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AUTOANTIBODIES IN CHRONIC MOTOR SYNDROMES

Indications: Measurement of anti-GM1 antibodies Interpretations: Positive results Laboratory standards Antibody patterns: Specificity for motor neuropathies Prevalence of anti-GM1 antibodies in MMN   detected in different laboratories Anti-GM1 antibodies in therapy: Guidelines	Anti-GM1 ganglioside antibodies: Summary of indications
	Indications Lower motor neuron syndromes Motor neuropathy: Chronic; Acute Clinical features   Predominantly motor   Distal; Asymmetric ↑ Likelihood of positive test:   Onset     Chronic: Slow progression     Acute: Diarrhea prodrome     Upper extremity: Often   No upper motor neuron signs   No prominent sensory changes   Motor conduction block Treatment follow-up   Document sufficient cytoxan     Best prognosis: Anti-GM1       titers ¯ by > 70% Lab standards: IgM vs Co-GM1 Sensitivity for MMN: 45% Specificity in clinical use: > 98% Lab standards: IgG vs GM1 Clinical specificity   > 90%: Acute motor neuropathy	+ Results Specific ELISA binding   IgM vs Co-GM1 or NP-9 > 2,000   IgG vs GM1 > 2,000 Clinical correlations   IgM vs Co-GM1+     Motor neuropathy: Chronic       45% Sensitivity       99% Specificity vs ALS   IgG vs GM1 +     Motor neuropathy: Acute       50% sensitivity       90% specificity Interpretation Diagnosis   Dx of immune neuropathy     Distinguish MMN vs CIDP & ALS Prognosis: Not ALS;   Slow progression Treatment   Cytoxan or HIG often useful   Prednisone not useful Follow-up: Cytoxan Rx   ­ anti-GM1 titer ® ? relapse

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Prevalence of IgM antibodies to GM1 ganglioside in MMN detected by different laboratories¹

Laboratory	IgM vs GM1 in MMN: Prevalence
Sadiq 1990 (Columbia)1	33%
Adams 1991 (Switzerland)2	30%
Specialty Lab (1996)3	20% or less
Mayo Clinic (Taylor 1996)4	50%
Washington University 5, 6, 7, 9	45%

I. Clinical Indications for Measurement of Serum anti-GM1 ⁷, NP-9 ⁸ & NS6S ⁹ Antibodies

• Diagnostic work-ups of disorders which are:
  • Predominantly restricted to lower motor neurons, or
  • Motor predominant neuropathies with minimal sensory involvement, or
  • Multifocal neuropathies with motor conduction block, or
  • Acute motor neuropathies (AMAN).
  
  
• Treatment follow-up
  • Document necessary and sufficient dose of immunosuppression
    • i.e. Anti-GM1 antibody titers reduced by > 60% after cyclophosphamide Rx
  
  
• Increased likelihood of positive test
  • Asymmetric weakness
  • No prominent upper motor neuron signs
  • Motor conduction block on electrodiagnostic testing

II. Patterns of Antibody Binding with Specificity for Motor Neuropathies

• Antibody Patterns
  • General principles: Antibody titers specific for a disease syndrome bind selectively
    • High vs test antigen
    • Low vs. control antigen
  • Control antigens
    • IgM: Histone H3; GD1a ganglioside
    • IgG: GM1 ganglioside or Sulfatide
  • Selective antibody patterns with specificity for motor neuropathies
    • IgM vs. GM1 > 2,000
    • IgM vs NP-9 antigen > 3,000
    • IgG vs GM1 > 2,000
    • IgM vs NS6S > 15,000
  
  
• Rationale
  • Selectivity of anti-GM1 antibody binding
    • Measured by comparing anti-GM1 titers to those vs Histone H3 or Sulfatide
  • Clinical sensitivity and specificity of testing
    • Low: Measurement of serum anti-GM1 antibodies alone
    • High: Measurement of antibodies vs. GM1 and other antigens including
      • IgM: GA1; Histone H3; NP-9 antigen
        
      • IgG: Sulfatide

III. Testing Laboratory Standards

• Sensitivity and specificity:
  • Anti-GM1 antibody testing methods & results in each laboratory should be compared to published series
  
  
• Clinical correlations: Should be documented between results in each lab and patient syndromes
  • Selective serum IgM anti-GM1 or NP-9 antibodies: High titers should be detected in
    • > 80% of patients with multifocal motor neuropathy
    • < 1% of patients with typical amyotrophic lateral sclerosis
  • Selective serum IgG anti-GM1 antibodies: High titers should be detected in
    • > 40% of patients with acute motor neuropathies
    • < 1% of controls

IV. Interpretations of Positive Results

• Diagnosis
  • Provides independent support for immune-mediated
    • Motor neuropathies
    • Lower motor neuron syndromes
  • Distinguishes these disorders from other polyneuropathies and ALS.
  
  
• Treatment
  • Indicate that IVIg, Rituximab or cyclophosphamide may produce useful increase in strength
  • Other immunomodulating treatments will usually be ineffective.

V. Guidelines During Cyclophosphamide Therapy

• Aim for reduction of antibody titer to <30% of initial level
• Serial titers help to determine
  • Appropriate duration and dose
  • Likelihood of efficacy of immunosuppressive treatment
  • Impending recurrence of clinical symptoms and signs: Rise in antibody titer

Go to Motor Syndromes: Differential Diagnosis
Go to Demyelinating Neuropathies
Go to Motor Syndromes: Treatment
Go to Diagnosis and treatment of motor neuropathies
Go to Anti-MAG Antibodies
Return to Neuromuscular Home Page



REFERENCES
1. Neurology 1990;40:1067-1072
2. J. Neuroimmunol 1991;32:223-230
3. Unpublished "in house" data. Phone Communication 1996
4. Neurology 1996;47:951-955
5. Ann Neurol 1990;27:316-326
6. Muscle & Nerve 1994;17:100-104
7. Neurology 1997;49:1289-1292; Neurology 2000;54: 2353-2354
8. Neurology 1997;48:1104-1106
9. J Neurol Neurosurg Psychiatry 2010;81:726-730

4/15/2013