Myasthenia gravis
Template:Short description Template:Use dmy dates Template:Infobox medical condition
Myasthenia gravis (MG) is a long-term neuromuscular junction disease that leads to varying degrees of skeletal muscle weakness.<ref name="NIH2016" /> The most commonly affected muscles are those of the eyes, face, and swallowing.<ref name="NIH2016" /><ref name="auto1">Template:Cite journal</ref> It can result in double vision, drooping eyelids, and difficulties in talking and walking.<ref name="NIH2016" /> Onset can be sudden.<ref name="NIH2016" /> Those affected often have a large thymus or develop a thymoma.<ref name="NIH2016">Template:Cite web</ref>
Myasthenia gravis is an autoimmune disease of the neuromuscular junction which results from antibodies that block or destroy nicotinic acetylcholine receptors (AChR) at the junction between the nerve and muscle.<ref>Template:Cite report</ref><ref>Template:Cite journal</ref><ref name="NIH2016" /> This prevents nerve impulses from triggering muscle contractions.<ref name="NIH2016" /> Most cases are due to immunoglobulin G1 (IgG1) and IgG3 antibodies that attack AChR in the postsynaptic membrane, causing complement-mediated damage and muscle weakness.<ref name="Pathogenesis of myasthenia gravis">Template:Cite journal</ref> Rarely, an inherited genetic defect in the neuromuscular junction results in a similar condition known as congenital myasthenia.<ref name="Kandel2012">Template:Cite book</ref><ref name="ReferenceA">Template:Cite journal</ref> Babies of mothers with myasthenia may have symptoms during their first few months of life, known as neonatal myasthenia<ref name="NIH2016" /> or more specifically transient neonatal myasthenia gravis.<ref name="pmid38398450">Template:Cite journal</ref> Diagnosis can be supported by blood tests for specific antibodies, the edrophonium test, electromyography (EMG), or a nerve conduction study.<ref name="NIH2016" />
Mild forms of myasthenia gravis may be treated with medications known as acetylcholinesterase inhibitors, such as neostigmine and pyridostigmine.<ref name="NIH2016" /> Immunosuppressants, such as prednisone or azathioprine, may also be required for more severe symptoms that acetylcholinesterase inhibitors are insufficient to treat.<ref name="NIH2016" /> The surgical removal of the thymus may improve symptoms in certain cases.<ref name="NIH2016" /> Plasmapheresis and high-dose intravenous immunoglobulin may be used when oral medications are insufficient to treat severe symptoms, including during sudden flares of the condition.<ref name="NIH2016" /> If the breathing muscles become significantly weak, mechanical ventilation may be required.<ref name="NIH2016" /> Once intubated acetylcholinesterase inhibitors may be temporarily held to reduce airway secretions.<ref>Template:Cite journal</ref>
Myasthenia gravis affects 50 to 200 people per million.<ref name="Kam2009">Template:Cite book</ref><ref name="Adams2012">Template:Cite book</ref> It is newly diagnosed in 3 to 30 people per million each year.<ref name="McG2010" /> Diagnosis has become more common due to increased awareness.<ref name="McG2010">Template:Cite journal</ref> Myasthenia gravis most commonly occurs in women under the age of 40 and in men over the age of 60.<ref name="NIH2016" /><ref name="auto1" /><ref name="auto2">Template:Cite journal</ref> It is uncommon in children.<ref name="NIH2016" /> With treatment, most live to an average life expectancy.<ref name="NIH2016" /> The word is from the Greek mys, "muscle" and asthenia "weakness", and the Latin gravis, "serious".<ref>Template:Cite book</ref>
Signs and symptoms
The initial, main symptom in myasthenia gravis is painless weakness of specific muscles, not fatigue.<ref name="Engel2012">Template:Cite book</ref> The muscle weakness becomes progressively worse (fatigue) during periods of physical activity and improves after periods of rest. Typically, the weakness and fatigue are worse toward the end of the day.<ref name="Scully2014">Template:Cite book</ref> Myasthenia gravis generally starts with ocular (eye) weakness; it might then progress to a more severe generalized form, characterized by weakness in the extremities or in muscles that govern basic life functions.<ref name="Goldenberg">Template:EMedicine</ref>
Eyes
In about two-thirds of people, the initial symptom of myasthenia gravis is related to the muscles around the eye.<ref name="Engel2012" /> Eyelid drooping (ptosis may occur due to weakness of m. levator palpebrae superioris)<ref name="Nair2014" /> and double vision (diplopia,<ref name="Engel2012" /> due to weakness of the extraocular muscles).<ref name="Scully2014" /> Eye symptoms tend to get worse when watching television, reading, or driving, particularly in bright conditions.<ref name="Engel2012" /> Consequently, some affected individuals choose to wear sunglasses.<ref name="Engel2012" /> The term "ocular myasthenia gravis" describes a subtype of myasthenia gravis where muscle weakness is confined to the eyes, i.e. extraocular muscles, m. levator palpebrae superioris, and m. orbicularis oculi.<ref name="Nair2014" /> This subtype may evolve into generalized myasthenia gravis, usually after a few years.<ref name="Nair2014" /> If an individual with ocular myasthenia gravis does not generalize for three or more years after the onset of symptoms, then generalized myasthenia gravis is unlikely to occur.<ref>Template:Cite book</ref>
Eating
