Myasthenia Gravis - MG

Diagnosis

Indications for Testing

  • Confirmation of clinical diagnosis of myasthenia gravis (MG)
  • Assessment and management of individual with MG following immunomodulatory treatment or plasmapheresis
  • Prognostic predictor of thymoma in individual with acetylcholine receptor (AchR) antibody-positive MG

Laboratory Testing

  • Serum antibody testing – positive test in symptomatic individuals is diagnostic of MG
    • Anti-AChR
      • Positive in ~85% of individuals with confirmed MG
        • Specificity approaches 100%
      • Negative AChR does not exclude disease
        • Common for ocular MG
    • Anti-MuSK
      • Detectable in ~40% of anti-AChR-negative patients
        • Do not order if patient has isolated ocular MG
      • Bulbar symptoms more common if this antibody is present
      • Much more common closer to tropical latitudes
    • Striational/titin - antibodies
      • Detectable in >80% of thymomatous MG and some cases of nonthymomatous MG patients
      • May occur in the absence of acetylcholine receptor antibody in patients with MG
      • Rare in ocular MG
      • Presence of titin antibodies in early onset disease indicates ≥95% likelihood of an underlying thymoma
    • Absence of disease-associated antibodies does not exclude diagnosis – so-called seronegative disease
      • Predominantly female
      • Respiratory and bulbar muscles frequently involved

Other Testing

  • Consider anticholinesterase testing (Tensilon test using edrophonium) in AChR-negative patients – improvement in muscle strength is diagnostic of MG
  • Repetitive stimulation or single-fiber electromyogram
    • Positive in 90% of MG patients – demonstrates a primary postsynaptic neuromuscular junctional disorder
  • Chest x-ray/CT – rule out thymoma

Prognosis

  • May predict the presence of thymoma in patients with acetylcholine receptor antibody-positive myasthenia gravis who are <50 years

Differential Diagnosis

Clinical Background

Myasthenia gravis (MG) is an autoimmune disease usually caused by antibodies that block or destroy receptors for the neurotransmitter acetylcholine, leading to muscle weakness and fatigue.

Epidemiology

  • Prevalence – 0.5-14.2/100,000
  • Age – bimodal peaks for onset
    • Women – 20-30 years
    • Men – 40s
  • Sex – M<F, slight
    • No gender predominance for >60 years

Pathophysiology

  • Autoimmune disorder
    • Immune response creates acetylcholine receptor (AChR) antibodies
      •  AChR antibodies are IgG (predominantly IgG1 or IgG3); MuSK antibodies are predominantly IgG4
      • Binding and activation of complement at the neuromuscular junction can lead to loss of AChR
      • Modulating with accelerated internalization and degradation of AChR molecules crosslinked by antibody result in loss of AChR (correlates most closely with clinical severity of disease)
      • Blocking functional AChR impairs binding of acetylcholine to receptor, resulting in poor muscle contraction
    • Postsynaptic membrane is destroyed and decreases available binding sites for acetylcholine, leading to muscle weakness
  • Iatrogenic causes of MG – D. penicillamine, alfa-interferon, bone marrow transplantation

Clinical Presentation

  • Characteristic sporadic muscle weakness that worsens after affected muscles are used (fatigable weakness)
    • Usually presents first in the extrinsic ocular muscles and progresses to muscles in the extremities
  • Bulbar symptoms – dysphagia, dysarthria
  • Extraocular muscle (EOM) weakness – diplopia, ptosis
    • Symptoms are present in 2/3 of patients
    • Disease is considered ocular MG if symptoms remain limited to EOM (10% of patients)
  • Respiratory failure in small percentage of patients
    • Death in severe cases
    • May be associated with thymoma
  • Commonly associated autoimmune disorders (50% of patients)

Treatment

  • Anticholinesterase drugs, thymectomy, immunosuppression, and plasmapheresis

Pediatrics

Clinical Background

Epidemiology

  • Incidence – 1-5/1,000,000  in western countries
  • Age
    • Rare in infancy
    • Increases in puberty
  • Sex – prepubertal: M:F, equal; postpubertal: M<F
  • Ethnicity – much higher in Asian populations

Clinical Presentation

  • Severe generalized weakness
  • Bulbar symptoms
  • Thymoma incidence lower than in adults
  • Patients <10 years – aggressive tumor nature

Diagnosis

Indications for Testing

  • See Diagnosis tab

Laboratory Testing

  • Anti-AChR – lower rate of positivity than in adults
  • Anti-MuSK – rare in young children
  • Higher rate of seronegative disease

Indications for Laboratory Testing

  • Tests generally appear in the order most useful for common clinical situations
  • Click on number for test-specific information in the ARUP Laboratory Test Directory
Test Name and Number Recommended Use Limitations Follow Up
Acetylcholine Receptor Antibodies and Striated Muscle Antibody Reflexive Panels, and Titin Antibody 2005639
Method: Quantitative Radioimmunoassay/Semi-Quantitative Enzyme-Linked Immunosorbent Assay/Semi-Quantitative Indirect Fluorescent Antibody/Semi-Quantitative Flow Cytometry

Assist in diagnosis and monitoring of MG

Panel contains binding, blocking, and modulating antibodies; titin antibody; and SMA IgG screen and titer

If either binding or blocking antibody is positive, modulating antibody is added; if striated muscle antibody is ≥1:40, titer is added

Absence of AChR antibody does not rule out diagnosis of MG

Rare false-positive radioimmunoprecipitation assay results (~0.05%) are reported for AChR binding antibody

~15% of individuals with MG fail to demonstrate any AChR antibodies

 
Muscle Weakness Autoimmune Reflexive Panel 2005640
Method: Quantitative Radioimmunoassay/Qualitative Radiobinding Assay/Semi-Quantitative Flow Cytometry/Semi-Quantitative Indirect Fluorescent Antibody

Assist in diagnosis and monitoring of MG

Panel contains binding, blocking, and modulating antibodies; voltage-gated calcium and potassium channels;  titin antibody; and SMA IgG screen and titer

If either binding or blocking antibody is positive, modulating antibody is added; if striated muscle antibody is ≥1:40, titer is added

Absence of AChR antibody does not rule out diagnosis of MG

Rare false-positive radioimmunoprecipitation assay results (~0.05%) are reported for AChR binding antibody

~15% of individuals with MG fail to demonstrate any AChR antibodies

 
Additional Tests Available
 
Click the plus sign to expand the table of additional tests.
Test Name and NumberComments
Acetylcholine Receptor Antibody Reflexive Panel 2001571
Method: Quantitative Radioimmunoassay/Semi-Quantitative Flow Cytometry

Assist in diagnosis and monitoring of MG

Panel contains binding, blocking, and modulating antibodies

Titin Antibody 2005636
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Secondary diagnostic testing for MG

Acetylcholine Receptor Modulating Antibody 0099521
Method: Semi-Quantitative Flow Cytometry
Acetylcholine Receptor Binding Antibody 0080009
Method: Quantitative Radioimmunoassay
Acetylcholine Receptor Blocking Antibody 0099580
Method: Semi-Quantitative Flow Cytometry
Striated Muscle Antibody, IgG with Reflex to Titer 0050746
Method: Semi-Quantitative Indirect Fluorescent Antibody

Secondary diagnostic testing for MG