Myasthenia Gravis

Myasthenia gravis (MG) is an autoimmune neuromuscular disorder characterized by weakness and fatigability of skeletal muscles caused by dysfunction/destruction of acetylcholine receptors at the neuromuscular junction. Myasthenia gravis presents with fatigue, ptosis, diplopia, dysphagia, respiratory difficulties, and progressive weakness in the limbs, leading to difficulty in movement. Diagnosis is established based on clinical presentation, detection of antibodies, and electrophysiologic studies. Management is aimed at increasing the activity of acetylcholine at the neuromuscular junction and suppression of antibodies. This disease can be associated with thymomas and thymic hyperplasia, and thymectomy is sometimes indicated. Myasthenia gravis can progress to a life-threatening cholinergic crisis with respiratory failure, but this is preventable with appropriate management. Prognosis is generally good with treatment, and some patients can achieve a long-term remission.

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Overview

Definition

Myasthenia gravis (MG) is a chronic autoimmune disorder in which antibodies attack the acetylcholine receptor (AChR) complex at the neuromuscular junction.

Epidemiology

  • Annual incidence: 7–23 cases per million
  • Female-to-male ratio: 3:2
  • Can occur in any age group, but peak incidence observed in women in their 20s and 30s and men in their 50s and 60s
  • Commonly affects women in the postpartum period
  • 50% of patients initially present with ocular symptoms and within a year develop generalized symptoms such as weakness or fatigue.
  • There has been a dramatic decrease in mortality from 75% to 4.5% due to changes in treatment.

Etiology

  • Antibodies against AChRs:
    • Autoantibodies act at the neuromuscular junction and either block acetylcholine binding or destroy the receptor sites.
    • Autoantibodies can also block the action of muscle-specific tyrosine kinase (MuSK), which is a transmembrane component of the neuromuscular junction.
  • Thymus gland:
    • Research suggests that the thymus gland is involved in the maintenance of antibodies against AChRs.
    • Some patients diagnosed with MG have associated thymomas (10%), and the MG can present as paraneoplastic syndrome secondary to thymomas.
    • 60%–80% have thymic hyperplasia.
  • Antibodies against lipoprotein-related protein 4:
    • Some patients with MG do not have antibodies against AChRs or MuSK; instead, they develop antibodies against lipoprotein-related protein 4.
    • This type of MG is called antibody-negative MG.
    • Lipoprotein-related protein 4 is present on the postsynaptic membrane and induces clustering of AChRs.

Classification and Pathophysiology

Classification

There are 2 main clinical forms of MG:

  • Ocular myasthenia: weakness is limited to the eyelids and extraocular muscles and is characterized by ptosis and oculomotor paresis.
  • Generalized myasthenia:
    • Weakness not only occurs in the ocular muscles but also affects the bulbar, limb, and respiratory muscles.
    • Weakness can be proximal, distal, symmetric, or asymmetric.

In addition, rarer forms of MG exist that primarily affect the pediatric population:

  • Neonatal MGs:
    • A rare condition that occurs when mothers with MG have children who are born with the disorder.
    • Transplacental passage of maternal antibodies that attack the neuromuscular junction
    • Immediate treatment can resolve the condition within 2 months after birth.
  • Congenital myasthenic syndrome:
    • A rare, hereditary form of myasthenia that is present from birth.
    • This syndrome may be the result of rare mutations that affect the neuromuscular transmission.

Myasthenia gravis may also be classified on the basis of the serologic profile of antibodies present:

  • Presence of antibodies against either AChR or MuSK is referred to as seropositive MG:
    •  AChR-positive MG:
      • Presents primarily with proximal limb muscle weakness
      • Facial, bulbar, and respiratory weakness may also be present.
      • Present in about 80% of MG cases
      • Present in 30%–40% of ocular MG
      • 20% chance of remission 
    • MuSK-positive MG:
      • Presents primarily with facial, bulbar, and respiratory weakness
      • No or relatively mild limb weakness
      • Common in younger female patients
      • Present in 30%–40% of MG cases in which AChR antibody is absent
      • Less chance of remission
  • Absence of either AChR or MuSK in the presence of clinical signs/symptoms is referred to as seronegative MG (15% of cases).