The weakness of the muscles involved in swallowing may lead to swallowing difficulty (dysphagia). Typically, this means that some food may be left in the mouth after an attempt to swallow,<ref name="Scherer2005">Template:Cite journal</ref> or food and liquids may regurgitate into the nose rather than go down the throat (velopharyngeal insufficiency).<ref name="Scully2014" /> Weakness of the muscles that move the jaw (muscles of mastication) may cause difficulty chewing. In individuals with myasthenia gravis, chewing tends to become more tiring when chewing tough, fibrous foods.<ref name="Engel2012" /> Difficulty in swallowing, chewing, and speaking is the first symptom in about one-sixth of individuals.<ref name="Engel2012" />
Speaking
Weakness of the muscles involved in speaking may lead to dysarthria and hypophonia.<ref name="Engel2012" /> Speech may be slow and slurred,<ref name="Rajendran2014">Template:Cite book</ref> or have a nasal quality.<ref name="Scully2014" /> In some cases, a singing hobby or profession must be abandoned.<ref name="Scherer2005" />
Head and neck
Due to weakness of the muscles of facial expression and muscles of mastication, facial weakness may manifest as the inability to hold the mouth closed<ref name="Engel2012" /> (the "hanging jaw sign") and as a snarling expression when attempting to smile.<ref name="Scully2014" /> With drooping eyelids, facial weakness may make the individual appear sleepy or sad.<ref name="Engel2012" /> Difficulty in holding the head upright may occur.<ref name="Rajendran2014" />
Other
The muscles that control breathing and limb movements can also be affected; rarely do these present as the first symptoms of myasthenia gravis, but develop over months to years.<ref>Template:MedlinePlusEncyclopedia</ref> In a myasthenic crisis, a paralysis of the respiratory muscles occurs, necessitating assisted ventilation to sustain life.<ref name="Rosen2014">Template:Cite book</ref> Crises may be triggered by various biological stressors such as infection, fever, an adverse reaction to medication, or emotional stress.<ref name="Rosen2014" />
Causes
Medications that cause or worsen myasthenia gravis
Antibiotics: In the macrolide family of antibiotics, azithromycin, telithromycin (which is no longer available in the U.S. market), and erythromycin are reported to exacerbate myasthenia gravis. In the fluoroquinolone antibiotic family, ciprofloxacin, norfloxacin, ofloxacin, and moxifloxacin are reported to exacerbate myasthenia gravis.<ref name="pmid33917535">Template:Cite journal</ref> And, In the aminoglycoside family of antibiotics, gentamicin, streptomycin, and neomycin are reported to exacerbate myasthenia gravis.<ref name="pmid4568132">Template:Cite journal</ref> The aminoglycoside tobramycin has not been reported to exacerbate myasthenia gravis and may be used in people that require aminoglycoside treatment.<ref name="pmid33917535" /> Because of the rarity or absent reports on their exacerbation of myasthenia gravis, the following antibiotics are considered safe to use in people with myasthenia gravis: the cephalosporin class of drugs, sulfa drugs, the tetracycline group of drugs, clindamycin, polymyxin B, and nitrofurantoin.<ref name="pmid33917535" />
Immune checkpoint inhibitors: Immune checkpoint inhibitors promote certain types of autoimmune responses by blocking checkpoint pathways that inhibit these responses. They are used to treat cancers that promote their own growth and spread by stimulating checkpoint pathways. These checkpoint inhibitors include pembrolizumab, nivolumab, ipilimumab, avelumab, atezolizumab, and durvalumab. From a total 5,898 people who received these drugs, 52 developed new onset myasthenia gravis and 11 had a flare of their preexisting myasthenia gravis. The symptoms of myasthenia gravis developed within 6 days to 16 weeks (median time 4 weeks). Their medicine-induced myasthenia gravis symptoms were often severe with 29 people developing respiratory failure that required mechanical ventilation.<ref name="pmid31753014">Template:Cite journal</ref> Other studies have reported that these checkpoint inhibitors cause respiratory failure in 45% and death in 25–40% of people with myasthenia gravis.<ref name="pmid33917535" /><ref name="pmid30638612">Template:Cite journal</ref>
Statins: Statins are drugs that lower blood cholesterol levels in order to reduce the risk of developing a cardiovascular disease due to atherosclerosis. In a 2019 review of 169 people who were reported to develop myasthenia gravis or had worsened myasthenia gravis symptoms while taking a statin, 138 had developed generalized myasthenia gravis, 13 had developed ocular myasthenia gravis, and 18 had worsening of their myasthenia gravis. Following discontinuance of the statin and treatment of their myasthenia gravis, 63 people fully recovered, 27 people were recovering, 19 people had not yet recovered, 5 people recovered but had ongoing symptoms, 1 individual had died, and there was no follow-up data for 54 people. Among these cases, 56% were considered to be serious.<ref name="pmid31298743">Template:Cite journal</ref> A 2024 study evaluated 593 people who had myasthenia gravis and 790,399 people who did not have myasthenia gravis after being treated with a statin. The statin-treatment caused small but statistically significant increases in numbers of exacerbations of myasthenia gravis as well as new onsets of myasthenia gravis in people without the disorder. The development of myasthenia gravis in people without myasthenia gravis appeared to be more likely in people over 60 years of age.<ref name="pmid39609410">Template:Cite journal</ref> Six non-statin cholesterol-lowering drugs, nicotinic acid, cholestyramine, colestipol, colesevelam, alirocumab, and evolocumab, have been used in people without causing or worsening myasthenia gravis.<ref name="pmid33917535" />
