Myasthenia gravis is characterized by episodic muscle weakness and easy fatigability caused by autoantibody- and cell-mediated destruction of acetylcholine receptors. It is more common among young women and older men but may occur in men or women at any age. Symptoms worsen with muscle activity and lessen with rest. Diagnosis is by measurement of serum acetylcholine receptor (AChR) antibody levels, electromyography, and bedside tests (ice pack test, rest test). Treatment includes anticholinesterase medications, immunosuppressants, plasma exchange, IV immune globulin, and possibly thymectomy.
Myasthenia gravis develops most commonly in women aged 20 to 40 and men aged 50 to 80, but it can occur at any age, including childhood (1).
Myasthenia gravis results from an autoimmune attack on postsynaptic acetylcholine receptors, which disrupts neuromuscular transmission. The trigger for autoantibody production is unknown, but the disorder is associated with abnormalities of the thymus, autoimmune hyperthyroidism, and other autoimmune disorders (eg, rheumatoid arthritis [RA], systemic lupus erythematosus [SLE], pernicious anemia).
The role of the thymus in myasthenia is unclear, but 65% of patients have thymic hyperplasia, and 10% have a thymoma (2). About half of the thymomas are malignant.
Precipitating factors for myasthenia gravis include
Infection
Surgery
Certain medications (eg, aminoglycosides, quinine, magnesium sulfate, procainamide, calcium channel blockers, immune checkpoint inhibitors)Certain medications (eg, aminoglycosides, quinine, magnesium sulfate, procainamide, calcium channel blockers, immune checkpoint inhibitors)
Abnormal antibodies
Most patients with myasthenia gravis develop antibodies to acetylcholine receptors (AChRs); these antibodies bind to AChRs on the postsynaptic membrane at the neuromuscular junction and disrupt neuromuscular transmission. About 85% of patients with generalized myasthenia gravis have antibodies to acetylcholine receptors (AChR) (3); 30 to 60% of these AChR antibody‒negative patients (and 5 to 8 % of all patients with myasthenia) have antibodies to muscle-specific receptor tyrosine kinase (MuSK), a surface membrane enzyme that helps AChR molecules aggregate during development of the neuromuscular junction (3).
Patients with anti-MuSK antibodies are less likely to have thymic hyperplasia or a thymoma, may be less responsive to anticholinesterase medications, may require more aggressive early immunotherapy than patients who have AChR antibodies, and are more likely to present with bulbar rather than ocular weakness
Uncommon forms
Ocular myasthenia gravis involves only extraocular muscles. It represents about 15% of cases.
Congenital myasthenia is a rare autosomal recessive disorder that begins in childhood. It is not immune-mediated and results from presynaptic or postsynaptic abnormalities, including the following:
Reduced acetylcholine resynthesis due to choline acetyltransferase deficiency
End-plate acetylcholinesterase deficiency
Structural abnormalities in the postsynaptic receptor
Ophthalmoplegia is common in patients with congenital myasthenia.
Neonatal myasthenia affects approximately 10 to 15% of infants born to women with myasthenia gravis (4). It is due to IgG antibodies that passively cross the placenta. It causes generalized muscle weakness, which resolves in days to weeks as antibody titers decline. Thus, treatment is usually supportive.
General references
1. Carr AS, Cardwell CR, McCarron PO, McConville J. A systematic review of population based epidemiological studies in myasthenia gravis. BMC Neurol. 18:10:46, 2010. doi: 10.1186/1471-2377-10-46
2. Estévez DAG, Fernández JP. Myasthenia gravis. Update on diagnosis and therapy. Med Clin (Barc). 161 (3):119–127, 2023. doi: 10.1016/j.medcli.2023.04.006 .
3. Punga AR, Maddison P, Heckmann JM, Guptill JT, Evoli A. Epidemiology, diagnostics, and biomarkers of autoimmune neuromuscular junction disorders. Lancet Neurol. 2022;21(2):176-188. doi:10.1016/S1474-4422(21)00297-0
4. Lindroos JLV, Bjørk MH, Gilhus NE. Transient Neonatal Myasthenia Gravis as a Common Complication of a Rare Disease: A Systematic Review. J Clin Med. 2024;13(4):1136. Published 2024 Feb 17. doi:10.3390/jcm13041136
Symptoms and Signs of Myasthenia Gravis
The most common symptoms of myasthenia gravis are
Ptosis
Diplopia
Muscle weakness after use of the affected muscle
Weakness resolves when the affected muscles are rested but recurs when they are used again. Weakness due to myasthenia lessens in cooler temperatures.