Pathogenesis

  • AChR antibodies (produced in the thymus):
    • Are IgG1 and IgG3 subtypes and divalent
    • Antibodies target AChRs on the postsynaptic membrane.
    • Antibodies activate the classical complement pathway, which in turn activate the membrane attack complex (MAC).
    • The reaction is classified as type 2 hypersensitivity reaction (i.e., it causes cytotoxic injury).
    • MAC causes a calcium influx that damages the postsynaptic membrane, which in turn damages the AChRs.
  • MuSK antibodies:
    • Mostly IgG4 subtype
    • The pathogenesis is not exactly delineated.
  • Effects on neuromuscular junction:
    • Damage to the AChRs leads to decreased binding of acetylcholine, which in turn impairs signal transduction at the neuromuscular junction.
    • Decreased response causes failure of muscle contraction, which causes skeletal muscle weakness and fatigue.
Myasthenia gravis pathophysiology

Pathophysiology of myasthenia gravis

Image by Lecturio.

Clinical Presentation

General characteristics

  • Myasthenia gravis initially presents as a specific muscle weakness that progresses through the day and worsens with exertion.
  • Around 50% of patients initially present with ocular symptoms.
  • Fatigability is a hallmark feature, for example:
    • Diplopia onset or worsening after reading for a while
    • Adequate energy/strength at the onset of a task that wanes with time
  • Absence of sensory symptoms/findings
  • Normal deep tendon reflexes (DTRs)
  • Normal autonomic function

Ocular symptoms

  • Ptosis
  • Diplopia
  • Ophthalmoplegia
  • Lagophthalmos
  • Curtain sign: increase in ptosis due to sustained upward gaze
  • It is important to note that there are no pupillary findings.
Ptosis in myasthenia gravis

Ptosis in a patient with myasthenia gravis

Image: “Myasthenia Gravis” by Posey & Spiller. License: Public Domain

Bulbar symptoms

  • Dysarthria
  • Dysphagia
  • Nasal/hypophonic speech
  • Weak mastication
  • Nasal regurgitation/aspiration

Facial symptoms

  • Facial paralysis
  • Myasthenic sneer/snarling expression: drooping of the corner of the mouth

Neck and limb symptoms

  • Dropped head syndrome: Weakening of the extensor muscles leads to dropping of the head, which in turn causes pain in the posterior neck muscles owing to an effort to keep the head straight.
  • The proximal muscles are more involved than the distal muscles.
  • The arm muscles are more involved than the leg muscles.

Respiratory symptoms

  • Dyspnea
  • Weak breathing
  • Respiratory failure: rare but serious cause of morbidity and mortality (< 1%)

Cholinergic crisis

  • Life-threatening acute exacerbation of symptoms of MG
  • Myasthenia crisis presents as: 
    • Buildup of saliva that causes drooling
    • Jaw or tongue weakness
    • Dysarthria
    • Dyspnea/labored breathing/shallow breathing
    • Respiratory failure due to weakness in the diaphragmatic and intercostal muscles
  • Seen in around 15%–20% of patients with MG
  • Mechanical ventilation is often required.

Aggravating factors for disease exacerbation

  • Fatigue
  • Stress or exertion
  • Infection
  • Irregularity in taking MG medication
  • Sudden or inappropriate tapering of immunosuppressants
  • Medications:
    • Beta-blockers
    • Calcium channel blockers
    • Phenytoin
    • Quinidine 
    • Lithium
    • Aminoglycosides
    • Ketamine
    • Lidocaine
  • Pregnancy and the postpartum period
  • Menstruation, premenstrual syndrome
  • Progression of chronic conditions (cardiac/renal/autoimmune diseases)

Diagnosis

Serologic tests

  • Serum detection of antibodies against AChRs:
    • Performed with prominent objective weakness
    • Highly specific: around 80% in generalized MG and 30%–40% in ocular myasthenia
  • 3 variations of AChR antibodies: 
    • Binding antibodies:
      • Activate complement → loss of AChRs
      • Sensitivity is high.
      • False positives are rare.
    • Modulating antibodies:
      • Causes antigenic modulation → receptor endocytosis
      • 2%–4% of patients with negative binding antibodies will have modulating antibodies.
      • 73% of patients with thymoma and MG will have modulating antibodies.
    • Blocking antibodies:
      • Act as a competitive antagonist at the AChR
      • Present in 50% of patients with generalized MG and 30% of patients with ocular MG
      • < 1% of patients have only blocking antibodies (without detectable binding or modulating antibodies).
  • Other antibodies tested are:
    • Anti-MuSK antibody
    • Anti–striated muscle antibody (present in 80% of thymomatous MG)
    • Anti–lipoprotein-related protein 4 antibody
    • Anti-agrin antibody
  • Antinuclear antibodies and rheumatoid factor are tested to rule out systemic lupus erythematosus.

