What are the necessary CSF (Cerebrospinal Fluid) studies for the workup of acute encephalitis?

CSF Studies for Acute Encephalitis Workup

CSF analysis is essential (unless contraindicated) in all patients with suspected encephalitis and should include specific diagnostic studies to identify the causative agent. 1

Standard CSF Studies Required for All Patients

• Opening pressure measurement - typically normal or mildly elevated
• Visual inspection - clear and colorless (note any blood or xanthochromia)
• Cell count with differential
  • Typically shows mild mononuclear pleocytosis (5-100 cells/μL)
  • Note: Polymorphonuclear predominance may be seen early in viral encephalitis
  • Important: Up to 25% of encephalitis cases (including 23.7% of HSV-1 cases) may present without pleocytosis 2
• Protein concentration - usually mildly to moderately elevated (45-100 mg/dL)
• Glucose concentration - typically normal (>60% of serum glucose)
• Gram stain and culture - to rule out bacterial meningitis

Essential Molecular Testing

• Herpes simplex virus PCR - should be performed on all CSF specimens regardless of cell count 1
• Nucleic acid amplification tests (PCR) for:
  • Other herpesviruses (VZV, EBV, CMV, HHV-6/7)
  • Enteroviruses
  • Arboviruses (when epidemiologically appropriate)

Antibody Testing in CSF

• Virus-specific IgM antibodies - particularly useful for:
  • Flavivirus encephalitis (e.g., West Nile virus)
  • VZV (may be positive when PCR is negative)
• Autoimmune encephalitis panel - when infectious causes are negative:
  • NMDAR antibodies
  • VGKC antibodies
  • Other neural autoantibodies (LGI1, CASPR2, AMPA, GABA-B)

Additional CSF Studies Based on Clinical/Epidemiologic Clues

• Presence of eosinophils - consider:

  • Parasitic infections (helminths)
  • Fungal infections
  • Less commonly: T. pallidum, M. pneumoniae, R. rickettsii 1

• Significant RBCs - consider:

  • Hemorrhagic encephalitis
  • Naegleria fowleri (with CSF wet mount) 1

• Cryptococcal antigen and/or India ink staining - for immunocompromised patients

• Oligoclonal bands and IgG index - helpful for:

  • Multiple sclerosis
  • Acute disseminated encephalomyelitis (ADEM)
  • Autoimmune encephalitis 3

Collection and Processing Guidelines

• Collect 8-15 mL total CSF in 3-4 sequential tubes 3
• Process samples within 30-60 minutes of collection
• Separate cell pellet from supernatant by centrifugation
• Store at -80°C in dedicated CSF collection tubes if not testing immediately

Clinical Pitfalls and Caveats

1. Do not delay acyclovir in suspected HSV encephalitis while awaiting CSF results, especially since normal cell counts can occur in up to 23.7% of HSV encephalitis cases 2

2. Consider multiplex PCR panels (like FilmArray ME Panel) for simultaneous detection of multiple pathogens with rapid turnaround time (~1 hour) 4

3. Repeat lumbar puncture may be necessary if:

   • Initial studies are negative but clinical suspicion remains high
   • Patient fails to improve with empiric therapy
   • Alternative diagnosis is being considered

4. CSF biomarkers like vitamin D-binding protein may help distinguish specific types of encephalitis (e.g., Japanese encephalitis) but are not yet in routine clinical use 5

5. Timing matters - PCR sensitivity for HSV decreases after antiviral treatment is initiated, while antibody tests become more sensitive later in the disease course

By following this comprehensive approach to CSF analysis in encephalitis, clinicians can maximize the chances of identifying the causative agent and initiating appropriate therapy promptly, which is critical for improving outcomes in this potentially devastating condition.