• Clinical science

Myasthenia gravis

Abstract

Myasthenia gravis (MG) is an autoimmune neuromuscular disease characterized by generalized muscle weakness. The pathophysiology of MG involves autoantibodies directed against postsynaptic acetylcholine receptors (AchR), thereby impairing neuromuscular transmission. Women are more frequently affected and about 10–15% of cases are associated with thymoma. The most common initial symptoms are ptosis and/or diplopia due to ocular muscle weakness, with the disease usually progressing to generalized weakness within two years. At that point, patients have difficulties standing up, climbing stairs, and possibly even swallowing and/or chewing. Muscle weakness worsens throughout the day with increased activity and improves after rest. MG is diagnosed according to patient history, physical examination, antibody testing, and electromyographic evaluation. All patients should be screened for thymomas via CT as they can be surgically removed, allowing for possible curative treatment. The treatment of choice consists of acetylcholinesterase inhibitors, possibly in combination with immunosuppressive drugs if symptoms persist. Acute exacerbations, as seen in myasthenic crisis, should be treated with either IV immunoglobulins or plasma exchange.

Epidemiology

  • Sex: > (3:2)
  • Age of onset
    • Possible at any age
    • Occurs more often in:
      • : 20–40 years
      • : 60–80 years

Epidemiological data refers to the US, unless otherwise specified.

Etiology

References:[1]

Classification

  • Main clinical forms
    • Ocular myasthenia: only the extraocular and/or eyelid muscles
    • Generalized myasthenia: all skeletal muscles may be involved; especially the ocular, bulbar, limb, and respiratory muscles
  • Clinical classification
    • I. Pure ocular MG (symptoms: only ptosis and diplopia)
    • IIA. Mild generalized form
    • IIB. Moderate generalized form; no oropharyngeal muscle involvement
    • III. Acute und rapid progressive form; involvement of oropharyngeal muscles in the last 6 months
    • IV. Chronic, severe form

Pathophysiology

  • Thymus involvement: It is hypothesized that the thymus is involved in the pathogenesis of MG.
    • Muscle-like (myoid) cells in the thymus express AChRthymic T cells target myoid cells → AChR antibody productionantibodies target postsynaptic AChRs of normal muscle cells, competing with acetylcholine (ACh) → impaired signal transduction in the NMJ resulting in:
      • Skeletal muscle weakness and fatigue
      • AChR decay and reduced receptor density on the postsynaptic membrane
  • AChR antibodies
    • Seropositive MG (85% of cases): positive for antibodies against the acetylcholine receptor (AChR), or against muscle specific tyrosine kinase (MuSK)
    • Seronegative MG (15% of cases):negative assays for both AChR antibodies and MuSK antibodies

Clinical features

Clinical course

  • Symptoms worsen with increased muscle use throughout the day and improve with rest.
  • Sometimes associated with exacerbating factors, including:
  • Active phase
    • The disease typically progresses slowly during the first few years following onset.
    • Accompanied by periodic exacerbations that may fluctuate, but generally become more persistent and worsen in severity
    • Usually when myasthenic crises occur
  • Stable phase: progression of the disease peaks and symptoms remain stable, but still sensitive to exacerbating factors
  • Remission phase (common): remission may occur

Clinical manifestations

Smaller muscles responsible for fine movements (i.e., the eye muscles) tend to be affected first, while larger muscles become affected later on.

  • Eye muscle weakness: most common initial symptom
    • Ptosis
    • Diplopia
    • Blurred vision
  • Bulbar muscle weakness
    • Slurred speech, difficulty chewing and/or swallowing
  • Proximal limb weakness
    • Rising from a chair
    • Climbing stairs
    • Brushing hair
  • Weakness of respiratory muscles

Muscle fatigue worsens throughout the day and with increased activity!

References:[2]

Diagnostics

Suspected cases of MG are generally confirmed via EMG and AChR antibodies and should receive a chest CT to rule out thymoma.

Patients diagnosed with MG should be tested for other autoimmune disorders, such as thyroiditis, SLE, and/or rheumatoid arthritis!

References:[3]

Differential diagnoses

  • Lambert-Eaton myasthenic syndrome (LEMS)
    • Description: LEMS is a rare autoimmune disease that reduces neuromuscular transmission and leads to muscle weakness.
    • Pathophysiology: Autoantibodies are directed against presynaptic voltage-gated calcium channels → impaired acetylcholine release in the NMJ.
    • Association: small-cell lung carcinoma (in ⅔ of LEMS cases)
    • Clinical features
      • Proximal muscle weakness
      • Reduced or absent reflexes
      • Autonomic symptoms
    • Diagnostics
      • Physical examination
        • Active muscle contraction or repeated muscle tapping increases reflex activity.
        • Lambert's sign: Muscle strength improves after muscle use.
      • EMG: Repetitive nerve stimulation results in incremental responses.
      • Confirmatory test: serologic detection of antibodies directed against voltage-gated calcium channels
Myasthenia gravis vs. Lambert-Eaton myasthenic syndrome
Myasthenia gravis Lambert-Eaton myasthenic syndrome
Associated diseases
  • Thymoma
Weakness
  • Starts with weakness of the extraocular muscles
  • Worsens with exercise and throughout the day
  • Starts with weakness of the lower legs
  • Improves with exercise and throughout the day
Reflexes
  • Normal
  • Reduced or absent
Repetitive nerve stimulation (RNS)
  • Decremental response
  • Incremental response
Autonomic dysfunction
  • None
  • Common
Myasthenia gravis

Amyotrophic lateral sclerosis

Ptosis
  • Yes
  • No
Diplopia
  • Yes
  • No
Upper motor signs
  • No
  • Yes

Lower motor signs

  • Yes
  • Yes
Myasthenia gravis Chronic Progressive External Ophthalmoplegia (CPEO)

Thyroid ophthalmopathy
Ptosis
  • Worsens throughout the day
  • Often asymmetric
  • Stays constant
  • Symmetric
  • No
Diplopia
  • Common
  • Uncommon
  • No

Other findings
  • Generalized muscle weakness
  • Bulbar symptoms
  • No
  • Periorbital edema
  • Proptosis
  • Lid retraction

References:[4]

The differential diagnoses listed here are not exhaustive.

Treatment

Complications

  • Myasthenic crisis
    • Affects 15–20% of patients with MG
    • Generally occurs during the active phase within 5–7 years after onset
    • Acute, life-threatening exacerbation of myasthenic symptoms that leads to respiratory failure; early endotracheal intubation
    • Potential triggers
      • Infection
      • Surgery, anesthesia
      • Pregnancy
      • Medications
    • Not to be confused with cholinergic crisis
Myasthenic crisis Cholinergic crisis
Shared symptoms
  • Muscle weakness, dyspnea, sweating, agitation, disorientation, drowsiness, urinary and fecal urgency
Pupil
Fasciculations
  • None
  • Present
Heart rate
  • Tachycardia
  • Bradycardia
Skin
  • Cold and faint
  • Warm and flushed
Bronchial secretion
  • Normal
  • Increased

References:[3][5]

We list the most important complications. The selection is not exhaustive.

Prognosis

  • The prognosis of ocular MG is good.
  • Mortality
    • Without treatment: up to 30%
    • With treatment: less than 5%