What is the role of cerebrospinal fluid (CSF) analysis in diagnosing and managing encephalitis?

The Role of Cerebrospinal Fluid (CSF) Analysis in Encephalitis

CSF analysis is essential for the diagnosis and management of encephalitis and should be performed in all suspected cases unless contraindicated, as it provides critical information for identifying the etiology and guiding appropriate treatment.

Diagnostic Value of CSF in Encephalitis

Typical CSF Findings in Viral Encephalitis

• Mild mononuclear pleocytosis (though polymorphonuclear predominance may be seen early)
• Mildly to moderately elevated protein concentration
• Normal glucose concentration
• Possible presence of red blood cells (in hemorrhagic encephalitis)

Important Considerations

• Up to 25% of encephalitis cases may present without CSF pleocytosis (acellular CSF) 1
• Notably, 23.7% of HSV-1 encephalitis cases can have absence of pleocytosis on initial lumbar puncture 1
• Absence of pleocytosis is associated with decreased rates of acyclovir administration (47.7% vs 71.1%), potentially delaying critical treatment 1
• Initial negative HSV PCR can occur in 4% of cases, particularly in lumbar punctures performed less than 4 days after symptom onset 2

Specific CSF Testing in Encephalitis

Recommended CSF Analysis

1. Standard Parameters:

   • Opening pressure
   • Cell count with differential
   • Protein and glucose levels
   • Gram stain and bacterial culture 3

2. Molecular Testing:

   • PCR for herpes viruses (HSV-1/2, VZV)
   • Enterovirus PCR
   • Additional PCR based on clinical suspicion 3

3. Antibody Testing:

   • HSV CSF IgG and IgM (especially if PCR negative)
   • VZV CSF IgG and IgM
   • Specific antibody testing for suspected flavivirus encephalitis 3
   • Autoimmune antibody panels when suspected 4

4. Other Tests:

   • Oligoclonal bands and IgG index
   • Cryptococcal antigen and/or India ink staining
   • VDRL for syphilis 3
   • CSF lactate (elevated in bacterial meningitis) 5

Diagnostic Algorithms Based on CSF Findings

Bacterial vs. Viral Differentiation

• Bacterial encephalitis/meningitis indicators:

  • Elevated CSF lactate
  • Decreased CSF:serum glucose ratio (most reliable predictor, AUROC 0.870) 6
  • Neutrophilic pleocytosis

• Viral encephalitis indicators:

  • Increased CSF mononuclear cells (though less reliable predictor, AUROC 0.669) 6
  • Normal glucose
  • Moderate protein elevation

Special Considerations

Immunocompromised Patients

• May have acellular CSF despite CNS infection 3
• Additional testing recommended:
  • CMV PCR
  • HHV-6/7 PCR
  • HIV PCR
  • Toxoplasma gondii serology/PCR
  • Fungal testing 3

Autoimmune Encephalitis

• CSF findings similar to viral encephalitis but pleocytosis may be less marked or absent
• Markers of intrathecal immunoglobulin synthesis (oligoclonal bands, elevated IgG index) may be present 3
• CSF autoantibody testing has 80-90% sensitivity 4

Timing Considerations

HSV Encephalitis

• PCR may be negative early in disease course (within first 4 days of symptoms) 2
• If initial PCR is negative but clinical suspicion remains high:
  • Repeat lumbar puncture after 3-4 days
  • Consider HSV-specific IgG antibody testing in CSF at 10-14 days after illness onset 3
• CSF lymphoid reaction may persist for months or even years after infection 7

Pitfalls and Caveats

1. Normal CSF does not exclude encephalitis

   • Up to 25% of encephalitis cases may have normal CSF cell counts 1
   • Treatment should not be delayed if clinical suspicion is high

2. False negative PCR results

   • Early testing (<4 days from symptom onset) may yield false negatives 2
   • Negative initial PCR is associated with worse neurological outcomes due to treatment delays 2

3. Interpretation challenges

   • CSF eosinophils may be mistaken for neutrophils in automated cell counters 3
   • Traumatic lumbar puncture may require correction formula for accurate WBC count 3

4. Diagnostic delays

   • Absence of pleocytosis is associated with decreased rates of appropriate antiviral therapy 1
   • Multimodal approach (including MRI and EEG) is crucial when CSF findings are equivocal 2

Conclusion

CSF analysis remains a cornerstone in the diagnosis and management of encephalitis, providing valuable information about the inflammatory process and potential causative agents. However, clinicians must be aware that normal CSF findings, particularly early in the disease course, do not exclude encephalitis. A comprehensive approach including molecular testing, antibody detection, and consideration of timing is essential for accurate diagnosis and timely treatment.