Patients often present with ocular symptoms that later generalize; 50% of patients with ocular myasthenia will go on to develop limb or bulbar symptoms. Ocular muscles are affected initially in 40% of patients, eventually in 85%, and are the only muscles affected in 15% (1). When generalized myasthenia develops following ocular symptoms, it occurs within 1 year in about 80% of patients, and within 3 years in about 90%.
Hand grip may alternate between weak and normal. Neck muscles may become weak. Proximal limb weakness is common. Some patients present with bulbar symptoms (eg, altered voice, nasal regurgitation, choking, dysphagia). Sensation and deep tendon reflexes are normal. Manifestations fluctuate in intensity over minutes to hours to days.
Myasthenic crisis, a severe generalized quadriparesis or life-threatening respiratory muscle weakness, occurs in about 15 to 20% of patients at least once in their life (2). It is often due to a supervening infection that reactivates the immune system. Once respiratory insufficiency begins, respiratory failure may occur rapidly.
Cholinergic crisis is muscular weakness that can result when the dose of anticholinesterase medications (eg, neostigmine, pyridostigmine) is too high. A mild crisis may be difficult to differentiate from worsening myasthenia. Severe cholinergic crisis can usually be differentiated because, unlike myasthenia gravis, it results in muscle fasciculations, increased lacrimation and salivation, tachycardia, and diarrhea.is muscular weakness that can result when the dose of anticholinesterase medications (eg, neostigmine, pyridostigmine) is too high. A mild crisis may be difficult to differentiate from worsening myasthenia. Severe cholinergic crisis can usually be differentiated because, unlike myasthenia gravis, it results in muscle fasciculations, increased lacrimation and salivation, tachycardia, and diarrhea.
Symptoms and signs references
1. Kerty E, Elsais A, Argov Z, et al. EFNS/ENS [European Federation of Neurological Societies/European Neurological Society]. Guidelines for the treatment of ocular myasthenia. Eur J Neurol. 21 (5):687–693, 2014. doi: 10.1111/ene.12359
2. Spillane J, Higham E, Kullmann DM. Myasthenia gravis. BMJ. 345:e8497, 2012. doi: 10.1136/bmj.e8497
Diagnosis of Myasthenia Gravis
Clinical evaluation
Bedside tests (ice pack test, rest test)
Serum antibody tests (AChR antibodies, MuSK antibodies, LRP4 antibodies, cell-based assay)
Electromyography, or both
The diagnosis of myasthenia gravis is suggested by symptoms and signs and confirmed by tests.
Bedside testing
Because weakness due to myasthenia lessens in cooler temperature, patients with ptosis can be tested using the ice pack test. For this test, an icepack is applied to a patient's closed eyes for 2 minutes, then removed. A positive result is full or partial resolution of ptosis. Sensitivity may be about 80% (1). The ice pack test usually does not work if patients have ophthalmoparesis.
Patients with opthalmoparesis can be tested using the rest test. For this test, patients are asked to lie quietly in a dark room for 5 minutes with their eyes closed. If ophthalmoparesis resolves after this rest, the result is positive.
Testing with a short-acting anticholinesterase (edrophonium) was a traditional test, but it is no longer routinely performed; edrophonium is no longer available in the United States.
Antibody testing and electromyography
Even if a bedside test is unequivocally positive, one or both of the following are required to confirm the diagnosis:
Serum antibody levels
Electromyography (EMG)
AChR antibodies are present in 80 to 90% of patients with generalized myasthenia but in only 50% with the ocular form. Antibody levels do not correlate with disease severity. Between 30 and 60% of patients without AChR antibodies test positive for anti-MuSK antibodies (1).
EMG using slow repetitive stimuli (2 to 3Hz) shows a > 10% decrease in amplitude of the compound muscle action potential response in 60% of patients, with the yield being higher in clinically affected muscles (2). Single-fiber EMG can detect abnormal neuromuscular transmission in > 95% (3). These findings are not specific to myasthenia but can also be seen in other neuromuscular junctionopathies, motor neuron disease, and muscles impacted by a neurogenic process.