Beta blockers: Beta blockers (i.e., β-blockers) are drugs that block the binding of two stress hormones, epinephrine and norepinephrine, to their target beta receptors. They are used to decrease the heart rate, reduce the force of heart contractions, and relax blood vessels in order to lower blood pressure and reduce the workload on the heart. In one study the odds of an myasthenia gravis exacerbation after taking a beta blocker was increased 2.7-fold compared with people with myasthenia gravis not taking a beta blocker. These exacerbations generally did not occur immediately after their usage and therefore may have reflected other comorbidities in people with myasthenia gravis being treated with beta blockers.<ref name="pmid31469909">Template:Cite journal</ref><ref name="pmid36373673">Template:Cite journal</ref> In a study of 20 people with myasthenia gravis treated with a beta blocker, 3 who received oral metoprolol, 9 who received intravenous metoprolol, 1 who received oral labetalol, and 9 who received intravenous labetalol, only one (i.e., 5%) of the 20 participants (who received intravenous labetalol) reacted with an exacerbation of myasthenia gravis symptoms.<ref name="pmid">Template:Cite journal</ref>
Ia antiarrhythmic agents: A type Ia antiarrhythmic agent (see Vaughan Williams classification), i.e., procainamide, which is used to treat cardiac arrhythmias, has caused respiratory failure in people with myasthenia gravis who, prior to being treated with it, did not have respiratory symptoms. Furthermore, this drug has caused MG-like symptoms in people who have kidney failure but do not have myasthenia gravis. And, procainamide worsened muscle dysfunction in a rat model of human myasthenia gravis.<ref name="pmid33917535" />
Depolarizing neuromuscular blockers: Depolarizing neuromuscular blockers suppress the neurons' signaling at neuromuscular junctions thereby reducing the affected skeletal muscles contractibility. These blockers are used as muscle relaxants in people undergoing surgery.<ref name="pmid35322378">Template:Cite journal</ref> Succinylcholine is the only depolarizing neuromuscular blocker available in the US market.<ref name="pmid33917535" /> Succinylcholine's ability to induce or worsen myasthenia gravis is unclear. It has been suggested to cause life-threatening side effects such as rhabdomyolysis, myotonia, and hyperkalemia in people with muscle disease although the role of succinylcholine in causing these side effects also remains unclear.<ref name="pmid35322378" /><ref name="pmid33917535" />
Inhalation anesthetics: Inhalation anesthetics are general anesthetics that are delivered by inhalation generally for people undergoing surgery. People with myasthenia gravis undergoing surgery with inhaled anesthetics (i.e., halothane, isoflurane, enflurane, and sevoflurane) may develop neuromuscular blockage and have an increased incidence of developing a life-threatening myasthenia crisis which must be treated by prolonged mechanical ventilation. In a study of 795 people with myasthenia gravis undergoing surgical removal of their thymus under general anesthesia, sugammadex, a neuromuscular-blocking drug (i.e., a drug that reverses neuromuscular blockade) significantly reduced the development of this crisis.<ref name="pmid33917535" /><ref name="pmid31124838">Template:Cite journal</ref>
Glucocorticoids: Glucocorticoids are anti-inflammatory agents that in initial studies were used at high dosages and found to worsen myasthenia gravis in 25-75% of cases.<ref name="pmid25069701">Template:Cite journal</ref> However, further studies found that glucocorticoids do have favorable effects on myasthenia gravis when taken long term. Two glucocorticoids, oral prednisone and prednisolone, are the first-line immunosuppressive treatment for myasthenia gravis.<ref name="pmid33917535" /><ref name="pmid35350948">Template:Cite journal</ref><ref name="pmid38306763">Template:Cite journal</ref> A review published in 2020 on 27 earlier publications found that myasthenia gravis was worsened by glucocorticoids in 33.3% of patients. These myasthenia gravis exacerbations seemed significantly greater for cortisone, intermediate for prednisone, and lowest for methylprednisolone. High dosages or alternate day dosages of prednisone were associated with exacerbation more frequently than low-dose treatments. Most of these exacerbations were mild to moderately severe and developed more often in patients who were older in age or had generalized myasthenia gravis, myasthenia gravis with bulbar symptoms, severe symptoms, a thymoma, or a history of thymectomy to remove a thymoma. These studies, however, were mostly of low quality. Prospective studies comparing the effects of the different corticosteroids and corticosteroids to define the rate and severity of the myasthenia exacerbations are needed.<ref name="pmid33064188">Template:Cite journal</ref>
Calcium channel blockers: Calcium channel blockers (e.g., felodipine, nifedipine, and verapamil) are drugs that lower blood pressure in people with hypertension. Felodipine and nifedipine are reported to worsen myasthenia gravis and nifedipine and verapamil are reported to cause respiratory failure in people with severe generalized myasthenia gravis.<ref name="pmid33917535" />
Penicillamine: Penicillamine is a chelation therapy drug used to treat various diseases (e.g., Wilson's disease). About 1-2% of individuals treated long term with penicillamine develop myasthenia gravis and/or develop low concentrations of antibodies to AChR.<ref name="pmid11445126">Template:Cite journal</ref> Their myasthenia gravis is often mild and predominantly ocular myasthenia gravis, becomes evident usually 6–7 months (range one month to 8 years) after starting the drug, and goes into complete remission in 70% of the cases within 6–10 months after discontinuing the drug.<ref name="pmid33917535" />
