Should a cerebrospinal fluid (CSF) or serum paraneoplastic panel be used first in patients suspected of having a paraneoplastic syndrome?

Cerebrospinal Fluid Testing Should Be Performed First in Suspected Paraneoplastic Syndromes

In patients with suspected paraneoplastic syndrome, cerebrospinal fluid (CSF) testing should be performed first rather than serum testing, as CSF analysis is the most important diagnostic test and can provide critical information for diagnosis and management. 1

Rationale for CSF Testing First

Superior Diagnostic Value

• CSF analysis is considered the most important test in autoimmune encephalitis evaluation and is typically the second step in workup after brain MRI 1
• Inflammatory CSF may be the only abnormality found on initial testing, serving as the sole indication for empiric immunotherapy after infection is excluded 1
• CSF detection is more sensitive for certain antibodies (e.g., NMDAR and GFAP antibodies) while serum is more sensitive for others (e.g., onconeuronal, LGI1, and AQP4 antibodies) 1

Characteristic CSF Findings

• Common findings in autoimmune encephalitis include:
  • Mild to moderate lymphocytic pleocytosis (commonly 20-200 cells but can be as high as 900 cells)
  • Hyperproteinorrachia
  • Elevated IgG index and/or IgG synthesis rate
  • Positive intrathecal oligoclonal bands (unmatched in serum) 1

Diagnostic Algorithm

1. Brain MRI first (if possible)

   • If MRI cannot be performed due to patient agitation or lack of access, proceed with lumbar puncture after screening head CT 1

2. CSF Analysis should include:

   • Cell count and differential
   • Protein, glucose, CSF/serum glucose ratio
   • Albumin quotient, IgG index and synthesis rate
   • Oligoclonal bands
   • Viral studies (HSV1/2 PCR, VZV PCR, and IgG/IgM)
   • Bacterial/fungal cultures when appropriate
   • Cytology and flow cytometry
   • Autoimmune encephalopathy/encephalitis panel
   • Paraneoplastic antibody panel 1

3. Serum Testing (concurrent with CSF):

   • Paraneoplastic antibody panel
   • Autoimmune encephalitis panel
   • Blood samples should be collected prior to treatment with intravenous immunoglobulins or plasmapheresis to avoid false results 1

Special Considerations

Intrathecal Antibody Synthesis

• Calculating intrathecal synthesis of antibodies (particularly anti-Hu) can help discriminate between peripheral neuropathy and encephalitis in paraneoplastic syndromes 2
• Oligoclonal bands representing paraneoplastic antibodies are often found in CSF but may be absent in serum 3

Cancer Screening

• Cancer screening should be considered in most adult patients with suspected autoimmune encephalitis 1
• The NCCN SCLC Panel recommends that if neurological paraneoplastic syndrome is suspected, a comprehensive paraneoplastic antibody panel should be considered 1

Common Pitfalls to Avoid

1. Delaying lumbar puncture: Do not wait for antibody results before performing LP and initiating treatment if clinically indicated 1

2. Testing only serum: Some antibodies are more reliably detected in CSF than serum, and CSF-specific findings may be the only abnormality 1

3. Missing the cancer connection: Paraneoplastic neurological syndromes often develop before the cancer becomes clinically evident 4

4. Overlooking treatment timing: Early immunotherapy is critical in well-defined syndromes, without waiting for antibody results 1

5. Failing to retest: In patients with refractory symptoms or positive antibodies but no initial evidence of neoplasia, repeat cancer screening is recommended as neoplasia can manifest years after neurological symptoms 5

By following this approach, clinicians can optimize the diagnostic workup for suspected paraneoplastic syndromes, leading to earlier diagnosis and treatment with potential improvements in morbidity, mortality, and quality of life.