Further testing
Once myasthenia is diagnosed, CT or MRI of the thorax should be done to check for thymic hyperplasia and a thymoma.
Other tests should be done to screen for autoimmune disorders frequently associated with myasthenia gravis (eg, pernicious anemia, autoimmune hyperthyroidism, RA, SLE).
Patients in myasthenic crisis should be evaluated for an infectious trigger.
Bedside pulmonary function tests (eg, forced vital capacity) help detect impending respiratory failure.
Diagnosis references
1. Golnik KC, Pena R, Lee AG, Eggenberger ER. An ice test for the diagnosis of myasthenia gravis. Ophthalmology. 106 (7):1282–1286. doi: 10.1016/S0161-6420(99)00709-5
2. Oh SJ, Kim DE, Kuruoglu R, et al. Diagnostic sensitivity of the laboratory tests in myasthenia gravis. Muscle Nerve. 15 (6):720–724, 1992. doi: 10.1002/mus.880150616
3. Padua L, Caliandro P, Di Iasi G, et al.Reliability of SFEMG [single-fibre electromyography] in the diagnosis of myasthenia gravis} in diagnosing myasthenia gravis: sensitivity and specificity calculated on 100 prospective cases. Clin Neurophysiol. 125 (6):1270–1273, 2014. doi: 10.1016/j.clinph.2013.11.005.
Treatment of Myasthenia Gravis
Anticholinesterase medications to relieve symptoms
Immunosuppressants (eg, glucocorticoids)
IV immune globulin [IVIG] or plasma exchange for acute exacerbations (including myasthenic crisis)
Sometimes thymectomy
Supportive care
In patients with congenital myasthenia, anticholinesterase medications and immunomodulating treatments are not beneficial and should be avoided. Patients with respiratory failure require intubation and mechanical ventilation.
Symptomatic treatment
Anticholinesterase medications are the mainstay of symptomatic treatment but do not alter the underlying disease process. Moreover, they rarely relieve all symptoms, and myasthenia may become refractory to these medications.
Pyridostigmine is administered orally, with dose titrated based on symptoms. When parenteral therapy is necessary (eg, because of dysphagia), neostigmine may be substituted. Anticholinesterase medications can cause abdominal cramps and diarrhea, which are treated with oral atropine or propantheline.Pyridostigmine is administered orally, with dose titrated based on symptoms. When parenteral therapy is necessary (eg, because of dysphagia), neostigmine may be substituted. Anticholinesterase medications can cause abdominal cramps and diarrhea, which are treated with oral atropine or propantheline.
Patients who initially respond well to treatment and then deteriorate require respiratory support because they may have cholinergic crisis, and anticholinesterase medications must be stopped for several days.
Immunomodulating treatment
Immunosuppressants (eg, glucocorticoids, azathioprine, mycophenolate mofetil, cyclosporine, tacrolimus) interrupt the autoimmune reaction and slow the disease course, but they do not relieve symptoms rapidly. Thus, patients with myasthenic crisis require treatment with IVIG or plasma exchange. After being given IVIG 400 mg/kg once a day for 5 days, 70% of patients improve in 1 to 2 weeks (Immunosuppressants (eg, glucocorticoids, azathioprine, mycophenolate mofetil, cyclosporine, tacrolimus) interrupt the autoimmune reaction and slow the disease course, but they do not relieve symptoms rapidly. Thus, patients with myasthenic crisis require treatment with IVIG or plasma exchange. After being given IVIG 400 mg/kg once a day for 5 days, 70% of patients improve in 1 to 2 weeks (1). Effects may last 1 to 2 months. Plasma exchange (performed over 7 to 14 days) can have similar effects.
Glucocorticoids are necessary as maintenance therapy for many patients but have little immediate effect in myasthenic crisis. Over half of patients worsen acutely after starting high-dose glucocorticoids. Initially, prednisone 10 mg orally once a day is given; dose is increased by 10 mg weekly up to 60 mg, which is given for about 2 months, then tapered slowly. Improvement may take several months; then, the dose should be reduced to the minimum necessary to control symptoms.Glucocorticoids are necessary as maintenance therapy for many patients but have little immediate effect in myasthenic crisis. Over half of patients worsen acutely after starting high-dose glucocorticoids. Initially, prednisone 10 mg orally once a day is given; dose is increased by 10 mg weekly up to 60 mg, which is given for about 2 months, then tapered slowly. Improvement may take several months; then, the dose should be reduced to the minimum necessary to control symptoms.