Botulinum toxin A: Botulinum toxin A (sold under the brand name Botox, Jeuveau, and Xeomin) blocks transmission at neuromuscular junctions to paralyze the muscles into which it is injected. Local botulinum toxin A injections for cosmetic purposes have on occasion caused weaknesses in distant muscles, symptoms resembling ocular or generalized myasthenia gravis in individuals with subclinical myasthenia gravis, and exacerbations of previously controlled myasthenia gravis. Botulinum toxin A has also been used to treat spasmodic torticollis (i.e., involuntarily neck turning), blepharospasm (involuntary contraction of the eye lids), and other uncontrolled facial muscle spasms in people with myasthenia gravis without side effects or with only short-lived dysphagia or diplopia.<ref name="pmid33917535" />
Magnesium: Magnesium is a chemical element that blocks skeletal muscle contraction by inhibiting the release or acetylcholine at the neuromuscular junction and also by lowering the sensitivity of these muscles to acetylcholine.<ref name="pmid33917535" /> Respiratory failure has occurred after systemic use of magnesium (mainly in the form of intravenous magnesium sulfate injections) for pre-eclampsia and after magnesium replacement during the course of a hospitalization in people with underlying myasthenia gravis.<ref name="pmid33917535" /><ref name="pmid38235027">Template:Cite journal</ref>
Local anesthetics: Local anesthetics cause absence of pain and all other sensations in a specific body part without loss of consciousness. There are two broad classes of these anesthetics: esters (i.e., procaine, cocaine, tetracaine benzocaine, and chloroprocaine) and amides (i.e. lidocaine, bupivacaine, etidocaine, levobupivacaine, mepivacaine, prilocaine, and ropivacaine). Ester local anesthetics are metabolized by pseudocholinesterases which in people with myasthenia gravis taking anticholinesterase drugs may lead to excessive levels of these ester anesthetics. Amide local anesthetics are not metabolized by psuedocholineesterases. Based on these considerations, amide local anesthetics are strongly preferred over ester local anesthetics in people with myasthenia gravis.<ref name="pmid29980408">Template:Cite journal</ref><ref name="pmid30859135">Template:Cite journal</ref>
Other Drugs: Rare cases of myasthenia gravis exacerbations have been reported in people treated with: 1) penicillins, i.e., ampicillin and amoxicillin; 2) anti-cancer medications, i.e., lorlatinib, nilotinib, imatinib (these three drugs are tyrosine kinase inhibitors that may also cause myasthenia gravis), dabrafenib, and trametinib; 3) antipsychotic drugs, i.e., chlorpromazine, pimozide, thioridazine, clozapine, olanzapine, haloperidol, quetiapine, risperidone, and olanzapine; 4) IFN-α (may also cause myasthenia gravis); and 5) the chemical element, lithium. These agents can be used in people with myasthenia gravis because reports on their exacerbation (or induction) of myasthenia gravis are rare.<ref name="pmid33917535" />
Pathophysiology
Myasthenia gravis is an autoimmune synaptopathy. The disorder occurs when the immune system malfunctions and generates antibodies that attack the body's tissues. The antibodies in MG attack a normal human protein, the nicotinic acetylcholine receptor, or a related protein called MuSK, a muscle-specific kinase.<ref>Template:Cite journal</ref><ref>Template:Cite web</ref> Other, less frequent antibodies are found against LRP4, agrin, and titin proteins.<ref name="Pathogenesis of myasthenia gravis" /><ref>Template:Cite journal</ref>
Human leukocyte antigen haplotypes are associated with increased susceptibility to myasthenia gravis and other autoimmune disorders. Relatives of people with myasthenia gravis have a higher percentage of other immune disorders.<ref>Template:Cite journal</ref><ref>Template:Cite web</ref>
The thymus gland cells form part of the body's immune system. In those with myasthenia gravis, the thymus gland is large and abnormal. It sometimes contains clusters of immune cells that indicate lymphoid hyperplasia, and the thymus gland may give wrong instructions to immune cells.<ref>Template:Cite web</ref>
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Neuromuscular junction: 1. Axon 2. Muscle cell membrane 3. Synaptic vesicle 4. Nicotinic acetylcholine receptor 5. Mitochondrion -
A juvenile thymus shrinks with age. -
In pregnancy
For women who are pregnant and already have MG, in a third of cases, they have been known to experience an exacerbation of their symptoms, and in those cases, it usually occurs in the first trimester of pregnancy.<ref name=":4">Template:Cite journal</ref> Signs and symptoms in pregnant mothers tend to improve during the second and third trimesters. Complete remission can occur in some mothers.<ref name="tellez">Template:Cite journal</ref> Immunosuppressive therapy should be maintained throughout pregnancy, as this reduces the chance of neonatal muscle weakness, and controls the mother's myasthenia.<ref name="OTM3" />
