Where is the GAD65 (Glutamic Acid Decarboxylase 65) antibody found in cerebrospinal fluid (CSF) and serum?

GAD65 Antibody Distribution in CSF and Serum

GAD65 antibodies are found in both cerebrospinal fluid (CSF) and serum, with evidence of intrathecal antibody production in the CNS compartment, showing different epitope specificity compared to serum antibodies.

Characteristics of GAD65 Antibodies in CSF and Serum

CSF Findings

• GAD65 antibodies in CSF demonstrate:
  • Intrathecal synthesis with increased GAD65-specific IgG index in 85% of patients with stiff person syndrome (SPS) 1
  • Higher binding avidity (up to 10 times higher) than serum antibodies in some patients 2
  • Concentrations ranging from 30-400 U/mL in SPS patients 3
  • Different epitope specificity compared to paired serum samples, suggesting local B cell stimulation within the CSF compartment 4
  • Presence of oligoclonal IgG bands in 67% of patients 1

Serum Findings

• GAD65 antibodies in serum show:
  • Higher absolute concentrations compared to CSF (24,000-200,000 U/mL in SPS) 3
  • Predominantly IgG1 subclass 2
  • Persistent pattern of oligoclonal bands that remain stable for up to 7 years 2

Clinical Significance and Diagnostic Considerations

High vs. Low Antibody Concentrations

• High concentrations (>10,000 IU/mL) in serum are associated with:

  • Classical GAD65-associated syndromes (94% of cases) 5
  • Stiff person syndrome, cerebellar ataxia, chronic epilepsy, limbic encephalitis, or overlap syndromes 5
  • Potential response to immunotherapy (70% show improvement) 5

• Low concentrations (<10,000 IU/mL) in serum:

  • Associated with heterogeneous symptom spectrum 5
  • May indicate alternative diagnoses 5

Functional Impact

• GAD65 antibodies can inhibit the enzymatic activity of GAD65, blocking GABA formation 4
• CSF GABA levels are lower in SPS patients compared to controls 1
• The inhibitory mechanism appears to be noncompetitive 4

Monitoring Considerations

• Antibody titers in serum and CSF do not correlate with disease severity or duration in SPS 3
• However, reduction in antibody concentration (median 69%) has been observed in patients responding to immunotherapy 5
• Patients with unchanged antibody concentrations after treatment typically show no clinical improvement 5

Diagnostic Approach

When suspecting GAD65 antibody-associated neurological disorders:

1. Test both serum and CSF samples on the same day 6
2. Use multiple detection methods (ELISA, immunohistochemistry, cell-based assay) 5
3. Consider the 10,000 IU/mL threshold in serum as clinically significant 5
4. Evaluate for intrathecal antibody synthesis by calculating the CSF/serum IgG ratio 6

Pitfalls to Avoid

• Don't rely solely on serum testing, as CSF may show intrathecal synthesis with different epitope specificity 4
• Avoid using antibody titers alone to monitor disease activity, as they don't correlate well with clinical severity 3
• Be cautious with low-titer GAD65 antibodies, especially without typical clinical phenotypes, as alternative diagnoses should be considered 5