Myasthenia gravis

Myasthenia gravis (MG) is an autoimmune disease of the neuromuscular junction (NMJ) characterized by muscle weakness that worsens with activity and improves with rest. MG is caused by autoantibodies directed against postsynaptic molecules, most commonly acetylcholine receptors (AchR), resulting in impaired neuromuscular transmission. Women are more frequently affected; ∼ 10–15% of cases are associated with thymoma. The most common initial symptom is ocular muscle weakness (e.g., ptosis and/or diplopia), with progression to generalized weakness typically occurring within two years. The diagnosis is clinical and confirmed by antibody testing and electromyographic evaluation. Treatment of choice consists of acetylcholinesterase inhibitors; immunosuppressive drugs can be added if symptoms persist. All patients with MG should be screened for thymoma with CT chest. Thymectomy is indicated for patients with confirmed thymoma. Acute exacerbations, as seen in myasthenic crises, are generally treated with either IV immunoglobulins or plasma exchange.

• Prevalence: most common neuromuscular junction disorder ^[1]
• Sex: ♀ > ♂ (3:2)
• Peak incidence ^[2]
  • ♂ : 40–70 years
  • ♀ : 20–40 years

Epidemiological data refers to the US, unless otherwise specified.

Autoimmune

• Autoantibodies directed against postsynaptic acetylcholine receptors or receptor-associated proteins
  • Most common: acetylcholine receptor antibodies (AChR-Ab)
  • Less common: muscle-specific tyrosine kinase antibodies (MuSK-Ab), lipoprotein receptor-related protein antibodies (LRP4-Ab), or no detectable antibodies
• Association with other autoimmune diseases, including:
  • Hashimoto thyroiditis
  • Rheumatoid arthritis
  • Sarcoidosis
  • Systemic lupus erythematosus

A minority of patients with myasthenia gravis have no detectable antibodies (i.e., seronegative MG). 100% of patients with thymoma have autoantibodies.

Associated conditions ^[3]

• Thymoma (the most common primary tumor in the anterior mediastinum) in 10–15% of patients
• Thymic hyperplasia in 65% of patients
• Graft-versus-host reaction after allogeneic stem cell transplantation (especially in children)

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

Thymus involvement

• Muscle-like (myoid) cells in the thymus express AChR → autoreactive targeting by T cells → production of acetylcholine receptor antibodies (AChR antibodies)

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 muscle-specific tyrosine kinase antibodies (MuSK antibodies)

Symptoms ^[5]

Severity typically varies during the day and from day to day

• Fatigable weakness of skeletal muscles that worsens with increased muscle use and improves with rest.
• Generalized disease can involve all skeletal muscles, especially:
  • Eye muscles: diplopia, blurred vision ^[6]
  • Bulbar muscles: dysarthria, difficulty chewing and/or swallowing, dyspnea
  • Proximal muscles: difficulty standing from a chair , climbing stairs, brushing hair ^[6]
  • Respiratory muscles: dyspnea, respiratory failure
• Localized disease most commonly affects the eye muscles.

Eye muscle involvement is the most common initial symptom in generalized disease; larger muscles are involved later in the disease course. ^[6]

Physical examination findings ^[5]

Physical examination may be completely normal in patients with myasthenia gravis, especially in mild cases.

• Normal deep tendon reflexes
• Limb weakness is typically symmetrical.
• Ocular weakness (e.g., ptosis) is typically asymmetrical. ^[1]
• Examination and proactive maneuvers can elicit typical ocular findings. ^[1]
  • The eyebrow of the unaffected eye is usually lower than the affected eyebrow. ^[5]
  • Ice-pack test: An ice pack placed on the affected eyelid for 5 minutes improves ptosis by ≥ 2 mm. ^[5][6]
  • Curtain sign: Lifting the more ptotic eyelid worsens ptosis in the contralateral eyelid; eyebrow elevation and furrowing of the forehead can also occur.
  • Cogan lid twitch sign: brief eyelid twitching when looking straight ahead after 10–20 seconds of downward gaze ^[5]
  • Simpson test: historically used to reproduce eyelid fatigue; positive if looking upward for > 1 minute (without lifting the head) provokes eyelid fatigue

Exacerbating factors of myasthenia gravis ^[7]

The following factors may worsen symptoms of MG and/or trigger a myasthenic crisis.