About 10–20% of infants with mothers affected by the condition are born with transient neonatal myasthenia gravis (TNMG), which generally produces feeding and respiratory difficulties that develop about 12 hours to several days after birth.<ref name=":4" /><ref name="OTM3">Template:Cite book</ref> A child with TNMG typically responds very well to acetylcholinesterase inhibitors, and the condition generally resolves over a period of three weeks, as the antibodies diminish, and generally does not result in any complications.<ref name=":4" /> However, a small percentage of fetuses and newborns with TNMG, particularly those who have antibodies directed against the fetal form of the AChR (their disorder is a subtype of TNMG termed the "acetylcholine receptor inactivation syndrome") have a more severe form of TNMG which includes weakness in skeletal muscles regulating breathing, respiratory failure, and various deformities such as arthrogryposis multiplex congenita. In some of these cases, the mother remains asymptomatic.<ref name="OTM3" /><ref name="pmid37186601">Template:Cite journal</ref>
Diagnosis
Myasthenia gravis can be difficult to diagnose, as the symptoms can be subtle and hard to distinguish from both normal variants and other neurological disorders.<ref name="Scherer2005" />
Three types of myasthenic symptoms in children can be distinguished:<ref>Template:Cite book</ref>
- Transient neonatal myasthenia gravis occurs in 10 to 15% of babies born to mothers afflicted with the disorder, and disappears after a few weeks.
- Congenital myasthenia, the rarest form, occurs when genes are present from both parents.
- Juvenile myasthenia gravis is most common in females.
Congenital myasthenias cause muscle weakness and fatigability similar to those of MG.<ref name="EngelShen2015">Template:Cite journal</ref> The signs of congenital myasthenia usually are present in the first years of childhood, although they may not be recognized until adulthood.<ref>Template:Cite web</ref>
Subgroup classification
| Class | Description |
|---|---|
| I | Any eye muscle weakness, possible ptosis, no other evidence of muscle weakness elsewhere |
| II | Eye muscle weakness of any severity, mild weakness of other muscles |
| IIa | Predominantly limb or axial muscles |
| IIb | Predominantly bulbar and/or respiratory muscles |
| III | Eye muscle weakness of any severity, moderate weakness of other muscles |
| IIIa | Predominantly limb or axial muscles |
| IIIb | Predominantly bulbar and/or respiratory muscles |
| IV | Eye muscle weakness of any severity, severe weakness of other muscles |
| IVa | Predominantly limb or axial muscles |
| IVb | Predominantly bulbar and/or respiratory muscles |
| V | Intubation needed to maintain airway |
When diagnosed with myasthenia gravis, an individual can be stratified into distinct subgroups based on the clinical features and serological status, e.g. affected muscle group, age of onset, thymic abnormalities, and profile of serum autoantibodies.<ref>Template:Cite journal</ref>
Based on the affected muscle group, people with myasthenia gravis can be sub-grouped into ocular myasthenia gravis or generalized myasthenia gravis. Ocular myasthenia gravis is characterized by exclusively ocular symptoms, droopy eyelids, or double vision. Generalized myasthenia gravis has muscle weakness with a variable combination of the bulbar, axial, or limb and respiratory muscles.<ref>Template:Cite journal</ref>
People with myasthenia gravis can also be sub-grouped by the age of onset: juvenile-onset myasthenia gravis (onset age ≤ 18 years of age), early-onset MG (EOMG; 19–50 years of age), late-onset MG (LOMG; onset > 50 years of age), and very late-onset (VLOMG; onset age ≥ 65 years of age).<ref>Template:Cite journal</ref>
The subgroup of the autoantibody profile includes AChR seropositive, MuSK seropositive, LRP4 seropositive, and agrin seropositive.<ref>Template:Cite journal</ref>
Physical examination
During a physical examination to check for MG, a doctor might ask the person to perform repetitive movements. For instance, the doctor may ask one to look at a fixed point for 30 seconds and to relax the muscles of the forehead, because a person with MG and ptosis of the eyes might be involuntarily using the forehead muscles to compensate for the weakness in the eyelids.<ref name="Scherer2005" /> The clinical examiner might also try to elicit the "curtain sign" in a person by holding one of the person's eyes open, which in the case of MG will lead the other eye to close.<ref name="Scherer2005" />
Train of four ratio test
The train of four ratio (i.e., ToFr) is a neuromuscular test for monitoring neuromuscular function (see monitoring neuromuscular blockade). In this test, a peripheral nerve (most commonly the ulnar nerve) is stimulated by an electrical impulse 4 times (i.e., T1, T2, T3, T4) and the strength of contraction is measured in a muscle(s) (i.e., the abductor pollicis longus and brevis muscles for the ulnar nerve). The ratio of the amplitude of muscle contraction in response to the fourth impulse (T4) divided by the amplitude of muscle contraction in response to the first impulse is calculated. The ratio of these two contractions should be 1.0. Values less that this are regarded as abnormal.<ref name="pmid29365307">Template:Cite journal</ref> ToFr is used to determine when the effects of an administered neuromuscular-blocking drug have worn off (see postoperative residual curarization)<ref name="pmid29365307"/> or as the most objective, accurate, and sensitive test for determining the presence and severity of myasthenia gravis: myasthenia gravis is considered to afflict the tested muscle if its ToFr ratio (i.e., T4/T1) is less than 0.9.<ref name="pmid10910480">Template:Cite journal</ref>
Blood tests
If the diagnosis is suspected, serology can be performed:
- One test is for antibodies against the acetylcholine receptor;<ref name="Scherer2005" /> the test has a reasonable sensitivity of 80–96%, but in ocular myasthenia, the sensitivity falls to 50%.
