• Clinical science

Myasthenia gravis

Summary

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

Epidemiological data refers to the US, unless otherwise specified.

Etiology

Autoimmune

Associated conditions [3]

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

Classification

Main clinical forms

  • Ocular myasthenia: only the extraocular and/or eyelid muscles
  • Generalized myasthenia
    • All skeletal muscles may be involved.
    • Especially ocular, bulbar, limb, and respiratory muscles

Pathophysiology

Thymus involvement

Acetylcholine receptor antibodies [4]

  • Responsible for inhibition of signal transduction at the neuromuscular junction (NMJ)
  • Antibodies target postsynaptic AChRs of normal muscle cells → competitive inhibition of acetylcholine (ACh) → AChR decay through receptor internalization (↓ receptor density at the postsynaptic membrane) and activation of complement (→ muscle cell lysis) → impaired signal transduction at the NMJ skeletal muscle weakness and fatigue
    • Seropositive MG (80–90% of cases): positive assays for antibodies (in blood) against the acetylcholine receptor (AChR-Ab)
    • Seronegative MG (10–20% of cases): negative for AChR antibodies, but may be positive for MuSK antibodies

Clinical features

Clinical course

Clinical manifestations [5]

Fatigable weakness of skeletal muscles in which smaller muscles responsible for fine movements (e.g., eye muscles) tend to be affected first, while larger muscles become affected later on.

Muscle fatigue worsens throughout the day and with increased activity.

Diagnostics

Approach

Laboratory studies

Electrodiagnostics

Imaging

  • Chest CT: every newly diagnosed MG patient to rule out thymoma

Other tests

Differential diagnoses

Lambert-Eaton myasthenic syndrome (LEMS)

  • Definition: rare autoimmune disease that reduces neuromuscular transmission, leading to muscle weakness
  • Etiology
  • Pathophysiology: autoantibodies directed against presynaptic voltage-gated calcium channels (anti-VGCC antibodies) → Ca2+ influx → ↓ presynaptic vesicle fusion → impaired acetylcholine release in the NMJ
  • Clinical features
    • Proximal muscle weakness
    • Reduced or absent reflexes
    • Autonomic symptoms
      • Dry mouth
      • Constipation
      • Erectile and ejaculatory dysfunction [7]
      • Orthostatic dysregulation
  • Diagnostics
  • Treatment [8]

Comparison of MG and LEMS

Myasthenia gravis vs. Lambert-Eaton myasthenic syndrome
Myasthenia gravis Lambert-Eaton myasthenic syndrome
Associated diseases
Weakness
  • Starts with weakness of proximal limb muscles
  • Improveswith exercise and throughout the day
Reflexes
  • Normal
  • Reduced or absent
Repetitive nerve stimulation (RNS)
  • Decremental response
  • Incremental response
Autonomic dysfunction
  • None
  • Common
Response to cholinesterase inhibitors
  • Symptomatic relief
  • No response

Other differential diagnoses

The differential diagnoses listed here are not exhaustive.

Treatment

Pharmacotherapy

Surgery

  • Thymectomy
    • Can be beneficial even if a thymoma is not present
    • Not for patients with MuSK antibody-associated MG without a thymoma

Complications

Myasthenic crisis [9]

  • Definition: acute, life-threatening exacerbation of myasthenic symptoms that leads to respiratory failure
  • Epidemiology
    • Affects 15–20% of patients with MG
    • Most commonly occurs within 8–12 months after onset
  • Etiology
    • Infection
    • Surgery, anesthesia
    • Pregnancy
    • Medications
  • Differential diagnosis: cholinergic crisis
  • Treatment

Differential diagnosis of mysthenic crisis and cholinergic crisis

Myasthenic crisis vs. cholinergic crisis
Myasthenic crisis Cholinergic crisis
Shared symptoms
Pupil
  • Normal
Fasciculations
  • None
  • Present
Heart rate
Skin
  • Cold and faint
  • Warm and flushed
Bronchial secretion
  • Normal
  • Increased

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

Prognosis

  • The prognosis of ocular MG is good.
  • 1. Gilhus NE. Myasthenia Gravis. N Engl J Med. 2016; 375(26): pp. 2570–2581. doi: 10.1056/nejmra1602678.
  • 2. Asmail A, Kesler A, Kolb H, Drory VE, Karni A. A tri-modal distribution of age-of-onset in female patients with myasthenia gravis is associated with the gender-related clinical differences. Int J Neurosci. 2018; 129(4): pp. 313–319. doi: 10.1080/00207454.2018.1529669.
  • 3. Priola AM, Priola SM. Imaging of thymus in myasthenia gravis: From thymic hyperplasia to thymic tumor. Clin Radiol. 2014; 69(5): pp. e230–e245. doi: 10.1016/j.crad.2014.01.005.
  • 4. Romi F, Aarli JA, Gilhus NE. Seronegative myasthenia gravis: disease severity and prognosis. European Journal of Neurology. 2005; 12(6): pp. 413–418. doi: 10.1111/j.1468-1331.2005.01137.x.
  • 5. Gwathmey K, Burns T. Myasthenia Gravis. Semin Neurol. 2015; 35(04): pp. 327–339. doi: 10.1055/s-0035-1558975.
  • 6. Romi F. Thymoma in Myasthenia Gravis: From Diagnosis to Treatment. Autoimmune Diseases. 2011; 2011: pp. 1–5. doi: 10.4061/2011/474512.
  • 7. Waterman SA. Autonomic dysfunction in Lambert-Eaton myasthenic syndrome. Clinical Autonomic Research. 2001; 11(3): pp. 145–154. doi: 10.1007/bf02329922.
  • 8. Anwar A, Saleem S, Ahmed MF, Ashraf S, Ashraf S. Recent Advances and Therapeutic Options in Lambert-Eaton Myasthenic Syndrome. Cureus. 2019. doi: 10.7759/cureus.5450.
  • 9. Wendell LC, Levine JM. Myasthenic Crisis. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3726100/. Updated January 1, 2011. Accessed April 3, 2017.
last updated 11/23/2020
{{uncollapseSections(['JFasQm', 'rFafjm', '7Fa4jm', 'HFaKjm', 'sFatjm', 'GFaBjm', '8FaOPm', 'EFa8Pm', 'vFaAPm', 'DFa14m', 'wFah4m'])}}