Author(s): Dana Sheng, MD, Lisa Williams, MD
Originally published: November 11, 2011 Last updated: March 9, 2021
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Disease/ Disorder

Definition

Myasthenia Gravis (MG) is an uncommon heterogenous neuromuscular junction disorder categorized into adult and pediatric MG. It is clinically characterized by fluctuating skeletal muscle weakness (without sensory or autonomic dysfunction), as well as fatigability, including a predilection for oculobulbar musculature. These symptoms can occur in isolation or in combination.1,2,3,4

Pediatric MG includes juvenile autoimmune MG, congenital myasthenia gravis (CMS), including several inherited disorders of the neuromuscular junction, and transient neonatal MG caused by vertical transmission of autoantibodies from mother to newborn. Adult MG is characterized by autoantibodies to the presynaptic nicotinic acetylcholine receptor. We will focus our discussion on adult MG.

Epidemiology including risk factors and primary prevention

  • Myasthenia gravis is a disease of woman and older men with a bimodal peak age of onset: 20-35 and 70-75.1 Early-onset cases are predominantly in women, and late-onset cases more predominant in men. Women outnumber men below the age of 40 with a female to male predominance 7:3. Men outnumber woman at a rate of 3:2 after the age of 50. Although rare, with improved diagnostics and recognition, the current prevalence rate is 20/100,000. Disease incidence is between 1 and 9 per million1 and ranging from 0.3 to 2.8 per 100,000.5
  • Genetic testing has shown TNFRSF11A and HLA-DQA1 association signals to be more associated with older onset cases.6
  • Advanced age may be positively correlated with increased response to autoantigens.6

Etiology

  • The etiology is multifactorial involving both environmental and genetic risk factors. Autoimmune disturbances or abnormalities in the thymus gland, including thymoma in some cases, result in impairment of neuromuscular transmission.  The most common etiology includes autoantibodies targeting the nicotinic acetylcholine receptor (AChR).
  • Less common antibody targets are the muscle-specific (tyrosine) kinase (MuSK), low-density lipoprotein receptor-related protein 4 (LRP4), and agrin.6,7
  • Genetics has identified susceptibility loci within genes involved in immune response, including variation in the major histocompatibility complex (MHC) class II, protein tyrosine phosphatase nonreceptor type 22 (PTPN22), TNFAIP3 interacting protein 1 (TNIP1), and the cytotoxic T lymphocyte-associated protein 4 gene (CTLA4).6,7
  • Personal or family history of autoimmune disease (such as autoimmune thyroid disease, rheumatoid arthritis, and type 1 diabetes) is commonly seen in MG patients, with genetic data showing heritability up to 38%.6
  • An autosomal dominant pattern of inheritance may be seen in those with a family history of MG.

Patho-anatomy/physiology

  • In MG patients, the thymus undergoes hyperplastic changes leading to abnormal activation of Toll-like receptors (TLRs) and production of type 1 interferons (IFN-1), promoting anti-AChR autosensitization and abnormal immune system activation.7
  • Sensitization against AChRs occurs within the thymus gland resulting in an autoimmune attack on AChR present within myoid cells within the thymus gland. Autoantibodies then exit the thymus gland and bind to their NMJ targets, altering neuromuscular transmission by causing morphological and functional alterations of the postsynaptic membrane.8
  • There is also downregulation of regulatory T cells in MG patients with thymomas and thymus hypersplasia.7
  • MG patients have a higher frequency of AChR CD4 T cells with an inflammatory phenotype.8
  • Anti-AChR IgG antibodies bind to AChR at the post-synaptic NMJ. This causes decreased binding of the acetylcholine on AChR by multiple potential mechanisms: binding, blocking, or modulating antibodies. Binding activates complement, resulting in muscle membrane damage, degradation of the AChR, and blocking of the AChR binding site.
    • Physically blocking the AChR binding site prevents conformational changes necessary to carry out function.
    • Endocytosis of AChR-autoantibody complexes is accelerated by cross-linking of antibodies.
    • Complement-mediated destruction of the post-synaptic membrane occurs.
    • Flattening of the post-synaptic NMJ with fewer invaginations translates to less surface area and synaptic space.
  • Anti-MuSK antibodies inhibit binding of LRP4 to MuSK and reduce the postsynaptic density of AChRs.7
  • Anti-LRP4 antibodies disrupt the LRP4-agrin interaction, agrin-induced MuSK activation, and AChR clustering.7
  • Anti-agrin antibodies also disrupt LRP4 binding to MuSK and to collagen-like tail subunit of asymmetric acetylcholinesterase (ColQ), which anchors acetylcholinesterase to the basal lamina.8
  • All of the above mechanisms decrease acetylcholine on AChR binding, reducing the size of the resultant end-plate potential and decreasing the likelihood of crossing the necessary threshold voltage to cause an action potential.
  • The intermittent failure to reach action potential has electrophysiological and clinical effects: increased jitter/blocking on single fiber EMG (SFEMG), fluctuating motor unit action potentials (MUAP), decremental response on slow repetitive stimulation, and weakness1.

Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time)

  • Initial symptoms may be transient but may become generalized and persistent.
  • Symptoms may be limited to only the ocular muscles. 15-40% of MG patients with isolated oculomotor symptoms will not develop generalized disease. Those who develop generalized disease will usually do so in the first 2 years.1,5
  • Refractory MG may present with ventilator insufficiency along with dysphagia.
  • Myasthenic crisis refers to rapid, life-threatening, worsening of MG with potential airway compromise from respiratory or bulbar dysfunction.
  • Spontaneous remission is rare. However, children with juvenile ocular MG are more likely than adults to go into spontaneous remission.5
  • Transient neonatal myasthenia occurs within 3 days of life and lasts about 18-20 days.

Specific secondary or associated conditions and complications

  • MG is associated with other autoimmune diseases: rheumatoid arthritis, lupus, Sjogren syndrome, ulcerative colitis, sarcoidosis, Addison’s disease, and hyper- or hypo-thyroidism.2
  • Thymic abnormalities are commonly associated with MG. 70% of MG patients have thymic hyperplasia and 10% have thymoma. 55% of patients with a thymoma have MG.1
  • Epstein-Barr virus (EB) and Parvovirus presence in the thymus of MG patients suggests a link between viruses B-cell dysregulation and autoimmunity in thymomatous MG.7
  • Pregnancy may improve, worsen, or have no impact on symptoms.
  • Transient neonatal autoimmune MG occurs in newborns of mothers with MG. Antibodies to AChR are transferred passively through the placenta. Transient neonatal myasthenia occurs in 10% of neonates born to mothers with MG.
  • Penicillamine may induce immune-mediated MG, which remits on withdrawal of drug.

Essentials of Assessment

Myasthenia gravis is better represented as multiple syndromes or sub-groups. These can be categorized by the distinct type of auto-antibody.  Important associations including age at onset, sex, thymic histology, presence of additional autoantibodies, and clinical presentation may influence disease course. Please refer to Mantegazza et al 2018 Table 1 for more details.

Myasthenia-Gravis-Table-1Download

History

  • Painless weakness and fatigue involving any voluntary muscles is seen, with preference for proximal and oculobulbar muscles. Symptoms often fluctuate from day to day or hour to hour but are generally worse towards the end of the day.
  • Asymmetric ptosis with ocular weakness and binocular diplopia is the most common initial presentation, followed by characteristically fatigable proximal greater than distal muscle weakness. Bulbar involvement, often described as food bolus getting caught or stuck in the oropharynx, is less common on initial presentation and is not often found in isolation.   
  • Common bulbar symptoms include dysarthria, dysphagia, and difficulty with chewing, managing secretions, whistling, or puffing out the cheeks.
  • Shortness of breath may be reported due to diaphragmatic weakness and is often noticed when lying flat. Acute respiratory failure, one of the few true neuromuscular emergencies, is seen in severe cases and may be the presenting feature in ~15% of cases.
  • Cognition, muscle stretch reflexes, sensory, autonomic fibers, and bowel and bladder are spared.
  • Exacerbating factors include exercise, warmth, infections, anxiety, stress, and menses. Certain medications have been associated with MG exacerbation including macrolides, fluroquinolones, and aminoglycosides to name a few. NMJ blockers (e.g. curare, botulinum toxin) may also be causative. Other drugs including quinidine, procainamide, magnesium, beta-blockers and statins have also been associated with MG exacerbations. These exacerbations typically occur days to weeks after initiation of drug.
  • Drug-induced MG is clinically similar to autoimmune MG and is usually of slower onset, occurring weeks to months after treatment. It is most characteristically seen with penicillamine, associated with HLA-DR1. Other drugs including chloroquine and anti-programmed cell death (PD-1) antibodies have also been implicated.
  • Transient neonatal myasthenia is characterized by a weak cry, difficulty feeding, and respiratory difficulty.

