Myasthenia Gravis (MG)

What is Myasthenia Gravis (MG)

Myasthenia gravis is a long-term (chronic) condition that causes weakness in the muscles you can control (voluntary muscles). MG can affect any voluntary muscle. The muscles most often affected are the ones that control:

• Eye movement.
• Facial movements.
• Swallowing.

MG is a disease in which the body’s disease-fighting system (immune system) attacks its own healthy tissues (autoimmune disease).

When you have MG, your immune system makes proteins (antibodies) that block the chemical (acetylcholine) that your body needs to send nerve signals to your muscles. This causes muscle weakness.

7 Interesting Facts of Myasthenia Gravis

1. Myasthenia gravis is an autoimmune disorder affecting postsynaptic neuromuscular transmission, wherein antibodies target the nicotinic acetylcholine receptor of the neuromuscular junction and cause a reduction in functional postsynaptic acetylcholine receptors with resultant weakness
2. Patients present with ptosis or diplopia in the majority of cases; however, limb weakness and difficulty chewing, swallowing, or talking can also be initial presenting features
3. Respiratory failure, the most common complication, may occur during exacerbations
4. Diagnosis is clinical, based primarily on history and physical examination
5. Anti–acetylcholine receptor antibody test is the confirmatory diagnostic test of choice 
6. Cholinesterase inhibitors may provide some symptomatic relief of myasthenia gravis symptoms, but generalized illness usually requires maintenance immunosuppressant agents, possible thymectomy, and plasmapheresis or IV immunoglobulin to treat exacerbations
   • Cholinesterase inhibitors (eg, pyridostigmine) are first line agents that help to improve neuromuscular transmission and muscle weakness by preventing the degradation of acetylcholine in the synaptic cleft 
   • Immunosuppressant agents (eg, prednisone, azathioprine, cyclosporine, mycophenolate mofetil, cyclophosphamide, tacrolimus) may help to improve muscle strength by suppressing the production of autoantibodies 
   • If myasthenia gravis is associated with thymoma, thymectomy is indicated 
   • When cholinesterase inhibitors, thymectomy, and immunosuppressants are not sufficient to control symptoms, IV immunoglobulin and plasmapheresis are short-term options to treat exacerbations
7. Course of disease is variable but typically progressive

What are the causes?

The exact cause of MG is not known.

What increases the risk?

The following factors may make you more likely to develop this condition:

• Having an enlarged thymus gland. The thymus gland is located under the breastbone. It makes certain cells for the immune system.
• Having a family history of MG.

What are the symptoms?

Symptoms of MG may include:

• Drooping eyelids.
• Double vision.
• Muscle weakness that gets worse with activity and gets better after rest.
• Difficulty walking.
• Trouble chewing and swallowing.
• Trouble making facial expressions.
• Slurred speech.
• Weakness of the arms, hands, and legs.

Sudden, severe difficulty breathing (myasthenic crisis) may develop after having:

• An infection.
• A fever.
• A bad reaction to a medicine.

Myasthenic crisis requires emergency breathing support.

Sometimes symptoms of MG go away for a while (remission) and then come back later.

How is this diagnosed?

This condition may be diagnosed based on:

• Your symptoms and medical history.
• A physical exam.
• Blood tests.
• Tests of your muscle strength and function.
• Imaging tests, such as a CT scan or an MRI.

How is this treated?

The goal of treatment is to improve muscle strength. Treatment may include:

• Taking medicine.
• Making lifestyle changes that focus on saving your energy.
• Doing physical therapy to gain strength.
• Having surgery to remove the thymus gland (thymectomy). This may result in a long remission for some people.
• Having a procedure to remove the acetylcholine antibodies (plasmapheresis).
• Getting emergency breathing support, if you experience myasthenic crisis.

If you experience remission, you may be able to stop treatment and then resume treatment when your symptoms return.

Follow these instructions at home:

• Take over-the-counter and prescription medicines only as told by your health care provider.
• Get plenty of rest and sleep. Take frequent breaks to rest your eyes, especially when in bright light or working on a computer.
• Maintain a healthy diet and a healthy weight. Work with your health care provider or a diet and nutrition specialist (dietitian) if you need help.
• Do exercises as told by your health care provider or physical therapist.
• Do not use any products that contain nicotine or tobacco, such as cigarettes and e-cigarettes. If you need help quitting, ask your health care provider.
• Prevent infections by:
  • Washing your hands often with soap and water. If soap and water are not available, use hand sanitizer.
  • Avoiding contact with other people who are sick.
  • Avoiding touching your eyes, nose, and mouth.
  • Cleaning surfaces in your home that are touched often using a disinfectant.
• Keep all follow-up visits as told by your health care provider. This is important.