Clinical tests

  • Ice-pack test:
    • Principle: Lower temperatures improve neuromuscular transmission.
    • Procedure: Bag filled with ice is placed on the closed eyelid for 2 minutes, after which the bag is removed to assess the extent of ptosis.
    • Inference: Improvement in ptosis after 1-minute application is a positive result.
    • Sensitivity is around 80%.
  • Edrophonium/tensilon test: 
    • This test is used only in areas where edrophonium is available. This test is currently not used in the United States, as the drug is not available.
    • Only used in patients with obvious ptosis or ophthalmoparesis
    • Principle: Edrophonium chloride is an acetylcholinesterase (AChE) inhibitor with a rapid onset and short duration of action.
    • Procedure: 
      • An initial test dose of 2 mg is given, followed by another dose of 2 mg every 60 seconds until a response is elicited.
      • The maximum dose given is 10 mg.
    • Inference: Improvement in ptosis is a positive result.

Electrodiagnostic tests

  • Nerve conduction velocity:
    • Measures transmission speed of sensory or motor nerves
    • Decremental response with repetitive nerve stimulation: present in > 90% of MG cases
  • Single-fiber electromyography (EMG): 
    • This test measures the electrical activity of the impulses between the brain and the muscle.
    • Small needles are inserted around the eyes, forehead, and arms.
    • Disruption of signal transduction (also known as “jitter”): present in > 90% MG cases

Imaging

MRI or CT of the chest is done to rule out the possibility of a thymoma.

CT thymoma

CT scan showing a large thymoma

Image: “Association between thymoma and persistent hypothermia: a case report” by Johns RH, Reinhardt AK. License: CC BY 2.0

Management

Pharmacotherapy

Acetylcholinesterase inhibitors:

  • Useful for mild and moderate forms of MG
  • Increase the amount of acetylcholine available by preventing its breakdown
  • The most commonly used drug is pyridostigmine, an oral AChE inhibitor.
  • Usually combined with the immunosuppressive agents:
    • In generalized MG
    • In patients symptomatic even after being on pyridostigmine therapy
  • Adverse effects (muscarinic):
    • Abdominal cramps
    • Diarrhea
    • Bradycardia
    • Increased salivation
    • Increased bronchial secretions

Chronic immunosuppressive drugs:

  • Glucocorticoids:
    • The most common glucocorticoid used is prednisone.
    • Transient worsening of symptoms is a common adverse effect of glucocorticoids; hence, an initial dose-escalation regimen is considered.
    • After the required dose is achieved, the dose is kept constant for a while and gradual tapering of the drug is considered to avoid a relapse.
    • Adverse effects:
      • Weight gain
      • Easy bruising
      • Hypertension
      • Diabetes
      • Osteoporosis 
    • Monitoring: 
      • Appropriate diet, calcium and vitamin supplementation
      • Periodic measurement of bone density
      • Routine monitoring of blood pressure and serum glucose
      • Yearly cataract and glaucoma test
      • Pneumocystis pneumonia prophylaxis in patients on a higher dosage of prednisone
  •  Nonsteroidal immunosuppressive drugs:
    • Azathioprine: 
      • Purine analog that inhibits the synthesis of nucleic acids
      • Interferes with T- and B-cell proliferation
      • Lowers AChE antibodies 
    • Mycophenolate mofetil: inhibits lymphocyte proliferation by blocking purine synthesis 
    • Tacrolimus: 
      • Inhibits calcineurin and the production of IL-2 
      • Inhibits T-lymphocyte–dependent immune response
      • Adverse effects:
        • Hyperglycemia
        • Hypomagnesemia
        • Tremors
        • Paresthesia
    • Cyclosporin: 
      • Action is similar to that of tacrolimus
      • Adverse effects: nephrotoxicity and hypertension

IV immune therapy

  • Plasmapheresis:
    • Removes AChR or MuSK antibodies from the circulation
    • Plasmapheresis is considered only in an emergency such as dysphagia or respiratory failure, as it is associated with adverse effects and is expensive.
    • Adverse effects observed are:
      • Hypotension
      • Infection
      • Thrombosis
    • Contraindicated in patients with sepsis
    • 1 session/day × 5 days
    • Onset of action: 3–10 days
    • Duration of action: 3–6 weeks
  • IV immunoglobulin (IVIG): 
    • IV immunoglobulin is also a treatment option considered only when there is an emergency, especially if respiratory failure is the presenting symptom.
    • IV infusion of donor immunoglobulin can modulate the immune system and reduce the effects of autoantibodies (can be performed through a peripheral IV).
    • Less effective in mild or moderate MG
    • Adverse effects:
      • Headache
      • Chills
      • Dizziness
      • Fluid retention
      • Thrombosis
      • Anaphylaxis
      • Aseptic meningitis
      • Acute renal failure
    • Contraindicated in patients with renal failure
    • 0.4 g/kg/day × 5 days
    • Onset of action: 14 days
    • Duration of action: 30 days
  • Monoclonal antibodies:
    • Rituximab: effective in the treatment of MuSK MG
    • Eculizumab: 
      • Monoclonal antibody directed toward complement 5
      • Effective in patients with generalized MG who are AchR antibody–positive 

Thymectomy

  • Research suggests that in patients who undergo thymectomy when indicated, remission and decreased drug dependency are observed.
  • Indications are: 
    • Patients with thymoma
    • Patients without thymoma:
      • Positive anti-AChR antibody
      • < 60 years of age with generalized MG
  • Thymectomy is not recommended in patients with MuSK antibodies.