- A proportion of the people without antibodies against the acetylcholine receptor have antibodies against the MuSK protein.<ref name="pmid18515870">Template:Cite journal</ref>
- Less than 1% of patients with myasthenia gravis have antibodies against low-density lipoprotein receptor-related protein 4 (i.e., LRP4).<ref name="pmid38494283">Template:Cite journal</ref>
- In specific situations, testing is performed for Lambert-Eaton syndrome.<ref>Template:MedlinePlusEncyclopedia</ref>
Electrodiagnostics
Muscle fibers of people with MG are easily fatigued, which the repetitive nerve stimulation test can help diagnose. In single-fiber electromyography, which is considered to be the most sensitive (although not the most specific) test for MG,<ref name="Scherer2005" /> a thin needle electrode is inserted into different areas of a particular muscle to record the action potentials from several samplings of different individual muscle fibers. Two muscle fibers belonging to the same motor unit are identified, and the temporal variability in their firing patterns is measured. Frequency and proportion of particular abnormal action potential patterns, called "jitter" and "blocking", are diagnostic. Jitter refers to the abnormal variation in the time interval between action potentials of adjacent muscle fibers in the same motor unit. Blocking refers to the failure of nerve impulses to elicit action potentials in adjacent muscle fibers of the same motor unit.<ref name="Selvan">Template:Cite journal</ref>
Ice test
Applying ice for 2–5 minutes to the muscles reportedly has a sensitivity and specificity of 76.9% and 98.3%, respectively, for the identification of MG. Acetylcholinesterase is thought to be inhibited at the lower temperature, which is the basis for this diagnostic test. This generally is performed on the eyelids when ptosis is present and is deemed positive if a ≥2-mm rise in the eyelid occurs after the ice is removed.<ref>Template:Cite journal</ref>
Edrophonium test
This test requires the intravenous administration of edrophonium chloride or neostigmine, drugs that block the breakdown of acetylcholine by cholinesterase (acetylcholinesterase inhibitors).<ref>Template:MedlinePlusEncyclopedia</ref> This test is no longer typically performed, as its use can lead to life-threatening bradycardia (slow heart rate) which requires immediate emergency attention.<ref name=":2">Template:Cite journal</ref> Production of edrophonium was discontinued in 2008.<ref name="Rosen2014" />
Imaging
A chest X-ray may identify widening of the mediastinum suggestive of thymoma, but computed tomography or magnetic resonance imaging (MRI) are more sensitive ways to identify thymomas and are generally done for this reason.<ref name="Kraker">Template:Cite journal</ref> MRI of the cranium and orbits may also be performed to exclude compressive and inflammatory lesions of the cranial nerves and ocular muscles.<ref>Allan H. Ropper, Robert H. Brown Adams and Victor's Principles of Neurology McGraw-Hill Professional; 8 edition (2005)</ref>
Pulmonary function test
The forced vital capacity may be monitored at intervals to detect increasing muscular weakness. Acutely, negative inspiratory force may be used to determine adequacy of ventilation; it is performed on those individuals with MG.<ref>Template:MedlinePlusEncyclopedia</ref><ref>Template:EMedicine</ref>
Differential diagnoses
The muscle weakness that worsens with activity (abnormal muscle fatigue) in myasthenia gravis<ref name=":0">Template:Cite journal</ref> is a symptom shared by other neuromuscular diseases. Most of the metabolic myopathies, such as McArdle disease (GSD-V), have abnormal muscle fatigue rather than fixed muscle weakness.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> Also, like myasthenia gravis,<ref name=":0" /> exercise intolerance in McArdle disease improves with regular physical activity (performed safely using activity adaptations such as getting into second wind, the "30 for 80 rule," and "six second rule").<ref>Template:Cite book</ref><ref>Template:Cite journal</ref> A small minority of people with McArdle disease also have the comorbidity of ptosis (drooping upper eyelid).<ref>Template:Cite journal</ref> Late-onset GSD-II (Pompe disease) and GSD-XV also have muscle weakness or fatigue with comorbidities of ptosis and ophthalmoplegia; as do many of the mitochondrial myopathies.<ref name=":3">Template:Cite journal</ref>
Other diseases that involve abnormal muscle fatigue (which may be described as exercise-induced muscle weakness, reversible muscle weakness, or muscle weakness that improves with rest) include: endocrine myopathies (such as Hoffman syndrome), Tubular aggregate myopathy (TAM), ischemia (such as intermittent claudication, popliteal artery entrapment syndrome, and chronic venous insufficiency), and poor diet or malabsorption diseases that lead to vitamin D deficiency (osteomalic myopathy). Although limb-girdle muscular dystrophies (LGMDs) involve fixed muscle weakness, LGMDR8 also involves muscle fatigue;<ref>Template:Cite web</ref> as do some limb-girdle muscular dystrophy-dystroglycanopathies such as MDDGC3 (a.k.a. LGMDR15 and LGMD2O).<ref name=":3" /><ref>Template:Cite web</ref> Myofibrillar myopathy 10,<ref>Template:Cite web</ref> dimethylglycine dehydrogenase deficiency,<ref>Template:Cite web</ref> erythrocyte lactate transporter defect,<ref>Template:Cite web</ref> and myopathy with myalgia, increased serum creatine kinase, with or without episodic rhabdomyolysis (MMCKR)<ref>Template:Cite web</ref> also include muscle fatigue.