Contact a health care provider if:

• Your symptoms change or get worse, especially after having a fever or infection.

Get help right away if:

• You have trouble breathing.

Pitfalls

• Never administer anticholinesterase agents to patients with respiratory difficulties without the availability of respiratory support
  • Respiratory difficulties in a patient with myasthenia gravis may be due to either myasthenic crisis or cholinergic crisis; a patient experiencing a cholinergic crisis will have worsening symptoms with anticholinesterase agents
• Treat concurrent illnesses and diseases with agents that do not aggravate muscle weakness of myasthenia gravis; avoid medications such as:
  • Certain antibiotic agents (eg, aminoglycosides, ciprofloxacin, chloroquine)
  • Some mood stabilizers (eg, lithium, phenothiazines)
  • Certain antiarrhythmic medications or agents to lower blood pressure (eg, phenytoin, procainamide, quinidine, β-blockers, calcium channel blockers)
  • Magnesium-containing antacids
  • Iodinated contrast agents
  • Penicillamine and interferon alfa
• Anticholinergic agents are used to treat a variety of conditions, including motion sickness, Parkinson disease, asthma, chronic obstructive pulmonary disease, and gastrointestinal disorders; these agents will antagonize the beneficial actions of acetylcholinesterase inhibitor

Myasthenia gravis is an autoimmune disorder affecting postsynaptic neuromuscular transmission, wherein antibodies target the nicotinic acetylcholine receptor of the neuromuscular junction and cause a reduction in functional postsynaptic acetylcholine receptors with resultant weakness

Antibodies targeting muscle-specific tyrosine kinase may impact both pre- and postsynaptic function of the neuromuscular junction

Respiratory failure may occur during exacerbations

Classification

• Ocular myasthenia gravis
  • Initial, milder form of illness that progresses to the more severe generalized form in most patients
• Generalized myasthenia gravis
  • Weakness tends to spread from ocular muscles to facial and bulbar muscles, then to truncal and limb muscles
  • Weakness progresses from mild to severe over weeks or months, with exacerbations and remissions
  • Most patients have generalized disease within 13 months of mild ocular disease onset
• Myasthenia Gravis Foundation of America Clinical Classification divides myasthenia gravis into 5 main classes and several subclasses: 
  • Class I: any ocular muscle weakness; may have weakness of eye closure; all other muscle strength is normal
  • Class II: mild weakness affecting other nonocular muscles; may also have ocular muscle weakness of any severity
    • Class IIa: predominantly affecting limb, axial muscles, or both; may also have lesser involvement of oropharyngeal muscles
    • Class IIb: predominantly affecting oropharyngeal, respiratory muscles, or both; may also have lesser or equal involvement of limb, axial muscles, or both
  • Class III: moderate weakness affecting other nonocular muscles; may also have ocular muscle weakness of any severity
    • Class IIIa: predominantly affecting limb, axial muscles, or both; may also have lesser involvement of oropharyngeal muscles
    • Class IIIb: predominantly affecting oropharyngeal, respiratory muscles, or both; may also have lesser or equal involvement of limb, axial muscles, or both
  • Class IV: severe weakness affecting other nonocular muscles; may also have ocular muscle weakness of any severity
    • Class IVa: predominantly affecting limb, axial muscles, or both; may also have lesser involvement of oropharyngeal muscles
    • Class IVb: predominantly affecting oropharyngeal, respiratory muscles, or both; may also have lesser or equal involvement of limb, axial muscles, or both; use of a feeding tube without intubation
  • Class V: defined by the need for intubation, with or without mechanical ventilation, except when used during routine postoperative management

Clinical Presentation

History

• Patients present with ptosis or diplopia in the majority of cases; however, limb weakness and difficulty chewing, swallowing, or talking can also be initial presenting features
• Weakness typically worsens as the day progresses or with use of the affected muscle; weakness improves with rest
• Sensation should not be affected
• Muscle fatigue after exercise
• Difficulty walking, sitting, or holding head erect
• Choking
• Drooling
• Straightened smile
• Nasal sound to speech; slurred speech
• Proximal limb weakness
• Most severe disease presentation is usually early in the course of the illness; highest risk of crisis is during the first 6 months and many patients stabilize within 3 years