Management of cholinergic crisis

  • Intubation/mechanical ventilation may be performed electively prior to the development of emergent situations.
  • Cholinesterase inhibitor therapy is stopped temporarily.
  • Rapid therapies include plasmapheresis and IVIG.
  • Immunosuppressive drugs are started at a moderate to high dose.

Prognosis

  • With the development in treatment over the decades, the prognosis of patients has significantly improved, and patients can lead nearly normal lives.
  • Few cases can go into remission either temporarily or permanently.
  • In 50% of the cases, thymectomy can lead to stable and complete remission.

Differential Diagnosis

  • Eaton–Lambert syndrome: autoimmune neuromuscular junction syndrome associated with small-cell lung carcinoma: Symptoms include muscle weakness (temporarily relieved on exertion), ptosis, dry mouth, bladder and bowel changes, erectile dysfunction, and paresthesia. Eaton–Lambert syndrome is diagnosed by antibody detection, electromyography, and imaging of lungs. Treatment includes immunosuppressants and addressing the malignancy.
  • Guillain–Barré syndrome: autoimmune disorder of the peripheral nervous system triggered by an acute bacterial or viral infection: Guillain–Barré syndrome presents with initial paresthesias in the feet and legs progressing to ascending paralysis. The syndrome is diagnosed by CSF analysis, electromyography, and nerve conduction studies. Guillain–Barré syndrome is managed with plasmapheresis and immunoglobulin therapy, analgesics, blood thinners, and physiotherapy.
  • Amyotrophic lateral sclerosis: group of neurologic disorders that involve neurons associated with voluntary movement: Clinical presentation includes fasciculations, muscle cramps, spasticity, and dysarthria, which are progressive over time. There is no definitive test, and diagnosis relies heavily on history and physical examination. Treatment includes supportive care, as no cure has been found yet.
  • Botulism: foodborne infectious neuromuscular junction disease caused by the organism Clostridium botulinum. Clinically, botulism presents with ptosis, abdominal cramps, symmetric neurologic deficits, diplopia, and blurred vision. Botulism is diagnosed by isolation of the organism and detection of toxin in the serum or food source. Botulism is treated with botulinum antitoxin, immunoglobulin, and physiotherapy.
  • Tick paralysis: Tick paralysis is caused by injection of toxin through the bite of a tick. Symptoms occur within 2–7 days after the bite. Clinical presentation includes initial numbness and weakness in both legs that progresses to ascending paralysis and respiratory distress within hours. Deep tendon reflexes are decreased or absent. Diagnosis is based on symptoms and finding an embedded tick, usually on the scalp. Managed by finding and removing the tick, cleaning the site of the bite, and monitoring for respiratory distress.

References

  1. Mayo Clinic. Myasthenia gravis (2019). https://www.mayoclinic.org/diseases-conditions/myasthenia-gravis/symptoms-causes/syc-20352036
  2. Goldenberg, W.D., Sinert, R.H. (2018). Emergent management of myasthenia gravis. Medscape. https://emedicine.medscape.com/article/793136-overview#a1
  3. Bird, S.J. (2020). Pathogenesis of myasthenia gravis. UpToDate. https://www.uptodate.com/contents/pathogenesis-of-myasthenia-gravis
  4. Bird, S.J. (2019). Clinical manifestations of myasthenia gravis. UpToDate. https://www.uptodate.com/contents/clinical-manifestations-of-myasthenia-gravis
  5. Philips, W.D., Vincent, A. (2016). Pathogenesis of myasthenia gravis. NCBI. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4926737/
  6. Jowkar, A., Goldenberg, W.D (2018). Myasthenia gravis. Medscape. https://emedicine.medscape.com/article/1171206-overview#a1
  7. Longo, D. L. Fauci, A. S. Kasper, Hauser, S., Jameson, J. L., Loscalzo, J. (2011). Myasthenia gravis and other diseases of the neuromuscular junction. Harrison’s Principles of Internal medicine. 18th ed. pp. 6813–6824.

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