X-linked episodic muscle weakness (EMWX) includes general muscle weakness, ptosis, and fluctuations in strength. In some individuals, fatiguability was demonstrable, the phenotype having features comparable to congenital myasthenic syndromes and channelopathies.<ref>Template:Cite web</ref>
Signs and symptoms of myasthenia presenting from infancy or childhood may be one of the congenital myasthenic syndromes, which can be inherited in either an autosomal dominant or recessive manner. There are currently over two dozen types of congenital myasthenic syndromes.<ref>Template:Cite web</ref>
Limb–girdle myasthenia gravis is a distinct condition from myasthenia gravis. It is an adult-onset, autoimmune condition affecting the neuromuscular junction. However, it lacks eye abnormalities and is associated with autoimmune conditions such as systemic lupus erythematosus, Hashimoto's thyroiditis, and thymoma.<ref>Template:Cite web</ref>
Lambert–Eaton myasthenic syndrome (LEMS) is an autoimmune condition that attacks the neuromuscular junction, either as a paraneoplastic syndrome (typically older people) or associated with a non-cancerous primary autoimmune condition (typically younger people). It usually involves lower limb weakness and exercise-induced fatiguability, although the upper limbs and eyes may also be involved. Lambert's sign is the unusual improvement of grip strength that follows after squeezing the hand at maximum intensity for 2–3 seconds.<ref>Template:Cite journal</ref>
Management
Treatment is by medication and/or surgery. Medication consists mainly of acetylcholinesterase inhibitors to directly improve muscle function and immunosuppressant drugs to reduce the autoimmune process.<ref name="auto1" /><ref name="Mehndiratta_2014">Template:Cite journal</ref> Thymectomy is a surgical method to treat MG.<ref>Template:Cite journal</ref><ref name="pmid39434135">Template:Cite journal</ref>
Medication
About 10% of people with generalized MG are considered treatment-refractory.<ref>Template:Cite journal</ref> Autologous hematopoietic stem cell transplantation (HSCT) is sometimes used in severe, treatment-refractory MG. Available data provide preliminary evidence that HSCT can be an effective therapeutic option in carefully selected cases.<ref>Template:Cite journal</ref>
Efgartigimod alfa (Vyvgart) was approved for medical use in the United States in December 2021.<ref name="FDA PR 20211217">Template:Citation-attribution</ref><ref>Template:Cite press release</ref><ref>Template:Cite press release</ref>
Efgartigimod alfa/hyaluronidase (Vyvgart Hytrulo) was approved for medical use in the United States in June 2023.<ref>Template:Cite press release</ref><ref>Template:Cite press release</ref>
Rozanolixizumab (Rystiggo) was approved for medical use in the United States in June 2023.<ref>Template:Cite web</ref><ref>Template:Cite press release</ref>
Acetylcholinesterase inhibitors
Acetylcholinesterase inhibitors can provide symptomatic benefit and may not fully remove a person's weakness from MG.<ref name="Mehndiratta_2014"/> While they might not fully remove all symptoms of MG, they still may allow a person the ability to perform normal daily activities.<ref name="Mehndiratta_2014" /> Usually, acetylcholinesterase inhibitors are started at a low dose and increased until the desired result is achieved. If taken 30 minutes before a meal, symptoms will be mild during eating, which is helpful for those who have difficulty swallowing due to their illness. Another medication used for MG, atropine, can reduce the muscarinic side effects of acetylcholinesterase inhibitors.<ref>Template:Cite web</ref> Pyridostigmine is a relatively long-acting drug (when compared to other cholinergic agonists), with a half-life around four hours with relatively few side effects.<ref name=":1">Template:Cite journal</ref> Generally, it is discontinued in those who are being mechanically ventilated, as it is known to increase the amount of salivary secretions.<ref name=":1" /> A few high-quality studies have directly compared cholinesterase inhibitors with other treatments (or placebo); their practical benefit may be so significant that conducting studies in which they would be withheld from some people would be difficult.<ref name="Mehndiratta_2014"/>
Immune suppressants
The steroid prednisone might also be used to achieve a better result, but it can lead to the worsening of symptoms and takes weeks to achieve its maximal effectiveness.<ref name=":1" /> Research suggests that up to 15% of people with myasthenia gravis do not positively respond to immune suppressants.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref name="auto1" /> Due to the myriad symptoms that steroid treatments can cause, it is not the preferred method of treatment.<ref name=":1" /> Other immune suppressing medications may also be used including rituximab<ref>Template:Cite journal</ref> or azathioprine.<ref name="NIH2016" />
Nipocalimab (Imaavy) was approved for medical use in the United States in April 2025.<ref>Template:Cite web</ref><ref name="JandJ PR 20250430">Template:Cite press release</ref>
Plasmapheresis and IVIG