Physical examination

• Extraocular weakness or ptosis presents in the majority of patients
• Furrowed brow to compensate for eye weakness
• Weakness of facial muscles
• Dysarthria
• Proximal and symmetrical weakness affecting upper more than lower extremity muscles
• Weakness also common in neck muscles, with neck flexors usually more affected than neck extensors
• Respiratory weakness may produce acute respiratory failure
• Prominent respiratory involvement with weakness of neck and proximal shoulder girdle muscles (in the absence of ocular findings) may be seen in the muscle-specific tyrosine kinase variant of myasthenia gravis
• Peek sign
  • Patient gently closes the eyes and apposition of the lid margins is observed
  • Abnormal result: after a few seconds the sclera begins to show, suggesting fatigable weakness of the orbicularis oculi

Causes

• Idiopathic in most patients
• Penicillamine and interferon alfa 

Risk factors and/or associations

Age 

• Typically presents in the second and third decades of life
• Later peak in incidence occurs after age 50

Sex

• More common in women during first 40 years of life; thereafter, incidence is similar, though it may be more common in men older than 50 years 

Genetics

• Family history 
  • Transmission is not by classic Mendelian inheritance, but family members are approximately 1000 times more likely to develop the disease
  • Certain HLA types (-DR2, -DR3, -B8, -DR1) predispose to disease

Other risk factors/associations

• Associated conditions
  • Hyperplasia of thymus
  • Thymoma
  • Thyroid disease
  • Rheumatoid arthritis
  • Scleroderma
  • Systemic lupus erythematosus
• Factors causing exacerbation
  • Medications
    • Certain antibiotic agents (eg, aminoglycosides, ciprofloxacin, chloroquine)
    • Some mood stabilizers (eg, lithium, phenothiazines)
    • Certain antiarrhythmic medications or agents to lower blood pressure (eg, phenytoin, procainamide, quinidine, β-blockers, calcium channel blockers)
    • Magnesium-containing antacids
    • Iodinated contrast agents
  • Exposure to bright sunlight
  • Surgery
  • Immunizations
  • Concurrent infection
  • Stress
  • Menstruation

Diagnostic Procedures

Primary diagnostic tools

• Myasthenia gravis is a clinical diagnosis, based primarily on history and physical examination
• Anti–acetylcholine receptor antibody test is the confirmatory diagnostic test of choice 
• Edrophonium test can show strength improvement in patients with myasthenia gravis; often diagnostic with ptosis or ophthalmoparesis, but less helpful in assessing other muscles 
• EMG is also used to directly evaluate muscle function 
• Obtain thyroid function tests to detect thyroid disease and chest imaging (CT or MRI) to evaluate for thymoma (a rare finding) 

Laboratory

• Anti–acetylcholine receptor antibodies 
  • Diagnostic test of choice; presence of antibodies strongly suggests myasthenia gravis
  • Antibodies detected in serum of 85% of patients with generalized myasthenia gravis and 50% of patients with ocular myasthenia gravis
  • Serum concentration of antibodies does not predict severity of disease
  • In a subset of patients with negative results, muscle-specific tyrosine kinase antibody test results may be positive
• Muscle-specific tyrosine kinase antibodies 
  • Antibodies to muscle-specific tyrosine kinase are identified in up to 50% of patients who test negative for anti–acetylcholine receptor antibodies and who have generalized myasthenia gravis; these antibodies are also identified in some patients with ocular myasthenia gravis
• Thyroid function tests 
  • Obtain in all patients diagnosed with myasthenia gravis, to evaluate for thyroid disease

Imaging

• CT or MRI 
  • Obtain chest imaging (CT or MRI) in all patients diagnosed with myasthenia gravis to evaluate for thymoma (rare)

Functional testing

• Edrophonium test 
  • Often diagnostic with ptosis or ophthalmoparesis; less helpful in assessing other muscles
  • Unequivocal improvement in strength of affected muscle is required for a positive result; resolution of eyelid ptosis, improved strength of a single paretic extraocular muscle, or clearly improved dysarthria are considered valid endpoints
  • Determine lowest effective dose by injecting in small increments up to maximum total dose of 10 mg
    • Inject initial test dose of 2 mg and monitor response for 60 seconds; subsequent injections of 3 and 5 mg can then be given
    • If improvement is clearly seen within 60 seconds after any dose, result is positive and no further injections are needed
  • Atropine should be readily available for treating severe bradycardia that may result from the test
• Repetitive nerve stimulation EMG 
  • Most commonly used electrophysiologic test
  • Abnormal result: decrement of greater than 10% in cumulative compound muscle action potential
• Single fiber EMG 
  • More sensitive than repetitive nerve stimulation
  • Shows increased jitter in some muscles of most myasthenia gravis patients
  • Jitter is greatest in weak muscles; result is typically abnormal, even in muscles with normal strength

Differential Diagnosis

Most common

• Hyperthyroidism
• Polymyositis
• Amyotrophic lateral sclerosis
• Lambert Eaton myasthenic syndrome
• Sarcoidosis
• Botulism
• Chronic fatigue syndrome

