- Clinical science
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.
- 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.
- Autoimmune: autoreactive antibodies directed against postsynaptic acetylcholine receptors or receptor-associated proteins
- Associated with
- In rare cases, can also be caused by graft-versus-host reaction after allogeneic stem cell transplantation (especially in children)
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
- 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
Thymus involvement: It is hypothesized that the thymus is involved in the pathogenesis of MG.
Muscle-like (myoid) cells in the thymus express AChR → thymic T cells target myoid cells → AChR antibody production → antibodies 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
- Muscle-like (myoid) cells in the thymus express AChR → thymic T cells target myoid cells → AChR antibody production → antibodies target postsynaptic AChRs of normal muscle cells, competing with acetylcholine (ACh) → impaired signal transduction in the NMJ resulting in:
- AChR antibodies
- Symptoms worsen with increased muscle use throughout the day and improve with rest.
- Sometimes associated with exacerbating factors, including:
- 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
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
- 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!
Suspected cases of MG are generally confirmed via EMG and AChR antibodies and should receive a chest CT to rule out thymoma.
- AChR antibody test (most specific test)
- Other associated antibodies: anti-MuSK, anti-smooth muscle, anti-titin, and anti-ryanodine antibodies
- Electromyography (EMG): a decremental response following repetitive nerve stimulation
- Chest CT: always indicated in newly diagnosed MG patients to rule out thymoma
- Edrophonium test ( )
- Simpson's test
- Ice test: : An ice pack is placed on one eye for 5 minutes → ptosis temporarily improves
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)
- Proximal muscle weakness
- Reduced or absent reflexes
- Dry mouth
- Orthostatic dysregulation
- 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
- Physical examination
|Myasthenia gravis vs. Lambert-Eaton myasthenic syndrome|
|Myasthenia gravis||Lambert-Eaton myasthenic syndrome|
|Associated diseases|| || |
|Weakness|| || |
|Reflexes|| || |
|Repetitive nerve stimulation (RNS)|| || |
|Autonomic dysfunction|| || |
- Congenital myasthenic syndrome
|Ptosis|| || |
|Diplopia|| || |
|Upper motor signs|| || |
Lower motor signs
| || |
- (for ocular symptoms)
|Myasthenia gravis|| Chronic Progressive External Ophthalmoplegia (CPEO) |
|Ptosis|| || || |
|Diplopia|| || || |
|Other findings|| || || |
The differential diagnoses listed here are not exhaustive.
- First line: cholinesterase inhibitors
- Supplemental immunosuppressants: if symptoms persist despite anticholinesterase treatment
Rapid immunomodulating therapies: in cases of myasthenic crisis
- IV immune globulin
Thymectomy: can be beneficial even if a thymoma is not present
- Not for patients with MuSK antibody-associated MG without a thymoma
- 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
- Surgery, anesthesia
- Not to be confused with cholinergic crisis
|Shared symptoms|| |
|Fasciculations|| || |
|Heart rate|| || |
|Skin|| || |
|Bronchial secretion|| || |
We list the most important complications. The selection is not exhaustive.
- The prognosis of ocular MG is good.
- Without treatment: up to 30%
- With treatment: less than 5%