3
• Remember that high CSF lactate may also indicate metabolic disorders, particularly mitochondrial encephalopathy 4