Physical examination

  • Prolonged sustained contraction can elucidate muscle fatiguability seen as diplopia, ptosis, and bulbar and limb weakness.6 This can be accomplished by having patient repeatedly get in and out of a chair or sustain prolonged isometric muscle contractions. Ptosis is in some patients seen only with sustained upward gaze.
  • Disconjugate gaze and diplopia are due to extraocular muscle weakness.
  • Weakness may be seen with tongue protrusion, jaw opening, palate elevation, and neck flexion/extension.
  • Facial muscle weakness is usually present and produces an expressionless, sagging face and horizontal smile due to failure to withdraw the corners of the mouth.
  • 10% of cases may present focally with distal limb weakness, foot or wrist drop, or head drop.
  • Vital capacity (VC) can be measured with formal spirometry and can assist with the diagnosis and disease management.
  • Sensory exam is normal.
  • Deep tendon reflexes are normal.

Diagnostic Assessment:

Laboratory studies

  • Note: seronegative MG is not truly “seronegative”.
    • Seronegative MG classically refers to patients without anti-AChR antibodies.
    • Double-seronegative MG refers to patients without antibodies to AChR or MuSK.
  • AChR antibodies are seen in ~85% of patients with MG. MuSK or LRP4 antibodies are less common. (Renton et al 2015)) See below for details of specific antibodies.
    • Anti-AChR antibodies
      • 80-90% sensitive in generalized MG and 50% in ocular MG.1,2,9
      • May have false positives in thymoma without MG, Lambert-Eaton myasthenic syndrome (LEMS), lupus, rheumatoid arthritis, and autoimmune liver disease.
      • Associated with incidence of thymoma.
      • AChR antibody-negative MG is less common in elderly patients.6
    • Anti-Muscle specific tyrosine kinase (MuSK) antibodies
      • Seen in 1-5% of MG patients.7
      • Seen in 30-40% of AChR-negative patients.8
      • Associated with facial, oculobulbar, neck and respiratory symptoms.
      • Positive patients are more likely to be women.6,7
    • Anti-LRP4 antibodies
      • Seen in 1-33% of MG patients including double-seronegative MG.7
      • Positive patients more likely to be women.7
    • Anti-agrin antibodies
    • Antibodies to intracellular muscle proteins: Anti-titin, Anti-Ryanodine receptor, Anti-cortactin.8
      • Seen in 53% of AChR-positive and 27% of AChR-negative patients.
      • Often are  associated with thymoma. Rise in titers may indicate recurring thymoma post thymectomy.4
      • Also seen more frequently with late-onset MG.
    • Creatine kinase (CK) – normal.

Imaging

Chest CT scan is useful to evaluate for presence of thymoma.

