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SERUM IgM BINDING TO MYELIN-ASSOCIATED GLYCOPROTEIN (MAG)
  IN SENSORY-MOTOR NEUROPATHIES

Clinical Indications for measurement Interpretations of positive results Laboratory standards Patterns with specificity for   demyelinating neuropathies Therapy: Guidelines	Anti-MAG antibodies: Summary of indications		MAG staining on Western blot
	Indications Adult onset neuropathy:   Distal; Symmetric;   Sensory > Motor ↑ Likelihood of positive test:   Age > 50   Gait disorder   Tremor   Disability 2° sensory     or motor loss   Demyelination     Usually with       ↑ Distal latency       No conduction block   Serum IgM M-protein: 85% Treatment follow-up   Document sufficient cytoxan   Best prognosis:     Anti-MAG titers ↓ by > 60%     Usually with cytoxan Rx	+ Results ELISA   IgM vs MAG > 1,500   Low IgM vs Histone H3 Western blot confirmation Clinical correlation: Titer > 6,000   Demyelinating neuropathy   90% specificity; 95% sensitivity Lab standards Document 90% clinical specificity Interpretation Diagnosis   Dx of immune neuropathy     Distinguish from CIDP Prognosis: Slow progression Treatment   Cytoxan may be useful   Prednisone & HIG not useful Follow-up   ↑ Anti-MAG titer → ? Relapse

I. Clinical Indications for Measurement of anti-MAG antibodies

• Diagnostic work-ups of adult onset, symmetric polyneuropathies, especially with:
  
  1. Clinical features
     • Predominantly distal numbness ± weakness
     • Symmetry
     • Sensory > motor
     • Age > 50
  2. Electrodiagnostic studies: Demyelination, usually with
     • Prolonged distal latencies, and
     • No focal conduction block
  3. Serum IgM M-protein
• Treatment follow-up: Document necessary & sufficient dose of immunosuppression
  • Best prognosis: Anti-MAG antibody titers are reduced by > 60%
• Characteristics that increase the likelihood of a positive test
  1. Age > 50
  2. Gait disorder
  3. Tremor
  4. Functionally significant disability from motor or sensory loss
  5. Demyelinating neuropathy: Usually slowly progressive
  6. Serum IgM M-protein
     • 50% of IgM M-proteins bind to MAG
     • 85% of serums with anti-MAG antibodies have IgM M-protein

II. Results with Specificity and Sensitivity for Sensory-Motor Neuropathies

• ELISA results
  • IgM vs specially purified MAG (Z-MAG) > 1,500
  • Low IgM vs Histone H3
• Western blot analysis: Necessary to confirm IgM binding to MAG.
  
  
• Associations of titers of IgM binding to MAG
  • > 6,000: 90% specificity for demyelinating polyneuropathy.
  • 1,500 to 6,000: Less association with demyelination.

III. Testing Laboratory Standards for anti-MAG Antibodies.

• Optimal testing utilizes:
  1. Highest sensitivity
     • ELISA screening methods with highly purified MAG¹
  2. Highest specificity
     • Western blot confirmation of positive results
     • > 85% correlation with ELISA
  
  
• Sub-optimal procedures:
  1. Low sensitivity:
     • Initial screening vs glycolipids using thin-layer chromatography.
     • ELISA assays with
       • Short antibody binding periods less than 5 hours, or
         
       • procedures conducted at room temperature (optimal at 4 °C).
  2. Low specificity:
     • Testing only by ELISA without Western blot confirmation.
     • ELISA assays utilizing semi-pure MAG containing lipid impurities.
  3. The sensitivity of anti-MAG antibody testing should be documented by:
     • Technical comparison with known positive and negative serums.
     • Clinical correlation with patients having
       • Sensory-motor neuropathies: > 90%
       • Evidence of demyelination in peripheral nerve: > 90%
       • IgM M-proteins: > 50%

IV. Interpretations of Confirmed Positive anti-MAG Results

• Diagnosis
  • Provide independent support for presence of immune-mediated sensory-motor polyneuropathy.
  • Distinguish anti-MAG polyneuropathy from chronic inflammatory demyelinating polyneuropathy (CIDP).
• Treatment: Indicate that
  • Combined cyclophosphamide and plasma exchange treatment may produce functionally useful improvement in strength, sensation, and gait.
  • Other therapy such as prednisone, IVIg, or plasma exchange is unlikely to be of benefit

V. Guidelines during Treatment

• Aim for reduction of antibody titer to 30% of initial level.
• Serial titers help to determine
  • Appropriate duration and dose of immunosuppressive treatment.
  • Likelihood of efficacy
• A rise in anti-MAG titer after treatment may predict recurrence of clinical symptoms and signs.