Treatment Goals

• Alleviate muscle weakness and control symptoms
• Provide respiratory support during severe episodes that lead to acute respiratory failure

Admission criteria

Admit to hospital for airway support and monitoring if respiratory or swallowing impairments are severe

Patients undergoing plasmapheresis may require admission

Criteria for ICU admission

• Patients in acute respiratory failure requiring intubation and mechanical ventilation

Recommendations for specialist referral

• Refer to neurologist to confirm diagnosis and begin treatment
  • Obtain neurologic consultation before immune modulation therapy
• Obtain surgical consultation for patients requiring thymectomy

Treatment Options

Cholinesterase inhibitors may provide some symptomatic relief of myasthenia gravis symptoms, but generalized illness usually requires maintenance immunosuppressant agents, possible thymectomy, and plasmapheresis or IV immunoglobulin to treat exacerbations

• Cholinesterase inhibitors (eg, pyridostigmine) are first line agents that help to improve neuromuscular transmission and muscle weakness by preventing the degradation of acetylcholine in the synaptic cleft 
  • Begin treatment with pyridostigmine before immune modulation is started
  • Never administer anticholinesterase agents to patients with respiratory difficulties without the availability of respiratory support
    • Respiratory difficulties in a patient with myasthenia gravis may be due to either myasthenic crisis or cholinergic crisis; a patient experiencing a cholinergic crisis will have worsening symptoms with anticholinesterase agents
  • Asthma, chronic obstructive pulmonary disease, and cardiac dysrhythmias are relative contraindications to cholinesterase inhibitor therapy
• Immunosuppressant agents (eg, prednisone, azathioprine, cyclosporine, mycophenolate mofetil, cyclophosphamide, tacrolimus) may help to improve muscle strength by suppressing the production of autoantibodies 
  • Among the immunosuppressant agents, prednisone is often the first drug of choice
  • Obtain neurologic consultation before immune modulation is started
• If disease is associated with thymoma, thymectomy is indicated 
  • Thymectomy improves symptoms, remission rate, and clinical course of disease in some patients without thymoma; consider as an option for all patients with generalized symptoms who are otherwise healthy
• When cholinesterase inhibitors, thymectomy, and immunosuppressants are insufficient to control symptoms, IV immunoglobulin and plasmapheresis are short-term options to treat exacerbations 
  • High-dose IV immunoglobulin may temporarily modify the immune system and suppress autoantibody production to improve moderate to severe symptoms
  • Plasmapheresis may be useful to remove abnormal antibodies from the body in patients with severe generalized or fulminating myasthenia gravis refractory to other treatments 
  • Follow immediate treatments (eg, IV immunoglobulin, plasma exchange) with long-term immune-modulating therapy

Treat concurrent illnesses and diseases with agents that do not aggravate muscle weakness of myasthenia gravis

Lifestyle measures, such as eating a well-balanced diet and getting plenty of rest, may also be beneficial in alleviating muscle weakness; there must be a balance between rest and maintaining activity to prevent atrophy 

Physical therapy is essential, especially after an episode of myasthenic crisis, to regain ambulation and limb strength 

Drug therapy

• Pyridostigmine
  • Injectable
    • Pyridostigmine Bromide Solution for injection; Neonates and Children: 0.05—0.15 mg/kg IV or IM. Max single dose is 10 mg.
    • Pyridostigmine Bromide Solution for injection; Adults: 2 mg IV or IM q2—3h.
  • Oral
    • Pyridostigmine Bromide Oral syrup; Neonates: 5 mg PO q4—6h.
    • Pyridostigmine Bromide Oral syrup; Children and Adolescents: 1 mg/kg PO q 4—6h.
    • Pyridostigmine Bromide Oral tablet; Adults: On average, 600 mg/day PO in divided doses (range, 60—1500 mg/day PO). Space doses for maximum relief when maximum strength is needed. Adjust regimen to needs of the patient.
• Immunosuppressant agents
  • Prednisone
    • Prednisone Oral tablet; Adults: Initially, 15 mg/day to 20 mg/day PO. Increase by 5 mg every 2 to 3 days as needed. Max: 60 mg/day PO. For chronic use, may change to every other day therapy.
  • Azathioprine
    • Azathioprine Oral tablet; Adults: The following regimen has been recommended: 50 mg PO daily for 1 week, then increase to 2 to 3 mg/kg/day PO.
  • Cyclosporine
    • Cyclosporine Oral capsule; Adults: An initial dose of 5 mg/kg/day PO in 2 divided doses has been recommended.
  • Mycophenolate mofetil
    • Mycophenolate Mofetil Oral tablet; Adults: Dosage not established. 1 gram PO twice daily has been used with adjunctive corticosteroids or other non-steroidal immunosuppressive medications. Data from randomized, controlled trials do not support use. Some experts suggest use in poorly responsive disease where azathioprine is not tolerated or has failed.
  • Cyclophosphamide
    • Cyclophosphamide Oral tablet; Adults: 1 to 2 mg/kg PO given once daily. 
  • Tacrolimus 
    • Tacrolimus Oral capsule; Adults: 3 mg PO daily has been used in studies. 
• IV immunoglobulin
  • Immune Globulin (Human) Solution for injection; Infants, Children, and Adolescents: 2 g/kg IV total dose divided over 1 to 5 days. Improvement typically seen within 1 week. Duration of clinical effect is 4 to 6 weeks. If additional therapy required, adjust dose based on response; use minimum effective dose.
  • Immune Globulin (Human) Solution for injection; Adults: 400 mg/kg IV daily for 5 days has been recommended.