Electrodiagnostic studies

  • Nerve conductions studies (NCS):
    • Both motor and sensory nerve conduction studies will be normal. (In contrast, in the pre-synaptic NMJ disorder, LEMS, the compound muscle action potential (CMAP) amplitude is usually low or borderline low at rest.)
  • Repetitive stimulation:
    • Slow repetitive nerve stimulation (RNS): with 2 or 3 Hz can be performed at abductor digiti minimi, biceps, deltoid, trapezius, or the nasalis. In MG, the yield of abnormal findings will be greater with evaluation of facial or proximal muscles than distal musculature. An abnormal decrement of >10% of CMAP amplitude or area can be elicited at baseline.
      • Technical factors must be controlled (e.g. maintaining isometric electrode position, supramaximal stimulation, temperature at least 33 degrees Celsius). Acetylcholinesterase inhibitors should have been held beforehand. Otherwise, the NMJ disorder can be missed.
    • Post-exercise facilitation with 10 seconds of maximal voluntary contraction may normalize the decrement created at baseline by slow repetitive stimulation. (In contrast, in LEMS, there is more than 100% increment from baseline seen after facilitation
      • Post-exercise facilitation is more notable in MG. Slow RNS performed 2-4 minutes after prolonged exercise results in a greater decline in endplate potential (compared to a normal subject) so that the threshold required to generate a muscle fiber action potential is not reached.
  • Needle Electromyography (EMG): EMG is useful in distinguishing an NMJ disease from other neuromuscular diseases (e.g. motor neuronopathy, polyneuropathy, radiculopathy and myopathy). see Tables 2 and 3 for a recommended protocol for evaluating NMJ disorders and MG specifically.9
    • Spontaneous activity: A key feature on EMG in MG or other NMJ diseases is the absence of abnormal spontaneous activity (fibrillations and positive sharp waves), except in botulism where abnormal spontaneous activity is commonly seen.
    • Motor Unit Activation: Due to intermittent junctional blockade and loss of individual myofibers, short duration, low amplitude motor unit action potential (MUAP) with early recruitment may be seen. MUAP morphology also fluctuates on triggered analysis, which is not seen in muscle disorders. Distal as well as proximal muscles should be examined, including biceps, triceps, and deltoid, which are involved in MG.9
  • Single fiber electromyography (SFEMG): SFEMG is the most sensitive test for MG (>95%), though nonspecific. Common muscles tested include the extensor digitorum communis, nasalis, or frontalis. Positive findings include abnormal jitter (variation in NMJ transmission), blocking (loss of NMJ transmission). It is important to test weak muscles, and if there is absence of jitter in a weak muscle, this would essentially exclude an NMJ disorder.9
Myasthenia-Gravis-Table-2Download
Myasthenia-Gravis-Table-3Download

Tensilon test

  • This is a bedside test for MG that uses Edrophonium (Tensilon), a short-acting acetylcholinesterase (AChE) inhibitor, which increases Ach availability at the NMJ and increases strength for several minutes. However, it is not as sensitive nor as specific as the serological test or RNS/SFEMG for MG. This test is also no longer commonly used.

Disease Management

Available or current treatment guidelines

  • Therapies range from symptomatic therapy to immunomodulation to immunosuppression, including cholinesterase inhibitors, thymectomy, corticosteroids, immunosuppressive agents, plasma exchange (PLEX), and intravenous immunoglobulin (IVIG).  
  • The benefit of some therapies such as thymectomy includes steroid sparing.
  • Thymectomy is recommended in generalized MG with thymoma under age 55. MG Report of the Quality Standards Subcommittee of the American Academy of Neurology:
    “…The benefit of thymectomy in non-thymomatous autoimmune myasthenia gravis has not been established conclusively.”4
  • Ocular myasthenia:
    “Given the absence of evidence, it is not possible to make any evidence-based recommendations regarding the effects of cholinesterase inhibitor, corticosteroids, or other immunosuppressive agents in improving the symptoms of ocular myasthenia.”10
  • Plasmapheresis in MG:
    “Because of the lack of randomized controlled studies with masked outcomes, there is insufficient evidence to support or refute the efficacy of plasmapheresis in the treatment of myasthenic crisis (Level U) or MG.”11,12
  • The Myasthenia Gravis Foundation of America (MGFA) Clinical Classification groups patients into different classes with by clinical features with increasing severity of diseases.13 The classes may correlate with prognosis or therapy response.
  • Quantitative MG score is an objective evaluation for disease severity as recommended by MGFA, with 13 items including evaluation of ocular, bulbar, respiratory, neck, and limb function.13
  • Therapy response can be assessed with the MGFA Postintervention Status in addition to the Quantitative MG Score (QMG Score).13
  • In October 2013, the Myasthenia Gravis Foundation of America appointed a task force to develop treatment guidance. Recommendations are below.5
  • Goals for treatment: MGFA Task Force Post-Intervention Status (PIS) classification Minimal Manifestation Status (MMS) or better,3 with no more than grade 1 Common Terminology Criteria for Adverse Events (CTCAE) medication side effects.5,13
    • “MMS: The patient has no symptoms or functional limitations from MG but has some weakness on examination of some muscles. This class recognizes that some patients who otherwise meet the definition of remission have mild weakness.”
    • “CTCAE grade 1 medication side effects: asymptomatic or only mild symptoms; intervention not indicated.”
  • Approximately 10% of patients are considered treatment-refractory.7,8