Azathioprine 2.5 to 3.5 mg/kg orally once a day may be as effective as glucocorticoids, although significant benefit may not occur for many months. Cyclosporine 2 to 2.5 mg/kg orally twice a day may allow the prednisone dose to be reduced. These medications require the usual precautions.Azathioprine 2.5 to 3.5 mg/kg orally once a day may be as effective as glucocorticoids, although significant benefit may not occur for many months. Cyclosporine 2 to 2.5 mg/kg orally twice a day may allow the prednisone dose to be reduced. These medications require the usual precautions.
Therapies targeting the neonatal Fc receptor as well as complement have been rapidly expanding in the treatment of myasthenia gravis. Several medications are approved for the treatment of generalized myasthenia, including efgartigimod (anti-AChr antibody positive), rozanolixizumab (anti-AchR or anti-MuSK antibody positive), nipocalimab (anti-AchR or anti-MuSK antibody positive), eculizumab (anti-AChR antibody positive), ravulizumab (anti-AChR antibody positive), and zilucoplan (anti-AChR antibody positive). Complement inhibitors require meningococcal vaccination prior to initiating treatment, or prophylactic antibiotics if treatment is started urgently. Rituximab, a monoclonal antibody targeting CD20 on lymphocytes, is used off-label in the treatment of generalized myasthenia (Therapies targeting the neonatal Fc receptor as well as complement have been rapidly expanding in the treatment of myasthenia gravis. Several medications are approved for the treatment of generalized myasthenia, including efgartigimod (anti-AChr antibody positive), rozanolixizumab (anti-AchR or anti-MuSK antibody positive), nipocalimab (anti-AchR or anti-MuSK antibody positive), eculizumab (anti-AChR antibody positive), ravulizumab (anti-AChR antibody positive), and zilucoplan (anti-AChR antibody positive). Complement inhibitors require meningococcal vaccination prior to initiating treatment, or prophylactic antibiotics if treatment is started urgently. Rituximab, a monoclonal antibody targeting CD20 on lymphocytes, is used off-label in the treatment of generalized myasthenia (2).
Thymectomy may be indicated for patients < 65 years with generalized myasthenia (3, 4) and should be done in all patients with a thymoma. Following thymectomy, remission or a decrease in the required maintenance medication dose occurs in 80% of patients.
Plasma exchange or IVIG (the usual treatment for myasthenic crisis) may also be useful if patients are unresponsive to medications before thymectomy.
Treatment references
1. Barth D, Nouri MN, Ng E, et al. Comparison of IVIg and PLEX in patients with myasthenia gravis. Neurology. 76 (23):2017–2023, 2011. doi: 10.1212/WNL.0b013e31821e5505
2. Ndegwa S, Mierzwinski-Urban M. Emerging Drugs for Generalized Myasthenia Gravis: CADTH Horizon Scan [Internet]. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2022 Feb.
3. Gronseth GS, Barohn R, Narayanaswami P. Practice advisory: Thymectomy for myasthenia gravis (practice parameter update): Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology. 94 (16):705–709, 2020. doi: 10.1212/WNL.0000000000009294
4. Wolfe GI, Kaminski HJ, Aban IB, et al. Randomized trial of thymectomy in myasthenia gravis. N Engl J Med. 375 (6):511–522, 2016.
Key Points
Consider myasthenia gravis in patients with ptosis, diplopia, and muscle weakness after use of the affected muscle.
To confirm the diagnosis, measure serum levels of AChR antibody (usually present in myasthenia gravis), do electromyography (EMG), or both.
After the diagnosis is confirmed, test for thymic hyperplasia, thymomas, hyperthyroidism, and autoimmune disorders, which commonly accompany myasthenia gravis.
For most patients, use anticholinesterase medications to relieve symptoms and immunomodulating treatment to slow disease progression and help relieve symptoms; do not use these treatments in patients with congenital myasthenia.
If patients have a myasthenic crisis, treat with IVIG or plasma exchange.
If patients suddenly deteriorate after responding well to treatment, provide respiratory support and stop anticholinesterase medications for several days because they may have cholinergic crisis.
Drug Information for the Topic