• Infection
• Surgery, anesthesia
• Pregnancy ^[5]
• Medications
  • Antibiotics (e.g., fluoroquinolones, aminoglycosides, macrolides)
  • Cardiovascular drugs (e.g., procainamide, quinidine, beta blockers)
  • Psychiatric drugs (e.g., chlorpromazine, risperidone, lithium)
  • Glucocorticoids
• Stress, heat

In patients with characteristic fatigable muscle weakness, confirm the diagnosis with serum auto-antibodies or; , if negative, by electromyography (EMG). ^[5]

Laboratory studies ^[5][6]

Results can confirm the diagnosis and be used to classify MG into subgroups depending on the antibody profile.

• Initial test: anti-AChR antibodies (highly specific for MG) ^[5][6][8]
• Subsequent tests
  • If intial AChR-Ab test is negative: anti-MuSK antibodies
  • Further Ab testing in consultation with a neurologist ^[1][5]

Consider diagnostic studies for other autoimmune disorders (e.g., Hashimoto thyroiditis, rheumatoid arthritis, SLE) in patients with suggestive symptoms.

Additional studies ^[5][6]

• EMG of affected muscles ; ^[5]
  • Indication: patients with clinical features of myasthenia gravis and negative autoantibodies
  • Findings: decremental response to repetitive nerve stimulation
• Chest CT: indicated in all patients with confirmed myasthenia gravis to assess for a thymoma or thymic hyperplasia
• Edrophonium test: administration of a rapid-acting, short-duration acetylcholinesterase inhibitor to assess for symptom improvement in patients with suspected myasthenia gravis
  • Historically used to diagnose myasthenia gravis; currently replaced by the more specific and sensitive anti-AChR antibody test
  • No longer available in the U.S.

The edrophonium test was discontinued by the FDA in 2018 because of high false-positive rates.

Lambert-Eaton myasthenic syndrome (LEMS) ^[9]

• Definition: rare neuromuscular junction disorder characterized by proximal muscle weakness and autonomic dysfunction
• Etiology
  • Paraneoplastic: associated with small-cell lung carcinoma (in ⅔ of patients with LEMS)
  • Primary autoimmune disorder
• 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; muscle strength improves with repetitive or ongoing use
  • Reduced or absent reflexes
  • Autonomic symptoms
    • Dry mouth
    • Constipation
    • Erectile and ejaculatory dysfunction
    • Orthostatic dysregulation
• Diagnostics
  • Physical examination
    • Active muscle contraction or repeated muscle tapping increases reflex activity.
    • Lambert sign: hand grip strength gradually increases over several seconds ^[10]
  • EMG: Repetitive nerve stimulation results in incremental responses.
  • Confirmatory test: anti-VGCC antibodies in serum
  • Other: CT chest, abdomen, and pelvis to screen for underlying malignancy
• Treatment ^[11]
  • Paraneoplastic LEMS: Treat the underlying malignancy.
  • First-line to improve neuromuscular transmission: amifampridine
    • Orphan drug used as first-line treatment of Lambert-Eaton myasthenic syndrome
    • Blockade of presynaptic potassium channels → ↑ AP duration → ↑ presynaptic calcium concentrations

Comparison of Myasthenia gravis and LEMS

Other differential diagnoses

• Congenital myasthenic syndrome
  • Genetic defects in proteins of the neuromuscular junction (NMJ) lead to neuromuscular disease.
  • Presents similarly to myasthenia gravis (depending on the type of defect), but typically starts during infancy or childhood
• Amyotrophic lateral sclerosis
• Chronic progressive external ophthalmoplegia (for ocular symptoms)

The differential diagnoses listed here are not exhaustive.