Summary of consensus guidance treatment statements:

Symptomatic and immunosuppressive treatment

  1. The acetylcholinesterase inhibitor Pyridostigmine should be part of the initial treatment in most patients.
  2. Steroids and/or non-steroidal immunosuppressants should be used when pyridostigmine fails, usually in combination, but dictated by steroid contraindication/risk of side effects.
  3. Non-steroidal immunosuppressants: Azathioprine, Cyclosporine, Mycophenolate mofetil, Methotrexate (MTX), Tacrolimus.
  4. Therapy options for refractory MG:
    • Chronic IVIG + PLEX
    • Cyclophosphamide
    • Rituximab
  5. Immunosuppressant treatment should be tapered as tolerated to maintain treatment goals
  6. Monitor for adverse effects.
  • IVIG and PLEX:
    1. They should be short-term treatments in notable situations especially myasthenic crisis, when rapid response is needed, or when other treatments are not effective.
    2. PLEX may be more efficacious in milder or ocular MG.
    3. IVIG and PLEX may be equally effective in severe, generalized MG.
    4. PLEX may be a better treatment in MuSK MG.
    5. IVIG may be used as maintenance in select cases e.g. in refractory MG.
  • Impending and manifest myasthenic crisis:
    1. Impending crisis should be admitted to the hospital, manifest crisis requires intensive care unit (ICU) or step-down unit care.
    2. PLEX and IVIG are used in manifest, and steroid or non-steroidal agents are started a few days after if not at the same time (Note: steroids may temporarily worsen symptoms).
    3. Despite clinical trial data suggesting equal effectiveness of IVIG and PLEX, expert consensus is that in impending or manifest myasthenic crisis, PLEX is better (quicker and more effective). As always, the choices are weighed based patient comorbidities.
  • Thymectomy:
    1. Can be used in non-thymomatous MG to avoid or limit immunosuppressant use (e.g if the patient does not respond well to such therapy).
    2. Can consider thymectomy in children with AChR antibody-positive MG.
    3. In general, MG patients with thymoma should have thymectomy (for the purpose of tumor removal; symptom improvement is not guaranteed).
  • Juvenile MG:
    1. The lowest effective dose of steroids, when needed, should be used given children have higher risk of steroid side effects.
    2. Chronic PLEX or IVIG can be used in lieu of immunosuppressant in juvenile MG.
  • MuSK-positive MG:
    1. These patients tend to respond poorly or not tolerate cholinesterase inhibitors.
    2. They respond well to steroids and non-steroidal immunosuppressant but often remain steroid-dependent.
    3. PLEX seems to be more effective than IVIG for these patients.
    4. Rituximab can be used early in MuSK MG patients who did not respond well to initial immunosuppressant.
  • Management of MG during pregnancy: Exacerbations of MG are more likely to occur during the first trimester and post-partum both the disease and treatments can have harmful effects on the fetus. Treatment should be individualized and avoidance of factors that may cause MG exacerbations is crucial (ie urinary tract infections, emotional stress, exertion). Several studies have shown pyridostigmine is safe during pregnancy. Steroids may also be safe, however, have a low risk of cleft palate. Further, mycophenolate, methotrexate and cyclophosphamide may have teratogenic affects.5

