Myasthenia gravis

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.

• 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

• Autoreactive antibodies directed against postsynaptic acetylcholine receptors or receptor-associated proteins
• Association with other autoimmune diseases, including:
  • Hashimoto thyroiditis
  • Rheumatoid arthritis
  • Sarcoidosis
  • Systemic lupus erythematosus

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)

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

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

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)

Clinical course

• Symptoms worsen with increased muscle use throughout the day and improve with rest.
• Sometimes associated with exacerbating factors, including:
  • Medications
    • Muscle relaxants
    • Beta blockers
    • Benzodiazepines
    • Aminoglycosides, fluoroquinolones
    • Low-potency antipsychotics
    • Tricyclic antidepressants
    • D-penicillamine
  • Pregnancy
  • Stress
  • Infection

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.

• 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
  • Deep tendon reflexes are not affected.
• Respiratory muscle weakness: causes dyspnea

Muscle fatigue worsens throughout the day and with increased activity.

Approach

• Suspected cases of MG are generally confirmed via EMG and AChR antibodies.
• Chest CT to rule out thymoma

Laboratory studies

• AChR antibody test (most specific test)
  • 80–90% of patients with generalized MG have antibodies ^[4]
  • 100% of patients with thymoma have antibodies ^[6]
• Other associated antibodies: anti-MuSK

Electrodiagnostics

• Electromyography (EMG): shows decremental response following repetitive nerve stimulation

Imaging

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

Other tests

• Edrophonium test (Tensilon test)
  • Used to diagnose MG before AChR antibody test became the common method
  • Symptoms improve rapidly after administration of a short-acting acetylcholinesterase inhibitor
  • High false positive rate
• Simpson test
  • Provocation test used to reproduce eyelid fatigue
  • Positive if looking upward for > 1 minute (without lifting the head) provokes eyelid fatigue
• Ice test: ice pack placed on one eye for 5 minutes → temporary improvement of eyelid fatigue

Lambert-Eaton myasthenic syndrome (LEMS)

• Definition: rare autoimmune disease that reduces neuromuscular transmission, leading to muscle weakness
• Etiology
  • Paraneoplastic: associated with small-cell lung carcinoma (in ⅔ of LEMS cases)
  • Associated with other autoimmune diseases
• 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
  • Physical examination
    • Active muscle contraction or repeated muscle tapping increases reflex activity.
    • Lambert sign: physical examination finding in which a patient's muscle strength improves with repetitive or ongoing use (e.g., muscle force gradually increases when a patient with LEMS is asked to squeeze the examiner's hand)
  • EMG: Repetitive nerve stimulation results in incremental responses.
  • Confirmatory test: serologic detection of anti-VGCC antibodies
  • Other: chest, abdomen, and pelvic CT for evaluation of an underlying malignancy
• Treatment ^[8]
  • Paraneoplastic LEMS: therapy of 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 MG and LEMS

Other differential diagnoses

• Congenital myasthenic syndrome
  • Genetic defects in proteins of the neuromuscular junction (NMJ) lead to neuromuscular disease
  • Presents with similar symptoms as MG (depends on the type of defect), but typically start during infancy or childhood
• Amyotrophic lateral sclerosis
• Chronic progressive external ophthalmoplegia (for ocular symptoms)

The differential diagnoses listed here are not exhaustive.

Pharmacotherapy

• First line: cholinesterase inhibitors
  • Drug of choice: pyridostigmine
  • Only improve symptoms (no causal treatment)
  • See “Indirect parasympathomimetics.”
• Supplemental immunosuppressants: if symptoms persist despite anticholinesterase treatment
  • Glucocorticoids
  • Alternatives are azathioprine, cyclosporine, mycophenolate mofetil

Surgery

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

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
  • IVIg 400mg/kg for 5 days
  • Plasmapheresis
  • Early endotracheal intubation

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 ^[10]

• 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.