General principles

• For patients with MG and difficulty breathing, admit to the hospital to rule out or treat myasthenic crisis.
• Provide supportive therapy and avoid exacerbating factors for myasthenia gravis.
• Treatment aims to control symptoms but is not curative.
  • Titrate pharmacotherapy to minimize adverse effects, usually in consultation with a neurologist.
  • Refer for thymectomy based on disease subtype and adequacy of pharmacological symptom management.

Supportive therapy ^[5]

• Provide age-appropriate immunizations; see “Overview of ACIP Immunization Schedule.”
• Encourage low-to-moderate intensity physical activity, and provide obesity management.
• Correct visual impairment.
• Educate patients about common exacerbating factors of MG (e.g., fluoroquinolones).

Avoid the use of muscle relaxants, fluoroquinolones, macrolides, and aminoglycosides in patients with myasthenia gravis because of the risk of worsening muscle weakness. ^[12]

Pharmacotherapy

• Cholinesterase inhibitor: first-line agent is pyridostigmine titrated to symptom relief ^[6]
• Immunosuppressants (off-label)
  • Indications: inadequate symptom control with (or intolerance to) pyridostigmine
  • Common initial regimen: glucocorticoids (e.g., prednisone ) and/or azathioprine ^[1]

Glucocorticoids may be a part of the management of myasthenia gravis; however, caution is required as they have been associated with myasthenic crises in 9–18% of patients, especially within the first two weeks of initiating treatment. ^[7][12]

Thymectomy ^[5]

• Consider for:
  • Most patients with thymoma, based on surgical risk factors and adequacy of medical management
  • Select patients without thymoma in whom immunotherapy is not successful or not tolerated
• Potential benefits include:
  • Reduced symptoms and exacerbations
  • Decreased doses of pharmacotherapy

Patients with rare subtypes of MG (e.g., MuSK-Ab) generally do not benefit from thymectomy. ^[12]

Myasthenic crisis ^[6][7]

• Definition: acute, life-threatening exacerbation of myasthenic symptoms that leads to respiratory failure
• Epidemiology
  • Affects 15–20% of patients with myasthenia gravis ^[6][7]
  • Most commonly occurs within 3 years of disease onset ^[6]
• Precipitating factors: unidentifiable in up to 50% of cases ^[7]
  • Physiologic stress, e.g., infection (most common), surgery, anesthesia, pregnancy
  • Medications
  • See also “Exacerbating factors of myasthenia gravis.”
• Differential diagnosis: cholinergic crisis due to an excessive dose of acetylcholinesterase inhibitors (very rare) ^[7]
• Management: Treat as a life-threatening emergency in consultation with neurology and critical care. ^[5]
  • Consider serial spirometry and respiratory muscle function testing.
  • Intubate early if risk of respiratory failure is high, e.g.: ^[13]
    • Increasing generalized weakness, dysphonia, or dyspnea at rest
    • Vital capacity < 15 mL/kg or maximal inspiratory pressure is less negative than –30 cm H₂O
  • Follow ventilation strategy for neuromuscular weakness.
  • Review new medications; consider stopping known exacerbating factors of myasthenia gravis. ^[12]
  • Consider pharmacotherapy with specialist guidance.
    • High-dose prednisone
    • PLUS IVIg; or plasma exchange ^[7]

∼ 60–90% of patients with myasthenic crises require intubation with mechanical ventilation. Elective intubation is preferred over emergent intubation. ^[7]

Differential diagnosis of myasthenic crisis and cholinergic crisis

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

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

Myasthenia gravis during pregnancy ^[14]

• Risk of developing myasthenia gravis is increased in pregnant and postpartum individuals.
• Myasthenic symptoms often worsen during pregnancy, most commonly during the first trimester.
• Pregnant individuals are at increased risk of myasthenic crisis.
• Cesarean sections are commonly required for pregnant patients with MG because of ineffective contractions due to muscle weakness and risk of exhaustion during vaginal delivery.
• In about 10% of cases, newborns develop transient neonatal myasthenia (due to the transfer of maternal antibodies), which usually manifests with swallowing and sucking difficulties.

In the case of preeclampsia, individuals with myasthenia gravis should not be treated with magnesium sulfate since it worsens myasthenia symptoms.