Specific Interventions at different disease stages

  • Ocular symptoms
    1. Many recommend symptomatic pharmacologic or non-pharmacologic treatments, including; pyridostigmine, patches or prism lenses for diplopia. Other adaptive devices include ptosis eye crutches, an addition to glasses to physically support the eyelid. This is accomplished with a bar that is placed along the inside of an eyewear frame that supports the drooping eyelid. The crutch is positioned where the orbital fold would typically be without Ptosis. The crutch should create a fold above the eye, tucking the lid in and raising it above the pupil.
    2. The benefit and risk of immunomodulating agents for ocular symptoms are controversial.
  • Generalized symptoms
    1. Initiate with pyridostigmine for acute symptomatic control.
    2. Immunomodulating agents are usually used. Steroids are ordered most commonly, though steroid-sparing agents are commonly used in combination with or instead of steroids (azathioprine, cyclosporine, mycophenylate mofetil, methotrexate, rituximab and others). Pyridostigmine, steroids, and a steroid-sparing immunomodulator are frequently started simultaneously, with the goal of weaning steroids to avoid long-term complications.12
  • Myasthenic crisis with respiratory failure requires immediate intensive care unit (ICU) monitoring and possibly mechanical ventilation (monitor negative inspiratory force [NIF] and VC). Plasma exchange should be initiated and is more effective than IVIG during crisis. IV methylprednisolone or oral prednisone may be started at the same time but used with caution due to initial exacerbation of symptoms.

Rehabilitation Management

  • Rehabilitation alone or in combination with medical treatment can improve symptoms in MG. A multidisciplinary rehabilitation approach is important to optimize functional abilities. This approach also has the goal of preventing further disease-associated illness (e.g. recurrent pneumonias). Such an approach includes therapy (physical therapy, occupational therapy, speech therapy, respiratory therapy) as well as evaluation for and training with assistive device, other durable medical equipment (DME), and/or orthotics.
  • Physical therapy evaluation includes assessment of strength, flexibility, mobility, balance, safety/fall prevention, gait, endurance/activity tolerance, and transfers.
  • Speech therapy evaluation includes assessment of dysphonia, dysarthria, and dysphagia.
  • Occupational therapy evaluation includes evaluation of ADLs including endurance/activity tolerance and areas of improvement for energy conservation and assistive device use in ADLs (e.g. bathing and grooming, dressing, eating, household management), physical environment modification.
  • The benefit of a rehabilitation program has been also been seen pre- and post-thymectomy, with not only significant reduction in operative risk and postoperative morbidity but also significantly faster recovery.14,15,16,17,18,19

Management of Airway Disease:

  • Extraparenchymal lung disease shown by a pattern of restrictive lung disease on pulmonary function testing (PFT) should be assessed if airway involvement is suspected. Oftentimes diaphragmatic weakness is present causing symptoms of shortness of breath, especially when lying supine. Pulmonary function is often improved with treatment. Routine PFTs should be monitored in the setting of acute exacerbation. Chest physical therapy involves respiratory and upper limb rehabilitation, diaphragmatic breathing, postural drainage, chest percussion and vibration, turning, deep breathing exercises, and coughing. In more severe cases, nocturnal non-invasive ventilation may be required.1,2,3,16

Management of Impaired Mobility and Activities of Daily Living:

  • Though muscle weakness from MG worsens with repeated muscle use, this should not preclude patients from being or staying active in some way. In fact, patients with stable MG should find an optimal balance between physical activity and rest to maintain/gain as much function as possible. Maintaining activity limits significant muscle atrophy and physical deconditioning and addresses skeletal as well as respiratory strengthening / cardiovascular health.14
  • During an exacerbation, energy conservation is the goal rather than exercise. Mobility should be safe and supervised, utilizing assistive devices if necessary. Use of electric appliances can help with energy conservation. Safety precautions should also be used at home including home modification for fall prevention (e.g. adding grab bars, removing throw rugs.
  • Patients with stable MG should undergo an aerobic and resistance exercise program as discussed below.
  • The recommended intensity of physical activity/training is of low to medium intensity, avoiding exercise-related fatigue (including but not limited to worsening of MG symptoms e.g. ptosis or diplopia during exercise). Not only is physical activity tolerated in MG; clear benefit has been seen in these patients from strength training.14,16
  • General exercise programs for patients with MG should focus on strengthening large muscle groups, particularly of the shoulder and hip girdle.14
  • Timing of exercise is also key and should be targeted to the time of day when the patients are not feeling tired (often the morning).14 If a patient takes pyridostigmine, exercise should be timed with the peak dose effect (1.5-2 hours after taking a dose).14
  • In addition to strength testing, aerobic exercise and balance strategy training may be effective and should be supervised.17
  • If swimming is part of the exercise program, supervision is important, and patients should only swim in water where they can touch the bottom. Swimming in deeper water may lead to over-exertion which can be dangerous.
  • Care should be taken to control other factors that can worsen MG symptoms e.g. heat. Aerobic exercise may improve respiratory function as well as stamina.
  • Depending on the level of weakness, an assistive device and/or orthotic may be necessary for gait support. Assistive devices range from a cane to a walker to powered mobility. Orthotics such as an ankle foot orthosis (AFO) may be helpful as well to assist with ankle dorsiflexion.