If the myasthenia is serious (myasthenic crisis), plasmapheresis can be used to remove the putative antibodies from the circulation. Also, intravenous immunoglobulins (IVIGs) can be used to bind the circulating antibodies. Both of these treatments have relatively short-lived benefits, typically measured in weeks, and often are associated with high costs, which make them prohibitive; they are generally reserved for when MG requires hospitalization.<ref name=":1" /><ref name="Juel2004">Template:Cite journal</ref>
Surgery
As thymomas are seen in 10% of all people with the MG, they are often given a chest X-ray and CT scan to evaluate their need for surgical removal of their thymus glands and any cancerous tissue that may be present.<ref name="Rosen2014" /><ref name=":2" /> Even if surgery is performed to remove a thymoma, it generally does not lead to the remission of MG.<ref name=":1" /> Surgery in the case of MG involves the removal of the thymus, although in 2013, no clear benefit was indicated except in the presence of a thymoma.<ref name="Cea2013">Template:Cite journal</ref> A 2016 randomized, controlled trial, however, found some benefits.<ref>Template:Cite journalTemplate:Erratum</ref>
Physical measures
People with MG should be educated regarding the fluctuating nature of their symptoms, including weakness and exercise-induced fatigue. Exercise participation should be encouraged with frequent rest.<ref name="Goldenberg" /> In people with generalized MG, some evidence indicates a partial home program including training in diaphragmatic breathing, pursed-lip breathing, and interval-based muscle therapy may improve respiratory muscle strength, chest wall mobility, respiratory pattern, and respiratory endurance.<ref>Template:Cite journal</ref>
Medical imaging
In people with myasthenia gravis, older forms of iodinated contrast used for medical imaging have caused an increased risk of exacerbation of the disease, but modern forms have no immediate increased risk.<ref name="MehriziPascuzzi2014">Template:Cite journal</ref>
Prognosis
The prognosis of people with MG is generally good, as is quality of life, when given very good treatment.<ref>Template:Cite journal</ref> Monitoring of a person with MG is very important, as at least 20% of people diagnosed with it will experience a myasthenic crisis within two years of their diagnosis, requiring rapid medical intervention.<ref name=":1" /> Generally, the most disabling period of MG might be years after the initial diagnosis.<ref name="Mehndiratta_2014" /> Assistive devices may be needed to assist with mobility.<ref name="NIH2016" /> In the early 1900s, 70% of detected cases died from lung problems; now, that number is estimated to be around 3–5%, an improvement attributed to increased awareness and medications to manage symptoms.<ref name=":1" />
Epidemiology
MG occurs in all ethnic groups and both sexes. It most commonly affects women under 40 and people from 50 to 70 years old of either sex, but it has been known to occur at any age. Younger people rarely have thymoma. Prevalence in the United States is estimated at between 0.5 and 20.4 cases per 100,000, with an estimated 60,000 Americans affected.<ref name="Rosen2014" /><ref name="Cea2013"/> In the United Kingdom, an estimated 15 cases of MG occur per 100,000 people.<ref name=":2" /> The mortality rate of MG is around 5-9%.<ref>Template:Cite journal</ref>
History
The first to write about MG were Thomas Willis, Samuel Wilks, Erb, and Goldflam.<ref name="Nair2014">Template:Cite journal</ref> The term "myasthenia gravis pseudo-paralytica" was proposed in 1895 by Jolly, a German physician.<ref name="Nair2014" /> Mary Walker treated a person with MG with physostigmine in 1934.<ref name="Nair2014" /> Simpson and Nastuck detailed the autoimmune nature of the condition.<ref name="Nair2014" /> In 1973, Patrick and Lindstrom used rabbits to show that immunization with purified muscle-like acetylcholine receptors caused the development of MG-like symptoms.<ref name="Nair2014" />
Research
Immunomodulating substances, such as drugs that prevent acetylcholine receptor modulation by the immune system, are currently being researched.<ref name="Losen2008">Template:Cite journal</ref> Some research recently has been on anti-c5 inhibitors for treatment research as they are safe and used in the treatment of other diseases.<ref name="auto2" /> Ephedrine seems to benefit some people more than other medications, but it has not been properly studied as of 2014.<ref name="ReferenceA" /> In the laboratory, MG is mostly studied in model organisms, such as rodents. In addition, in 2015, scientists developed an in vitro functional, all-human, neuromuscular junction assay from human embryonic stem cells and somatic-muscle stem cells. After the addition of pathogenic antibodies against the acetylcholine receptor and activation of the complement system, the neuromuscular co-culture shows symptoms such as weaker muscle contractions.<ref>Template:Cite journal</ref> Recent years, scientists have been working on finding the reliable biomarkers for MG to monitor the disease development and assess the severity.
References
Further reading
External links
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