Myasthenia Gravis - MG

Diagnosis

Indications for Testing

• Initial testing based on classic symptoms of fluctuating weakness and muscle fatigability as an adjunct to clinical findings
• Confirm clinical history – testing should not be performed in the absence of appropriate clinical presentation

Laboratory Testing

• Serum antibody testing – positive test is diagnostic of myasthenia gravis (MG)
  • Anti-AChR
    • Positive in 90% of patients
      • Specificity approaches 100%
    • Negative AChR does not exclude disease
      • ~50% of ocular MG patients are negative for this antibody
  • 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

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

• Infectious
  • Enterovirus (poliomyelitis)
  • Clostridium botulinum
• Autoimmune
  • Polymyositis
• Neuropathic 
  • Guillain-Barré syndrome
  • Eaton-Lambert syndrome
  • Miller Fisher syndrome
  • Limbic encephalitis
• CNS disease
  • Amyotrophic lateral sclerosis (Lou Gehrig disease)
  • Brainstem/cavernous sinus lesions
• Acute intermittent porphyria
• Drug-related myopathy
  • Corticosteroids
• Neuromuscular disease
  • Mitochondrial disorders
  • Muscular dystrophy syndromes

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 – 77/1,000,000
  • 20/100,000 in U.S.
• Age – bimodal peaks for onset
  • Women – 20-30 years
  • Men – 55-60 years
• Sex – M<F, slight

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)
  • Rheumatoid arthritis
  • Systemic lupus erythematosus
  • Pernicious anemia

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

Click the plus sign to expand the table of additional tests.

Test Name and Number	Comments
Acetylcholine Receptor Antibody Reflexive Panel 2001571 Method: Quantitative Radioimmunoassay/Semi-Quantitative Radioimmunoassay/Semi-Quantitative Flow Cytometry
Titin Antibody 2005636 Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay
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 Radioimmunoassay
Striated Muscle Antibody, IgG with Reflex to Titer 0050746 Method: Semi-Quantitative Indirect Fluorescent Antibody