Management of Oculo-bulbar Dysfunction:

  • A swallow evaluation should be ordered for dysphagia. A modified diet and liquid texture/consistency may be warranted for bulbar/chewing weakness. Consider thickened liquids to prevent aspiration pneumonia.
  • Further rehabilitation with speech language pathologists is indicated for those with bulbar deficits.14 Exercises may work on breath control, voice quality, swallowing, and articulation. Postural exercises also assist with breathing, speaking, and swallowing.14
  • A formal neuroophthalmological exam is recommended. Corrective surgeries for ptosis often provide relief, however, may lead to dry eyes. Adaptive glasses with ptosis crutch or support can also be used. Ocular may require surgical intervention.

Coordination of care

An interdisciplinary approach is important, including neuromuscular medicine, physical medicine and rehabilitation, as well as physical and occupational therapy, speech/swallow therapy, and respiratory therapy.

Patient & family education

  • Home and exercise safety should be practiced as above.
  • Though less frequent, the patient/family should be educated on cholinergic crisis as a potential cause for clinical deterioration.5 Cholinergic crisis in this setting results from excessive cholinesterase inhibitor use, leading to overaccumulation of acetylcholine at the NMJ. Symptoms of cholinergic crisis are characteristic of muscarinic and nicotinic toxicity and include increased secretions (bronchorrhea, salivation, tearing, swelling,), miosis/blurred vision, chest tightness, wheezing, bradycardia, symptoms of increased gastrointestinal motility, as well cramps, muscle fasciculations, and paralysis.15
  • Patients/families should be counseled on the long-term complications of immunomodulating agents.
  • Steroid-associated risks include: infection, diabetes, hypertension, glaucoma, osteoporosis, peptic ulcer disease, myopathy, and aseptic necrosis of joint.
  • June is Myasthenia Gravis Awareness Month!

Measurement of treatment outcomes

  • Therapy response can be assessed with the MGFA Postintervention Status in addition to the Quantitative MG Score (QMG Score).13

Translation into practice: practice “pearls”/performance improvement in practice (PIPs)/changes in clinical practice behaviors and skills

  • MG is a chronic disease with a low spontaneous remission rate.
  • MG has a characteristic clinical profile with fatigable and fluctuating weakness, usually of oculobulbar and proximal musculature, in the absence of sensory or autonomic symptoms.
  • Patients need to recognize respiratory insufficiency which requires immediate hospitalization and close monitoring.
  • Possible exacerbation while starting steroids before improvement can be seen; this is particularly important to be aware of in the setting of myasthenic crisis.