Nondrug and supportive care

Lifestyle measures may be beneficial in alleviating muscle weakness 

• Eating a well-balanced diet
• Getting plenty of rest
• Ensuring a balance between rest and maintaining activity to prevent atrophy

Physical therapy 

• Essential to regain ambulation and limb strength, particularly after an episode of myasthenic crisis

Procedures

Thymectomy 

General explanation

• Surgical removal of the thymus
• Improves symptoms in many patients without thymoma; may increase remission rate and improve the clinical course in such patients, though evidence is limited

Indication

• For removal of thymoma
• Can be considered as an elective option for all patients with generalized symptoms who are otherwise healthy

Contraindications

• Generally not recommended for ocular myasthenia gravis

Plasmapheresis

General explanation

• Removal of plasma in exchange for fresh frozen plasma, albumin, or a plasma substitute
• Removes acetylcholine antibodies from the body to temporarily lessen symptoms of myasthenia gravis 
• May reduce moderate to severe muscle weakness
• Improvements are noticed within a few days and may last for 1 to 3 months 
• Hospitalization is usually required

Indication

• Severe generalized or fulminating myasthenia gravis refractory to other treatments 

Contraindications

• Patient is unable to tolerate central line placement
• Patient is septic or hemodynamically unstable

Complications

• Transfusion-related reactions
• Hypotension 
• Hypocalcemia 
• Hypomagnesemia
• Thrombocytopenia

Comorbidities

• Hyperthyroidism 
  • Control is important, as thyroid disease can adversely affect myasthenic weakness

Special populations

• Pregnant women 
  • Begin planning well in advance of any potential pregnancy to allow time for myasthenic status stabilization and drug optimization
  • Involve multidisciplinary team of relevant specialists throughout pregnancy, during delivery, and during neonatal period
  • Provided that myasthenia is under good control before pregnancy, the majority of women can be reassured that disease will remain stable throughout pregnancy and postpartum months
  • Spontaneous vaginal delivery is the goal and should be actively encouraged
  • Infants born to myasthenic mothers are at risk for transient myasthenic weakness (even if the mother’s myasthenia is well controlled) and should have rapid access to neonatal high-dependency support

Monitoring

• Regular follow-up evaluations by a neurologist are recommended to monitor the condition

Complications

• Respiratory failure is the most common complication
• Pneumonia is also common; aspiration pneumonia occurs owing to poor oropharyngeal muscle function

Prognosis

• Course of disease is variable but typically progressive 
• In 10% to 15% of cases, weakness affects only the ocular muscles 
• In two-thirds of patients, maximum weakness occurs during the first year 
• Improvement may occur early but is rarely permanent; symptoms can fluctuate initially, then become more severe 
• Weakness left untreated for years becomes fixed; the most severely involved muscles can become atrophic 
• Most patients respond to treatment and many have long periods of improvement
• Many patients require long-term immunosuppressive therapy

Summary

• Myasthenia gravis (MG) is a long-term (chronic) condition that causes weakness in the muscles you can control (voluntary muscles).
• A symptom of MG is muscle weakness that gets worse with activity and gets better after rest.
• Sudden, severe difficulty breathing (myasthenic crisis) may develop after having an infection, a fever, or a bad reaction to a medicine.
• The goal of treatment is to improve muscle strength. Treatment may include medicines, lifestyle changes, physical therapy, surgery, plasmapheresis, or emergency breathing support.

Sources

Kerty E et al: EFNS/ENS guidelines for the treatment of ocular myasthenia. Eur J Neurol. 21(5):687-93, 2014 Reference