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Myasthenia Gravis

By

Michael Rubin

, MDCM, New York Presbyterian Hospital-Cornell Medical Center

Reviewed/Revised Mar 2024
View PATIENT EDUCATION

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.

The role of the thymus in myasthenia is unclear, but 65% of patients have thymic hyperplasia, and 10% have a thymoma (2 General references 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... read more ). 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)

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 interrupt neuromuscular transmission. About 10 to 20% of patients with generalized myasthenia have no antibodies to acetylcholine receptors (AChR) in serum. Up to 70% of these AChR antibody‒negative patients 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 General references 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... read more ). However, anti-MuSK antibodies do not occur in most patients with AChR antibodies or with isolated ocular myasthenia.

The clinical significance of anti-MuSK antibodies is still under study, but patients with these antibodies are much less likely to have thymic hyperplasia or a thymoma, may be less responsive to anticholinesterase medications, and may require more aggressive early immunotherapy than patients who have AChR antibodies.

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 General references 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... read more ). 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 Epub 2023 May 27.

  • 3. Hoch W, McConville J, Helms S, et al: Auto-antibodies to the receptor tyrosine kinase MuSK in patients with myasthenia gravis without acetylcholine receptor antibodies. Nat Med 7 (3):365–368, 2001. doi: 10.1038/85520

  • 4. Bardhan M, Dogra H; Samanta. D: Neonatal myasthenia gravis. 2023. In StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan–.

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.

Ocular muscles are affected initially in 40% of patients and eventually in 85% and are the only muscles affected in 15% (1 Symptoms and signs references 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... read more ). If generalized myasthenia is going to develop after ocular symptoms, it develops in 78% of patients within 1 year and in 94% within the first 3 years.

Hand grip may alternate between weak and normal (milkmaid’s grip). 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.

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 it, unlike myasthenia gravis, 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

  • Bedside tests (ice pack test, rest test)

  • AChR antibody levels, electromyography, or both

The diagnosis of myasthenia gravis is suggested by symptoms and signs and confirmed by tests.

Bedside testing

The traditional anticholinesterase test, done at bedside and using the short-acting (< 5 minutes) medication edrophonium, is not used in the United States and in many other countries, and edrophonium is no longer available in the United States.

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 Diagnosis references 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... read more ). 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.

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 AChR 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. Up to 50% of patients without AChR antibodies test positive for anti-MuSK antibodies (1 Diagnosis references 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... read more ).

Further testing

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 Epub 2013 Nov.

Treatment of Myasthenia Gravis

  • Anticholinesterase medications to relieve symptoms

  • Immunosuppressants (eg, corticosteroids)

  • IV immune globulin [IVIG] or plasma exchange for acute exacerbations (including myasthenic crisis)

  • Sometimes thymectomy

  • Supportive care

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 begun at 60 mg orally every 3 to 4 hours and titrated up to a maximum of 120 mg/dose based on symptoms. When parenteral therapy is necessary (eg, because of dysphagia), neostigmine (1 mg = 60 mg of pyridostigmine) may be substituted. Anticholinesterase medications can cause abdominal cramps and diarrhea, which are treated with oral atropine 0.4 to 0.6 mg (given with pyridostigmine or neostigmine) or propantheline 15 mg 3 to 4 times a day.

Patients who have been responding 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, corticosteroids, 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 Treatment references 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... read more ). Effects may last 1 to 2 months. Plasma exchange Plasma exchange Apheresis refers to the process of separating the cellular and soluble components of blood using a machine. Apheresis is often done on donors where whole blood is centrifuged to obtain individual... read more (eg, 5 exchanges of 3 to 5 L plasma over 7 to 14 days) can have similar effects.

Corticosteroids 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 corticosteroids. 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 corticosteroids, although significant benefit may not occur for many months. Cyclosporine 2 to 2.5 mg/kg orally twice a day may allow the corticosteroid dose to be reduced. These medications require the usual precautions.

For patients with refractory disease, monoclonal antibodies (eg, rituximab, eculizumab), efgartigimod, zilucoplan, and ravulizumab may be beneficial.

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 Epub 2011 May 11.

  • 2. 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 Epub 2020 Mar 25.

  • 3. 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.

Drugs Mentioned In This Article

Drug Name Select Trade
Qualaquin
Procanbid, Pronestyl, Pronestyl-SR
BLOXIVERZ, Prostigmin
Mestinon, Mestinon Timespan, Regonol
Atreza, Atropine Care , Atropisol , Isopto Atropine, Ocu-Tropine, Sal-Tropine
Pro-Banthine
Azasan, Imuran
CellCept, Myfortic
Cequa, Gengraf , Klarity-C, Neoral, Restasis, Sandimmune, SangCya, Verkazia, Vevye
ASTAGRAF XL, ENVARSUS, HECORIA, Prograf, Protopic
Deltasone, Predone, RAYOS, Sterapred, Sterapred DS
RIABNI, Rituxan, RUXIENCE, truxima
Soliris
ZILBRYSQ
ULTOMIRIS
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