Cutting Edge/ Emerging and Unique Concepts and Practice

  • The myasthenia gravis thymectomy (MGTX) trial, which compared thymectomy with prednisone versus prednisone alone in nonthymomatous AChR MG, demonstrated the effectiveness in primary and secondary outcomes (e.g. MG score, prednisone requirement, azathioprine usage, hospitalization rate) though this benefit was not seen in late-onset patients8, and the sample size could be larger.
  • Many RCTs have been and/or are being done looking at biological drugs,7,8 The studies that have been completed have overall provided supportive data.
    • Monoclonal antibodies
      • Rituximab – targets B-cell CD20
      • Belimumab – inhibits B-cell activating factor (BAFF)
      • Eculizumab – binds complement protein C5
    • Immunogobulin modulators
      • Efgartigimod – blocks the Fc receptor, reducing IgGs
    • Drugs targeting TLRs
      • Oligonucleotides
      • Small molecule inhibitors
      • Antibodies
    • Autologous hematopoietic stem cell transplantation (for refractory MG)
    • Other
      • Ephedrine – sympathomimetic agent
      • Terasemtiv – increases muscle response to calcium
  • With the advances in insight into the disease process including associated antibodies and genetic targets, therapies should be as disease- and patient-targeted as possible (moving towards precision medicine).
  • Genetic contribution to drug efficacy has been seen (e.g. certain haplotypes are associated with response for azathioprine, and CYP3A5*3 polymorphism correlates with Tacrolimus serum levels and incidence of drug adverse reactions).7

Gaps in the Evidence- Based Knowledge

  • The MGTX trial demonstrated effectiveness of thymectomy with prednisone in non-thymomatous AChR MG though not in the late-onset patients. More research would be beneficial looking at thymectomy in other MG subtypes and late-onset patients.
  • Though improving, further development can address nonspecific immunosuppression and feature more RCTs.
  • Further research is needed to better understand the role of, and patient selection for, the above biological drugs.
  • There continues to be a need to identify biomarkers to predict drug efficacy.
  • Further investigation could look into the role of the intracellular proteins as disease biomarkers.

References

  1. Amato A, Russell J. Neuromuscular Disorders. 2nd Ed. McGraw-Hill, 2015.
  2. Shah AK. “Myasthenia Gravis.” eMedicine Clinical Knowledge Base. 07 October 2015. http://reference.medscape.com. Accessed 18 October 2015.
  3. Juel VC, Massey JM. Review: Myasthenia Gravis. Orphanet Journal of Rare Disease 2007 (2): 44
  4. Gronseth GS, Barohn RJ. Practice parameter: Thymectomy for autoimmune myasthenia gravis (an evidence-based review): Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology.2000 (55) :7-15.
  5. Sanders DB et al. International consensus guidance for managmenet of myasthenia gravis. Neurology. 2016;87(4):419-25.
  6. Renton AE et al. A genome-wide association study of myasthenia gravis. JAMA Neurol. 2015;72(4):396-404.
  7. Mantegazza R, Bernasconi P, Calvalcante P. Myasthenia gravis from autoantibodies to therapy. Cur Opin Neurol. 2018;31(5):517-25.
  8. Evoli A. Myasthenia gravis new developments in research and treatment. Cur Opin Neurol. 2017;30(5):464-70.
  9. Preston DC & Shapiro BE. Electromyography and neuromuscular disorders: clinical-electrophysiologic correlations. 3rd edition. China: Elsevier; 2013.
  10. Benatar M, Kaminski HJ.  Practice parameter: The medical treatment of ocular myasthenia (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. Prepublished online April 25, 2007; DOI 10.1212/01.wnl.0000263481.14289.90
  11. Cortese I, Chaudhry V, So YT, Cantor F, Cornblath DR, Rae-Grant A. Evidence-based guideline update: Plasmapheresis in neurologic disorders. Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. 2011; (76):294‑300.
  12. Hart IK, Sathasivam S, Sharshar T. Immunosuppressive agents for Myasthenia Gravis (Review). Cochrane Collaboration, 2009.
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  18. https://www.myastheniagravis.org/wp-content/uploads/2015/01/MG-and-Physical-Therapy-Oct-2014.pdf White B & Adam K. Myasthenia gravis and therapies. Myastheniagravis.org. October 2014.
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Original Version of the Topic:

Chiawen Lucy Liang, MD. Myasthenia Gravis. Published 11/11/2011

Previous Revision(s) of the Topic:

Chiawen Lucy Liang, MD. Myasthenia Gravis. Published 4/7/2016

Author Disclosure

Dana Sheng, MD
Nothing to Disclose

Lisa Williams, MD
Nothing to Disclose